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Journal articles on the topic 'Conjugate mixture models'
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Khalidov, Vasil, Florence Forbes, and Radu Horaud. "Conjugate Mixture Models for Clustering Multimodal Data." Neural Computation 23, no. 2 (February 2011): 517–57. http://dx.doi.org/10.1162/neco_a_00074.
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The problem of multimodal clustering arises whenever the data are gathered with several physically different sensors. Observations from different modalities are not necessarily aligned in the sense there there is no obvious way to associate or compare them in some common space. A solution may consist in considering multiple clustering tasks independently for each modality. The main difficulty with such an approach is to guarantee that the unimodal clusterings are mutually consistent. In this letter, we show that multimodal clustering can be addressed within a novel framework: conjugate mixture models. These models exploit the explicit transformations that are often available between an unobserved parameter space (objects) and each of the observation spaces (sensors). We formulate the problem as a likelihood maximization task and derive the associated conjugate expectation-maximization algorithm. The convergence properties of the proposed algorithm are thoroughly investigated. Several local and global optimization techniques are proposed in order to increase its convergence speed. Two initialization strategies are proposed and compared. A consistent model selection criterion is proposed. The algorithm and its variants are tested and evaluated within the task of 3D localization of several speakers using both auditory and visual data.
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Gustafson, Paul. "The effect of mixing-distribution misspecification in conjugate mixture models." Canadian Journal of Statistics 24, no. 3 (September 1996): 307–18. http://dx.doi.org/10.2307/3315741.
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Song, Yuntao, Anrong Li, Hui Li, Xianfeng Li, Zeao Huang, Junbao Yang, Yi Ding, and Grace Szu. "Abstract 2094: Conjugates of TLR9 and STING agonists achieved profound synergistic effects in vitro and in vivo." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2094. http://dx.doi.org/10.1158/1538-7445.am2022-2094.
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Abstract Introduction: Both Toll-like receptor 9 (TLR9) and STING pathways are two important pathways involved in immune activation. We reasoned that concurrent activation of TLR9 and STING pathways could activate immunity with an efficacy and safety profile that could not be achieved by activating either pathway alone, and we designed a series of conjugates where TLR9 and STING agonists were linked together by a releasable or stable linker. The conjugates have been evaluated in in vitro assays and in vivo mouse models in comparison with TLR9 agonist or STING agonist alone and combination of the two agonists. Methods: Cellular potency was assessed using THP-1 monocyte cells and human PBMC. In vivo efficacy was evaluated in mouse tumor models, where tumor cells were inoculated into either the right flank or both flanks of C57BL/6 or BALB/c mice, test compounds were injected intratumorally into the right flank three times at every three days when tumors reached a volume of 90-100 mm3, muDX400 was dosed via IP injection six times at every four days. In MC38 murine model, compounds-treated mice free from tumor for 30 days were re-challenged with MC38 tumor cells. Results: Conjugates CS-2554, 2571 and 2600 showed five to ten folds improvement in potency over the corresponding STING agonist alone or a mixture of the corresponding STING and TLR9 agonists (1/1molar ratio) in THP1 assay, a similar fold of increase in EC50 was observed in human PBMC assay, where induction of IFNα, IFNβ, TNFα and IL6 were measured. In MC38 murine model, CS-2554 at the dose of 9 ug/injection resulted in CR in all treated mice; whereas no CR was obtained when a mixture of an equivalent amount of the corresponding STING agonist and TLR9 agonist was used. The tumor-free mice remained tumor-free after re-challenge study. In MC38 dual tumor model, when combined with aPD-1, a mixture of 50 ug of TLR9 agonist and 5 ug of STING agonist resulted in CR in 38% treated mice, whereas the same level was achieved with only 4 ug of the corresponding conjugate CS-2571. Comparisons of a conjugate and either the corresponding agonist alone or the two in combination were also carried out in CT26 dual tumor model. On day 13, for the injected tumor, the tumor growth inhibition rate (TGI) of an equivalent amount of a TLR9 agonist, a STING agonist, a mixture of the two, and the corresponding conjugate CS-2600 was 29.65%, 31.3%, 61.00%, and 91.93%, respectively. For the distal tumor, only the conjugate CS-2600 showed significant inhibition of tumor growth with 57% TGI, whereas no tumor growth inhibition was observed with a TLR9 agonist, a STING agonist, or a mixture of the two. Conclusions: The conjugates harnessed significant synergy between TLR9 and STING pathways in vitro and in vivo and resulted in over ten times enhancement of potency in certain assays over either agent alone or a combination of the two. The preclinical studies of the conjugates support clinical evaluation of this class of novel compounds. Citation Format: Yuntao Song, Anrong Li, Hui Li, Xianfeng Li, Zeao Huang, Junbao Yang, Yi Ding, Grace Szu. Conjugates of TLR9 and STING agonists achieved profound synergistic effects in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2094.
