Journal articles on the topic 'J.T Bigge'

AbstractBy using Lebesgue’s dominated convergence theorem and constructing a suitable Lyapunov functional, we study the following almost-periodic Lotka–Volterra model with $M$ predators and $N$ prey of the integro-differential equations\begin{alignat*}{2} \dot{x}_i(t)\amp=x_i(t)\biggl[b_i(t)-a_{ii}(t)x_i(t)-\sum_{k=1,k\neq i}^{N}a_{ik}(t)\int_{-\infty}^tH_{ik}(t-\sigma)x_k(\sigma)\,\mathrm{d}\sigma\\ \amp\hskip45mm-\sum_{l=1}^{M}c_{il}(t)\int_{-\infty}^tK_{il}(t-\sigma)y_l(\sigma)\,\mathrm{d}\sigma\biggr],\amp\quad i\amp=1,2,\dots,N,\\ \dot{y}_j(t)\amp=y_j(t)\biggl[-r_j(t)-e_{jj}(t)y_j(t) +\sum_{k=1}^{N}d_{jk}(t)\int_{-\infty}^tP_{jk}(t-\sigma)x_k(\sigma)\,\mathrm{d}\sigma \\ \amp\hskip45mm-\sum_{l=1,l\neq j}^{M} e_{jl}(t)\int_{-\infty}^tQ_{jl}(t-\sigma)y_l(\sigma)\,\mathrm{d}\sigma\biggr],\amp\quad j\amp=1,2,\dots,M. \end{alignat*}Some sufficient conditions are obtained for the existence of a unique almost-periodic solution of this model. Several examples show that the obtained criteria are new, general and easily verifiable.

Abstract In this paper, we obtain some norm inequalities involving convex and concave functions, which are the generalizations of the classical Clarkson inequalities. Let A 1, …, A n be bounded linear operators on a complex separable Hilbert space H $\mathcal{H}$ and let α 1, …, α n be positive real numbers such that ∑ j = 1 n α j = 1 $\sum\limits^{n}_{j=1}\alpha_{j}=1$ . We show that for every unitarily invariant norm, If f is a non-negative function on [0, ∞) such that f(0) = 0 and g ( t ) = f ( t ) $g(t)=f(\sqrt{t})$ is convex, then | | | ∑ j = 1 n α j f ( | A j | ) | | | ≥ | | | ∑ j , k ∈ S ℓ ( f ( α j α k 4 α ℓ ( 1 − α ℓ ) | A j + A k − 2 ∑ j = 1 n α j A j | ) + f ( α j α k ( 2 α ℓ − 1 ) 4 α ℓ ( 1 − α ℓ ) | A j − A k | ) ) + f ( | ∑ j = 1 n α j A j | ) | | | $$\begin{align*} \bigg|\bigg|\bigg|\sum\limits^{n}_{j=1}\alpha_{j}f(|A_{j}|)\bigg|\bigg|\bigg| &\geq\bigg|\bigg|\bigg|\sum\limits_{j,k\in S_{\ell}}\bigg(f\bigg(\sqrt{\frac{\alpha_{j}\alpha_{k}}{4\alpha_{\ell}(1-\alpha_{\ell})}}\;\bigg|A_{j}+A_{k}-2\sum\limits^{n}_{j=1}\alpha_{j}A_{j}\bigg|\bigg)\\ &\qquad+f\bigg(\sqrt{\frac{\alpha_{j}\alpha_{k}(2\alpha_{\ell}-1)}{4\alpha_{\ell}(1-\alpha_{\ell})}}|A_{j}-A_{k}|\bigg)\bigg)+f\bigg(\bigg|\sum\limits^{n}_{j=1}\alpha_{j}A_{j}\bigg|\bigg)\bigg|\bigg|\bigg| \end{align*}$$ for ℓ = 1, …, n. If f is a non-negative function on [0, ∞) such that g ( t ) = f ( t ) $g(t)=f(\sqrt{t})$ is concave, then the inverse inequality holds. Here, the symbol S ℓ = {1, …, n} ∖ {ℓ} for ℓ ∈ {1, …, n}. In addition, we provide some applications of the above inequalities.

Abstract A class of third order differential equations with several sublinear neutral terms of the type ( a ( t ) ( b ( t ) ( x ( t ) + ∑ j = 1 n p j ( t ) x α j ( τ j ( t ) ) ) ′ ) ′ ) ′ + ∑ i = 1 m f i ( t , x ( σ i ( t ) ) ) = 0 , t ≥ t 0 > 0 $$\begin{array}{} \displaystyle \bigg( a(t)\Big( b(t)\Big(x(t)+\sum\limits_{j=1}^{n}p_{j}(t)x^{\alpha _{j}}(\tau _{j}(t))\Big)'\Big)'\bigg)' +\sum\limits_{i=1}^{m}f_{i}(t,x(\sigma _{i}(t)))=0,\qquad t\geq t_{0} \gt 0 \end{array}$$ is considered. Some oscillation criteria are presented to improve and complement those in the literature. Two examples are established to illustrate the main results.

AbstractWe consider the system of difference equations$\Delta\bigg{(}\frac{\Delta u_{n-1}}{\sqrt{1-|\Delta u_{n-1}|^{2}}}\bigg{)}=% \nabla V_{n}(u_{n})+h_{n},\quad u_{n}=u_{n+T}\quad(n\in\mathbb{Z}),$with${\Delta u_{n}=u_{n+1}-u_{n}\in{\mathbb{R}}^{N}}$,${V_{n}=V_{n}(x)\in C^{2}({\mathbb{R}}^{N},\mathbb{R})}$,${V_{n+T}=V_{n}}$,${h_{n+T}=h_{n}}$for all${n\in\mathbb{Z}}$and some positive integerT,${V_{n}(x)}$is${\omega_{i}}$-periodic (${\omega_{i}>0}$) with respect to each${x_{i}}$(${i=1,\ldots,N}$) and${\sum_{j=1}^{T}h_{j}=0}$. Applying a modification argument to the corresponding problem with a left-hand member ofp-Laplacian type, and using Morse theory, we prove that if all its solutions are non-degenerate, then the difference system above has at least${2^{N}}$geometrically distinctT-periodic solutions.

AbstractFollowing the first demonstration of a levitated nanosphere cooled to the quantum ground state in 2020 (U. Delić, et al. Science, vol. 367, p. 892, 2020), macroscopic quantum sensors are seemingly on the horizon. The nanosphere’s large mass as compared to other quantum systems enhances the susceptibility of the nanoparticle to gravitational and inertial forces. In this viewpoint, we describe the features of experiments with optically levitated nanoparticles (J. Millen, T. S. Monteiro, R. Pettit, and A. N. Vamivakas, “Optomechanics with levitated particles,” Rep. Prog. Phys., vol. 83, 2020, Art no. 026401) and their proposed utility for acceleration sensing. Unique to the levitated nanoparticle platform is the ability to implement not only quantum noise limited transduction, predicted by quantum metrology to reach sensitivities on the order of 10−15 ms−2 (S. Qvarfort, A. Serafini, P. F. Barker, and S. Bose, “Gravimetry through non-linear optomechanics,” Nat. Commun., vol. 9, 2018, Art no. 3690) but also long-lived quantum spatial superpositions for enhanced gravimetry. This follows a global trend in developing sensors, such as cold-atom interferometers, that exploit superposition or entanglement. Thanks to significant commercial development of these existing quantum technologies, we discuss the feasibility of translating levitated nanoparticle research into applications.

Xuan, Z., Blanchette, J., Nelson, T., Heeren, T., Nguyen, T., & Naimi, T. (2015). Alcohol policies and impaired driving in the United States: Effects of driving- vs. drinking-oriented policies. The International Journal Of Alcohol And Drug Research, 4(2), 119-130. doi:http://dx.doi.org/10.7895/ijadr.v4i2.205Aims: To test the hypotheses that stronger policy environments are associated with less impaired driving and that driving-orientedand drinking-oriented policy subgroups are independently associated with impaired driving.Design: State-level data on 29 policies in 50 states from 2001-2009 were used as lagged exposures in generalized linearregression models to predict self-reported impaired driving.Setting: Fifty United States and Washington, D.C.Participants: A total of 1,292,245 adults (≥ 18 years old) biennially from 2002–2010.Measures: Alcohol Policy Scale scores representing the alcohol policy environment were created by summing policies weightedby their efficacy and degree of implementation by state-year. Past-30-day alcohol-impaired driving from 2002–2010 wasobtained from the Behavioral Risk Factor Surveillance System surveys.Findings: Higher Alcohol Policy Scale scores are strongly associated with lower state-level prevalence and individual-level risk of impaired driving. After accounting for driving-oriented policies, drinking-oriented policies had a robust independent association with reduced likelihood of impaired driving. Reduced binge drinking mediates the relationship between drinking-oriented policies and impaired driving, and driving-oriented policies reduce the likelihood of impaired driving among binge drinkers.Conclusions: Efforts to reduce alcohol-impaired driving should focus on reducing excessive drinking in addition to preventing driving among those who are impaired.

Xuan, Z., Blanchette, J., Nelson, T., Heeren, T., Nguyen, T., & Naimi, T. (2015). Alcohol policies and impaired driving in the United States: Effects of driving- vs. drinking-oriented policies. The International Journal Of Alcohol And Drug Research, 4(2), 119-130. doi:http://dx.doi.org/10.7895/ijadr.v4i2.205Aims: To test the hypotheses that stronger policy environments are associated with less impaired driving and that driving-orientedand drinking-oriented policy subgroups are independently associated with impaired driving.Design: State-level data on 29 policies in 50 states from 2001-2009 were used as lagged exposures in generalized linearregression models to predict self-reported impaired driving.Setting: Fifty United States and Washington, D.C.Participants: A total of 1,292,245 adults (≥ 18 years old) biennially from 2002–2010.Measures: Alcohol Policy Scale scores representing the alcohol policy environment were created by summing policies weightedby their efficacy and degree of implementation by state-year. Past-30-day alcohol-impaired driving from 2002–2010 wasobtained from the Behavioral Risk Factor Surveillance System surveys.Findings: Higher Alcohol Policy Scale scores are strongly associated with lower state-level prevalence and individual-level risk of impaired driving. After accounting for driving-oriented policies, drinking-oriented policies had a robust independent association with reduced likelihood of impaired driving. Reduced binge drinking mediates the relationship between drinking-oriented policies and impaired driving, and driving-oriented policies reduce the likelihood of impaired driving among binge drinkers.Conclusions: Efforts to reduce alcohol-impaired driving should focus on reducing excessive drinking in addition to preventing driving among those who are impaired.

Xuan, Z., Blanchette, J., Nelson, T., Heeren, T., Nguyen, T., & Naimi, T. (2015). Alcohol policies and impaired driving in the United States: Effects of driving- vs. drinking-oriented policies. The International Journal Of Alcohol And Drug Research, 4(2), 119-130. doi:http://dx.doi.org/10.7895/ijadr.v4i2.205Aims: To test the hypotheses that stronger policy environments are associated with less impaired driving and that driving-orientedand drinking-oriented policy subgroups are independently associated with impaired driving.Design: State-level data on 29 policies in 50 states from 2001-2009 were used as lagged exposures in generalized linearregression models to predict self-reported impaired driving.Setting: Fifty United States and Washington, D.C.Participants: A total of 1,292,245 adults (≥ 18 years old) biennially from 2002–2010.Measures: Alcohol Policy Scale scores representing the alcohol policy environment were created by summing policies weightedby their efficacy and degree of implementation by state-year. Past-30-day alcohol-impaired driving from 2002–2010 wasobtained from the Behavioral Risk Factor Surveillance System surveys.Findings: Higher Alcohol Policy Scale scores are strongly associated with lower state-level prevalence and individual-level risk of impaired driving. After accounting for driving-oriented policies, drinking-oriented policies had a robust independent association with reduced likelihood of impaired driving. Reduced binge drinking mediates the relationship between drinking-oriented policies and impaired driving, and driving-oriented policies reduce the likelihood of impaired driving among binge drinkers.Conclusions: Efforts to reduce alcohol-impaired driving should focus on reducing excessive drinking in addition to preventing driving among those who are impaired.

Xuan, Z., Blanchette, J., Nelson, T., Heeren, T., Nguyen, T., & Naimi, T. (2015). Alcohol policies and impaired driving in the United States: Effects of driving- vs. drinking-oriented policies. The International Journal Of Alcohol And Drug Research, 4(2), 119-130. doi:http://dx.doi.org/10.7895/ijadr.v4i2.205Aims: To test the hypotheses that stronger policy environments are associated with less impaired driving and that driving-orientedand drinking-oriented policy subgroups are independently associated with impaired driving.Design: State-level data on 29 policies in 50 states from 2001-2009 were used as lagged exposures in generalized linearregression models to predict self-reported impaired driving.Setting: Fifty United States and Washington, D.C.Participants: A total of 1,292,245 adults (≥ 18 years old) biennially from 2002–2010.Measures: Alcohol Policy Scale scores representing the alcohol policy environment were created by summing policies weightedby their efficacy and degree of implementation by state-year. Past-30-day alcohol-impaired driving from 2002–2010 wasobtained from the Behavioral Risk Factor Surveillance System surveys.Findings: Higher Alcohol Policy Scale scores are strongly associated with lower state-level prevalence and individual-level risk of impaired driving. After accounting for driving-oriented policies, drinking-oriented policies had a robust independent association with reduced likelihood of impaired driving. Reduced binge drinking mediates the relationship between drinking-oriented policies and impaired driving, and driving-oriented policies reduce the likelihood of impaired driving among binge drinkers.Conclusions: Efforts to reduce alcohol-impaired driving should focus on reducing excessive drinking in addition to preventing driving among those who are impaired.

Interlaboratory comparisons (ILCs) are one of the key activities in metrology. Estimates x = (x1,…, xn) T of a measurand α along with their associated standard uncertainties u0 = (u0,1,…, u0,n) T, u0,j = u0 (xj) are provided by each of n laboratories. Employing a model of the form xj ∈ N(α, v0,j), j = 1,…,n, v0,j = u0,j2, we may wish to find a consensus value for α. A χ2 test can be used to assess the degree to which the spread of the estimates x are consistent with the stated uncertainties u0. If they are judged to be inconsistent, then an adjustment procedure can be applied to determine vj ≥ v0,j, so that x and v represent consistency. The underlying assumption behind this approach is that some or all of the laboratories have underestimated or neglected some uncertainty contributions, sometimes referred to as ‘dark uncertainty’, and the adjusted v provides an estimate of this dark uncertainty derived from the complete set of laboratory results. There are many such adjustment procedures, including the Birge and Mandel–Paule (M-P) procedures. In implementing an adjustment procedure, a desirable objective is to make as minimal an adjustment as necessary in order to bring about the required degree of consistency. In this paper, we discuss the use of relative entropy, also known as the Kullback–Leibler divergence, as a measure of the degree of adjustment. We consider parameterising v = v (b) as a function of parameters b with the input v0 = v (b0) for some b0. We look to perturb b from b0 to bring about consistency in a way that minimises how far b is from b0 in terms of the relative entropy or Kullback–Leibler divergence.

Let $1,-1,-1,1,-1,1,1,-1,-1,1,1,\ldots$ be the $\{-1,1\}$-valued Thue–Morse sequence. Its correlation dimension is $D_{2}$, satisfying $$\begin{eqnarray}\mathop{\sum }_{k=0}^{K-1}|{\it\gamma}(k)|^{2}\asymp K^{1-D_{2}}\end{eqnarray}$$ in the sense that the ratio between the left- and right-hand sides is bounded away from 0 and $\infty$ as $K\rightarrow \infty$, where ${\it\gamma}$ is the correlation function; its value is known [Zaks, Pikovsky and Kurths. On the correlation dimension of the spectral measure for the Thue–Morse sequence. J. Stat. Phys.88(5/6) (1997), 1387–1392] to be $$\begin{eqnarray}D_{2}=1-\log \frac{1+\sqrt{17}}{4}\bigg/\log 2=0.64298\ldots .\end{eqnarray}$$ Under its spectral measure ${\it\mu}$ on $[0,1)$, consider the transformation $T$ with $Tx=2x$ ($\text{mod}~1$). It is shown to be of Kolmogorov type having entropy at least $D_{2}\log 2$. Moreover, a random walk is defined by $T^{-1}$ which has the transition probability $$\begin{eqnarray}P_{1}((1/2)x+(1/2)j\mid x)=(1/2)(1-\cos ({\it\pi}(x+j)))\quad (j=0,1).\end{eqnarray}$$ It is proved that this random walk is mixing and ${\it\mu}$ is the unique stationary measure. Moreover, $$\begin{eqnarray}\lim _{N\rightarrow \infty }\int P_{N}((x-{\it\varepsilon},x+{\it\varepsilon})|x)\,d{\it\mu}(x)\asymp {\it\varepsilon}^{D_{2}}\quad (\text{as}~{\it\varepsilon}\rightarrow 0),\end{eqnarray}$$ where $P_{N}(\cdot \mid \cdot )$ is the $N$-step transition probability.

Accurate interatomic potentials were calculated for the interaction of a singly charged carbon cation, C + , with a single rare gas atom, RG (RG = Ne–Xe). The RCCSD(T) method and basis sets of quadruple-ζ and quintuple-ζ quality were employed; each interaction energy was counterpoise corrected and extrapolated to the basis set limit. The lowest C + ( 2 P ) electronic term of the carbon cation was considered, and the interatomic potentials calculated for the diatomic terms that arise from these: 2 Π and 2 Σ + . Additionally, the interatomic potentials for the respective spin-orbit levels were calculated, and the effect on the spectroscopic parameters was examined. In doing this, anomalously large spin-orbit splittings for RG = Ar–Xe were found, and this was investigated using multi-reference configuration interaction calculations. The latter indicated a small amount of RG → C + electron transfer and this was used to rationalize the observations. This is taken as evidence of an incipient chemical interaction, which was also examined via contour plots, Birge–Sponer plots and various population analyses across the C + -RG series (RG = He–Xe), with the latter showing unexpected results. Trends in several spectroscopic parameters were examined as a function of the increasing atomic number of the RG atom. Finally, each set of RCCSD(T) potentials was employed, including spin-orbit coupling to calculate the transport coefficients for C + in RG, and the results were compared with the limited available data. This article is part of the theme issue ‘Modern theoretical chemistry’.

Hicks, M., Tough, S., Johnston, D., Siever, J., Clarke, M., Sauve, R., Brant, R., & Lyon, A. (2014). T-ACE and predictors of self-reported alcohol use during pregnancy in a large, population-based urban cohort. The International Journal Of Alcohol And Drug Research, 3(1), 51-61. doi:10.7895/ijadr.v3i1.117Aims: To determine 1) the relationship between T-ACE score and maternal self-reported alcohol use prior to and during pregnancy, and 2) the relationship between T-ACE score and maternal demographics, mental health and life circumstances.Design: Prospective, population-based cohort study.Setting: Three urban maternity clinics in Calgary, Canada.Participants: 1,929 pregnant women attended by family physicians at low-risk maternity clinics.Measures: Women completed three standardized questionnaires over the telephone in the first and third trimesters and eight weeks post-delivery, including the T-ACE and questions about drug and alcohol use, demographics, mental health and life circumstances.Findings: 43.6% of subjects had a positive T-ACE score at intake (score 2 or greater). A positive T-ACE score was predictive of alcohol use throughout pregnancy, although most women reported no alcohol after the first trimester (93.1%). Multivariate analysis indicated that a positive T-ACE score was significantly associated with being less than 30 years of age; being Caucasian; smoking during pregnancy; having an income of less than $80,000 per annum; having a history of depression; having a history of alcohol use and binge drinking during a previous pregnancy; lower social support; and poor network orientation.Conclusions: There was a positive association between the T-ACE score and maternal self-report of alcohol use, poor mental health and poor social support. Routine use of the T-ACE to assess for risk of an alcohol-exposed pregnancy may also help identify women with complex needs who could benefit from additional prenatal support.

Src homology 2 (SH2) domains provide specificity to intracellular signaling by binding to specific phosphotyrosine (phospho-Tyr)-containing sequences. We recently developed a technique using a degenerate phosphopeptide library to predict the specificity of individual SH2 domains (src family members, Abl, Nck, Sem5, phospholipase C-gamma, p85 subunit of phosphatidylinositol-3-kinase, and SHPTP2 (Z. Songyang, S. E. Shoelson, M. Chaudhuri, G. Gish, T. Pawson, W. G. Haser, F. King, T. Roberts, S. Ratnofsky, R. J. Lechleider, B. G. Neel, R. B. Birge, J. E. Fajardo, M. M. Chou, H. Hanafusa, B. Schaffhausen, and L. C. Cantley, Cell 72:767-778, 1993). We report here the optimal recognition motifs for SH2 domains from GRB-2, Drk, Csk, Vav, fps/fes, SHC, Syk (carboxy-terminal SH2), 3BP2, and HCP (amino-terminal SH2 domain, also called PTP1C and SHPTP1). As predicted, SH2 domains from proteins that fall into group I on the basis of a Phe or Tyr at the beta D5 position (GRB-2, 3BP2, Csk, fps/fes, Syk C-terminal SH2) select phosphopeptides with the general motif phospho-Tyr-hydrophilic (residue)-hydrophilic (residue)-hydrophobic (residue). The SH2 domains of SHC and HCP (group III proteins with Ile, Leu, of Cys at the beta D5 position) selected the general motif phospho-Tyr-hydrophobic-Xxx-hydrophobic, also as predicted. Vav, which has a Thr at the beta D5 position, selected phospho-Tyr-Met-Glu-Pro as the optimal motif. Each SH2 domain selected a unique optimal motif distinct from motifs previously determined for other SH2 domains. These motifs are used to predict potential sites in signaling proteins for interaction with specific SH2 domain-containing proteins. The Syk SH2 domain is predicted to bind to Tyr-hydrophilic-hydrophilic-Leu/Ile motifs like those repeated at 10-residue intervals in T- and B-cell receptor-associated proteins. SHC is predicted to bind to a subgroup og these same motifs. A structural basis for the association of Csk with Src family members is also suggested from these studies.