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Ali, Sajid, Muhammad Aslam, and Mohsin Ali. "Heterogeneous data analysis using a mixture of Laplace models with conjugate priors." International Journal of Systems Science 45, no. 12 (March 4, 2013): 2619–36. http://dx.doi.org/10.1080/00207721.2013.775381.
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Jun-Uk Chu and Yun-Jung Lee. "Conjugate-Prior-Penalized Learning of Gaussian Mixture Models for Multifunction Myoelectric Hand Control." IEEE Transactions on Neural Systems and Rehabilitation Engineering 17, no. 3 (June 2009): 287–97. http://dx.doi.org/10.1109/tnsre.2009.2015177.
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Ali, Abdullah Masoud, Matteo Angelino, and Aldo Rona. "Physically Consistent Implementation of the Mixture Model for Modelling Nanofluid Conjugate Heat Transfer in Minichannel Heat Sinks." Applied Sciences 12, no. 14 (July 11, 2022): 7011. http://dx.doi.org/10.3390/app12147011.
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As much as two-phase mixture models resolve more physics than single-phase homogeneous models, their inconsistent heat transfer predictions have limited their use in modelling nanofluid cooled minichannel heat sinks. This work investigates, addresses, and solves this key shortcoming, enabling reliable physically sound predictions of minichannel nanoflows, using the two-phase mixture model. It does so by applying the single-phase and the two-phase mixture model to a nine-passages rectangular minichannel, 3 mm deep and 1 mm wide, cooled by a 1% by volume suspension of Al2O3 nanoparticles in water, over the Reynolds number range 92 to 455. By varying the volume fraction αnf of the second phase between 2% and 50%, under a constant heat flux of 16.67 W/cm2 and 30 Celsius coolant inflow, it is shown that the two-phase mixture model predicts heat transfer coefficient, pressure loss, friction factor, exergy destruction rate, exergy expenditure rate, and second law efficiency values converging to the single-phase model ones at increasing αnf. A two-phase mixture model defined with 1% second phase volume fraction and 100% nanoparticles volume fraction in the second phase breaks the Newtonian fluid assumption within the model and produces outlier predictions. By avoiding this unphysical regime, the two-phase mixture model matched experimental measurements of average heat transfer coefficient to within 1.76%. This has opened the way for using the two-phase mixture model with confidence to assess and resolve uneven nanoparticle dispersion effects and increase the thermal and mass transport performance of minichannels.
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Colichio, Gabriela B. C., Giuliana S. Oliveira, Tasson C. Rodrigues, Maria Leonor S. Oliveira, and Eliane N. Miyaji. "Efficacy of a Protein Vaccine and a Conjugate Vaccine Against Co-Colonization with Vaccine-Type and Non-Vaccine Type Pneumococci in Mice." Pathogens 9, no. 4 (April 10, 2020): 278. http://dx.doi.org/10.3390/pathogens9040278.
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Widespread use of pneumococcal conjugate vaccines (PCVs) has led to substitution of vaccine-type (VT) strains by non-vaccine type (NVT) strains in nasopharyngeal carriage. We compared the efficacy of PCV13 and a nasal protein formulation containing pneumococcal surface protein A (PspA) adjuvanted with the whole-cell pertussis vaccine (wP) in the protection against co-colonization challenge models in mice with VT and NVT strains expressing different PspAs. Immunized mice were challenged with two different mixtures: i. VT4 (PspA3) + NVT33 (PspA1) and ii. VT23F (PspA2) + NVT15B/C (PspA4). Results from the first mixture showed a reduction in loads of VT4 strain in the nasopharynx of mice immunized with PCV13. A statistical difference between the loads of the VT and NVT strains was observed, indicating a competitive advantage for the NVT strain in PCV13-immunized animals. In the second mixture, no reduction was observed for the VT23F strain, probably due to low levels of anti-23F polysaccharide IgG induced by PCV13. Interestingly, a combination of the PspA formulation containing wP with PCV13 led to a reduction in colonization with both strains of the two mixtures tested, similar to the groups immunized nasally with wP or PspA plus wP. These results indicate that a combination of vaccines may be a useful strategy to overcome pneumococcal serotype replacement.