Src homology 2 (SH2) domains provide specificity to intracellular signaling by binding to specific phosphotyrosine (phospho-Tyr)-containing sequences. We recently developed a technique using a degenerate phosphopeptide library to predict the specificity of individual SH2 domains (src family members, Abl, Nck, Sem5, phospholipase C-gamma, p85 subunit of phosphatidylinositol-3-kinase, and SHPTP2 (Z. Songyang, S. E. Shoelson, M. Chaudhuri, G. Gish, T. Pawson, W. G. Haser, F. King, T. Roberts, S. Ratnofsky, R. J. Lechleider, B. G. Neel, R. B. Birge, J. E. Fajardo, M. M. Chou, H. Hanafusa, B. Schaffhausen, and L. C. Cantley, Cell 72:767-778, 1993). We report here the optimal recognition motifs for SH2 domains from GRB-2, Drk, Csk, Vav, fps/fes, SHC, Syk (carboxy-terminal SH2), 3BP2, and HCP (amino-terminal SH2 domain, also called PTP1C and SHPTP1). As predicted, SH2 domains from proteins that fall into group I on the basis of a Phe or Tyr at the beta D5 position (GRB-2, 3BP2, Csk, fps/fes, Syk C-terminal SH2) select phosphopeptides with the general motif phospho-Tyr-hydrophilic (residue)-hydrophilic (residue)-hydrophobic (residue). The SH2 domains of SHC and HCP (group III proteins with Ile, Leu, of Cys at the beta D5 position) selected the general motif phospho-Tyr-hydrophobic-Xxx-hydrophobic, also as predicted. Vav, which has a Thr at the beta D5 position, selected phospho-Tyr-Met-Glu-Pro as the optimal motif. Each SH2 domain selected a unique optimal motif distinct from motifs previously determined for other SH2 domains. These motifs are used to predict potential sites in signaling proteins for interaction with specific SH2 domain-containing proteins. The Syk SH2 domain is predicted to bind to Tyr-hydrophilic-hydrophilic-Leu/Ile motifs like those repeated at 10-residue intervals in T- and B-cell receptor-associated proteins. SHC is predicted to bind to a subgroup og these same motifs. A structural basis for the association of Csk with Src family members is also suggested from these studies.

ABSTRACT Aim The aim of our study was to measure the frontal sinus morphology that could aid us in gender determination and also to assess the difference in measurements between the right and left frontal sinus. Materials and methods A retrospective study was done using 100 cone beam computed tomography (CBCT) images (50 males and 50 females) matched with age and gender with full field of view (FOV). The examinations were carried out using Promax 3DMid (Planmeca Oy., Helsinki, Finland) CBCT unit. The frontal sinus was assessed in coronal, sagittal, and axial planes, and the maximum measurements in each section were recorded. The results to compare the right and left frontal sinus were analyzed using paired t-tests, and independent Student's t-test was used to compare the difference in measurements of frontal sinus between males and females. Results We found that the left side of the frontal sinus was bigger than the right side, and while comparing between the genders, it was found that the measurements were greater in males. Statistically significant results were obtained on comparing between the sides and gender. Conclusion As mentioned in previous studies, frontal sinus measurements are significantly higher in males compared with females which can, therefore, be used in gender identification in cases of mass disasters. Clinical significance Frontal sinus measurements can be used as an adjunct in gender identification in mass disasters and with advances in technology. Cone beam computed tomography, in addition to providing accurate measurements, has overcome all the disadvantages with two-dimensional imaging. How to cite this article Denny C, Jacob AS, Ahmed J, Natarajan S, Binnal A, Sujir N. Frontal Sinus as an aid in Gender Identification in Forensic Dentistry: A Retrospective Study using Cone Beam Computed Tomography. World J Dent 2018;9(1):34-37.

A change in teaching delivery at a large Australian university, from two semesters to three trimesters, was the occasion for using more formative assessment in a core first-year mathematics unit. This study compared evidence about learning outcomes for two cohorts in adjacent years. Cohort 1 was the last taught over a semester, and Cohort 2 the first taught over a trimester. There was no change in overall workload, and no change in the unit's total teaching hours, syllabus or materials. Assessments were changed for class tests during the teaching period by giving Cohort 2 access to unlimited practice and computer-assisted feedback on the questions in the test database, followed by doing the tests under examination conditions. For Cohort 2, a written assignment was also added, focused on giving a clear solution to a mathematics problem, and awareness of the need for appropriate evidence, both background and internal to the problem. 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Online Learn. Teach., 5(4):618–629, 2009. URL https://jolt.merlot.org/vol5no4/hodge_1209.htm. D. Holton and D. Clarke. Scaffolding and metacognition. Int. J. Math. Ed. Sci. Tech., 37(2):127–143, 2006. doi:10.1080/00207390500285818. A. H. Jonsdottir, A. Bjornsdottir, and G. Stefansson. Difference in learning among students doing pen-and-paper homework compared to web-based homework in an introductory statistics course. J. Stat. Ed., 25(1):12–20, 2017. doi:10.1080/10691898.2017.1291289. M. McAlinden and A. Noyes. Mathematics in the disciplines at the transition to university. Teach. Math. App., 38(2):61–73, 2019. doi:10.1093/teamat/hry004. J. Nicholas, L. Poladian, J. Mack, and R. Wilson. Mathematics preparation for university: entry pathways and their effect on performance in first year mathematics and science subjects. Int. J. Innov. Sci. Math. Ed., 23(1):37–51, 2015. https://openjournals.library.sydney.edu.au/index.php/CAL/article/view/8488. M. I. Nunez-Pena, R. Bono, and M. Suarez-Pellicioni. Feedback on students' performance: a possible way of reducing the negative effect of math anxiety in higher education. Int. J. Ed. Res., 70(1):80–87, 2015. doi:10.1016/j.ijer.2015.02.005. J. T. E. Richardson. Student learning in higher education: a commentary. Ed. Psych. Rev., 29(1):353–362, 2017. doi:10.1007/s10648-017-9410-x. L. J. Rylands and D. Shearman. Mathematics learning support and engagement in first year engineering. Int. J. Math. Ed. Sci. Tech., 49(8):1133–1147, 2018. doi:10.1080/0020739X.2018.1447699. K. A. Seaton. Efficacy and efficiency in formative assessment: an informed reflection on the value of partial marking. Int. J. Math. Ed. Sci. Tech., 44(7):963–971, 2013. doi:10.1080/0020739X.2013.831490. D. Wood, J. S. Bruner, and G. Ross. The role of tutoring in problem solving. J. Child Psychol. Psych., 17(1):89–100, 1976. doi:10.1111/j.1469-7610.1976.tb00381.x. L. Zetterqvist. Applied problems and use of technology in an aligned way in basic courses in probability and statistics for engineering students—a way to enhance understanding and increase motivation. Teach. Math. App., 36(2):108–122, 2017. doi:10.1093/teamat/hrx004.

Photography has been, from its early stages, a powerful tool for the anthropologist, both as a mechanical technique to record data and as a heuristic tool used to reflect on the anthropologist’s approach as such. At the same time, its iconicity and indexicality have allowed for a different epistemic regime, an allegedly privileged connection to “the facts” or “the truth”, in opposition to the written notes of the anthropologist, vulnerable to subjectivity, bias or error. A substantial direction in visual culture studies questions the articulation of image and text, and acknowledges a power relation between the two, as if despite its iconicity and indexicality, photography needs taming by the text that clarifies its meaning and incorporates it in bigger narratives. It is in this context that W. J. T. Mitchell echoes the famous question “Can the subaltern speak?” in relation to photography, asking “What do pictures want?” (Mitchell, 2005, pp. 28-30). It is within this vision of photography as a potential site of resistance to the narrative in which they are embedded that I will try to raise some critical points about Bruce O’Neill’s book, The Space of Boredom, by focusing on the photos included in this book.

Dark clouds within a few hundred pc of the Sun contain hundreds of condensations with typical size 0.1 pc, density 104 molecules per cubic cm, mass 1 M⊙, and temperature 10 K. These “dense cores” are defined by maps of molecular lines, such as the (J,K)=(1,1) line of ammonia at 1.3 cm wavelength. They are associated with regions of opaque visual obscuration, groups of T Tauri stars, and other cores. They are closely correlated with steep-spectrum, low-luminosity (1-10 L⊙) IRAS sources! of about 60 cores with ammonia maps, half have an IRAS source within one map diameter. Thus cores form low-mass stars, which are probably precursors of T Tauri stars. Simple models indicate that time for a core to wait before collapsing, to collapse and form a star, and to disperse are each of order 105 yr. Cores with stars have broader lines and bigger velocity gradients than cores without stars, suggesting interaction between the star and the core due to gravity and/or outflow. Stars in cores have about 30 mag greater circumstellar extinction, and greater likelihood of CO outflow, than stars near, but not in, cores. Models of the 1-100 μm spectra of stars in cores suggest that inside of ∼100 A.U., the typical star suffers relatively little line-of-sight extinction but is accompanied by a source of significant luminosity at 5-25 μm. Models involving circumstellar disks provide good fits to the observed spectra.

Arsenic and Protein Expression: It might help to know the mechanism of As toxicity is described Introduction One of the largest public health problems at present is the drinking of water containing levels of Inorg-As that are known to be carcinogenic. The chronic ingestion of Inorg-As can results in skin cancer, urinary bladder cancer, lungs cancer, kidneys cancer, liver cancer, and cancer of other human organs 1-6. The molecular mechanisms of the carcinogenicity and toxicity of inorganic arsenic are not well understood 7–9. Many mechanisms of arsenic toxicity and carcinogenicity have been suggested 1, 7, 10 including chromosome abnormalities 11, oxidative stress 12, 13, altered growth factors 14, cell proliferation 15, altered DNA repair 16, altered DNA methylation patterns 17, inhibition of several key enzymes 18, gene amplification 19 etc. Some of these mechanisms result in alterations in protein expression. Proteomics is a powerful tool developed to enhance the study of complex biological system 20. This technique has been extensively employed to investigate the proteome response of cells to drugs and other diseases 21, 22. A proteome analysis of the Na-As (III) response in cultured lung cells found in vitro oxidative stress-induced apoptosis 23. In one of the study, hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days and several protein spots were over expressed and several were under expressed in the livers and urinary bladders of hamsters (Fig.) 24, 25. Hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days. The control hamsters were given tap water. The spot pairs of (A) equally expressed, (B) overexpressed, and (C) under expressed proteins in the liver tissues were shown. The amount of the protein is proportional to the volume of the protein peak. Transgelin was down-regulated, and GST-pi was up-regulated in the urinary bladder tissues of hamsters. In the liver tissues ornithine aminotransferase (OAT) was up-regulated, and senescence marker protein 30 (SMP 30), and fatty acid binding protein (FABP) were down-regulated. Down-regulation of transgelin has been noted in the urinary bladders of rats having bladder outlet obstruction 26. Ras-dependent and Ras-independent mechanisms can cause the down regulation of transgelin in human breast and colon carcinoma cell lines and patient-derived tumor samples 27. The loss of transgelin expression has been found in prostate cancer cells 28 and in human colonic neoplasms 29. It has been suggested that the loss of transgelin expression may be an important early event in tumor progression and a diagnostic marker for cancer development 26-29. Figure. Three-dimentional simulation of over-and under expressed protein spots in the livers of hamsters using Decyder software. Over-expression of GST-pi has been found in colon cancer tissues 30. Strong expression of GST-pi also has been found in gastric cancer 31, malignant melanoma 32, lung cancer 33, breast cancer 34 and a range of other human tumors 35. GST-pi has been up-regulated in transitional cell carcinoma of human urinary bladder 36. OAT has a role in regulating mitotic cell division and it is required for proper spindle assembly in human cancer cell 37. Ornithine amino transferase knockdown in human cervical carcinoma and osteosarcoma cells by RNA interference blocks cell division and causes cell death 37. It has been suggested that ornithine amino transferase has a role in regulating mitotic cell division and it is required for proper spindle assembly in human cancer cells 37. SMP 30 expressed mostly in the liver. By stimulating membrane calcium-pump activity it protects cells against various injuries 38. High levels of saturated, branched chain fatty acids are deleterious to cells and resulting in lipid accumulation and cytotoxicity. FABP expression has protected the cells against branched chain saturated fatty acid 39. Proteomics would be a powerful tool to know the unknown cellular mechanisms of arsenic toxicity in humans. References. NRC (National Research Council). (2001). Arsenic in Drinking Water. Update to the 1999 Arsenic in Drinking Water Report. National Academy Press, Washington, DC. Chen, C. J., Chen, C. , Wu, M. M., Kuo, T. L. (1992). Cancer potential in liver, lung, bladder, and kidney due to ingested inorganic arsenic in drinking water. Br. J. Cancer 66, 888-892. Hopenhayn-Rich, C., M.L. Biggs, A. Fuchs, et al. 1996. Bladder cancer mortality with arsenic in drinking water in Argentina. Epidemiology 7: 117–124. International Agency for Research on Cancer. (1987). In IARC Monograph on the Evaluation of Carcinogenicity Risk to Humans. Overall Evaluation of Carcinogenicity:An Update of IARC Monographs 1–42 (Suppl. 7). Lyon, France: International Agency for Research on Can-cer, pp. 100–106. Rossman, T.G., Uddin, A.N., and Burns, F.J. (2004). Evidence that arsenite acts as a cocarcinogen in skin cancer. Toxicol. Appl. Pharmacol. 198: 394–404. Smith, A.H., Hopenhayn-Rich, C., Bates, M.N., et al. (1992). Cancer risks from arsenic in drinking water. Environ. Health Perspect. 97: 259–267. Aposhian, H.V. & Aposhian, M.M. (2006). Arsenic toxicology: five questions. Chem. Res. Toxicol. 19: 1–15. Goering, P.L., Aposhian, H.V., Mass, M.J., et al. (1999). The enigma of arsenic carcinogenesis: role of metabolism. Toxicol. Sci. 49: 5–14. Waalkes, M.P., Liu, J., Ward, J.M., et al. (2004). Mechanisms underlying arsenic carcinogenesis: hypersensitivity of mice exposed to inorganic arsenic during gestation. Toxicology 198: 31–38. Kitchin, K. T., Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. Appl. Pharmacol. 2001, 172, 249-261. Beckman, G., Beckman, L., Nordenson, I., Chromosome aberrations in workers exposed to arsenic. Environ. Health Perspect. 1977, 19, 145-146. Yamanaka, K., Hoshino, M., Okanoto, M., Sawamura, R., et al., Induction of DNA damage by dimethylarsine, a metabolite of inorganic arsenics, is for the major part likely due to its peroxyl radical. Biophys. Res. Commun. 1990, 168, 58-64. Yamanaka, K., Okada, S., Induction of lung-specific DNA damage by metabolically methylated arsenics via the production of free radicals. Health Perspect. 1994, 102, 37-40. Simeonova, P., Luster, M. I., Mechanisms of arsenic carcinogenicity:Genetic or epigenetic mechanisms? J. Environ. Pathol. Toxicol. Oncol. 2000, 19, 281-286. Popovicova, J., Moser, G. J., Goldsworthy, T. , Tice, R. R., Carcinogenicity and co-carcinogenicity of sodium arsenite in p53+/- male mice. Toxicologist 2000, 54, 134. Li, J. H., Rossman, T. G., Mechanism of co-mutagenesis of sodium arsenite with N-methyl-N-nitrosourea. Bi Trace Elem. 1989, 21, 373-381. Zhao, C. Q., Young, M. R., Diwan, B. A., Coogan, T. P., et , Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc. Natl. Acad. Sci. USA 1997, 94, 10907-10912. Abernathy, C. O., Lui, Y. P., Longfellow, D., Aposhian, H. , et al., Arsenic: Health effects, mechanisms of actions and research issues. Environ. Health Perspect. 1999, 107, 593-597. Lee, T. C., Tanaka, N., Lamb, P. W., Gilmer, T. M., et al., Induction of gene amplification by arsenic. Science 1988, 241, 79-81. Lau, A. T., He, Q. Y., Chiu, J. F. (2003). Proteomic technology and its biomedical applications. Acta Biochim. Bioph Sin. 35, 965-975. Jungblut, P. R., Zimny-Arndt, U., Zeindl-Eberhart, E., Stulik, J., Koupilova, K., Pleissner, K. P., Otto, A., Muller, E. C., Sokolowska-Kohler, W., Grabher, G., Stoffler, G. (1999). Proteomics in human disease: cancer, heart and infectious diseases. Electrophoresis 20, 2100-2110. Hanash, S. M., Madoz-Gurpide, J., Misek, D. E. (2002). Identification of novel targets for cancer therapy using expression proteomics. Leukemia 16, 478-485. Lau, A. T., He, Q. Y., Chiu, J. F. (2004). A proteome analysis of the arsenite response in cultured lung cells: evidence for in vitro oxidative stress-induced apoptosis. J. 382, 641-650. Chowdhury, U. K., Aposhian, H. V. (2008). Protein expression in the livers and urinary bladders of hamsters exposed to sodium arsenite. A N. Y. Acad. Sci. 1140, 325-334. Chowdhury, U.K. Expression of proteins in the tissues of hamsters exposed to sodium arsenite. Int. J. of Toxicol., 2021, 1, 1-8. Kim, H-J., Sohng, I., Kim, D-H., Lee, D-C., et al., 2005. Investigation of early protein changes in the urinary bladder following partial bladder outlet obstruction by proteomic approach. J. Korean Med. Sci. 20, 1000-1005. Shields, J.M., Rogers-Graham, K., Der, C.J., 2002. Loss of transgelin in breast and colon tumors and in RIE-1 cells by Ras deregulation of gene expression through Raf-independent pathways. J. Biol. Chem. 277, 9790-9799. Yang, Z., Chang, Y- J., Miyamoto, H., Ni, J., et al., Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell grown. Mol. Endocrinol. 2007, 21, 343-358. Yeo, , Kim, D- K., Park, H. J., Oh, T. Y., et al., Loss of transgelin in repeated bouts of ulcerative colitis-induced colon carcinogenesis. Proteomics 2006, 6, 1158-1165. Tsuchida, S., Sekine, Y., Shineha, R., Nishihira, T., et al., Elevation of the placental glutathione S-transferase form (GST-PI) in tumor tissues and the levels in sera of patients with cancer. 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High-impact photoelectrode materials for photoelectrochemical (PEC) water splitting are distinguished by synergistically attaining high photoactivity and stability at the same time. With numerous efforts toward optimizing the activity, the bigger challenge of tailoring the durability of photoelectrodes to meet industrially relevant levels remains. In situ photostability measurements using flow cells hold great promise in understanding stability-related properties1-3 compared to traditional procedures, such as measuring the drop in photocurrent over time at 1.23 VRHE. In this work, a photoelectrochemical scanning flow cell connected to an inductively coupled plasma mass spectrometer (PEC-ICP-MS) and equipped with a solar simulator, Air Mass 1.5 G filter, and monochromator was developed (Figure 1A). The established system is capable of independently assessing basic PEC metrics, such as photopotential, photocurrent, incident photon to current efficiency (IPCE), and band gap in a high-throughput manner, as well as the in situ photocorrosion behavior of photoelectrodes under standardized and realistic light conditions by coupling it to an ICP-MS.4 In situ photocorrosion measurements conducted on spray-coated WO3 revealed that dissolution starts at 0.8 VRHE with the dissolution rate rapidly increasing past 1.2 VRHE, coinciding with the onset of the saturation photocurrent (Figure 1B). Wavelength-dependent photodegradation measurements show that WO3 only dissolved when irradiated with wavelengths lower than its band gap (Figure 1C). By using standardized illumination conditions such as AM 1.5 G under 1 Sun, the obtained dissolution characteristics are translatable to actual devices under realistic light conditions. The gained insights can then be utilized to advance synthesis and design approaches of novel PEC materials with improved photostability. Another aspect of flow cell systems is that they are well suited for operation in a high-throughput manner. In fact, scanning droplet cells have been successfully employed for rapid (photo)electrochemical screening of (photo)electrocatalyst libraries.5, 6 In here, we demonstrate proof-of-concept approaches for a full automation of the presented system to establish a platform that is capable of not only performing complete sets of PEC measurements but at the same time assess the in situ photostability of a photoelectrode material library. Such a platform would enable material discovery, which is tailored to search not only for the most active but also for the most stable PEC material. References Knöppel, J.; Zhang, S.; Speck, F. D.; Mayrhofer, K. J. J.; Scheu, C.; Cherevko, S., Time-resolved analysis of dissolution phenomena in photoelectrochemistry – A case study of WO3 photocorrosion. Electrochem. Commun. 2018, 96, 53-56. Dworschak, D.; Brunnhofer, C.; Valtiner, M., Photocorrosion of ZnO Single Crystals during Electrochemical Water Splitting. ACS Appl Mater Interfaces 2020, 12 (46), 51530-51536. Zhang, S.; Rohloff, M.; Kasian, O.; Mingers, A. M.; Mayrhofer, K. J. J.; Fischer, A.; Scheu, C.; Cherevko, S., Dissolution of BiVO4 Photoanodes Revealed by Time-Resolved Measurements under Photoelectrochemical Conditions. The Journal of Physical Chemistry C 2019, 123 (38), 23410-23418. Jenewein, K. J.; Kormányos, A.; Knöppel, J.; Mayrhofer, K. J. J.; Cherevko, S., Accessing In Situ Photocorrosion under Realistic Light Conditions: Photoelectrochemical Scanning Flow Cell Coupled to Online ICP-MS. ACS Measurement Science Au 2021, 1 (2), 74-81. Gregoire, J. M.; Xiang, C.; Liu, X.; Marcin, M.; Jin, J., Scanning droplet cell for high throughput electrochemical and photoelectrochemical measurements. Rev. Sci. Instrum. 2013, 84 (2), 024102. Sliozberg, K.; Schafer, D.; Erichsen, T.; Meyer, R.; Khare, C.; Ludwig, A.; Schuhmann, W., High-throughput screening of thin-film semiconductor material libraries I: system development and case study for Ti-W-O. ChemSusChem 2015, 8 (7), 1270-8. Figure 1

Kinesin is known as a representative cytoskeletal motor protein that is engaged in cell division and axonal transport. In addition to the mutant assay, recent advances using the PCR cloning technique have elucidated the existence of many kinds of kinesin-related proteins in yeast, Drosophila, and mice. We previously cloned five different members of kinesin superfamily proteins (KIFs) in mouse brain (Aizawa, H., Y. Sekine, R. Takemura, Z. Zhang, M. Nangaku, and N. Hirokawa. 1992. J. Cell Biol. 119:1287-1296) and demonstrated that one of them, KIF3A, is an anterograde motor (Kondo, S., R. Sato-Yashitake, Y. Noda, H. Aizawa, T. Nakata, Y. Matsuura, and N. Hirokawa. J. Cell Biol. 1994. 125:1095-1107). We have now characterized another axonal transport motor, KIF2. Different from other KIFs, KIF2 is a central type motor, since its motor domain is located in the center of the molecule. Recombinant KIF2 exists as a dimer with a bigger head and plus-end directionally moves microtubules at a velocity of 0.47 +/- 0.11 microns/s, which is two thirds that of kinesin's. Immunocytological examination showed that native KIF2 is abundant in developing axons and that it accumulates in the proximal region of the ligated nerves after a 20-h ligation. Soluble KIF2 exists without a light chain, and KIF2's associated-vesicles, immunoprecipitated by anti-KIF2 antibody, are different from those carried by existing motors such as kinesin and KIF3A. They are also distinct from synaptic vesicles, although KIF2 is accumulated in so-called synaptic vesicle fractions and embryonal growth cone particles. Our results strongly suggest that KIF2 functions as a new anterograde motor, being specialized for a particular group of membranous organelles involved in fast axonal transport.

In this paper, we describe how commonly present in tissue substances - sodium chloride and glucose - affect the optical spectrum of an immunosuppressive drug (Cyclaid® by Apotex). Prepared samples were investigated using the spectrophotometer in the spectrum range from 250 nm to 1100 nm. The maximum wavelength shift calculated on the basis of measurement results is not bigger than the measurement wavelength step. So, it can be concluded, that the small amount of sodium chloride or glucose does not influence the measurement and it is possible to apply spectrophotometry in a point-of-care sensor of the Cyclaid® by Apotex level. Full Text: PDF ReferencesL. Taylor, C. J. E. Watson, and J. A. Bradley, "Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy", Crit. Rev. Oncol. Hematol. 56, 23 (2005). CrossRef C. C. Mok, "Calcineurin inhibitors in systemic lupus erythematosus", Best Pract. Res. Clin. Rheumatol. 31, 429 (2017). CrossRef C. E. M. Griffiths et al., "Striae gravidarum in primiparae", Br. J. Dermatol. 155, 1 (2006). CrossRef F. Stucker and D. Ackermann, "Immunsuppressiva - Wirkungen, Nebenwirkungen und Interaktionen", Ther. Umschau. Rev. thérapeutique, 68 ,679 (2011). CrossRef A. Fahr, "Cyclosporin Clinical Pharmacokinetics", Clin. Pharmacokinet. 24, 472 (1993). CrossRef Cyclosporine – UpToDate, DirectLink P. Strakowska, R. Beutner, M. Gnyba et al., "Electrochemically assisted deposition of hydroxyapatite on Ti6A14V substrates covered by CVD diamond films – coating characterization and first cell biological results", Mater Sci Eng C Mater Biol Appl. 59, 624 (2016). CrossRef M. Gnyba, M. S. Wróbel, K. Karpienko et al., "Combined analysis of whole human blood parameters by Raman spectroscopy and spectral-domain low-coherence interferometry", Proc. SPIE 9537, 95371N (2015). CrossRef M. S. Wróbel, M. Gnyba, R. Urniaz et al., "Detection of propofol concentrations in blood by Raman spectroscopy", Proc. SPIE 9537, 95370Z (2015). CrossRef M. Gnyba, et al., "SAVE TO MY LIBRARY Raman spectroscopic investigation of blood and related materials", Proc. SPIE 9448, 944809 (2015). CrossRef H. S. Cho et al., "High frame-rate intravascular optical frequency-domain imaging in vivo", Biomed. Opt. Express 5, 223 (2013). CrossRef T. A. Valdez et al., "Multi-color reflectance imaging of middle ear pathology in vivo", Anal. Bioanal. Chem. 407, 3277 (2015). CrossRef M. Ali Ansari, S. Alikhani, and E. Mohajerani, "A hybrid imaging method based on diffuse optical tomography and optomechanical method to detect a tumor in the biological phantom", Opt. Commun. 342, 12 (2015). CrossRef M. S. Wróbel et al., "Multi-layered tissue head phantoms for noninvasive optical diagnostics", J. Innov. Opt. Health Sci. 08, 1541005 (2015). CrossRef D. A. Skoog, F. J. Holler, and S. R. Crouch, Principles of instrumental analysis, (Belmont, CA, Thomson Brooks/Cole 2007). CrossRef M. Hof, Basics of Optical Spectroscopy in Handbook of Spectroscopy, (Weinheim , Wiley-VCH Verlag GmbH & Co. KGaA 2005). CrossRef M. Marzejon et al,. "Optical-Spectrometry-Based Method for Immunosuppressant Medicine Level Detection in Aqueous Solutions", Sensors, 18, 2001 (2018). CrossRef UV-9000 Double Beam UV/VIS, http://en.metash.com/ProductShow_172.html CrossRef

Abstract Introduction: Daratumumab (DARA) is a human monoclonal IgG1κ CD38-targeting antibody that functions through several mechanisms of action (MOA), including CDC, ADCC, ADCP and induction of apoptosis. An additional, novel role of immune modulation and increased adaptive immune response was revealed from translational studies of DARA (16 mg/kg) in single-agent, phase 1/2 studies (SIRIUS [MMY2002] and GEN501; Krejcik J et al, Blood 2016;128:384-94). To further explore the ability of DARA to promote adaptive T-cell responses, we profiled T-cell repertoires (TCR) to evaluate T-cell clonality, expansion, and diversity from samples collected in POLLUX (MMY3003), a phase 3, randomized, open-label, multicenter study for patients with relapsed/refractory MM, in which DARA was tested in combination with lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone alone (DRd vs. Rd; Dimopoulos MA et al, N Engl J Med 2016; in press). Methods: T-cell receptor beta (TCRβ) sequencing for repertoire profiling was conducted on whole blood samples collected at baseline and eight weeks after DARA treatment (cycle 3 [C3]) from subjects on both arms using the ImmunoSEQ assay (Adaptive Biotechnologies. Seattle, WA, USA). 133 subjects in DRd and 124 subjects in Rd treatment groups were included in this analysis and represented a balanced subgroup of the POLLUX clinical trial subjects. T-cell metric changes were compared between arms with ANOVA, including the treatment arm and visit interaction term. Within treatment-arm changes were evaluated with a Wilcoxon signed-rank test comparing baseline to on-treatment values per patient. Results: Consistent with the randomized treatment groups, no baseline differences were observed in T-cell repertoire metrics between the treatment arms, including T-cell clonality, diversity (or richness), and T-cell fraction. Similar to prior findings from DARA monotherapy studies, significantly larger increase of TCRβ clonality was observed in the DRd arm (median of 0.166 at baseline to 0.263 at C3). Interestingly, there was no increase in TCRβ clonality in the Rd arm (median of 0.175 at baseline to 0.175 at C3). The change in TCRβ clonality between C1 and C3 was significantly different between DRd and Rd (p=3.26E-10), demonstrating that the addition of DARA to Rd induces a specific clonal expansion of T cells. Estimated richness (diversity), on the other hand, slightly decreased with DRd treatment but not with Rd treatment (median of 503,951 at baseline to 427,096 at C3 [p= 1.01E-04] vs 572,182 to 532,806 [p= 3.58-01]). Among patients in both treatment groups, a bigger increase in T-cell fraction was observed in DRd vs Rd (median of 0.231 at baseline to 0.278 at C3 [p= 2.62E-3] vs 0.228 to 0.249 [p= 1.91E-01]). Although there were no significant differences in baseline characteristics in T-cell clonality, richness, and T-cell fraction, quartile analysis demonstrated that high baseline TCR richness predicted for better PFS with DRd but not for Rd. Conclusion: DARA in combination with lenalidomide plus dexamethasone specifically induced robust increases in T-cell clonality, which was not observed within the control lenalidomide plus dexamethasone arm. Interestingly, baseline TCR richness was associated with improved PFS in DRd subjects. This observation is similar to results with immune checkpoint inhibitors (Postow MA et al, J Immunother Cancer 2015;3:23), and together with the significant increase in T-cell clonality, provides further evidence for the immunomodulatory activity of DARA, even in combination therapy. These data support DARA's immune-modulatory MOA and provide additional insights into DARA's effect on the TCR in combination with standard of care treatment. Figure Figure. Disclosures Chiu: Janssen: Employment. Casneuf:Janssen R&D, Beerse, Belgium: Employment; Johnson & Johnson: Equity Ownership. Axel:Janssen Pharmaceuticals Research and Development: Employment. Lysaght:Immuneering Corp: Employment; Janssen: Research Funding. Bald:Janssen: Employment. Khokhar:Janssen: Employment. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Amgen: Consultancy, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding. Goldschmidt:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Ahmadi:Janssen: Employment. Chan:Adaptive Biotechnologies: Employment; University of Washington: Other: Visiting scholar. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment.

ABSTRACT Background The aim of the study was to evaluate serumlevels of interleukin-1, beta (IL-1β) and tumor necrosis factoralpha (TNF-α) at birth and compare the values in case of preterm birth and normal birth groups of mothers considering the mothers’ periodontal status. Materials and methods Blood samples from 81 women (preterm birth, 41 women, and term birth, 40 women) were collected within half an hour of after delivery. Serum levels of IL-1β and TNF-α were measured. Periodontal status was characterized by bleeding on probing (BOP) and probing depth (PD). Results The frequency of BOP differed significantly between preterm and term groups; however, mean PD did not show a significant difference. Serum IL-1β levels were significantly higher in the preterm birth group. The levels TNF-α were slightly bigger in the term birth group, the difference was significant. The rank correlation showed a significant negative relationship between serum IL-1β and TNF-α level and birth weight and the length of pregnancy, and also between BOP frequency and the length of pregnancy. Conclusion Within the limitations of the study, it was found that IL-1β and TNF-α levels were higher when the delivery occurred preterm and the birth weight was smaller; however, a significant increase of cytokines in the serum in connection with maternal periodontal disease was not detected. Periodontics of mothers was not associated with preterm birth in the sample. How to cite this article Radnai M, Novák T, Orvos H, Kovács M, Bóka B, Kele B, Gorzó I. Serum Cytokine Levels in Term and Preterm Deliveries Relating to the Periodontal Health of Mothers: A Pilot Study. Int J Experiment Dent Sci 2015;4(2):109-115.

We prove absolute continuity of the spectrum of a periodic $n$-dimensional Schrödinger operator for $n\geqslant 4$. Certain conditions on the magnetic potential $A$ and the electric potential $V+\sum f_j\delta_{S_j}$ are supposed to be fulfilled. In particular, we can assume that the following conditions are satisfied. (1) The magnetic potential $A\colon{\mathbb{R}}^n\to{\mathbb{R}}^n$ either has an absolutely convergent Fourier series or belongs to the space $H^q_{\mathrm{loc}}({\mathbb{R}}^n;{\mathbb{R}}^n)$, $2q>n-1$, or to the space $C({\mathbb{R}}^n;{\mathbb{R}}^n)\cap H^q_{\mathrm{loc}}({\mathbb{R}}^n;{\mathbb{R}}^n)$, $2q>n-2$. (2) The function $V\colon{\mathbb{R}}^n\to\mathbb{R}$ belongs to Morrey space ${\mathfrak{L}}^{2,p}$, $p\in \big(\frac{n-1}{2},\frac{n}{2}\big]$, of periodic functions (with a given period lattice), and $$\lim\limits_{\tau\to+0}\sup\limits_{0<r\leqslant\tau}\sup\limits_{x\in{\mathbb{R}}^n}r^2\bigg(\big(v(B^n_r)\big)^{-1}\int_{B^n_r(x)}|{\mathcal{V}}(y)|^pdy\bigg)^{1/p}\leqslant C,$$ where $B^n_r(x)$ is a closed ball of radius $r>0$ centered at a point $x\in{\mathbb{R}}^n$, $B^n_r=B^n_r(0)$, $v(B^n_r)$ is volume of the ball $B^n_r$, $C=C(n,p;A)>0$. (3) $\delta_{S_j}$ are $\delta$-functions concentrated on (piecewise) $C^1$-smooth periodic hypersurfaces $S_j$, $f_j\in L^p_{\mathrm{loc}}(S_j)$, $j=1,\ldots,m$. Some additional geometric conditions are imposed on the hypersurfaces $S_j$, and these conditions determine the choice of numbers $p\geqslant n-1$. In particular, let hypersurfaces $S_j$ be $C^2$-smooth, the unit vector $e$ be arbitrarily taken from some dense set of the unit sphere $S^{n-1}$ dependent on the magnetic potential $A$, and the normal curvature of the hypersurfaces $S_j$ in the direction of the unit vector $e$ be nonzero at all points of tangency of the hypersurfaces $S_j$ and the lines $\{x_0+te\colon t\in\mathbb{R}\}$, $x_0\in{\mathbb{R}}^n$. Then we can choose the number $p>\frac{3n}{2}-3$, $n\geqslant 4$.

Abstract Introduction Increasing global awareness that interprofessional team working is essential within modern healthcare systems has led to regulatory bodies mandating the inclusion of interprofessional education (IPE) within undergraduate curricula. The General Pharmaceutical Council specifies in the 2021 initial education and training standards the requirement for an interprofessional learning plan in which “IPE must mirror practice”.1 Pharmacy educators are intensifying their efforts to ensure student pharmacists are presented with opportunities to develop collaborative competencies. Curricular development and implementation initiatives must explore structures and processes to ensure that experiential learning (EL) environments are conducive to supporting student pharmacists’ interprofessional learning. Aim To explore structures and processes needed to support effective planned and unplanned IPE during EL placements for student pharmacists. Methods A mixed methods approach underpinned by the Biggs 3P theoretical framework was adopted.2 This included (1) A document analysis reviewing resources including student pharmacist/EL facilitator university handbooks and NHS Education for Scotland Preparation for Facilitating Experiential Learning (PFEL) training - a mandatory requirement for all EL facilitators hosting student pharmacists on placement in Scotland. (2) A pre-piloted online survey distributed to EL facilitators. Survey development, guided by the Interprofessional Facilitation Scale, aimed to encourage EL facilitators to self-evaluate their own IPE facilitation skills.3 The final survey tool included ten items with responses rated on a 4-point Likert scale (Poor, Fair, Good and Excellent) and a demographic section (3) Online semi-structured focus groups/dyadic interviews conducted with six EL facilitators, four practice educators and two academic staff were recorded and transcribed. Descriptive statistics were employed for quantitative data generated from the survey tool; for qualitative data content analysis was applied to develop emerging themes. Ethical approval was granted (S292) from the School of Pharmacy and Life Sciences Ethics Review Committee at Robert Gordon University. Results (1) The document analysis concluded that although the resources reviewed could not be specifically classed as training to support IPE, data collected provided context to EL placements and the training and pre-activities that student pharmacists and EL facilitators complete. Three main themes emerged: “Lack of specific IPE training focus”, “Varied terminology”, “Lack of IPE pre-learning activities”. (2) The survey was completed by ninety EL facilitators working in various practice settings: hospital 41.1% (n=37); primary care 25.6% (n=23); community 21.1% (n=19); academia 2.2% (n=2); other 8.9% (n=8). Survey responses indicated that 51.1% (n=46) and 42.2% (n=38) of respondents rated their ability to role model positive interactions with other healthcare professionals as good and excellent. However, responses to items relating more specifically to IPE facilitation skills indicated a lower confidence level. (3) Initial themes emerging from focus groups/dyadic interviews include “Profession-related perceptions of IPE”, “Factors influencing IPE delivery and student learning”, “Factors influencing future developments”. Discussion/Conclusion This exploratory study has provided valuable insight into multifactorial aspects affecting IPE during EL placements; this will be used to guide future development of IPE initiatives. One limitation is that student pharmacists were not included in this study; the next phase of this research programme will explore student pharmacists’ perceptions of IPE in EL. References 1. General Pharmaceutical Council. Standards for the initial education and training of pharmacists. [homepage on the Internet]. London: GPhC; 2021. Available from: https://www.pharmacyregulation.org/sites/default/files/document/standards-for-the-initial-education-and-training-of-pharmacists-january-2021.pdf 2. Biggs, J.B. From Theory to Practice: A Cognitive Systems Approach. High Educ Res Dev, 1993, 12(1), 73-85 3. Sargeant J., Hill T., Breau L. Development and testing of a scale to assess interprofessional education (IPE) facilitation skills. J Cont Educ Health Prof, 2010, 30(2), 126-131

Background:Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease, usually involving multiple systems of the whole body (1). A variety of factors can affect SLE, such as genetic, environmental, immunoregulatory, hormonal and epigenetic (2). Long non-coding RNA is a type of RNA greater than 200 nucleotides that does not encode proteins. With the development of research, lncRNA gradually becomes the key regulator of gene expression in the immune system (3). Studies have shown that several lncRNAs, such as NEAT1 and GAS5 are dysregulated in SLE and are involved in the pathogenesis of SLE (4,5). These results suggest that lncRNA can be used as a potential biomarker for disease diagnosis and treatment. However, our current understanding of SLE related lncRNAS is still limited.Objectives:The purpose of this study was to find new lncRNAs in peripheral blood monouclear cells of SLE patients by transcriptome sequencing and explore their potential as biomarkers and their correlation with clinical features.Methods:Transcriptome sequencing was used to screen differentially expressed lncRNAs (DELs) and mRNAs (DEMs). DAVID and WebGestalt were used to perform enrichment analysis. Cytoscape was used to constructed protein-protein network, co-expression network and competitive endogenous RNA network to reveal the regulatory mechanism of lncRNAs in transcriptome level. The expression of these selected lncRNAs in SLE patients and healthy controls were verified by qPCR.Results:A toal of 1737 DELs and 4078 DEMs were identified between 5 SLE patients and 5 healthy controls. Most of upregulated genes were enriched in defense and immune response, while downregulated genes were mainly enriched in SLE related pathways. Topology network analysis reveal the regulatory mechanism of lncRNAs in transcriptome level including directly acting on mRNA or indirectly affecting gene expression after acting on miRNA. Ten lncRNAs and eight genes was verified by qPCR in bigger samples including 77 SLE patients and 25 healthy controls. LncRNA NONHSAT101022.2 was significantly downregulated in SLE patients (p=0.001) and the expression of NONHSAT101022.2 showed a significant negative correlation with SLE disease activity index (SLEDAI, r=-0.3592, p=0.0013).Conclusion:In this work, we identified a large number of mRNAs and novel lncRNAs by transcriptome sequence. The function and regulatory mechanism of these lncRNAs were analyzed by bioinformatics methods. LncRNA NONHSAT101022.2 is significantly downregulated in SLE patients and significantly related to the activity and severity of disease. Additionally, we put forward that NONHSAT101022.2 may enhance the signal transduction of β2-AR by cis-regulating its target gene, LMBRD2, which induces NK cells to produce high levels of IFN-γ, thereby exacerbating SLE.References:[1]Carter EE, Barr SG, Clarke AE. The global burden of SLE: prevalence, health disparities and socioeconomic impact. Nat Rev Rheumatol. 2016;12(10):605-20.[2]Han EC. Systemic lupus erythematosus. N Engl J Med. 2012;366(6):573-4; author reply.[3]Chen YG, Satpathy AT, Chang HY. Gene regulation in the immune system by long noncoding RNAs. Nat Immunol. 2017;18(9):962-72.[4]Zhang F, Wu L, Qian J, Qu B, Xia S, La T, et al. Identification of the long noncoding RNA NEAT1 as a novel inflammatory regulator acting through MAPK pathway in human lupus. Journal of autoimmunity. 2016;75:96-104.[5]Liu Q, Deng Y, Li C, Xie H, Liu Q, Ming S, et al. LncRNA GAS5 suppresses CD4(+) T cell activation by upregulating E4BP4 via inhibiting miR-92a-3p in systemic lupus erythematosus. Immunol Lett. 2020;227:41-7.Disclosure of Interests:None declared

Botryosphaeria dothidea (Moug.:Fr.) Ces. De Not. causes perennial cankers on apple trees and causes white rot on apple fruit in the field and during storage (1). Prolonged periods of warm wet weather favor rapid disease outbreaks that result in severe losses, which range from 25 to 50% for the southeastern United States (3). A B. dothidea isolate was obtained from decayed ‘Fuji’ apple fruit exhibiting white rot symptoms from a local farm market in Beltsville, MD, in May 2010. The fruit had characteristic large dark brown lesions with irregular margins and decay expanded unevenly toward the core and the tissue was soft. The pathogen was isolated from symptomatic tissue by spraying the lesion surface with 70% ethanol. The skin with aseptically removed with a scalpel and small pieces of tissue were placed on potato dextrose agar (PDA) and incubated at 20°C. Once fungal growth was evident, the cultures were hyphal-tip transferred to individual PDA plates and incubated at 20°C. The B. dothidea isolate produced black aerial mycelium with a white margin on PDA and had a black reverse. Conidiomata were evident after 10 to 14 days at 20°C only on oatmeal agar. Conidia were hyaline, smooth and straight, fusiform with an subobtuse apex and a truncate base 20 to 26 (24.33) × 4 to 7 (5) μm (n = 50). Genomic DNA was isolated from the fungus and amplified with gene specific primers (ITS 4 and 5) for the ribosomal DNA internal transcribed spacer region ITSI-5.8S-ITS2 as described by White et al. (4). Both forward and reverse strands of the 542-bp amplicon were sequenced and assembled into a contig. The nucleotide sequence (GenBank Accession No. KC473852) indicated 99% identity to B. dothidea isolate CMM3938 (JX513645.1) and to voucher specimens CMW 25686, 25696, and 25222 (FM955381.1, FM955379.1, and FM955377,1). Koch's postulates were conducted using three ‘Golden Delicious’ apple fruit that were wound-inoculated with 50 μl of a mycelial suspension of the fungus, obtained from aseptically scraping a 7-day-old PDA culture, and was also repeated using ‘Fuji’ apple fruit. Large, brown, slightly sunken, soft lesions with undefined edges developed 5 days after inoculation at 20°C and water-only inoculated fruit were symptomless. The fungus was reisolated from infected tissue and was morphologically identical to the original isolate from decayed apple fruit. To determine if the B. dothidea isolate was resistant to postharvest fungicides, the minimum inhibitory concentration (MIC) was conducted using the 96 well plate method with a mycelial suspension of the fungus as described by Pianzzola et al. (2). The MIC for the isolate was >1 ppm for Mertect and Scholar and 50 ppm for Penbotec, which are well below the labeled rates for these postharvest fungicides and the experiment was repeated. To our knowledge, this is the first report of B. dothidea causing white rot on apple fruit in Maryland. References: (1) A. R. Biggs and S. S. Miller. HortScience 38:400, 2003. (2) M. J. Pianzzola et al. Plant Dis. 88:23, 2004. (3) T. B. Sutton. White rot and black rot. Pages 16-20 in: Compendium of Apple and Pear Diseases, A. L. Jones and H. S. Aldwinckle, eds. The American Phytopathological Society, St Paul, MN, 1991. (4) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Application. M. A. Innis et al., eds. Academic Press, San Diego, CA, 1990.