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Hamadani, Mehdi, Christopher N. Graham, Laura Liao, Katherine H. Zhang, Hannah Strat, David Ungar, Weiyun Z. Ai, Lei Chen, and Carmelo Carlo-Stella. "Long-term survival projections of loncastuximab tesirine-treated patients in relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e19551-e19551. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e19551.
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e19551 Background: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA approved CD19-directed antibody-drug conjugate for R/R DLBCL. From the LOTIS-2 trial primary data cut (April 6, 2020), overall response rate was 48.3% and median overall survival (OS) was 9.9 months. The OS Kaplan-Meier (KM) plot displayed a survival plateau suggesting the presence of long-term survivors (LTS). Survival analyses were conducted on a more mature data cut (March 1, 2021; median follow-up = 1.7 years, follow-up completeness at median = 81%) to estimate the percentage of LTS and expected lifetime survival (mean OS) for lonca-treated patients. Methods: Consistent with studies of other R/R DLBCL treatments, identified through a literature review, parametric and mixture cure models were fit utilizing multiple distributions. Flexible cubic spline (hazard scale 1-3 knots) and non-mixture cure analyses were also conducted. Age- and gender-matched United States life table hazards were used in projections for LTS and to ensure modeled hazards were not less than the general population. Best-fit models were determined through fit statistics, KM and fitted curve overlays, and clinical plausibility. The best-fit model from each method was a candidate for overall best fit. A hybrid model following the best-fit parametric/spline model to a defined time point and switching to general population mortality was also constructed. Results: Mixture and non-mixture cure models fit best (individual best fits gamma and Weibull, respectively). Parametric and spline models (individual best fits log-normal and 2 knot models, respectively) did not fit the observed data well nor fit the clinical expectation of long-term survival. Due to better fit, spline models were used in the hybrid model. LTS from the mixture cure and non-mixture cure models were 24-26%. Mixture cure, non-mixture cure, and hybrid model with a 2-year switch point were consistent in survival predictions (6.11-6.23 years). In a sensitivity analysis with 3-year switch point in the hybrid model, the estimated survival was shorter due to the switch point being below the observed survival plateau. Table presents full survival results and fit statistics. Conclusions: The observed survival plateau suggests lonca-treated patients may include LTS. Mixture cure, non-mixture cure, and hybrid models fit the trial data well and align on survival projections (6.11-6.23 years). Additional follow-up may help refine the switch point of the hybrid model and confirm presence of LTS.[Table: see text]
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Hamadani, Mehdi, Christopher N. Graham, Laura Liao, Katherine H. Zhang, Hannah Strat, David Ungar, Weiyun Z. Ai, Lei Chen, and Carmelo Carlo-Stella. "Long-term survival projections of loncastuximab tesirine-treated patients in relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e19551-e19551. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e19551.
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e19551 Background: Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA approved CD19-directed antibody-drug conjugate for R/R DLBCL. From the LOTIS-2 trial primary data cut (April 6, 2020), overall response rate was 48.3% and median overall survival (OS) was 9.9 months. The OS Kaplan-Meier (KM) plot displayed a survival plateau suggesting the presence of long-term survivors (LTS). Survival analyses were conducted on a more mature data cut (March 1, 2021; median follow-up = 1.7 years, follow-up completeness at median = 81%) to estimate the percentage of LTS and expected lifetime survival (mean OS) for lonca-treated patients. Methods: Consistent with studies of other R/R DLBCL treatments, identified through a literature review, parametric and mixture cure models were fit utilizing multiple distributions. Flexible cubic spline (hazard scale 1-3 knots) and non-mixture cure analyses were also conducted. Age- and gender-matched United States life table hazards were used in projections for LTS and to ensure modeled hazards were not less than the general population. Best-fit models were determined through fit statistics, KM and fitted curve overlays, and clinical plausibility. The best-fit model from each method was a candidate for overall best fit. A hybrid model following the best-fit parametric/spline model to a defined time point and switching to general population mortality was also constructed. Results: Mixture and non-mixture cure models fit best (individual best fits gamma and Weibull, respectively). Parametric and spline models (individual best fits log-normal and 2 knot models, respectively) did not fit the observed data well nor fit the clinical expectation of long-term survival. Due to better fit, spline models were used in the hybrid model. LTS from the mixture cure and non-mixture cure models were 24-26%. Mixture cure, non-mixture cure, and hybrid model with a 2-year switch point were consistent in survival predictions (6.11-6.23 years). In a sensitivity analysis with 3-year switch point in the hybrid model, the estimated survival was shorter due to the switch point being below the observed survival plateau. Table presents full survival results and fit statistics. Conclusions: The observed survival plateau suggests lonca-treated patients may include LTS. Mixture cure, non-mixture cure, and hybrid models fit the trial data well and align on survival projections (6.11-6.23 years). Additional follow-up may help refine the switch point of the hybrid model and confirm presence of LTS.[Table: see text]
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Ruiz, A., P. E. Lopez-de-Teruel, and M. C. Garrido. "Probabilistic Inference from Arbitrary Uncertainty using Mixtures of Factorized Generalized Gaussians." Journal of Artificial Intelligence Research 9 (October 1, 1998): 167–217. http://dx.doi.org/10.1613/jair.533.