BackgroundThe COVID-19 pandemic has led to widespread vaccination with effective results and a great safety profile. However, as the vaccination rate has increased, more cases of autoimmune diseases after the COVID-19 vaccine have been described. We present a systematic review of ANCA-associated glomerulonephritis after the COVID-19 vaccine.ObjectivesTo summarize the existing evidence on ANCA-associated glomerulonephritis after the COVID-19 vaccine.MethodsWe searched all studies from inception till January 27, 2022, that described ANCA-associated biopsy-proven glomerulonephritis after COVID-19 vaccine through Embase and Medline. Methodological quality was evaluated with the 4 domains tool. We included 13 patients from 2 case series and 9 case reports. We extracted demographics, history, lab results, outcomes. We then applied descriptive statistics.Results46% of the patients were males and 54% were females. The median age was 74 years. 54% developed symptoms after the second dose of the 2-dose vaccine. The median interval between the vaccine and the symptom onset was 10.5 days. 85% had anti-MPO antibodies, and the rest – anti-PR3 antibodies. 31% of patients had persistent creatinine (Cr) elevation on follow-up, and 3 patients were requiring hemodialysis. Of those 3 patients, 1 patient had normal renal function prior to presentation, and the rest had chronic kidney disease. The summary of the cases is presented in Table 1.Table 1.Gender, ageDe novo (1) or relapse (2)AZD1222 (1), or mRNA-1273 (2), or BNT162b2 (3)OutcomeM, 75121HemodialysisM, 74121Improved CrF, 82212Improved CrF, 70312Improved CrF, 78413Improved CrF, 79513RemissionF, 54613Improved CrF, 78623HemodialysisM, 58712RemissionM, 63811Improved CrF, 29913RemissionM, 521012HemodialysisM, 841113Worsened CrConclusionAlthough the causality cannot be established on current evidence, the COVID-19 vaccine can probably trigger glomerulonephritis associated with ANCA, primarily anti-MPO type. We need a bigger cohort to identify patients predisposed for disease development or relapse after the COVID-19 vaccine.References[1]David R, Hanna P, Lee K, et al. Relapsed ANCA associated vasculitis following Oxford AstraZeneca ChAdOx1-S COVID-19 vaccination: A case series of two patients. Nephrol. 2021;27(1):109-110.[2]Klomjit N, Alexander MP, Fervenza FC, et al. COVID-19 Vaccination and Glomerulonephritis. Kidney Int Rep. 2021;6(12):2969-2978.[3]Chen C-C, Chen H-Y, Lu C-C, et al. Case Report: Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis With Acute Renal Failure and Pulmonary Hemorrhage May Occur After COVID-19 Vaccination. Front Med. 2021;8.[4]Shakoor MT, Birkenbach MP, Lynch M. ANCA-Associated Vasculitis Following Pfizer-BioNTech COVID-19 Vaccine. Am J Kidney Dis. 2021;78(4):611-613.[5]Hakroush S, Tampe B. Case Report: ANCA-Associated Vasculitis Presenting With Rhabdomyolysis and Pauci-Immune Crescentic Glomerulonephritis After Pfizer-BioNTech COVID-19 mRNA Vaccination. Front Immunol. 2021;12.[6]Davidovic T, Schimpf J, Sprenger-Mahr H, et al. De Novo and Relapsing Glomerulonephritis following SARS-CoV-2 mRNA Vaccination in Microscopic Polyangiitis. Case Reports Nephrol. 2021.[7]Feghali EJ, Zafar M, Abid S, et al. De-novo Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Following the mRNA-1273 (Moderna) Vaccine for COVID-19. Cureus. 2021;13(11).[8]Villa M, Diaz-Crespo F, Perez de Jose A, et al. A case of ANCA-associated vasculitis after AZD1222 (Oxford–AstraZeneca) SARS-CoV-2 vaccination: casualty or causality? Kidney Int. 2021;100(4):937-938.[9]Dube GK, Benvenuto L, Batal I. Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis Following the Pfizer-BioNTech COVID-19 Vaccine. Kidney Int Rep. 2021;6(12):3087-3089.[10]Sekar A, Campbell R, Tabbara J, et al. ANCA glomerulonephritis after the Moderna COVID-19 vaccination. Kidney Int. 2021;100(2):473-474.[11]Obata S, Hidaka S, Yamano M, et al. MPO-ANCA-associated vasculitis after the Pfizer/BioNTech SARS-CoV-2 vaccination. Clin Kidney J. 2021.Disclosure of InterestsNone declared

A field survey conducted in September 2009 at five plantations of six different cultivars of southern highbush blueberries (Vaccinium spp.) in Huelva, Spain, yielded 35 diseased plants. Diseased plants exhibited red-brown cankers and stem dieback. Blueberry cultivation in Huelva rose from 290 ha in 2007 to 777 ha in 2012, and the increase of these symptoms is of concern to producers. Stem pieces cut from the edge of lesions on infected plants were surface-disinfected with 5% sodium hypochlorite and cultured on potato dextrose agar (PDA). Based on colony characteristics on PDA, 18 colonies (one each from 18 different plants) were identified as Botryosphaeria spp. Species identities were confirmed by analysis of nucleotide sequences of the internal transcribed spacer (ITS), rDNA, and elongation factor 1-alpha (EF1-α) sequences, using ITS1-ITS4 (3) and EF728f-EF986r (2) as primer pairs, respectively. BLAST searches of GenBank showed a high similarity of the isolate sequences to the reference sequences. Molecular results confirmed these species as Neofusicoccum parvum, N. australe, and B. dothidea. N. parvum was the most prevalent (on 34% of the plants analyzed), followed by N. australe and B. dothidea (9% each). In phylogenetic analyses, isolates that clustered in the same group belonged to the same species with a high homogeneity index (>99%). One representative isolate of each species was selected for a pathogenicity assay. Amplified sequences from each selected isolate were deposited in GenBank with the following accession numbers: N. parvum, KC556958 (ITS) and KC556961 (EF); N. australe, KC556959 (ITS) and KC556962 (EF); and B. dothidea, KC556960 (ITS) and KC556963 (EF). The pathogenicity assay of these three isolates was conducted using two cultivars of southern highbush blueberry, ‘Misty’ and ‘Star.’ The isolates were cultured on acidified PDA at 25°C for 5 days. Stems of the plants were wounded at a height of 10 cm with a drill (5 mm diameter and ~4 mm deep). Six replicates per cultivar were inoculated per isolate by placing a colonized agar plug (4 to 5 mm diameter) in the hole and wrapping the stem with Parafilm. Plants treated identically with sterile agar plugs were used as controls. The plants were then maintained at 100% relative humidity for 2 h. This trial was conducted in a growth chamber at 28°C (night) and 30°C (day) with a 14-h photoperiod for 3 months. Disease was measured on a six-point scale: 0 = healthy plant; 1 = plant with a canker smaller than 3.5 cm; 2 = plant with a canker bigger than 3.5 cm; 3 = plant with one dry shoot; 4 = plant with some dry shoots; 5 = dead plant. At the end of the trial, disease was expressed as area under the disease progress curve. The results showed the N. parvum isolate to be the most aggressive, followed by the N. australe isolate. Espinoza et al. (1) also found that N. parvum showed more aggressiveness than N. australe on blueberries in Chile. B. dothidea was not pathogenic and behaved similarly to the controls (P < 0.05). Each pathogen was reisolated from all the inoculated plants, fulfilling Koch's postulates. To our knowledge, this is the first report of isolates of these pathogens, N. parvum and N. australe, causing stem canker and dieback on blueberry bushes in Spain. References: (1) J. G. Espinoza et al. Plant Dis. 93:1187, 2009. (2) A. J. L. Phillips et al. Mycol. 97:513, 2005. (3) T. J. White et al. Pages 315-322 in: PCR Protocols: a Guide to Methods and Amplifications. M. A. Innis et al., eds. Academic Press, San Diego, CA. 1990.

Objectives: This study was performed to find out the extent and nature of arterial flow abnormality in diabetic patients with peripheral neuropathy compared to diabetic patients without neuropathy, using duplex colour Doppler technique. Materials and method: This cross sectional study was performed on diabetic subjects in the Department of Radiology and Imaging, BIRDEM from July 2008’ to May 2009. Patients were referred from Department of neurology and preventive foot care OPD, BIRDEM, for colour Doppler imaging of lower limb arteries. Total 88 consecutive diabetic patients were included in this study. Out of them 48 were diagnosed cases of diabetic neuropathy (group I) and 40 were diabetic without neuropathy (Group II). In all patients the Ankle Brachial Index (ABI) and Pulsatility Index (PI) were recorded on both left and right lower limb arteries, by using duplex colour Doppler technique. Total no. of patients were 88. 48 had neuropathy. They were 27-57 yrs of age. Result: Unpaired‘t’ test was used to find out relationship between the variables.P value <o.o5 was considered as statistically significant. The mean ABI was 1.44±0.07, ranged from 1.30 to 1.59 in group I (diabetic neuropathy) and 1.17±0.06, ranged from 1.05 to 1.26 in group II (diabetic without neuropathy). The mean ABI difference was found statistically significant (p<0.05) between group I and group II. The mean PI was 3.0±0.69, ranged from 1.18 to 3.68 and 7.97±2.29,ranged from 5.50 to 13.0 in group I (diabetic neuropathy) and group II (diabetic without neuropathy) respectively. The mean PI difference was found statistically significant (p<0.05) between group I (diabetic neuropathy) and group II (diabetic without neuropathy). Conclusion: In this study it was observed that Pulsatility Index (PI) decreased and Ankle Brachial Index (ABI) increased in diabetic neuropathic group. There was significant difference of Pulsatility Index (PI) and Ankle Brachial Index (ABI) found between diabetic subjects with and without neuropathy. So, from the finding of the present work, it can be said that diabetic neuropathy affect the arterial flow detected by non invasive duplex colour Doppler imaging may help in proper patient management and may prevent neuropathic arterial complications. But for any definine conclusion, bigger appropriate study should be done.DOI: http://dx.doi.org/10.3329/birdem.v2i2.12309 (Birdem Med J 2012; 2(2): 89-92)

Abstract—Wafer direct bonding is now a widely spread technique in microelectronics. However in many interesting applications, wafer bonding is not adapted due to size, material or technological node differences. Die to wafer bonding could then lead to innovative devices. After explaining some specific fundamental mechanisms, III/V die to wafer bonding and copper hybrid bonding will be presented for photonic and 3D applications. Introduction SOI or backside image sensors’ fabrication in mass production, for instance, calls upon direct wafer bonding that has become a standard technology available in many industrial microelectronic factories. Direct bonding of 200 mm or 300 mm silicon wafers are nowadays well mastered. For many innovative applications, it could be interesting to introduce new materials like InP, AsGa, GaN on a silicon platform. Heterostructure bonding then needs to be developed. This could be done with wafer-to-wafer bonding. However, wafers made of these new materials usually have diameters much smaller than that of silicon wafers, especially if CMOS are required on the silicon wafers. Indeed, advanced CMOS devices are nowadays only available on 200/300 mm silicon wafers. Even if the bonding of a small wafer on a bigger one is easily feasible, the silicon surface lost will be detrimental to the cost of the device. Moreover, usually, a very small surface of the new material is needed on the silicon wafer. With a wafer-to-wafer bonding (W2W), the new material surface loss will be quite important. Die-to-wafer (D2W) bonding is thus the solution to both issues in order to put only a small amount of new material where it is needed and populate all the active area on silicon wafers. D2W is also interesting in hybrid bonding with silicon wafers. Indeed, D2W enlarges design rules to mix different technologies (material, dies size) on the same bottom wafer while enabling high density of copper interconnects.. Hybrid D2W is then foreseen as being the next step for hybrid bonding in order to widen its application field. Results Starting with the well know fundamental mechanisms of silicon dioxide bonding [1] as well as copper and hybrid surface bonding [2], D2W bonding behavior will be discussed. Some specific features indeed have to be taken into account for die bonding. For instance, all the edge effects, during and after the bonding or the annealing, have a great impact on the bonding energy as well as on the interface defectivity. Moreover, specific bonding techniques using for instance liquid water films can be used only in D2W bonding. If these specific features are under control, very innovative structures can be obtained. It is possible for instance to bond small 3mm*3mm InP dies onto 200mm silicon photonic wafers as shown in Fig.1a [3]. Moreover, hybrid bonding interfaces can also be obtained between 6mm*4mm dies and a 300mm wafer as shown in Fig.1b. Obviously, alignment in mandatory during hybrid bonding. This can be obtained thanks to a die to wafer bonder. However, innovative technologies such as capillary assisted self-assembly can also be really interesting [4 -7]. The electrical characterization of the D2W hybrid bonding connection will be also discussed, showing roughly the same good results as for W2W hybrid bonding. Acknowledgment This work was funded thanks to the French National program “Programme d’Investissement d’Avenir IRT Nanoelec” ANR-10-AIRT-05. References 1 F. Fournel, et al., ECS J. Solid State Sci. Technol. 4, P124 (2015). 2 L.D. Cioccio, et al., J. Electrochem. Soc. 158, P81 (2011). 3 B. Szelag et al., Hybrid III-V/Silicon technology for laser integration on a 200 mm fully CMOS-compatible silicon photonics platform, IEEE J. Sel. Top. Quantum Electron., In Press (2019). 4 A. Jouve, et al., ECTC (2019). 5 T. Fukushima, et al., in 2011 IEEE 61st Electron. Compon. Technol. Conf. ECTC (2011), pp. 2050–2055. 6 E. Bourjot, et al., ECTC(2021) Figure 1

Hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days. Equal amounts of proteins from urinary bladder or liver extracts of control and arsenic-treated hamsters were labeled with Cy3 and Cy5 dyes, respectively. After differential in gel electrophoresis and analysis by the DeCyder software, several protein spots were found to be down-regulated and several were up regulated. Our experiments indicated that in the bladder tissues of hamsters exposed to arsenite, transgelin was down-regulated and GST-pi was up-regulated. The loss of transgelin expression has been reported to be an important early event in tumor progression and a diagnostic marker for cancer development [29-32]. Down-regulation of transgelin expression may be associated with the carcinogenicity of inorganic arsenic in the urinary bladder. In the liver of arsenite-treated hamsters, ornithine aminotransferase was up-regulated, and senescence marker protein 30 and fatty acid binding protein were down-regulated. The volume ratio changes of these proteins in the bladder and liver of hamsters exposed to arsenite were significantly different than that of control hamsters. Introduction Chronic exposure to inorganic arsenic can cause cancer of the skin, lungs, urinary bladder, kidneys, and liver [1-6]. The molecular mechanisms of the carcinogenicity and toxicity of inorganic arsenic are not well understood [7-9). Humans chronically exposed to inorganic arsenic excrete MMA(V), DMA(V) and the more toxic +3 oxidation state arsenic biotransformants MMA(III) and DMA (III) in their urine [10, 11], which are carcinogen [12]· After injection of mice with sodium arsenate, the highest concentrations of the very toxic MMA(III) and DMA(III) were in the kidneys and urinary bladder tissue, respectively, as shown by experiments of Chowdhury et al [13]. Many mechanisms of arsenic toxicity and carcinogenicity have been suggested [1, 7, 14] including chromosome abnormalities [15], oxidative stress [16, 17], altered growth factors [18], cell proliferation [19], altered DNA repair [20], altered DNA methylation patterns [21], inhibition of several key enzymes [22], gene amplification [23] etc. Some of these mechanisms result in alterations in protein expression. Methods for analyzing multiple proteins have advanced greatly in the last several years. In particularly, mass spectrometry (MS) and tandem MS (MS/MS) are used to analyze peptides following protein isolation using two-dimensional (2-D) gel electrophoresis and proteolytic digestion [24]. In the present study, Differential In Gel Electrophoresis (DIGE) coupled with Mass Spectrometry (MS) has been used to study some of the proteomic changes in the urinary bladder and liver of hamsters exposed to sodium arsenite in their drinking water. Our results indicated that transgelin was down-regulated and GST-pi was up-regulated in the bladder tissues. In the liver tissues ornithine aminotransferase was up-regulated, and senescence marker protein 30, and fatty acid binding protein were down-regulated. Materials and Methods Chemicals Tris, Urea, IPG strips, IPG buffer, CHAPS, Dry Strip Cover Fluid, Bind Silane, lodoacetamide, Cy3 and Cy5 were from GE Healthcare (formally known as Amersham Biosciences, Uppsala, Sweden). Thiourea, glycerol, SDS, DTT, and APS were from Sigma-Aldrich (St. Louis, MO, USA). Glycine was from USB (Cleveland, OH, USA). Acrylamide Bis 40% was from Bio-Rad (Hercules, CA, USA). All other chemicals and biochemicals used were of analytical grade. All solutions were made with Milli-Q water. Animals Male hamsters (Golden Syrian), 4 weeks of age, were purchased from Harlan Sprague Dawley, USA. Upon arrival, hamsters were acclimated in the University of Arizona animal care facility for at least 1 week and maintained in an environmentally controlled animal facility operating on a 12-h dark/12-h light cycle and at 22-24°C. They were provided with Teklad (Indianapolis, IN) 4% Mouse/Rat Diet # 7001 and water, ad libitum, throughout the acclimation and experimentation periods. Sample preparation and labelling Hamsters were exposed to sodium arsenite (173 mg) in drinking water for 6 days and the control hamsters were given tap water. On the 6th day hamsters were decapitated rapidly by guillotine. Urinary bladder tissues and liver were removed, blotted on tissue papers (Kimtech Science, Precision Wipes), and weighed. Hamster urinary bladder or liver tissues were homogenized in lysis buffer (30mMTris, 2M thiourea, 7M urea, and 4% w/w CHAPS adjusted to pH 8.5 with dilute HCI), at 4°C using a glass homogenizer and a Teflon coated steel pestle; transferred to a 5 ml acid-washed polypropylene tube, placed on ice and sonicated 3 times for 15 seconds. The sonicate was centrifuged at 12,000 rpm for 10 minutes at 4°C. Small aliquots of the supernatants were stored at -80°C until use (generally within one week). Protein concentration was determined by the method of Bradford [25] using bovine serum albumin as a standard. Fifty micrograms of lysate protein was labeled with 400 pmol of Cy3 Dye (for control homogenate sample) and Cy5 Dye (for arsenic-treated urinary bladder or liver homogenate sample). The samples containing proteins and dyes were incubated for 30 min on ice in the dark. To stop the labeling reaction, 1uL of 10 mM lysine was added followed by incubation for 10 min on ice in the dark. To each of the appropriate dye-labeled protein samples, an additional 200 ug of urinary bladderor liver unlabeled protein from control hamster sample or arsenic-treated hamster sample was added to the appropriate sample. Differentially labeled samples were combined into a single Microfuge tube (total protein 500 ug); protein was mixed with an equal volume of 2x sample buffer [2M thiourea, 7M urea, pH 3-10 pharmalyte for isoelectric focusing 2% (v/v), DTT 2% (w/v), CHAPS 4% (w/v)]; and was incubated on ice in the dark for 10 min. The combined samples containing 500 ug of total protein were mixed with rehydration buffer [CHAPS 4% (w/v), 8M urea, 13mM DTT, IPG buffer (3-10) 1% (v/v) and trace amount of bromophenol blue]. The 450 ul sample containing rehydration buffer was slowly pipetted into the slot of the ImmobilinedryStripReswelling Tray and any large bubbles were removed. The IPG strip (linear pH 3-10, 24 cm) was placed (gel side down) into the slot, covered with drystrip cover fluid (Fig. 1), and the lid of the Reswelling Tray was closed. The ImmobillineDryStrip was allowed to rehydrate at room temperature for 24 hours. First dimension Isoelectric focusing (IEF) The labeled sample was loaded using the cup loading method on universal strip holder. IEF was then carried out on EttanIPGphor II using multistep protocol (6 hr @ 500 V, 6 hr @ 1000 V, 8 hr @ 8000 V). The focused IPG strip was equilibrated in two steps (reduction and alkylation) by equilibrating the strip for 10 min first in 10 ml of 50mM Tris (pH 8.8), 6M urea, 30% (v/v) glycerol, 2% (w/v) SDS, and 0.5% (w/v) DTT, followed by another 10 min in 10 ml of 50mM Tris (pH 8.8), 6M urea, 30% (v/v) glycerol, 2% (w/v) SDS, and 4.5% (w/v) iodoacetamide to prepare it for the second dimension electrophoresis. Second dimension SDS-PAGE The equilibrated IPG strip was used for protein separation by 2D-gel electrophoresis (DIGE). The strip was sealed at the top of the acrylamide gel for the second dimension (vertical) (12.5% polyacrylamide gel, 20x25 cm x 1.5 mm) with 0.5% (w/v) agarose in SDS running buffer [25 mMTris, 192 mM Glycine, and 0.1% (w/v) SDS]. Electrophoresis was performed in an Ettan DALT six electrophoresis unit (Amersham Biosciences) at 1.5 watts per gel, until the tracking dye reached the anodic end of the gel. Image analysis and post-staining The gel then was imaged directly between glass plates on the Typhoon 9410 variable mode imager (Sunnyvale, CA, USA) using optimal excitation/emission wavelength for each DIGE fluor: Cy3 (532/580 nm) and Cy5 (633/670 nm). The DIGE images were previewed and checked with Image Quant software (GE Healthcare) where all the two separate gel images could be viewed as a single gel image. DeCyde v.5.02 was used to analyze the DIGE images as described in the Ettan DIGE User Manual (GE Healthcare). The appropriate up-/down regulated spots were filtered based on an average volume ratio of ± over 1.2 fold. After image acquisition, the gel was fixed overnight in a solution containing 40% ethanol and 10% acetic acid. The fixed gel was stained with SyproRuby (BioRad) according to the manufacturer protocol (Bio-Rad Labs., 2000 Alfred Nobel Drive, Hercules, CA 94547). Identification of proteins by MS Protein spot picking and digestion Sypro Ruby stained gels were imaged using an Investigator ProPic and HT Analyzer software, both from Genomic Solutions (Ann Arbor, MI). Protein spots of interest that matched those imaged using the DIGE Cy3/Cy5 labels were picked robotically, digested using trypsin as described previously [24] and saved for mass spectrometry identification. Liquid chromatography (LC)- MS/MS analysis LC-MS/MS analyses were carried out using a 3D quadrupole ion trap massspectrometer (ThermoFinnigan LCQ DECA XP PLUS; ThermoFinnigan, San Jose, CA) equipped with a Michrom Paradigm MS4 HPLC (MichromBiosources, Auburn, CA) and a nanospray source, or with a linear quadrupole ion trap mass spectrometer (ThermoFinnigan LTQ), also equipped with a Michrom MS4 HPLC and a nanospray source. Peptides were eluted from a 15 cm pulled tip capillary column (100 um I.D. x 360 um O.D.; 3-5 um tip opening) packed with 7 cm Vydac C18 (Vydac, Hesperia, CA) material (5 µm, 300 Å pore size), using a gradient of 0-65% solvent B (98% methanol/2% water/0.5% formic acid/0.01% triflouroacetic acid) over a 60 min period at a flow rate of 350 nL/min. The ESI positive mode spray voltage was set at 1.6 kV, and the capillary temperature was set at 200°C. Dependent data scanning was performed by the Xcalibur v 1.3 software on the LCQ DECA XP+ or v 1.4 on the LTQ [27], with a default charge of 2, an isolation width of 1.5 amu, an activation amplitude of 35%, activation time of 50 msec, and a minimal signal of 10,000 ion counts (100 ion counts on the LTQ). Global dependent data settings were as follows: reject mass width of 1.5 amu, dynamic exclusion enabled, exclusion mass width of 1.5 amu, repeat count of 1, repeat duration of a min, and exclusion duration of 5 min. Scan event series were included one full scan with mass range of 350-2000 Da, followed by 3 dependent MS/MS scans of the most intense ion. Database searching Tandem MS spectra of peptides were analyzed with Turbo SEQUEST, version 3.1 (ThermoFinnigan), a program that allows the correlation of experimental tandem MS data with theoretical spectra generated from known protein sequences. All spectra were searched against the latest version of the non redundant protein database from the National Center for Biotechnology Information (NCBI 2006; at that time, the database contained 3,783,042 entries). Statistical analysis The means and standard error were calculated. The Student's t-test was used to analyze the significance of the difference between the control and arsenite exposed hamsters. P values less than 0.05 were considered significant. The reproducibility was confirmed in separate experiments. Results Analysis of proteins expression After DIGE (Fig. 1), the gel was scanned by a Typhoon Scanner and the relative amount of protein from sample 1 (treated hamster) as compared to sample 2 (control hamster) was determined (Figs. 2, 3). A green spot indicates that the amount of protein from sodium arsenite-treated hamster sample was less than that of the control sample. A red spot indicates that the amount of protein from the sodium arsenite-treated hamster sample was greater than that of the control sample. A yellow spot indicates sodium arsenite-treated hamster and control hamster each had the same amount of that protein. Several protein spots were up-regulated (red) or down-regulated (green) in the urinary bladder samples of hamsters exposed to sodium arsenite (173 mg As/L) for 6 days as compared with the urinary bladder of controls (Fig. 2). In the case of liver, several protein spots were also over-expressed (red) or under-expressed (green) for hamsters exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days (Fig. 3). The urinary bladder samples were collected from the first and second experiments in which hamsters were exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days and the controls were given tap water. The urinary bladder samples from the 1st and 2nd experiments were run 5 times in DIGE gels on different days. The protein expression is shown in Figure 2 and Table 1. The liver samples from the 1st and 2nd experiments were also run 3 times in DIGE gels on different days. The proteins expression were shown in Figure 3 and Table 2. The volume ratio changed of the protein spots in the urinary bladder and liver of hamsters exposed to arsenite were significantly differences than that of the control hamsters (Table 1 and 2). Protein spots identified by LC-MS/MS Bladder The spots of interest were removed from the gel, digested, and their identities were determined by LC-MS/MS (Fig. 2 and Table 1). The spots 1, 2, & 3 from the gel were analyzed and were repeated for the confirmation of the results (experiments; 173 mg As/L). The proteins for the spots 1, 2, and 3 were identified as transgelin, transgelin, and glutathione S-transferase Pi, respectively (Fig. 2). Liver We also identified some of the proteins in the liver samples of hamsters exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days (Fig. 3). The spots 4, 5, & 6 from the gels were analyzed and were repeated for the confirmation of the results. The proteins for the spots 4, 5, and 6 were identified as ornithine aminotransferase, senescence marker protein 30, and fatty acid binding protein, respectively (Fig. 3) Discussion The identification and functional assignment of proteins is helpful for understanding the molecular events involved in disease. Weexposed hamsters to sodium arsenite in drinking water. Controls were given tap water. DIGE coupled with LC-MS/MS was then used to study the proteomic change in arsenite-exposed hamsters. After electrophoresis DeCyder software indicated that several protein spots were down-regulated (green) and several were up-regulated (red). Our overall results as to changes and functions of the proteins we have studied are summarized in Table 3. Bladder In the case of the urinary bladder tissue of hamsters exposed to sodium arsenite (173 mg As/L) in drinking water for 6 days, transgelin was down-regulated and GST-pi was up-regulated. This is the first evidence that transgelin is down-regulated in the bladders of animals exposed to sodium arsenite. Transgelin, which is identical to SM22 or WS3-10, is an actin cross linking/gelling protein found in fibroblasts and smooth muscle [28, 29]. It has been suggested that the loss of transgelin expression may be an important early event in tumor progression and a diagnostic marker for cancer development [30-33]. It may function as a tumor suppressor via inhibition of ARA54 (co-regulator of androgen receptor)-enhanced AR (androgen receptor) function. Loss of transgelin and its suppressor function in prostate cancer might contribute to the progression of prostate cancer [30]. Down-regulation of transgelin occurs in the urinary bladders of rats having bladder outlet obstruction [32]. Ras-dependent and Ras-independent mechanisms can cause the down regulation of transgelin in human breast and colon carcinoma cell lines and patient-derived tumorsamples [33]. Transgelin plays a role in contractility, possibly by affecting the actin content of filaments [34]. In our experiments loss of transgelin expression may be associated or preliminary to bladder cancer due to arsenic exposure. Arsenite is a carcinogen [1]. In our experiments, LC-MS/MS analysis showed that two spots (1 and 2) represent transgelin (Fig. 2 and Table 1). In human colonic neoplasms there is a loss of transgelin expression and the appearance of transgelin isoforms (31). GST-pi protein was up-regulated in the bladders of the hamsters exposed to sodium arsenite. GSTs are a large family of multifunctional enzymes involved in the phase II detoxification of foreign compounds [35]. The most abundant GSTS are the classes alpha, mu, and pi classes [36]. They participate in protection against oxidative stress [37]. GST-omega has arsenic reductase activity [38]. Over-expression of GST-pi has been found in colon cancer tissues [39]. Strong expression of GST-pi also has been found in gastric cancer [40], malignant melanoma [41], lung cancer [42], breast cancer [43] and a range of other human tumors [44]. GST-pi has been up-regulated in transitional cell carcinoma of human urinary bladder [45]. Up-regulation of glutathione – related genes and enzyme activities has been found in cultured human cells by sub lethal concentration of inorganic arsenic [46]. There is evidence that arsenic induces DNA damage via the production of ROS (reactive oxygen species) [47]. GST-pi may be over-expressed in the urinary bladder to protect cells against arsenic-induced oxidative stress. Liver In the livers of hamsters exposed to sodium arsenite, ornithine amino transferase was over-expressed, senescence marker protein 30 was under-expressed, and fatty acid binding protein was under-expressed. Ornithine amino transferase has been found in the mitochondria of many different mammalian tissues, especially liver, kidney, and small intestine [48]. Ornithine amino transferase knockdown inhuman cervical carcinoma and osteosarcoma cells by RNA interference blocks cell division and causes cell death [49]. It has been suggested that ornithine amino transferase has a role in regulating mitotic cell division and it is required for proper spindle assembly in human cancer cells [49]. Senescence marker protein-30 (SMP30) is a unique enzyme that hydrolyzes diisopropylphosphorofluoridate. SMP30, which is expressed mostly in the liver, protects cells against various injuries by stimulating membrane calcium-pump activity [50]. SMP30 acts to protect cells from apoptosis [51]. In addition it protects the liver from toxic agents [52]. The livers of SMP30 knockout mice accumulate phosphatidylethanolamine, cardiolipin, phosphatidyl-choline, phosphatidylserine, and sphingomyelin [53]. Liver fatty acid binding protein (L-FABP) also was down- regulated. Decreased liver fatty acid-binding capacity and altered liver lipid distribution hasbeen reported in mice lacking the L-FABP gene [54]. High levels of saturated, branched-chain fatty acids are deleterious to cells and animals, resulting in lipid accumulation and cytotoxicity. The expression of fatty acid binding proteins (including L-FABP) protected cells against branched-chain saturated fatty acid toxicity [55]. Limitations: we preferred to study the pronounced spots seen in DIGE gels. Other spots were visible but not as pronounced. Because of limited funds, we did not identify these others protein spots. In conclusion, urinary bladders of hamsters exposed to sodium arsenite had a decrease in the expression of transgelin and an increase in the expression of GST-pi protein. Under-expression of transgelin has been found in various cancer systems and may be associated with arsenic carcinogenicity [30-33). Inorganic arsenic exposure has resulted in bladder cancer as has been reported in the past [1]. Over-expression of GST-pi may protect cells against oxidative stress caused by arsenite. In the liver OAT was up regulated and SMP-30 and FABP were down regulated. These proteomic results may be of help to investigators studying arsenic carcinogenicity. The Superfund Basic Research Program NIEHS Grant Number ES 04940 from the National Institute of Environmental Health Sciences supported this work. Additional support for the mass spectrometry analyses was provided by grants from NIWHS ES06694, NCI CA023074 and the BIOS Institute of the University of Arizona. Acknowledgement The Author wants to dedicate this paper to the memory of his former supervisor Dr. H. VaskenAposhian who passed away in September 6, 2019. He was an emeritus professor of the Department of Molecular and Cellular Biology at the University of Arizona. 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The preliminary study showed that the main problem, however, faced by kindergarten students are lack of mathematics skill, such arithmetic ability in kindergarten Galis. Therefore, the present study aims to investigate the effectiveness of a modified bottle cap as an educational game tool towards enhancement of arithmetic ability. Samples were prepared for the quasi-experiment research design involving 60 children, aged 4-5 years. A detailed comparison is made between the experimental condition, consisted of 30 students, received the educational game tool activities and the control condition which consisted of 30 students, received the instructional activities as usual. Before and after two weeks of the intervention with the game tool of a modified bottle cap, measures of arithmetic ability were administered to either experiment or control class. The results of the study indicated that in the experiment class, children’s arithmetic ability increased significantly compared to children in the control class. The differences may have been due to the intervention. To conclude, the modified bottle cap as an educational game tool effective to improve children’s mathematics skill, especially for arithmetic ability. However, the findings required the extended study on other research methods and the bigger size of the samples. Keywords: Early Childhood, Modified bottle cap, Early Arithmetic Ability. References: Aqib, Zainal. (2010). Belajar dan Pembelajaran di Taman Kanak-Kanak. Bandung: Yrama Widya. Arsyad, A. (2017). Media Pembelajaran. PT Raja Grafindo Pursada. Aunio, Pirjo; Tapola, Anna; Mononen; and Niemivirta, M. (2016). Early Mathematics Skill Development, Low Performance, and Parental Support in the Finnish Context. In Blevins-Knabe; A.M.B. Austin (Ed.), Early Childhood Mathematic Skill Development in the home environment. Cham, Switzerland: Springer. Ayuni, D., & Setiawati, F. A. (2019). Kebun Buah Learning Media for Early Childhood Counting Ability. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 3(1), 1. https://doi.org/10.31004/obsesi.v3i1.128 Barblett, L., Knaus, M., & Barratt-Pugh, C. (2016). The Pushes and Pulls of Pedagogy in the Early Years: Competing Knowledges and the Erosion of Play-based Learning. Australasian Journal of Early Childhood, 41(4), 36–43. https://doi.org/10.1177/183693911604100405 Barth, H., La Mont, K., Lipton, J., & Spelke, E. S. (2005). Abstract number and arithmetic in preschool children. Proceedings of the National Academy of Sciences of the United States of America, 102(39), 14116–14121. https://doi.org/10.1073/pnas.0505512102 Blevins-Knabe, B. (2016). Early Mathematical Development : How the Home Environment Matters. In Belinda Blevins-Knabe; Ann M. Berghout Austin (Ed.), Early Childhood Mathematics Skill Development in the Home Environment (pp. 8–9). Cham, Swutzerland: Springer. Copley, J. V. (2016). The Young Child and Mathematics. In M. Hogarty (Ed.), Numbers and Stories: Using Children’s Literature to Teach Young Children Number Sense (Second, pp. 1–14). https://doi.org/10.4135/9781483330907.n1 Depdiknas. (2005). Pedoman Pembelajaran di Taman Kanak-Kanak. Jakarta: Direktorat Pembinaan Taman Kanak-Kanak Sekolah Dasar. Depdiknas. (2007). Modul Pembuatan dan Penggunaan APE anak Usia 2-6 Tahun. Jakarta: Dirjen Pendidikan Luar Sekolah Direktorat PAUD. Dunekacke, S., Jenßen, L., Eilerts, K., & Blömeke, S. (2016). Epistemological beliefs of prospective preschool teachers and their relation to knowledge, perception, and planning abilities in the field of mathematics: a process model. ZDM - Mathematics Education, 48(1–2), 125–137. https://doi.org/10.1007/s11858-015-0711-6 Elizabeth, W. (2011). Cross-curricular Teaching to Support Child-initiated Learning in EYFS and KEY Stage I. In Suzanne and Kristine (Ed.), Early Childhood Educaiton: Yesterday, Today, and Tomorrow. New York: Routledge. Fitri, F., & Syamsudin, A. (2019, May). The Effectiveness of Race Track Games on Counting Ability and Child Learning Motivation. https://doi.org/10.2991/icsie-18.2019.78 Grindheim, L. T. (2017). Children as playing citizens. European Early Childhood Education Research Journal, 25(4), 624–636. https://doi.org/10.1080/1350293X.2017.1331076 Guslinda; Kurnia, R. (2018). Media Pembelajaran Anak Usia Dini. Surabaya: Jakad Publiser. Harris, B., & Petersen, D. (2017). Developing Math Skills in Early Childhood. Issue Brief. Mathematica Policy Research, Inc., (February), 1–6. Retrieved from http://ezproxy.library.uvic.ca/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=eric&AN=ED587415&site=ehost-live&scope=site Haskell, S. H. (2000). The determinants of arithmetic skills in young children: Some observations. European Child and Adolescent Psychiatry, 9(SUPPL. 2), 77–86. https://doi.org/10.1007/s007870070011 Hurlock, Elisabeth, B. (1978). Perkembangan Anak, Jilid 2. Jakarta: Erlangga. Ismail, A. (2006). Education Games “Menjadi Cerdas dan Ceria dengan Permainan Edukatif.” Jacobi-Vessels, J. L., Todd Brown, E., Molfese, V. J., & Do, A. (2016). Teaching Preschoolers to Count: Effective Strategies for Achieving Early Mathematics Milestones. Early Childhood Education Journal, 44(1), 1–9. https://doi.org/10.1007/s10643-014-0671-4 Johnson, J. E., & Wu, M.-H. (2019). Perspectives on Play in Early Childhood Care and Educaiton. In M. B. Brown, Christopher; McMullen (Ed.), The Wiley Handbook of Early Childhood Care and Education (1st ed., p. 86). New Jersey: John Wiley & Sons. Kamus Besar Bahasa Indonesia Online. (2019). Retrieved from https://www.kamusbesar.com/prefix/nd Khasanah, I. (2013). Pembelajaran Logika Matematika Anak Usia Dini (Usia 4-5 Tahun) di TK Ikal Bulog Jakarta Timur. In Jurnal Penelitian PAUDIA (Vol. 2). Lai, N. K., Ang, T. F., Por, L. Y., & Liew, C. S. (2018). The impact of play on child development - a literature review. European Early Childhood Education Research Journal, 26(5), 625–643. https://doi.org/10.1080/1350293X.2018.1522479 Malapata, E., & Wijayanigsih, L. (2019). Meningkatkan Kemampuan Berhitung Anak Usia 4-5 Tahun melalui Media Lumbung Hitung. Jurnal Obsesi : Jurnal Pendidikan Anak Usia Dini, 3(1), 283. https://doi.org/10.31004/obsesi.v3i1.183 Manjale, N. B., & Abel, C. (2017). Significance and adequacy of instructional media as perceived by primary school pupils and teachers in. 4(6), 151–157. Martin, R. B., Cirino, P. T., Sharp, C., & Barnes, M. (2014). Number and counting skills in kindergarten as predictors of grade 1 mathematical skills. Learning and Individual Differences, 34, 12–23. https://doi.org/10.1016/j.lindif.2014.05.006 Naz, A. A., & Akbar, R. A. (2010). Use of Media for Effective Instruction its Importance : Some Consideration. Journal of Elementary Education, 18(1–2), 35–40. OECD. (2019). Mathematics Performance (PISA) 2015. https://doi.org/10.1787/04711c74-en Papadakis, S., Kalogiannakis, M., & Zaranis, N. (2017). Improving Mathematics Teaching in Kindergarten with Realistic Mathematical Education. Early Childhood Education Journal, 45(3), 369–378. https://doi.org/10.1007/s10643-015-0768-4 Passolunghi, M. C., Cargnelutti, E., & Pellizzoni, S. (2019). The relation between cognitive and emotional factors and arithmetic problem-solving. Educational Studies in Mathematics, 100(3), 271–290. https://doi.org/10.1007/s10649-018-9863-y Preeti. (2014). Education and role of media in education system. International Journal of Scientific Engineering and Research, 2(3), 174–175. Rahman, S. (2010). Alat Permainan Edikatif untuk Program PAUD. Palu: Tadulako University Press. Rohmah, N., & Waluyo, E. (2014). Arithmetic Dice Media as Counting Concept Introduction for Early Childhood. Naili Rohmah & Edi Waluyo / Indonesian Journal of Early Childhood Education Studies, 3(2), 127–133. https://doi.org/10.15294/ijeces.v3i2.9486 Rushton, S. (2011, June). Neuroscience, Early Childhood Education and Play: We are Doing it Right! Early Childhood Education Journal, 39(2), 89–94. https://doi.org/10.1007/s10643-011-0447-z Schacter, J., & Jo, B. (2017). Improving preschoolers’ mathematics achievement with tablets: a randomized controlled trial. Mathematics Education Research Journal, 29(3), 313–327. https://doi.org/10.1007/s13394-017-0203-9 Schwartz, S. (2005). Teaching YoungChildren Mathematics. Westport, Connecticut: Praeger. Selvi, K. (2010). Teachers’ competencies. Cultura. International Journal of Philosophy of Culture and Axiology, 7(1), 167–175. https://doi.org/10.5840/cultura20107133 Smaldino, S. E., Russel, J. D., & Lowther, D. L. (2014). Instructional Technology & Media for Learning (9th ed.). Jakarta: Kencana Prenada Media Group. Suryadi. (2007). Cara Efektif Memahami Perilaku Anak Usia Dini. Jakarta: Edsa Mahkota. Vogt, F., Hauser, B., Stebler, R., & Rechsteiner, K. (2018). Learning through play – pedagogy and learning outcomes in early childhood mathematics. 1807. https://doi.org/10.1080/1350293X.2018.1487160 Vogt, F., Hauser, B., Stebler, R., Rechsteiner, K., & Urech, C. (2018). Learning through play–pedagogy and learning outcomes in early childhood mathematics. European Early Childhood Education Research Journal, 26(4), 589–603. https://doi.org/10.1080/1350293X.2018.1487160 Wati, E. R. (2016). Ragam Media Pembelajaran (A. Jarot, Ed.). Yogyakarta: Kata Pena. Zulkardi, N. (2011). Building counting by traditional game: A Mathematics Program for Young Children. IndoMs. J.M.E, 2(1), 41–54.

The Master of Nursing Science (MNSc) has been developed as a Graduate Entry to Nursing (GEN) programme. It is an accelerated, intensive two-year degree involving the completion of 1100 clinical practice hours to meet New Zealand Nursing Council registration requirements, together with achieving a level of critical thinking that will support excellence in clinical practice. GEN programmes are well known to attract diverse, motivated graduates often with successful careers that want a change of direction (Stacey, Pollock & Crawford, 2016; Pellico, Terrill, White & Rico, 2012). In 2019 the MNSc was in its first iteration, therefore the three lecturers involved had scope to consider the design and delivery of the learning to best support student understanding and engagement. Together with institutional teaching and learning development mentors we brainstormed different approaches to teaching and learning. There is dearth of evidence regarding the development of clinical reasoning and critical thinking for post-graduate nursing students in Australasia. The aim was to develop teaching approaches that encouraged students to engage with the content and foster the development of critical thinking and clinical reasoning. Meyers and Nulty’s (2009) adoption of Biggs (2003) 3P Model of learning and teaching influenced the development of content across multiple discrete units of study. An evolving case study approach supported with podcasts was developed. The first evolving case study focused on a client with a rural New Zealand address and health status common to his age group and life experience. The podcasts aligned with the weekly development of the case. International content experts participated in topics as varied the management of analgesia, history of consent, and assisted dying and others. To iteratively explore and understand the effectiveness of this teaching approach the authors concurrently undertook research. Informed by educational design research (EDR) methodology we explore the process of constructing an authentic learning experience for students. Educational design research (EDR) evolved from design-based research and is recognised as being practical and eminently suitable to explore a small teaching and learning project (Jetinikoff, 2015; McKenney & Reeves, 2018). The aims of this research were to 1) explore and describe the process of constructing an authentic learning experience enabled by technology; and 2) understand and reflect on student learning using an evolving case-study with podcasted content. The research team is currently undertaking the reflection, adaption, and evaluation stage of the EDR methodology. The results of this and the theory stage will be resented at SoTEL. In this presentation, the analysis of the teaching teams’ reflections will be explored. Key to our discussion with the audience will be sharing our reflections and in turn seeking their advice to explore how to engage students in technology enhanced delivery in a fast-paced course. References: Biggs, J.B. (2003). Teaching for quality learning at university. (2nd ed.). Maidenhead: Open University Press. Jetnikoff, A. (2015). Design based research methodology for teaching with technology in English. English in Australia, 50(3), 56-60. McKenney, S., & Reeves, T. (2018). Conducting Educational Design Research (2nd ed.). Routledge: https://ebookcentral.proquest.com/lib Meyers, N. M., & Nulty, D. D. (2009). How to use (five) curriculum design principles to align authentic learning environments, assessment, students approaches to thinking and learning outcomes. Assessment & Evaluation in Higher Education, 34, (5), 565–577. Pellico, L.H., Terrill, E., White, P., & Rico, J. (2012). Integrative review of graduate entry programs. Journal of Nursing Education, 51(1), 29-37. http://dx.doi:10.3928/01484834-20111130-01. Stacey, G. Pollock, K., & Crawford, P. (2016). The rules of the game in graduate entry nursing: A longitudinal study. Nurse Education Today, 36, 184-189. http://dx.doi:10.org/10/1016/j.nedt.2015.09.016