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This paper presents a general and efficient framework for probabilistic inference and learning from arbitrary uncertain information. It exploits the calculation properties of finite mixture models, conjugate families and factorization. Both the joint probability density of the variables and the likelihood function of the (objective or subjective) observation are approximated by a special mixture model, in such a way that any desired conditional distribution can be directly obtained without numerical integration. We have developed an extended version of the expectation maximization (EM) algorithm to estimate the parameters of mixture models from uncertain training examples (indirect observations). As a consequence, any piece of exact or uncertain information about both input and output values is consistently handled in the inference and learning stages. This ability, extremely useful in certain situations, is not found in most alternative methods. The proposed framework is formally justified from standard probabilistic principles and illustrative examples are provided in the fields of nonparametric pattern classification, nonlinear regression and pattern completion. Finally, experiments on a real application and comparative results over standard databases provide empirical evidence of the utility of the method in a wide range of applications.
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Mimouni, Stéphane, Namane Mechitoua, and Mehdi Ouraou. "CFD Recombiner Modelling and Validation on the H2-Par and Kali-H2Experiments." Science and Technology of Nuclear Installations 2011 (2011): 1–13. http://dx.doi.org/10.1155/2011/574514.
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A large amount of Hydrogen gas is expected to be released within the dry containment of a pressurized water reactor (PWR), shortly after the hypothetical beginning of a severe accident leading to the melting of the core. According to local gas concentrations, the gaseous mixture of hydrogen, air and steam can reach the flammability limit, threatening the containment integrity. In order to prevent mechanical loads resulting from a possible conflagration of the gas mixture, French and German reactor containments are equipped with passive autocatalytic recombiners (PARs) which preventively oxidize hydrogen for concentrations lower than that of the flammability limit. The objective of the paper is to present numerical assessments of the recombiner models implemented in CFD solvers NEPTUNE_CFD and Code_Saturne. Under the EDF/EPRI agreement, CEA has been committed to perform 42 tests of PARs. The experimental program named KALI-H2, consists checking the performance and behaviour of PAR. Unrealistic values for the gas temperature are calculated if the conjugate heat transfer and the wall steam condensation are not taken into account. The combined effects of these models give a good agreement between computational results and experimental data.
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Jiang, Yuting, Qun Zheng, Guoqiang Yue, Ping Dong, Jie Gao, and Feilong Yu. "Conjugate heat transfer simulation of turbine blade high efficiency cooling method with mist injection." Proceedings of the Institution of Mechanical Engineers, Part C: Journal of Mechanical Engineering Science 228, no. 15 (February 9, 2014): 2738–49. http://dx.doi.org/10.1177/0954406214522436.
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The idea of utilizing a finely dispersed water-in-air mixture has been proven to be a feasible technique to produce very high cooling rates. The accuracy of numerical simulation program for conjugate heat transfer methodology is verified with the Mark II transonic high pressure turbine stator which is cooled by internal convection through radial round pipes, and different turbulence models and transition models are employed to analyze the influence on results. On the basis of it, the mist cooling is simulated under typical gas turbine operating conditions for internal convective cooling to discuss the improvement of cooling performance. Though the results indicate that mist cooling can decrease the temperature of boundary layer without impact on the temperature of the mainstream and the thickness of boundary layer, the cooling capacity is limited by inadequate evaporation of mist. Considering the distribution of thermal stress and mist evaporation, a compound cooling blade of film cooling with trailing edge ejection is acquired which is modified from the blade of Mark II internal convective cooling; the effects of various parameters including mist concentration and mist diameter on the improvement of cooling performance are investigated, meanwhile the impact of curvature on cooling efficiency and mist trajectory is analyzed finally.