Abstract Introduction:- Haploidentical Bone marrow transplantation has become one of the most commonly employed alternative donor techniques, with many centers applying T-cell-replete strategies developed by the Baltimore group using high-dose post-transplant cyclophosphamide. The usefulness of this technique is to reduce graft acquisition cost, lesser grade of GVHD, and reduction in non-relapse mortality. One problem we face in a country like India is the worry of engraftment delay leading to refractory multi-drug resistant gram-negative sepsis increasing the risk of transplant-related mortality. We took up this pilot study to check for the feasibility of a low dose (50%) 25mg/kg of cyclophosphamide as PTCy and its impact on transplant outcomes especially GVHD. Methodology:- This study was done from January 2016 to June 2019. 41 Haploidentical bone marrow transplants were done for Acute Myeloid leukemia at this time under this protocol. 23 Cases had Busulfan / Fludarabine as conditioning and in 18 cases; we used Treosulfan / Fludarabine-based conditioning regimen. The study protocol PTCy dose was 25mg/kg on Day +3 and Day +4. Cyclosporine / Tacrolimus was used from day -1 in all patients as GVHD prophylaxis. The parameters analyzed are engraftment dynamics, rates of gram-negative sepsis, hemorrhagic cystitis, rates of acute and chronic GVHD, and 2-year Non-relapse mortality. Results: Parents were the haploidentical donors in 22 cases whereas siblings in the rest 19 cases. Peripheral blood stem cell collection was chosen in all cases. The average CD34 dose was 6.8 x 10 6/Kg of the recipient. The mean number of days to achieve engraftment was around day 11. Culture-proven gram-negative sepsis was seen in 11 cases (26.8%). Two patients died within Day +30. Both due to sepsis. The rates of acute GVHD of grade I/2 was 18 (43.9%) and grade 3/4 acute GVHD was seen only in 2 patients (5%). No mortality was due to GVHD. With a median follow-up of two years, chronic skin and liver grade 1/2 GVHD was noted in 29 patients (74.3%) but were manageable with oral and topical medications not needing admission. Three patients had hemorrhagic cystitis. CMV reactivation needing medications was seen in 5(12.2%) patients indicating a higher incidence of post-transplant viral reactivation with PTCy. At data cut-off, we had lost 12 patients due to relapse and there was no non-relapse mortality except for the two sepsis-related death. Conclusion: The results of this pilot study indicate the feasibility of using a low dose PTCy (25mg/kg) in Haploidentical transplant as a methodology for in vivo T cell depletion without increased incidence of GVHD and Non-relapse mortality in Indian patients. This is a small study and it needs further follow-up with drug metabolism analysis and a bigger cohort to make this Chennai-Chezhian-Kishore PTCy Protocol a validated standard in Haplo-identical transplants. This is a pilot study and we are planning to incorporate genetic polymorphism in drug metabolism to validate the proposed protocol more scientifically. Reference: 1. Wang, Y et al. Low-dose post-transplant cyclophosphamide and anti-thymocyte globulin as an effective strategy for GVHD prevention in haploidentical patients. J Hematol Oncol 12, 88 (2019). https://doi.org/10.1186/s13045-019-0781-y 2. Shannon R. McCurdy, Leo Luznik How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide Blood (2019) 134 (21): 1802-1810. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Symptoms of bacterial wilt were observed on common beans (cv. Donna) in southeastern Spain. From samples collected in four different fields (coast of Granada), a bacterium was isolated with the following characteristics: gram positive, aerobic rods with yellow colonies, strictly oxidative, oxidase negative, galactose, sucrose, erythritol, mannitol, sorbitol and m-inositol were not used as a sole carbon source, and hydrolysis of casein was positive. These results coincide with what is expected for Curtobacterium flaccumfaciens pv flaccumfaciens (3). One isolate from each field was selected for pathogenicity tests using two different methods. Bacterial suspensions (approximately 108 CFU/ml) were spray inoculated on bean seedlings of cv. Andecha (10 plants with three true leaves for each isolate). Beans were covered with transparent plastic bags for 2 days and held at 25°C and 80% relative humidity with a 12-h photoperiod. In addition, 10 healthy seeds of cv. Andecha were soaked in bacterial suspensions (approximately 108 CFU/ml) for 1 h and incubated at 25°C (2). Seedlings sprayed with distilled sterile water and seeds soaked in water served as controls. With both methods of inoculation, assays were conducted twice. Results were recorded after 3 weeks. Symptoms that developed on plants after infection with the four isolates were similar to those observed in the field. They included golden yellow necrotic leaf lesions and wilting. Wilting was more pronounced in the field and when inoculation was performed by spraying seedlings rather than by soaking seeds. Control plants did not develop symptoms and grew bigger than the inoculated plants. Two pathogenic isolates were identified through sequencing of the 16S rRNA gene. The genes were amplified by polymerase chain reaction (1) and their nucleotide sequences (1,418 bp) proved to be identical (Accession No. AJ879110). Comparison of these sequences with databases showed that they were also identical to those of C. flaccumfaciens strains LMG 3645 and P 259/26 (Accession Nos. AJ312209 and AJ310414) and Curtobacterium sp. strains 2384 and 3426 (Accession Nos. AY688359 and AY688360). In Spain, the bean pathogen C. flaccumfaciens was first isolated from seeds during 2001 (4). However, to our knowledge, this is the first report of damage caused by this bacterium in the field. Bacterial wilt has been recorded, but often not substantiated, in several countries from North and South America, Africa, Asia, Oceania, and Europe. References: (1) U. Edwards et al. Nucleic Acid Res. 17:7843, 1989. (2) T. F. Hsieh et al. Plant Dis. 86:1275. 2002. (3) K. Komagata and K.-I. Suzuki. Pages 1313–1317 in: Bergey's Manual of Systematic Bacteriology. Vol. 2. Williams and Wilkins, Baltimore, MD, 1986. (4) J. L. Palomo et al. Page 154 in: XI Congreso de la Sociedad Española de Fitopatología, Almería, 2002.

BackgroundOngoing inflammatory episodes of familial Mediterranean fever (FMF) disease can cause damage in nearly all organ systems. Colchicine and interleukin1β blocking agents are successfully used to control the disease activity [1]. Although the effect of IL-1 blockers are known for controlling disease activity and amyloidosis [2], it is unclear whether they prevent organ damageObjectivesIn our study, we assessed the organ damage in patients with FMF treated with colchicine and IL-1 antagonists (IL-1A). It was evaluated whether new damage occurred after IL-1 antagonist treatment.MethodsA total of 111 patients fulfilling Tel-Hashomer criteria and treated with IL-1A due to colchicine resistance were included in the study. All patients were also treated with colchicine with a maximum-tolerable dose. Patients were grouped according to their recent damage status (no damage, pre-existing damage, and damage developed under IL-1A treatment). The degree of damage was determined using Autoinflammatory Disease Damage Index (ADDI) and modified form of ADDI (mADDI) [3, 4].Results44 patients (42,3%) had damage according to the modified ADDI (mADDI) index; three patients experienced new damage under IL-1 antagonist treatment while four patients showed progression of damage and mADDI score.In patients with a positive mADDI score, the most common damage was amyloidosis (n=28, 63%), the second most frequent was musculoskeletal findings (N=14, 31%), and the third was infertility (N=2, 0,04%). The most common domains of FMF-related damage with IL-1 antagonist treatment were musculoskeletal (n=4), renal (n=2) and reproductive system (n=2)ConclusionOur study was the first study to evaluate the progression of damage in patients with FMF and treated- with IL-1 antagonists. Although it is known that IL-1A is effective in colchicine-resistant patients, physicians should be aware that damage can still develop under IL-1A treatment.References[1]Chae JJ, Aksentijevich I, Kastner DL. Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. Br J Haematol 2009; 146:467–78.[2]Ozcakar ZB, Ozdel S, Yilmaz S, Kurt-Sukur ED, Ekim M et al. Anti-IL-1 treatment in familial Mediterranean fever and related amyloidosis. Clinical Rheumatology 2016; 35 (2): 441- 446. doi: 10.1007/s10067-014-2772-2[3]Ter Haar NM, Annink KV, Al-Mayouf SM et al.: Development of the autoinflammatory disease damage index (ADDI). Ann Rheum Dis 2017; 76: 821-30[4]Babaoglu H, Armagan B, Bodakci E, Satis H, Atas N, Sari A, Yasar Bilge NS, Bilici Salman R, Yardimci GK, Avanoglu Guler A, Karadeniz H, Kilic L, Ozturk MA, Goker B, Haznedaroglu S, Kalyoncu U, Kasifoglu T, Tufan A. Factors associated with damage in patients with familial Mediterranean fever. Clin Exp Rheumatol. 2020 Sep-Oct;38 Suppl 127(5):42-48.Table 1.Comparison of clinical and laboratory parameters between groups according to damageNo damageNew damageAny damageP valueAge (years)48,456,467,50,002Sex (K/E)34/332/525/19NSFollow-up time (years)4043560,33Dominant attack typePeritonitis(63,7%)NAArthritis(34,1%)NSPersistent inflammation33,642,344,30,05AIDAI score394048NSMutationsM694V/M694V26214NSM694V/any44438M694V/M680I314M680I/any119•SAIDAI: Auto-Inflammatory Diseases Activity IndexAcknowledgementsAll participants were confirmed for both participation and publication. Local Ethical Committee approved the studyDisclosure of InterestsNone declared

Abstract Background : The 2016 revision to the World Health Organization classification of myeloid neoplasms has recommended distinction between "proliferative" (WBC ≥ 13 x 10(9)/L) and "dysplastic" (WBC < 13 X 10(9)/L) subtypes of chronic myelomonocytic leukemia (CMML). In addition, CMML is characterized by a spectrum of cytogenetic and molecular abnormalities (Patnaik Leukemia 2014). In the current study, we looked for correlations between gene expression profiles (GEP) and morphologic or molecular categories of previously untreated patients with CMML. Methods : 35 patients with CMML were included in the study. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for 28 myeloid-relevant genes (Patnaik Blood C. J.). RNA sequencing (Stranded Total RNA- Illumina, San Diego, CA), was performed on 9 normal BM controls, and 35 CMML samples (25 peripheral blood (PB) and 10 BM). The RNA-Seq data was analyzed using MAPRSeq v.2.0. Normalization and differential expression analysis was performed using edgeR 2.6.2. We selected genes that were differentially expressed with a False Discovery Rate (FDR) <0.1 and a fold change bigger than 2. Pathway enrichment analysis was performed using Ingenuity Pathway Analysis (IPA). Results: Among the 35 study patients, 75% were males and median age was 71 years (range, 55-87). 21 (60%), 9 (25%) and 5 (15%) patients were classified as CMML-0, 1 and 2, respectively. 16 (45%) had a dysplastic while 19 (55%) had a proliferative phenotype. At a median follow-up of 16 months, 5 (14%) deaths and 4 (14%) leukemic transformations were documented. Mutational frequencies included; TET2 45%, ASXL1 45%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%, DNMT3A 6%, U2AF1 6%, SF3B1 5%, ZRSR2 4%, Tp53 4%, and IDH2 4%. Abnormal cytogenetics (n=9, 35%) included; -Y 8%, trisomy 8 6%, monosomy 7 3%, del(13q) 3% and monosomal karyotype 3%. i) Differential GEP in PB samples: 25 PB CMML samples were analyzed. Unsupervised GEP demonstrated two unique clusters (figure one); cluster one was enriched with dysplastic CMML (90%) and cluster two with proliferative CMML (64%). Consistent with the difference in the distribution of morphologic categories, in comparison to cluster one, patients in cluster two had a higher white blood count (p=0.003), higher monocyte count (p=0.02) and higher risk prognostication by the Mayo Model (p=0.016); there was no significant difference between the two clusters in terms of age and gender distribution, hemoglobin level, neutrophil and platelet counts, PB or BM blast content, cytogenetic risk stratification, ASXL1, TET2, RAS, CBL and SETBP1 mutational status. Genes significantly upregulated (FDR<1e-5 and fold change ≥ 16x); in cluster two (proliferative CMML) in comparison to cluster one included; PRG2, CTSG, BEX1, CD34, CRISP2, while those significantly down-regulated included (FDR<1e-15 and fold change ≥ 5x); IL2RB, PRF1, GNLY, PDGFRB. IPA analysis identified the following pathways preferentially expressed in cluster two (proliferative CMML) 1) mitotic roles of polo-like kinase (KIF23, WEE-1, PLK1, PLK4), 2) Cell cycle: G2/M checkpoint regulation (CDC25C, WEE-1, AURKA, CDK1), 3) Cell cycle: chromosomal replication (CDC45, RPA3, MCM2, CDC7), and 4) BRCA1 in DNA damage response (BARD1, RBBP8, PLK1, RAD51). Whereas in the cluster one (dysplastic CMML), preferentially expressed pathways included; 1) T-cell receptor signalling (CD247 PRKCQ, CD4, PLCG1, CD28) and 2) STAT3 signalling (SOCS3, MAP3K9). ii) Differential GEP in BM samples: 10 BM CMML samples were analyzed along with 10 normal controls. Samples and controls clustered separately and within the CMML samples two clusters were identified (figure two). These clusters had equal representations of dysplastic (n=5) and proliferative (n=5) CMML sub-types. Additional samples are being processed. Conclusions: Differential gene expression profiling in patients with CMML identifies two unique clusters, clinically demarcated, at least in PB samples, by "proliferative" and "dysplastic" CMML subtypes. The proliferative cluster is enriched in genes involved in cell cycle regulation and DNA damage response; whereas the dysplastic cluster is enriched in T-cell receptor and STAT3 signalling. The prognostic and therapeutic impact of these gene clusters remains to be assessed in a larger group of informative patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding; Celgene: Research Funding.

Magnesium-based next-generation batteries are of great interest since magnesium is not only very abundant, which allows economic and sustainable applications, but also less prone to dendrite formation than many other metals. Together with the bivalency of the magnesium cations the resulting possibility to safely use a metal anode enables batteries with high specific capacities. However, for a successful commercialization of magnesium batteries there are still some challenges to overcome. The high charge density of the bivalent cation causes strong coulomb interactions with anions and solvent molecules. Therefore, magnesium salts are prone to form ion pairs and bigger clusters – especially at high concentrations, which may adversely affect the transport in the electrolyte and the electrochemical reaction at the electrode.[1] Moreover, energetic barriers for desolvation and solid-state diffusion of the double-charged magnesium ion are usually very high, which can have a crucial impact on the battery performance. Former can significantly hinder the electron-transfer reaction,[2] whereas latter makes the choice of suitable cathode materials very challenging. Consequently, a good understanding of the limiting processes in rechargeable magnesium batteries is key to develop novel high-capacity / high-voltage cathode materials. For instance, it is well-known that the morphology of an intercalation material can strongly influence the battery performance and smaller particles as well as thinner electrodes are common strategies for avoiding adverse effects of transport limitations. However, high mass loadings as well as suitable separators are still essential bottlenecks for commercialization of magnesium-ion batteries. Up to date Chevrel phase (CP) Mo6S8 is considered as benchmark intercalation cathode and Mg[B(hfip)4]2 / DME is seen as most promising chloride-free magnesium electrolyte.[3,4] In our contribution we carefully study this model system of a magnesium-ion battery to get a better understanding of how to overcome undesired limitations. Therefore, we present a newly-developed continuum model, which is able to describe the complex intercalation process of magnesium cations into a CP cathode. The model considers not only the different thermodynamics and kinetics of the two intercalation sites of Mo6S8 and their interplay but also the impact of the desolvation on the electrochemical reactions and possible ion agglomeration. The parameterization and validation of the model is based on DFT calculations and experimental data. Different kind of (transport) limitations and their impact on the battery performance are studied in detail. All in all, the combination of different modelling techniques with experimental measurements provides important insights into the operation of magnesium ion batteries and enables an optimization of the cell design. Acknowledgements This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 824066 (E-MAGIC). Furthermore, this work contributes to the research performed at CELEST (Center for Electrochemical Energy Storage Ulm-Karlsruhe) and was funded by the German Research Foundation (DFG) under Project ID 390874152 (POLiS Cluster of Excellence). The simulations were carried out at JUSTUS 2 cluster supported by the state of Baden-Württemberg through bwHPC and the German Research Foundation (DFG) through grant No INST 40/575-1 FUGG. References Drews, T. Danner, P. Jankowski et al., ChemSusChem, 3 (2020), 3599-3604. Drews, P. Jankowski, J. Häcker et al., ChemSusChem, 14 (2021), 4820-4835. Aurbach, Z. Lu, A. Schlechter et al., Nature, 407 (2000), 724-727. Zhao-Karger, R. Liu, W. Dai et al., ACS Energy Lett. 3 (2018), 2005-2013.

To date, discrete event stochastic simulations of large scale biological reaction systems are extremely compute-intensive and time-consuming. Besides, it has been widely accepted that spatial factor plays a critical role in the dynamics of most biological reaction systems. The NSM (the Next Sub-Volume Method), a spatial variation of the Gillespie’s stochastic simulation algorithm (SSA), has been proposed for spatially stochastic simulation of those systems. While being able to explore high degree of parallelism in systems, NSM is inherently sequential, which still suffers from the problem of low simulation speed. Fine-grained parallel execution is an elegant way to speed up sequential simulations. Thus, based on the discrete event simulation framework JAMES II, we design and implement a PDES (Parallel Discrete Event Simulation) TW (time warp) simulator to enable the fine-grained parallel execution of spatial stochastic simulations of biological reaction systems using the ANSM (the Abstract NSM), a parallel variation of the NSM. The simulation results of classical Lotka-Volterra biological reaction system show that our time warp simulator obtains remarkable parallel speed-up against sequential execution of the NSM.I.IntroductionThe goal of Systems biology is to obtain system-level investigations of the structure and behavior of biological reaction systems by integrating biology with system theory, mathematics and computer science [1][3], since the isolated knowledge of parts can not explain the dynamics of a whole system. As the complement of “wet-lab” experiments, stochastic simulation, being called the “dry-computational” experiment, plays a more and more important role in computing systems biology [2]. Among many methods explored in systems biology, discrete event stochastic simulation is of greatly importance [4][5][6], since a great number of researches have present that stochasticity or “noise” have a crucial effect on the dynamics of small population biological reaction systems [4][7]. Furthermore, recent research shows that the stochasticity is not only important in biological reaction systems with small population but also in some moderate/large population systems [7].To date, Gillespie’s SSA [8] is widely considered to be the most accurate way to capture the dynamics of biological reaction systems instead of traditional mathematical method [5][9]. However, SSA-based stochastic simulation is confronted with two main challenges: Firstly, this type of simulation is extremely time-consuming, since when the types of species and the number of reactions in the biological system are large, SSA requires a huge amount of steps to sample these reactions; Secondly, the assumption that the systems are spatially homogeneous or well-stirred is hardly met in most real biological systems and spatial factors play a key role in the behaviors of most real biological systems [19][20][21][22][23][24]. The next sub-volume method (NSM) [18], presents us an elegant way to access the special problem via domain partition. To our disappointment, sequential stochastic simulation with the NSM is still very time-consuming, and additionally introduced diffusion among neighbor sub-volumes makes things worse. Whereas, the NSM explores a very high degree of parallelism among sub-volumes, and parallelization has been widely accepted as the most meaningful way to tackle the performance bottleneck of sequential simulations [26][27]. Thus, adapting parallel discrete event simulation (PDES) techniques to discrete event stochastic simulation would be particularly promising. Although there are a few attempts have been conducted [29][30][31], research in this filed is still in its infancy and many issues are in need of further discussion. The next section of the paper presents the background and related work in this domain. In section III, we give the details of design and implementation of model interfaces of LP paradigm and the time warp simulator based on the discrete event simulation framework JAMES II; the benchmark model and experiment results are shown in Section IV; in the last section, we conclude the paper with some future work.II. Background and Related WorkA. Parallel Discrete Event Simulation (PDES)The notion Logical Process (LP) is introduced to PDES as the abstract of the physical process [26], where a system consisting of many physical processes is usually modeled by a set of LP. LP is regarded as the smallest unit that can be executed in PDES and each LP holds a sub-partition of the whole system’s state variables as its private ones. When a LP processes an event, it can only modify the state variables of its own. If one LP needs to modify one of its neighbors’ state variables, it has to schedule an event to the target neighbor. That is to say event message exchanging is the only way that LPs interact with each other. Because of the data dependences or interactions among LPs, synchronization protocols have to be introduced to PDES to guarantee the so-called local causality constraint (LCC) [26]. By now, there are a larger number of synchronization algorithms have been proposed, e.g. the null-message [26], the time warp (TW) [32], breath time warp (BTW) [33] and etc. According to whether can events of LPs be processed optimistically, they are generally divided into two types: conservative algorithms and optimistic algorithms. However, Dematté and Mazza have theoretically pointed out the disadvantages of pure conservative parallel simulation for biochemical reaction systems [31]. B. NSM and ANSM The NSM is a spatial variation of Gillespie’ SSA, which integrates the direct method (DM) [8] with the next reaction method (NRM) [25]. The NSM presents us a pretty good way to tackle the aspect of space in biological systems by partitioning a spatially inhomogeneous system into many much more smaller “homogeneous” ones, which can be simulated by SSA separately. However, the NSM is inherently combined with the sequential semantics, and all sub-volumes share one common data structure for events or messages. Thus, directly parallelization of the NSM may be confronted with the so-called boundary problem and high costs of synchronously accessing the common data structure [29]. In order to obtain higher efficiency of parallel simulation, parallelization of NSM has to firstly free the NSM from the sequential semantics and secondly partition the shared data structure into many “parallel” ones. One of these is the abstract next sub-volume method (ANSM) [30]. In the ANSM, each sub-volume is modeled by a logical process (LP) based on the LP paradigm of PDES, where each LP held its own event queue and state variables (see Fig. 1). In addition, the so-called retraction mechanism was introduced in the ANSM too (see algorithm 1). Besides, based on the ANSM, Wang etc. [30] have experimentally tested the performance of several PDES algorithms in the platform called YH-SUPE [27]. However, their platform is designed for general simulation applications, thus it would sacrifice some performance for being not able to take into account the characteristics of biological reaction systems. Using the similar ideas of the ANSM, Dematté and Mazza have designed and realized an optimistic simulator. However, they processed events in time-stepped manner, which would lose a specific degree of precisions compared with the discrete event manner, and it is very hard to transfer a time-stepped simulation to a discrete event one. In addition, Jeschke etc.[29] have designed and implemented a dynamic time-window simulator to execution the NSM in parallel on the grid computing environment, however, they paid main attention on the analysis of communication costs and determining a better size of the time-window.Fig. 1: the variations from SSA to NSM and from NSM to ANSMC. JAMES II JAMES II is an open source discrete event simulation experiment framework developed by the University of Rostock in Germany. It focuses on high flexibility and scalability [11][13]. Based on the plug-in scheme [12], each function of JAMES II is defined as a specific plug-in type, and all plug-in types and plug-ins are declared in XML-files [13]. Combined with the factory method pattern JAMES II innovatively split up the model and simulator, which makes JAMES II is very flexible to add and reuse both of models and simulators. In addition, JAMES II supports various types of modelling formalisms, e.g. cellular automata, discrete event system specification (DEVS), SpacePi, StochasticPi and etc.[14]. Besides, a well-defined simulator selection mechanism is designed and developed in JAMES II, which can not only automatically choose the proper simulators according to the modeling formalism but also pick out a specific simulator from a serious of simulators supporting the same modeling formalism according to the user settings [15].III. The Model Interface and SimulatorAs we have mentioned in section II (part C), model and simulator are split up into two separate parts. Thus, in this section, we introduce the designation and implementation of model interface of LP paradigm and more importantly the time warp simulator.A. The Mod Interface of LP ParadigmJAMES II provides abstract model interfaces for different modeling formalism, based on which Wang etc. have designed and implemented model interface of LP paradigm[16]. However, this interface is not scalable well for parallel and distributed simulation of larger scale systems. In our implementation, we accommodate the interface to the situation of parallel and distributed situations. Firstly, the neighbor LP’s reference is replaced by its name in LP’s neighbor queue, because it is improper even dangerous that a local LP hold the references of other LPs in remote memory space. In addition, (pseudo-)random number plays a crucial role to obtain valid and meaningful results in stochastic simulations. However, it is still a very challenge work to find a good random number generator (RNG) [34]. Thus, in order to focus on our problems, we introduce one of the uniform RNGs of JAMES II to this model interface, where each LP holds a private RNG so that random number streams of different LPs can be independent stochastically. B. The Time Warp SimulatorBased on the simulator interface provided by JAMES II, we design and implement the time warp simulator, which contains the (master-)simulator, (LP-)simulator. The simulator works strictly as master/worker(s) paradigm for fine-grained parallel and distributed stochastic simulations. Communication costs are crucial to the performance of a fine-grained parallel and distributed simulation. Based on the Java remote method invocation (RMI) mechanism, P2P (peer-to-peer) communication is implemented among all (master-and LP-)simulators, where a simulator holds all the proxies of targeted ones that work on remote workers. One of the advantages of this communication approach is that PDES codes can be transferred to various hardwire environment, such as Clusters, Grids and distributed computing environment, with only a little modification; The other is that RMI mechanism is easy to realized and independent to any other non-Java libraries. Since the straggler event problem, states have to be saved to rollback events that are pre-processed optimistically. Each time being modified, the state is cloned to a queue by Java clone mechanism. Problem of this copy state saving approach is that it would cause loads of memory space. However, the problem can be made up by a condign GVT calculating mechanism. GVT reduction scheme also has a significant impact on the performance of parallel simulators, since it marks the highest time boundary of events that can be committed so that memories of fossils (processed events and states) less than GVT can be reallocated. GVT calculating is a very knotty for the notorious simultaneous reporting problem and transient messages problem. According to our problem, another GVT algorithm, called Twice Notification (TN-GVT) (see algorithm 2), is contributed to this already rich repository instead of implementing one of GVT algorithms in reference [26] and [28].This algorithm looks like the synchronous algorithm described in reference [26] (pp. 114), however, they are essentially different from each other. This algorithm has never stopped the simulators from processing events when GVT reduction, while algorithm in reference [26] blocks all simulators for GVT calculating. As for the transient message problem, it can be neglect in our implementation, because RMI based remote communication approach is synchronized, that means a simulator will not go on its processing until the remote the massage get to its destination. And because of this, the high-costs message acknowledgement, prevalent over many classical asynchronous GVT algorithms, is not needed anymore too, which should be constructive to the whole performance of the time warp simulator.IV. Benchmark Model and Experiment ResultsA. The Lotka-Volterra Predator-prey SystemIn our experiment, the spatial version of Lotka-Volterra predator-prey system is introduced as the benchmark model (see Fig. 2). We choose the system for two considerations: 1) this system is a classical experimental model that has been used in many related researches [8][30][31], so it is credible and the simulation results are comparable; 2) it is simple but helpful enough to test the issues we are interested in. The space of predator-prey System is partitioned into a2D NXNgrid, whereNdenotes the edge size of the grid. Initially the population of the Grass, Preys and Predators are set to 1000 in each single sub-volume (LP). In Fig. 2,r1,r2,r3stand for the reaction constants of the reaction 1, 2 and 3 respectively. We usedGrass,dPreyanddPredatorto stand for the diffusion rate of Grass, Prey and Predator separately. Being similar to reference [8], we also take the assumption that the population of the grass remains stable, and thusdGrassis set to zero.R1:Grass + Prey ->2Prey(1)R2:Predator +Prey -> 2Predator(2)R3:Predator -> NULL(3)r1=0.01; r2=0.01; r3=10(4)dGrass=0.0;dPrey=2.5;dPredato=5.0(5)Fig. 2: predator-prey systemB. Experiment ResultsThe simulation runs have been executed on a Linux Cluster with 40 computing nodes. Each computing node is equipped with two 64bit 2.53 GHz Intel Xeon QuadCore Processors with 24GB RAM, and nodes are interconnected with Gigabit Ethernet connection. The operating system is Kylin Server 3.5, with kernel 2.6.18. Experiments have been conducted on the benchmark model of different size of mode to investigate the execution time and speedup of the time warp simulator. As shown in Fig. 3, the execution time of simulation on single processor with 8 cores is compared. The result shows that it will take more wall clock time to simulate much larger scale systems for the same simulation time. This testifies the fact that larger scale systems will leads to more events in the same time interval. More importantly, the blue line shows that the sequential simulation performance declines very fast when the mode scale becomes large. The bottleneck of sequential simulator is due to the costs of accessing a long event queue to choose the next events. Besides, from the comparison between group 1 and group 2 in this experiment, we could also conclude that high diffusion rate increased the simulation time greatly both in sequential and parallel simulations. This is because LP paradigm has to split diffusion into two processes (diffusion (in) and diffusion (out) event) for two interactive LPs involved in diffusion and high diffusion rate will lead to high proportional of diffusion to reaction. In the second step shown in Fig. 4, the relationship between the speedups from time warp of two different model sizes and the number of work cores involved are demonstrated. The speedup is calculated against the sequential execution of the spatial reaction-diffusion systems model with the same model size and parameters using NSM.Fig. 4 shows the comparison of speedup of time warp on a64X64grid and a100X100grid. In the case of a64X64grid, under the condition that only one node is used, the lowest speedup (a little bigger than 1) is achieved when two cores involved, and the highest speedup (about 6) is achieved when 8 cores involved. The influence of the number of cores used in parallel simulation is investigated. In most cases, large number of cores could bring in considerable improvements in the performance of parallel simulation. Also, compared with the two results in Fig. 4, the simulation of larger model achieves better speedup. Combined with time tests (Fig. 3), we find that sequential simulator’s performance declines sharply when the model scale becomes very large, which makes the time warp simulator get better speed-up correspondingly.Fig. 3: Execution time (wall clock time) of Seq. and time warp with respect to different model sizes (N=32, 64, 100, and 128) and model parameters based on single computing node with 8 cores. Results of the test are grouped by the diffusion rates (Group 1: Sequential 1 and Time Warp 1. dPrey=2.5, dPredator=5.0; Group 2: dPrey=0.25, dPredator=0.5, Sequential 2 and Time Warp 2).Fig. 4: Speedup of time warp with respect to the number of work cores and the model size (N=64 and 100). Work cores are chose from one computing node. Diffusion rates are dPrey=2.5, dPredator=5.0 and dGrass=0.0.V. Conclusion and Future WorkIn this paper, a time warp simulator based on the discrete event simulation framework JAMES II is designed and implemented for fine-grained parallel and distributed discrete event spatial stochastic simulation of biological reaction systems. Several challenges have been overcome, such as state saving, roll back and especially GVT reduction in parallel execution of simulations. The Lotka-Volterra Predator-Prey system is chosen as the benchmark model to test the performance of our time warp simulator and the best experiment results show that it can obtain about 6 times of speed-up against the sequential simulation. The domain this paper concerns with is in the infancy, many interesting issues are worthy of further investigated, e.g. there are many excellent PDES optimistic synchronization algorithms (e.g. the BTW) as well. Next step, we would like to fill some of them into JAMES II. In addition, Gillespie approximation methods (tau-leap[10] etc.) sacrifice some degree of precision for higher simulation speed, but still could not address the aspect of space of biological reaction systems. The combination of spatial element and approximation methods would be very interesting and promising; however, the parallel execution of tau-leap methods should have to overcome many obstacles on the road ahead.AcknowledgmentThis work is supported by the National Natural Science Foundation of China (NSF) Grant (No.60773019) and the Ph.D. Programs Foundation of Ministry of Education of China (No. 200899980004). The authors would like to show their great gratitude to Dr. Jan Himmelspach and Dr. Roland Ewald at the University of Rostock, Germany for their invaluable advice and kindly help with JAMES II.ReferencesH. Kitano, "Computational systems biology." Nature, vol. 420, no. 6912, pp. 206-210, November 2002.H. Kitano, "Systems biology: a brief overview." 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BackgroundCyclophosphamide (CYC) is one of the first-line drugs for some serious manifestations of autoimmune diseases [1]. It has been associated with the appearance of a secondary cancer [2]. Several studies showing a higher incidence of cancer in small-vessel vasculitis in relation to CYC treatment have been carried out [3], but there is not much evidence about this complication in other autoimmune diseases.Objectives-Estimating the incidence of cancer in patients treated with CYC for serious manifestations of autoimmune diseases.-Comparing the incidence of cancer in autoimmune diseases treated with immunosuppressants (IS) against the incidence of cancer in the general population.MethodsThis is a single-center retrospective cohort study. We included patients over 18 years old assessed in outpatient clinics of the Rheumatology service at the Ramón y Cajal Hospital from 1990 to 2018. They had been diagnosed with: diffuse or limited cutaneous systemic sclerosis (dcSSc/LSScl), systemic lupus erythematosus (SLE), vasculitis or others. We divided the patients into two groups; those exposed to CYC throughout the follow-up and those not exposed to it (being treated with other IS). Patients who had an active cancer at the time of starting the immunosuppressive therapy were excluded.A descriptive analysis was carried out. The incidence of cancer was compared to the incidence of cancer in the general population according to the 2020 Spanish Network of Cancer Registries data. A multivariate analysis was subsequently performed.ResultsRegarding the baseline characteristics of the patients included, there were no significant statistical differences in the sex, median age, and personal history of cancer. There was a bigger percentage of smokers in the non-exposed group.The incidence of cancer was similar y both groups (7.5% vs. 4.1%; p0.211). The cumulative incidence of cancer in our sample was 55.55/1.000 patients (95% CI 32.1-94.6). The standardized incidence ratio was 2.19 (95% CI 3.30-11.92) and it was stratified by sex and age.The bivariate analysis is shown in Table 1.Table 1.Comparison between patients with or without appearance of cancer during the follow-up.Cancer (n 12)No cancer (n 204)P valueMale sex7 (58,33%)31 (15,19%)0,001Age at the time of the study69,92 (±7,54)53,88 (±16,75)0,001Smoking habit6 (50%)45 (22,06%)0,027Personal history of cancer5 (41,66%)5 (2,45%)<0,001Treatment with classical IS1 (8,33%)49 (24,02%)0,303Treatment with cDMARDs1 (8,33%)21 (10,29%)1Treatment with bDMARDs1 (8,33%)8 (3,92%)0,408Treatment with corticosteroids2 (16,66%)38 (18,63%)1Method of administration of CYC Intravenous7 (58,33%)78 (38,24%)1 Oral0 (0%)6 (2,94%)1 Both0 (0%)2 (0,98%)1Total administered dose of CYC (grams)7,28 (±2,36)6,59 (±3,68)0,626Regarding the multivariate analysis, the variables that demonstrated a statistically significant association with the appearance of cancer were age at the time of the study (OR 1.18 [1.02-1.36], p 0.024) and personal history of neoplasia (OR 7.86 [1.30-47.47], p 0.010).ConclusionThe incidence of cancer in patients with autoimmune diseases treated with CYC is not higher with respect to patients with similar diseases treated with other IS. The increased incidence of cancer is associated with the personal history of cancer and older age. Studies with a larger sample size and prospective studies are necessary to verify these results and determine more clearly the associated risk factors.References[1]Dan, D., et al. (2015). Cyclophosphamide: As bad as its reputation?: Long-term single centre experience of cyclophosphamide side effects in the treatment of systemic autoimmune diseases. Swiss Medical Weekly, 144.[2]Baltus, J. A. M., et al. (1983). The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up. In Annals of the Rheumatic Diseases (Vol. 42).[3]Kermani, T. A., et al. (2011). Malignancy Risk in Vasculitis. In Therapeutic Advances in Musculoskeletal Disease (Vol. 3, Issue 1, pp. 55–63).Disclosure of InterestsÁfrica Andreu-Suárez: None declared, Marta Serrano Warleta: None declared, Carlos De la Puente Bujidos Speakers bureau: Nordic, Janssen, Boehringer Ingelheim, Pfizer, Consultant of: Gebro, Nordic, Janssen, Boehringer Ingelheim

В статье рассматривается значение слова «рыба», не только в современном турецком языке, но и в древних исторических текстах. Кроме того, раскрывается роль рыболовного хозяйства в жизни тюркских племен, а также образ рыбы в искусстве. В данном отношении слово «рыба», которая соответствует значениям города и животного объясняется в свете письменных источников. У каких тюркских племен рыболовная деятельность, основная экономика которых − животноводство, мало упоминается в письменных источниках. За этим, вероятно, стоит тот факт, что животноводство было выдвинуто на первый план с точки зрения экономики. Тем не менее, в некоторых письменных источниках упоминается несколько турецких племен, занимающихся рыболовством. В этом отношении, у каких тюркских племен существовало рыболовное хозяйство, устанавливается на основании арабских и персидских географических источников. Помимо конкретных значений слова рыба, не связанных с рыболовной деятельностью, смысловая нагрузка, приписываемая этому изображению в тюркской устной письменной традиции и искусстве, кратко истолковывается с помощью фольклора и археологических материалов. Изучение изменений, которые претерпела рыба в историческом процессе, важно с точки зрения выявления меняющихся филологических, религиозных и социальных факторов в турецком обществе, как внутренних, так и внешних. Библиографические ссылки Aitkali A. Arkeolojik ve Tarihi Açıdan Doğu Kazakistan’daki Türk Dönemi Anıtları (VI−XII yy). Akdeniz Üniversitesi. Sosyal Bilimler Enstitüsü. Tarih ABD. Yayınlanmamış Doktora Tezi, 2021. 292 s. Akdeniz D., Sırtlı A. Erken Dönem Mitolojisinde Afrodizyak Yiyeceklere Ait İnanışlar // Journal of Tourism and Gastronomy Studies. 2020. 8 (4). S. 2745–2768. Artamanov M. İ. Hazar Tarihi. İstanbul: Selenge Yayınları, 2008. 670 s. Badakoğlu U. Antik Kaynaklar ve Güncel Çalışmalar Işığında Sarmatlar-İskitler. 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Bioclimatology is applied for growing tea in the West of Nghe An province, where the tea is considered as a high economic efficient plant to be priorly cultivated for reducing poverty and getting rich. Based on the bioclimatic characteristics of tea plant and regional climatic data from 1980 to 2014, the bioclimatic diagrams are built and the tea cultivability is mapped in term of annual average temperature and total precipitation, for this region with regarding its district of Con Cuong as an analytical key. The climate, including both temperature and precipitation, in Con Cuong is relatively suitable for the tea plantation. The Western Nghe An, a land of approx. 1.4 million ha, could be classified in five areas with different suitability for tea plant. The unfavorable area occupies only 1% of total region and the four favorable rests account for 99% of total, in which, the most favorable area is largest with about 746,355 ha, i.e. over 50% of whole region. The three other areas are cultivable but they are less favorable in terms of either temperature or precipitation. Growing tea in Western Nghe An, even in favorable areas, it should be taken into account of the weather disadvantages in certain moments of the year such as extreme dry, cold, hot and rainy events.ReferencesAhmed S., 2014. Tea and the taste of climate change, www.herbalgram.org, issue, 103, 44–51.Ahmed S., Stepp J.R., Orians C., Griffin T., Matyas C., 2014. Effects of extreme climate events on tea (Camellia sinensis) functional quality validate indigenous farmer knowledge and sensory preferences in tropical China. PloS one, 9(10), e109126.Bhagat R.M., Deb Baruah R., Safique S., 2010. climate and tea [camellia sinensis (l.) o. kuntze] Production with Special Reference to North Eastern India: A Review. Journal of Environmental Research And Development, 4(4), 1017–1028.Carr M., 1972. The Climatic Requirements of the Tea Plant: A Review. Experimental Agriculture, 8(01), 1–14. https://doi.org/10.1017/S0014479700023449.Carr M.K.V., Stephen W., 1992. Climate, weather and the yield of tea. In: Tea Cultivation to consumtpion. K.C. Wilson and M.N. Clifford (Eds). Chapman and Hall, 87–135.Daleen Lotter, David le Maitre, 2014. Modeling the distribution of Aspalathus linearis (Rooibos tea): implications of climate change for livelihoods dependent on both cultivation and harvesting from the wild. Ecology and Evolution, 4(8), 1209–1221.Ducan J.M.A., Saikia S.D., Gupta N., Biggs E.M., 2016. Observing climate impacts on tea yield in Assam, India. Applied Geogr., 77, 64–71.Institute of Geography, 2016. Department of Climatically Geography. The precipitation and temperature data at meteorological measuring stations in the West of Nghe An Province between 1984 and 2014. Data stored at Department of Climatically Geography, Institute of Geography, Ha Noi, 46p.Gaussen H., 1954. 8 ème Congrès international de Botanique. Section 7 et 3. Paris.Hadfield W., 1976. The effect of high temperature on some aspects of the physiology and cultivation of tea bush (Camellia sinensis) in North East India. In: Light as an Ecological factor. G.C. Evans, R. Bainbridge and O. Rackham (Eds.) Blackwel Sci. Publ., London, 477–495.Hoang Luu Thu Thuy, 2012. The comprehensive assessment of natural, socio-economic and environmental conditions for environmental protection planning in Nghe An Province. Doctoral Thesis. Institude of Geography, Hanoi, 150p.Huang Shoubo, 1989. Meteorology of tea plants in China: a review. Agri. Forest Meteorol., 47, 19–30.Huang Shoubo, 1991. A study on the ecological climates of some famous tea growing areas in high mountainous regions of China. Chinese Geographical Science, 1(2), 121–128.International Center for Tropical Agriculture, 2017. Identification of suitable tea growing areas in Malawi under climate change scenarios. Ciat report, Cali, Colombia, 39p.Kabir S.E., 2001. A study on Ecophysiology of Tea (Camellia sinensis) with special reference to the influence of climatic factors on physiology of a few selected Tea clones of Darjeering. International Journal of Tea Science, 1(4), 1–9.Kandiah S., Thevadasan T., 1980. Quantification of weather parameters to predict tea yields. Tea Q., Srilanka, 49(1), 25–33.Kaye L., 2014. Climate change threatens Sri Lanka’s tea industry. Triple Pundit: People, Planet, Profit. Available at: www.triplepundit.com/2014/06/climate-changethreatens-sri-lanka-tea-industry. Accessed July 25, 2014.Nakayama A., Harada S., 1962. Studies on the effect on the growth of tea plant. IV. The effect of temperature on the growth of young plants in summer. Bull. Tea Res. Station, Japan, 1, 28–40.Nguyen Bao Ve, 2005. The syllabus of industrial trees. Hanoi Argricultural Publishing House, 224p.Nguyen Dai Khanh, 2003. The assessment of agricultural climatic conditions for tea’s growth in major tea regions of Vietnam. Doctoral Thesis. Institute of Meteorology and Hydrology, 149p.Nguyen Khanh Van, Nguyen Thi Hien, Phan Ke Loc, Nguyen Tien Hiep, 2000. The bioclimatic diagrams of Vietnam. Vietnam National University Publishing House, Ha Noi, 126p.Nguyen Van Hong, 2017. Analyzing, assessing landscape for agriculture, forestry development and biodiversity conservation in the southwestern border districts in Nghe An province. Doctoral thesis. Vietnam National University, Hanoi, 150p.Nguyen Van Tao (ed.), 2004. Completing the asexual propagation process of LDP1 and LDP2 cultivars by cuttings in order to transfer to production. State Project of production pilot, coded KC.06.DA.09.NN. Institute of Tea Research, Phu Tho, 50p.Nkomwa E.C., Joshua M.K., Ngongondo C., Monjerezi M., Chipungu F., 2014. Assessing indigenous knowledge systems and climate change adaptation strategies in agriculture: A case study of Chagaka Village, Chikhwawa, Southern Malawi. Physics and Chemistry of the Earth, Parts A/B/C, 67–69, 164–172.Pham Hoang Ho, 2003. An Illustrated Flora of Vietnam, 2, 430–434. Youth Publishing House, 952p.Rebecca Boehm, Sean B. Cash, Bruce T. Anderson, Selena Ahmed, Timothy S. Griffin, Albert Robbat Jr., John Richard Stepp, Wenyan Han, Matt Hazel and Colin M. Orians, 2016. Association between Empirically Estimated Monsoon Dynamics and Other Weather Factors and Historical Tea Yields in China: Results from a Yield Response Model. Climate, 4, 20; doi:10.3390/cli4020020. www.mdpi.com/journal/climate.Schepp K., 2014. Strategy to adapt to climate change for Michimikuru tea farmers in Kenya. Adap CC Report. 2008. Available at: www.adapcc.org/en/kenya.htm. Accessed July 25, 2014.Sen A.R., Biswas A.K., Sanyal D.K., 1966. The Influence of Climatic Factors on the Yield of Tea in the Assam Valley, J. App. Meteo., 5(6), 789–800.Statistics Office of Nghe An Province, 2016. The annual abstracts of statistics 2015. Nghe An Publishing House, Nghe An, 453p.Tanton T.W., 1982. Environmental factors affecting yield of tea (camellia sinensis). Effect of air temperature. Expl. Agri., 18, 47–52.The People’s Committee of Nghe An Province, 2013. The Decision No. 448/QĐ-UBND dated 31/01/2013 to approve the hi-tech agriculture planning on the production of tea in Nghe An Province.The People’s Committee of Nghe An Province, 2013. The Decision No. 6290/QĐ-UBND dated 24/12/2013 to approve the adjustments and supplements for the development of Nghe An tea Industrial zone planning in 2013–2020.Walter H, Lieth, 1967. Klimadiagram - Weltatlas. Veb Gustav Fischer Verlag Jena.Wijeratne M.A., 1996. Vulnerability of Sri Lanka tea production to global climate change. Water, Air and Soil Pollution, 92(1-2), 87–94.Wijeratne M.A., Anandacoomaraswamy A., Amarathunga M., Ratnasiri J., 2007. Assessment of impact of climate change on productivity of tea (Camellia sinensis L.) plantations in Sri Lanka, 119–126.http://nghean.gov.vn, 05/06/2015. Many crops are withered in Con Cuong.http://baonghean.vn, 25/03/2013. Drought threaten rice and tea in Con Cuong. http://baonghean.vn/con-cuong-han-han-de-doa-lua-che-44581.html.