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Menéndez, R., R. Más, A. M. Amor, N. Ledón, J. Pérez, R. M. González, I. Rodeiro, M. Zayas, and S. Jiménez. "Inhibition of rat lipoprotein lipid peroxidation by the oral administration of D003, a mixture of very long-chain saturated fatty acids." Canadian Journal of Physiology and Pharmacology 80, no. 1 (January 1, 2002): 13–21. http://dx.doi.org/10.1139/y01-088.
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Previous results have demonstrated that policosanol, a mixture of aliphatic primary alcohols isolated and purified from sugar cane wax, whose main component is octacosanol, inhibited lipid peroxidation in experimental models and human beings. D003 is a defined mixture of very long-chain saturated fatty acids, also isolated and purified from sugar cane wax, whose main component is octacosanoic acid followed by traicontanoic, dotriacontanoic, and tetracontanoic acids. Since very long-chain fatty acids are structurally related to their corresponding alcohols, we investigated the effect of oral treatment with D003 (0.5, 5, 50, and 100 mg/kg) over 4 weeks in reducing the susceptibility of rat lipoprotein to oxidative modification. The combined rat lipoprotein fraction VLDL + LDL was subjected to several oxidation systems, including those containing metal ions (CuSO4), those having the capacity to generate free radicals 2,2-azobis-2-amidinopropane hydrochloride (AAPH), and a more physiological system (resident macrophages). D003 (5, 50, and 100 mg/kg) significantly inhibited copper-mediated conjugated-diene generation in a concentration-dependent manner. D003 increased lag phase by 53.1, 115.3, and 119.3%, respectively, and decreased the rate of conjugate-diene generation by 16.6, 21.5, and 19.6%, respectively. D003 also inhibited azo-compound initiated and macrophage-mediated lipid peroxidation as judged by the significant decrease in thiobarbituric acid reactive substance (TBARS) generation. In all the systems the maximum effect was attained at 50 mg/kg. There was also a parallel attenuation in the reduction of lysine amino groups and a significant reduction of carbonyl content after oxidation of lipoprotein samples. Taken together, the present results indicate that oral administration of D003 protects lipoprotein fractions against lipid peroxidation in the lipid as well in the protein moiety.Key words: D003, very long-chain saturated fatty acids, lipoprotein lipid peroxidation.
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Ihou, Koffi Eddy, Manar Amayri, and Nizar Bouguila. "Stochastic Variational Optimization of a Hierarchical Dirichlet Process Latent Beta-Liouville Topic Model." ACM Transactions on Knowledge Discovery from Data 16, no. 5 (October 31, 2022): 1–48. http://dx.doi.org/10.1145/3502727.
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In topic models, collections are organized as documents where they arise as mixtures over latent clusters called topics. A topic is a distribution over the vocabulary. In large-scale applications, parametric or finite topic mixture models such as LDA (latent Dirichlet allocation) and its variants are very restrictive in performance due to their reduced hypothesis space. In this article, we address the problem related to model selection and sharing ability of topics across multiple documents in standard parametric topic models. We propose as an alternative a BNP (Bayesian nonparametric) topic model where the HDP (hierarchical Dirichlet process) prior models documents topic mixtures through their multinomials on infinite simplex. We, therefore, propose asymmetric BL (Beta-Liouville) as a diffuse base measure at the corpus level DP (Dirichlet process) over a measurable space. This step illustrates the highly heterogeneous structure in the set of all topics that describes the corpus probability measure. For consistency in posterior inference and predictive distributions, we efficiently characterize random probability measures whose limits are the global and local DPs to approximate the HDP from the stick-breaking formulation with the GEM (Griffiths-Engen-McCloskey) random variables. Due to the diffuse measure with the BL prior as conjugate to the count data distribution, we obtain an improved version of the standard HDP that is usually based on symmetric Dirichlet (Dir). In addition, to improve coordinate ascent framework while taking advantage of its deterministic nature, our model implements an online optimization method based on stochastic, at document level, variational inference to accommodate fast topic learning when processing large collections of text documents with natural gradient. The high value in the predictive likelihood per document obtained when compared to the performance of its competitors is also consistent with the robustness of our fully asymmetric BL-based HDP. While insuring the predictive accuracy of the model using the probability of the held-out documents, we also added a combination of metrics such as the topic coherence and topic diversity to improve the quality and interpretability of the topics discovered. We also compared the performance of our model using these metrics against the standard symmetric LDA. We show that online HDP-LBLA (Latent BL Allocation)’s performance is the asymptote for parametric topic models. The accuracy in the results (improved predictive distributions of the held out) is a product of the model’s ability to efficiently characterize dependency between documents (topic correlation) as now they can easily share topics, resulting in a much robust and realistic compression algorithm for information modeling.