Seven spot ladybird beetle, (Coccinella septempunctata) is a widely distributed natural enemy of soft-bodied insect pests especially aphids worldwide. Both the adult and larvae of this coccinellid beetle are voracious feeders and serve as a commercially available biological control agent around the globe. Different techniques are adopted to enhance the mass rearing and storage of this natural enemy by taking advantage of its natural ability to withstand under extremely low temperatures and entering diapause under unfavorable low temperature conditions. The key objective of this study was to develop a cost effective technique for enhancing the storage life and predatory potential of the larvae of C. septempunctata through cold storage in conjunction with the use of nuclear techniques, gamma radiations. Results showed that the host eating potential of larvae was enhanced as the cold storage duration was increased. Gamma irradiation further enhanced the feeding potential of larvae that were kept under cold storage. Different irradiation doses also affected the development time of C. septempuntata larvae significantly. Without cold storage, the lower radiation doses (10 and 25 GY) prolonged the developmental time as compared to un-irradiated larvae. Furthermore, the higher dose of radiation (50GY) increased the developmental time after removal from cold storage. This study first time paves the way to use radiation in conjunction with cold storage as an effective technique in implementation of different biological control approaches as a part of any IPM programs.Key wordGamma irradiations; cold storage, Coccinella septempunctata larvae; predatory potential; integrated pest management programme.INTRODUCTIONNuclear techniques such as gamma radiations have a vast application in different programmes of biological control including continuous supply of sterilized host and improved rearing techniques (Greany and Carpenter, 2000; Cai et al., 2017). Similarly irradiation can be used for sentinel-host eggs and larvae for monitoring survival and distribution of parasitoids (Jordão-paranhos et al., 2003; Hendrichs et al., 2009; Tunçbilek et al., 2009; Zapater et al., 2009; Van Lenteren, 2012). Also, at the production level, such technique may facilitate the management of host rearing, improve quality and expedite transport of product (Fatima et al., 2009; Hamed et al., 2009; Wang et al., 2009). Gamma irradiations can also be used to stop insect’s development to enhance host suitability for their use in different mass rearing programs (Celmer-Warda, 2004; Hendrichs et al., 2009; Seth et al., 2009). Development and survival of all insects have a direct connection with temperatures which in turn affect the physical, functional and behavioral adaptations (Ramløy, 2000). Many insects living in moderate regions can survive at low temperature by process of diapause. A temperature between 0 to 10oC may cause some insects to become sluggish and they only become active when the temperature is suitable. Such insects show greater adaptations to flexible temperature regimes for better survival. Many studies have reported this concept of cold-hardiness in insects in general (Bale, 2002; Danks, 2006) and specifically in coccinellid beetles over past years (Watanabe, 2002; Koch et al., 2004; Pervez and Omkar, 2006; Labrie et al., 2008; Berkvens et al., 2010). Using this cold hardiness phenomenon, many coccinellids have been studied for the effect of cold storage such as Coccinella undecimpunctata (Abdel‐Salam and Abdel‐Baky, 2000), Coleomegilla maculata (Gagné and Coderre, 2001) and Harmonia axyridis (Watanabe, 2002). This natural phenomenon, therefore, can be a helpful tool in developing low temperature stockpiling for improving mass-rearing procedures (Mousapour et al., 2014). It may provide a significant output in terms of providing natural enemies as and when required during pest infestation peaks (Venkatesan et al., 2000). Use of irradiation in conjunction with cold storage proves to be an effective technique in implementation of different biological control approaches as a part of any IPM programme. A study reported that the pupate of house fly, Musca domestica irradiated at dose of 500 Gy and can stored up to 2 months at 6°C for future use for a parasitoid wasp Spalangia endius rearing (Zapater et al., 2009). Similarly, when irradiated at 20 GY, parasitic wasps Cotesia flavipes were stored safely up to two months without deterioration of their parasitic potential (Fatima et al., 2009). Similarly, bio-control program of sugarcane shoot borer Chilo infescatellus proved successful through the use of irradiation combined with cold storage of its egg and larval parasitoids Trichogramma chilonis and C. flavipes (Fatima et al., 2009). Less mobile life stages such as larvae are of significance in any IPM strategy because they remain on target site for more time period as compared to adults. Therefore, use of predatory larvae is very promising in different biological control approaches because of their immediate attack on pests and more resistance to unfavorable environmental conditions than delicate egg stage. In addition, with their augmentation into fields, larval stage shows their presence for longer time than adult stage and their feeding potential is also satisfactory as that of adults. For the best utilization of these predators in the field and maximum impact of 3rd and 4th larval instars on prey, we should encourage late 2nd second instar larvae of predatory beetles in the fields as these instars have more feeding capacity due to increased size and ability to handle larger preys.In spite of higher significance, there is little information available about the effect of cold storage on the survival of larval instars of different ladybird beetles and its effect on their predatory potential. Very few studies report the use of cold storage for non-diapausing larval stage like for Semiadalia undecimnotata and only one study reported the short-term storage (up to two weeks) of 2nd and 3rd instar coccinellid, C. maculate, without any loss in feeding voracity of larvae after storage (Gagné and Coderre, 2001). The survival of 3rd and 4th larval instars of C. undecimpunctata for 7 days after storage at 5oC was reported in a study but the survival rate declined after 15-60 days of storage (Abdel‐Salam and Abdel‐Baky, 2000). As C. septempunctata is considered one of the voracious predators (Afroz, 2001; Jandial and Malik, 2006; Bilashini and Singh, 2009; Xia et al., 2018) and diapause is a prominent feature of this beetle and it may undergo facultative diapause under suitable laboratory conditions (Suleman, 2015). No information is available to date about the combined effect of cold storage and irradiation on the larval instars of this species.OBJECTIVES The objective of this study was to devise a cost effective technique for the cold storage and its effect on the subsequent predatory potential of the seven spotted ladybird beetle larvae in conjunction with the use of gamma radiations. Hypothesis of the study was that an optimum length of low temperature treatment for storage purpose would not affect the predation capacity of C. septempunctata larvae and their developmental parameters including survival and pupation will remain unaffected. Furthermore, use of gamma irradiation will have some additional effects on survival and feeding capacity of irradiated C. septempunctata larvae. Such techniques can be utilized in different biocontrol programs where short term storage is required. So these larvae can be successfully imparted in different IPM programs against sucking complex of insect pests as a component of biological control strategyMATERIALS AND METHODSPlant materials: Collection and rearing of C. septempunctata: Adult C. septempunctata were collected from the wheat crop (in NIAB vicinity and farm area) in the month of March during late winter and early in spring season 2016-2017. They were kept in plastic jars and were fed with brassica aphids. Under controlled laboratory conditions (25+2oC, 16h: 8h L:D and 65+5% R.H.), eggs of C. septempuctata were obtained and after hatching, larvae were also given brassica aphids as dietary source. Larvae of second instar were selected for this experiment (as the first instar is generally very weak and vulnerable to mortality under low temperatures). As the larvae approached second instar, they were separated for the experimentation. Irradiation of larvae at different doses: Irradiation of larvae was carried out by the irradiation source 137CS at Radiation laboratory, and the larvae were then brought back to the IPM laboratory, Plant Protection Division, Nuclear Institute for Agriculture and Biology (NIAB) Faisalabad. Radiation doses of 10 GY (Grey), 25 GY and 50 GY were used to treat the second instar larvae. There were three replicates for each treatment and five larvae per replicate were used. Control treatment was left un-irradiated.Cold storage of irradiated larvae: In present work, second instar C. septempunctata larvae were studied for storage at low temperature of 8oC. The larvae were kept at 8oC for 0, I and II weeks where week 0 depicts no cold treatment and this set of larvae was left under laboratory conditions for feeding and to complete their development. For larvae that were kept under cold storage for one week at 8°C, the term week I was devised. Similarly, week II denotes the larvae that remained under cold conditions (8°C) for two continuous weeks. Larvae were removed from cold storage in their respective week i.e., after week I and week II and were left under laboratory conditions to complete their development by feeding on aphids. Data collection: For recording the predatory potential of C. septempunctata larvae, 100 aphids were provided per larva per replicate on a daily basis until pupation as this number was more than their feeding capacity to make sure that they were not starved (personal observation). Observations were recorded for survival rate, developmental time and feeding potential. Data analysis: Data were statistically analysed by Statistical Software SPSS (Version 16.0). The data were subjected to normality check through the One-sample Kolmogorov-Smirnov test. Non normal data were transformed to normal data which were then used for all parametric variance tests. One-way and two-way analyses of variance were used. For comparison between variables, LSD test at α 0.05 was applied.RESULTSFeeding potential of irradiated larvae after removal from cold storage: Results showed an increase in the feeding potential of C. septempunctata larvae with increased cold storage duration. The feeding potential was significantly higher for the larvae that spent maximum length of time (week II) under cold storage conditions followed by week I and week 0. Gamma irradiations further enhanced the feeding potential of larvae that were kept under cold storage. When larvae were irradiated at 10 GY, the eating capacity of larvae increased significantly with the duration of cold storage. Similarly, larvae that were irradiated at 25 GY, showed increase in feeding potential on aphids as the time period of cold storage increased. The feeding potential of larvae that were irradiated at 50 GY, was again significantly increased with increase of cold storage duration. When different radiation doses were compared to week 0 of storage, there was a significant difference in feeding potential and larvae irradiated at 50 GY consumed the maximum numbers of aphids when no cold storage was done followed by larvae irradiated at 10 and 25 GY. With the other treatment, where larvae were kept under cold storage for one week (week I) the larvae irradiated at 50GY again showed the highest feeding potential. The feeding potential of irradiated larvae was again significantly higher than the un-irradiated larvae that were kept for two weeks (week II) under cold storage (table 1).Two-way ANOVA was performed to check the interaction between the different radiation doses and different lengths of storage durations for feeding potential of C. septempunctata larvae on aphids. The feeding potential of larvae irradiated at different doses and subjected to variable durations of cold storage were significantly different for both the radiation doses and cold storage intervals. Furthermore, the interaction between the radiation doses and storage duration was also significant meaning that the larvae irradiated at different doses with different length of cold storage were having significant variations in feeding levels (table 2).Developmental time of irradiated larvae after removal from cold storage: Significant difference was found in the development time of the larvae of C. septempunctata when irradiated at different doses at week 0 (without cold storage). The larvae irradiated at 10 GY took the maximum time for development and with the increase in irradiation dosage, from 25 to 50 GY, the time of development was shortened. The larvae irradiated at 50 GY had the same development time as the un-irradiated ones. When, the irradiated larvae were subjected to cold storage of one week duration (week I), their development time after removal from storage condition varied significantly. The larvae irradiated at 25 GY took the maximum time for development followed by larvae irradiated at 50 GY and 10 GY. There was an indication that the development time was extended for irradiated larvae as compared to un-irradiated larvae.Results also depicted a significant difference in the time taken by irradiated larvae to complete their development after taken out from cold storage of two weeks duration (week II). As the storage time of irradiated larvae increased, the development time was prolonged. Results showed that the larvae that were irradiated at 25 and 50 GY, took the maximum time to complete their development. With the prolonged duration of cold storage up to two weeks (week II), this difference of development time was less evident at lower doses (10 GY). The larvae irradiated at 10 GY showed a significant difference in their developmental duration after being taken out of cold storage conditions of the week 0, I and II. There was no difference in the developmental duration of larvae that were un-irradiated and subjected to different regimes of storage. Un-irradiated larvae were least affected by the duration of storage. With the increase in the storage time, a decrease in the developmental time was recorded. Larvae that were irradiated at 10 GY, took the maximum period to complete their development when no cold storage was done (week 0) followed by week I and II of cold storage. When the larvae irradiated at 25 GY were compared for their development time, there was again significant difference for week 0, I and II of storage duration. Maximum time was taken by the larvae for their complete development when removed from cold storage after one week (week I). With the increase in storage duration the time taken by larvae to complete their development after removal from cold storage reduced.When the larvae were removed after different lengths of cold storage duration i.e., week 0, week I and week II, there was a significant difference in the developmental time afterwards. Results have shown that the higher dose of radiation, increased the developmental time after removal from cold storage. The larvae irradiated at 50 GY took the longest time to complete their development after removal from cold storage (week I and week II) as compared the larvae that were not kept under cold storage conditions (week 0) (table 3).Interaction between the different radiation doses and different lengths of storage durations for development time of larvae were checked by two-way ANOVA. The development time of larvae irradiated at different doses and subjected to variable durations of cold storage were significantly different for both the doses and cold storage intervals. Furthermore, the interaction between the radiation doses and storage duration was also significant meaning that the larvae irradiated at different doses with different length of cold storage were having significant variations in development times (table 4). DISCUSSIONThe present research work indicates the possibility of keeping the larval instars of C. septempunctata under cold storage conditions of 8oC for a short duration of around 14 days without affecting its further development and feeding potential. Furthermore, irradiation can enhance the feeding potential and increase the development time of larval instars. This in turn could be a useful technique in mass rearing and field release programmes for biological control through larval instars. Usually temperature range of 8-10oC is an optimal selection of low temperature for storage as reported earlier for eggs two spotted ladybird beetle, Adalia bipunctata and the eggs of C. septempunctata (Hamalainen and Markkula, 1977), Trichogramma species (Jalali and Singh, 1992) and fairyfly, Gonatocerus ashmeadi (Hymenoptra; Mymaridae) (Leopold and Chen, 2007). However, a study reported more than 80% survival rate for the coccinellid beetle, Harmonia axyridis for up to 150 days at moderately low temperature of 3-6oC (Ruan et al., 2012). So there is great flexibility in coccinellid adults and larvae for tolerating low temperature conditions. After removal from cold storage, larvae showed better feeding potential with consumption of more aphids when compared to normal larvae that were not placed under low temperature conditions. This indicates that when the adult or immature insect stages are subjected to low temperature environment, they tend to reduce their metabolic activity for keeping them alive on the reserves of their body fats and sustain themselves for a substantial length of time under such cold environment. Hereafter, the larval instars that were in cold storage were behaving as if starved for a certain length of time and showed more hunger. This behavior of improved or higher feeding potential of stored larvae has been reported previously (Chapman, 1998). Hence, the feeding potential of C. septempunctata larvae significantly increased after cold storage. Gagné and Coderre (2001) reported higher predatory efficacy in larvae of C. maculata when stored at the same temperature as in the present study i.e., 8oC. Similarly, Ruan et al. (2012) showed that the multicolored Asian ladybug, H. axyridis, when stored under cold conditions, had more eating capacity towards aphids Aphis craccivora Koch than the individuals that were not stored. Such studies indicate that the higher feeding potential in insects after being subjected to low temperature environmental conditions could be due to the maintenance of their metabolism rate to a certain level while utilizing their energy reserves to the maximum extent (Watanabe, 2002).The individuals coming out from cold storage are therefore capable of consuming more pray as they were in a condition of starvation and they have to regain their energy loss through enhanced consumption. Furthermore, the starvation in C. septempunctata has previously been reported to affect their feeding potential (Suleman et al., 2017). In the present study, the larval development was delayed after returning to normal laboratory conditions. Cold storage affects the life cycle of many insects other than coccinellids. The cold storage of green bug aphid parasitoid, Lysiphlebus testaceipes Cresson (Hymenoptra; Braconidae) mummies increased the life cycle 3-4 times. Nevertheless, in current study the development process of stored larvae resumed quickly after taking them out and larvae completed their development up to adult stage. Similar kinds of results were reported for resumption of larval development after removal from cold storage conditions. Such studies only report satisfactory survival rates and development for a short duration of cold storage but as the length of storage is increased, it could become harmful to certain insects. Gagné and Coderre (2001) reported that cold storage for longer period (three weeks) proved fatal for almost 40% of larvae of C. maculata. Furthermore, in the same study, the feeding potential of C. maculata larvae was also affected beyond two weeks of cold storage due to the loss of mobility after a long storage period. Many studies have reported that longer durations of low temperature conditions can either damage the metabolic pathways of body cells or may increase the levels of toxins within the bodies of insects. Also, low temperature exposure for longer duration may cause specific interruptions in the insect body especially neuro-hormones responsible for insect development, which could be dangerous or even life threatening.Chen et al. (2004) also reported that the biological qualities of parasitized Bemisia tabaci pupae on population quality of Encarsia formosa were affected negatively with increase in cold storage duration. Similarly, the egg hatchability of green lacewing Chrysoperla carnea Stephen was lost completely beyond 18 days of cold storage (Sohail et al., 2019). However, in the present study the cold storage was done for maximum two weeks and it is to be regarded as a short term storage hence the survival rate was satisfactory. Longer periods of cold storage for larvae are not considered safe due to their vulnerable state as compared to adults which are hardier. Also 2nd instar larvae used in the present study for cold storage for being bigger in size and physical stronger than 1st instar. Abdel‐Salam and Abdel‐Baky (2000) reported that in C. undecimpunctata the cold storage of 3rd and 4th larval instars was higher and considered safer than early larval instars. The same study showed sharp decline in survival rate after two weeks and there was no survival beyond 30-60 days of cold storage. The present study showed that short term storage of the larvae of C. septempunctata could be done without any loss of their feeding potential or development so the quality of predator remained unaffected. Similar kind of work for many other insects had been reported previously where cold storage technique proved useful without deteriorating the fitness of stored insects. For example, the flight ability of reared codling moth Cydia pomonella Linnaeus remained unaffected after removal from cold storage (Matveev et al., 2017). Moreover, a sturdy reported that pupae of a parasitoid wasp Trichogramma nerudai (Hymenoptera; Trichogrammatidae) could be safely put in cold storage for above than 50 days (Tezze and Botto, 2004). Similarly, a technique of cold storage of non-diapausing eggs of black fly Simulium ornaturm Meigen was developed at 1oC. Another study reported safe storage of a predatory bug insidious flower bug Orius insidiosus for more than 10 days at 8°C (Bueno et al., 2014).In present study without cold storage, the lower doses of 10 and 25 GY prolonged the developmental time as compared to un-irradiated larvae and higher doses of irradiations in conjunction with cold storage again significantly prolonged the developmental time of larvae when returned to the laboratory conditions. Salem et al. (2014) also reported that Gamma irradiations significantly increased the duration of developmental stages (larvae and pupae) in cutworm, Agrotis ipsilon (Hufnagel). In another study, where endoparasitic wasps Glyptapanteles liparidis were evaluated with irradiated and non-irradiated gypsy moth Lymantria dispar larvae for oviposition, it was found that non-irradiated larvae had a shorter time to reach the adult stage as compared to irradiated larvae (Novotny et al., 2003). Both for higher doses with cold storage and lower doses without cold storage extended the larval duration of C. septempunctata. In another study when the parasitoid wasp Habrobracon hebetor was irradiated at the dose of 10 GY, it resulted in prolonged longevity (Genchev et al., 2008). In the same study, when another parasitoid Ventruria canescens was irradiated at lower doses of 4GY and 3 GY, it resulted in increased emergence from the host larvae, while gamma irradiations at the dose of 1 GY and 2 GY significantly stimulated the rate of parasitism (Genchev et al., 2008). The current study also indicated higher rates of predation in the form of increased feeding potential of larvae as a result of irradiations at lower doses.CONCLUSIONThe outcome of the current study shows that storage of 2nd instar C. septempunctata at low temperature of 8oC for a short duration of about 14 days is completely safe and could have broader application in different biocontrol programs. Such flexibility in storage duration can also assist in different mass rearing techniques and commercial uses. The combination of gamma radiation with low temperature cold storage could be a useful tool in developing different biological pest management programs against sucking insect pests. Incidence of periodic occurrence of both the target insect pests with their predatory ladybird beetles in synchrony is an important aspect that could be further strengthened by cold storage techniques. Therefore, short or long term bulk cold storage of useful commercial biocontrol agents and then reactivating them at appropriate time of pest infestation is a simple but an advantageous method in mass rearing programs. Increased feeding capacity of stored larvae is another edge and hence such larvae may prove more beneficial as compared to unstored larvae. Both cold storage and improved feeding of the C. septempuctata larvae can be utilized for implementation of IPM for many sucking insect pests of various crops, fruits and vegetables. Due to some constraints this study could not be continued beyond two weeks but for future directions, higher doses and longer duration periods could further elaborate the understanding and better application of such useful techniques in future IPM programmes on a wider scale. Also, some other predatory coccinellid beetle species can be tested with similar doses and cold storage treatments to see how effective this technique is on other species as well.ACKNOWLEDGMENTS We acknowledge the Sugarcane Research and Development Board for providing a research grant (No. SRDB/P/4/16) to carry out this research work. 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A clinical decision report using: McElroy SL, Hudson J, Ferreira-Cornwell MC, Radewonuk J, Whitaker T, Gasior M. Lisdexamfetamine dimesylate for adults with moderate to severe binge eating disorder: Results of two pivotal phase 3 randomized controlled trials. Neuropsychopharmacology. 2016;41(5):1251-1260. https://doi.org/10.1038/npp.2015.275 for a young woman requesting a novel pharmacological intervention for a Binge Eating Disorder (BED).

Abstract In this paper, we show some refinements of generalized numerical radius inequalities involving the Young and Heinz inequality. In particular, we present w_{p}^{p}(A_{1}^{*}T_{1}B_{1},\dots,A_{n}^{*}T_{n}B_{n})\leq\frac{n^{1-\frac{1% }{r}}}{2^{\frac{1}{r}}}\bigg{\|}\sum_{i=1}^{n}[B_{i}^{*}f^{2}(|T_{i}|)B_{i}]^{% rp}+[A_{i}^{*}g^{2}(|T_{i}^{*}|)A_{i}]^{rp}\bigg{\|}^{\frac{1}{r}}-\inf_{\|x\|% =1}\eta(x), where {T_{i},A_{i},B_{i}\in\mathbb{B}(\mathscr{H})} {(1\leq i\leq n)} , f and g are nonnegative continuous functions on {[0,\infty)} satisfying {f(t)g(t)=t} for all {t\in[0,\infty)} , {p,r\geq 1} , {N\in\mathbb{N}} , and \displaystyle\eta(x)=\frac{1}{2}\sum_{i=1}^{n}\sum_{j=1}^{N}\Bigl{(}\sqrt[2^{j% }]{\big{\langle}(A_{i}^{*}g^{2}(|T_{i}^{*}|)A_{i})^{p}x,x\big{\rangle}^{2^{j-1% }-k_{j}}\big{\langle}(B_{i}^{*}f^{2}(|T_{i}|)B_{i})^{p}x,x\big{\rangle}^{k_{j}}} \displaystyle -\sqrt[2^{j}]{\big{\langle}(B_{i}^{*}f^{2}(|T_{i}|)B_{i}% )^{p}x,x\big{\rangle}^{k_{j}+1}\big{\langle}(A_{i}^{*}g^{2}(|T_{i}^{*}|)A_{i})% ^{p}x,x\big{\rangle}^{2^{j-1}-k_{j}-1}}\,\Big{)}^{2}.

A digraph is k-traceable if its order is at least k and each of its subdigraphs of order k is traceable. An oriented graph is a digraph without 2-cycles. The 2-traceable oriented graphs are exactly the nontrivial tournaments, so k-traceable oriented graphs may be regarded as generalized tournaments. It is well-known that all tournaments are traceable. We denote by t(k) the smallest integer bigger than or equal to k such that every k-traceable oriented graph of order at least t(k) is traceable. The Traceability Conjecture states that t(k) ≤ 2k-1 for every k ≥ 2 [van Aardt, Dunbar, Frick, Nielsen and Oellermann, A traceability conjecture for oriented graphs, Electron. J. Combin., 15(1):#R150, 2008]. We show that for k ≥ 2, every k-traceable oriented graph with independence number 2 and order at least 4k-12 is traceable. This is the last open case in giving an upper bound for t(k) that is linear in k.

This paper presents basic theoretical knowledge of critical thinking. It describes characteristics of critical thinking, which are used for the formation of critical thinking indicators. These indicators are needed for assessing students’ critical thinking levels and for designing lessons to develop critical thinking competence for students. The paper articulates arguments for highlighting the necessity of critical thinking education for students in Vietnam. The paper contributes to knowledge base of critical thinking education and supports further studies on critical thinking in order to enhance the effectiveness of education in Vietnam. Key words Critical thinking, competence, education, students References Arend, B. (2009). Encouraging critical thinking in online threaded discussions. The Journal of Educators Online, 6(1), doi: 10.1.1.412.1694Bacon, F. (1605). The Advancement of Learning. Edited by Joseph Devey, M.A. (New York: P.F. Collier and Son, 1901).Bailin, S. (2002). 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