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Resende, P. R., Mohsen Ayoobi, and Alexandre M. Afonso. "Numerical Investigations of Micro-Scale Diffusion Combustion: A Brief Review." Applied Sciences 9, no. 16 (August 15, 2019): 3356. http://dx.doi.org/10.3390/app9163356.
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With the increasing global concerns about the impacts of byproducts from the combustion of fossil fuels, researchers have made significant progress in seeking alternative fuels that have cleaner combustion characteristics. Such fuels are most suitable for addressing the increasing demands on combustion-based micro power generation systems due to their prominently higher energy density as compared to other energy resources such as batteries. This cultivates a great opportunity to develop portable power devices, which can be utilized in unmanned aerial vehicles (UAVs), micro satellite thrusters or micro chemical reactors and sensors. However, combustion at small scales—whether premixed or non-premixed (diffusion)—has its own challenges as the interplay of various physical phenomena needs to be understood comprehensively. This paper reviews the scientific progress that researchers have made over the past couple of decades for the numerical investigations of diffusion flames at micro scales. Specifically, the objective of this review is to provide insights on different numerical approaches in analyzing diffusion combustion at micro scales, where the importance of operating conditions, critical parameters and the conjugate heat transfer/heat re-circulation have been extensively analyzed. Comparing simulation results with experimental data, numerical approaches have been shown to perform differently in different conditions and careful consideration should be given to the selection of the numerical models depending on the specifics of the cases that are being modeled. Varying different parameters such as fuel type and mixture, inlet velocity, wall conductivity, and so forth, researchers have shown that at micro scales, diffusion combustion characteristics and flame dynamics are critically sensitive to the operating conditions, that is, it is possible to alter the flammability limits, control the flame stability/instability or change other flame characteristics such as flame shape and height, flame temperature, and so forth.
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Mota, Flávia Diniz, Rodrigo Máximo sánchez román, and Helenice De Oliveira Florentino. "MODELO MATEMÁTICO APLICADO À FERTIRRIGAÇÃO." IRRIGA 26, no. 1 (March 31, 2021): 77–93. http://dx.doi.org/10.15809/irriga.2021v26n1p77-93.
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MODELO MATEMÁTICO APLICADO À FERTIRRIGAÇÃO1 FLÁVIA DINIZ MOTA2; RODRIGO MÁXIMO SÁNCHEZ ROMÁN3 E HELENICE DE OLIVEIRA FLORENTINO SILVA4 1Trabalho originado da tese de doutorado do primeiro autor intitulada: “Modelo matemático para otimização na seleção de fertilizantes via fertirrigação” 2Departamento de Engenharia Rural, Universidade Estadual Paulista, Avenida Universitária, n° 3780, Altos do Paraíso, 18610-034, Botucatu, São Paulo, Brasil, fdmota@yahoo.com.br. 3 Departamento de Engenharia Rural, Universidade Estadual Paulista, Avenida Universitária, n° 3780, Altos do Paraíso, 18610-034, Botucatu, São Paulo, Brasil, rodrigo.roman@unesp.br. 4 Departamento de Bioestatística, Universidade Estadual Paulista, R. Prof. Dr. Antônio Celso Wagner Zanin, 250, 18618-689, Botucatu, São Paulo, Brasil, helenice.silva@unesp.br. 1 RESUMO O objetivo deste trabalho foi propor um modelo matemático que auxilie na determinação de uma mistura ótima de fertilizantes visando a minimização do custo da solução nutritiva. Dessa maneira, foi desenvolvida uma metodologia que permitisse identificar uma mistura ótima de fertilizantes capaz de auxiliar o produtor no manejo da fertirrigação. Essa metodologia consistiu no desenvolvimento de um modelo matemático de otimização para auxílio na determinação da quantidade ótima de fertilizante a ser inserida na mistura de forma a suprir as necessidades nutricionais da cultura a um custo mínimo. Para auxiliar o usuário desse modelo, foi desenvolvido um aplicativo para dispositivos móveis. Sendo, portanto, esse aplicativo uma ferramenta de apoio aos produtores no processo de tomada de decisões à campo. Dentre os métodos de resolução de problemas de programação não-linear, optou-se pelo Método do Gradiente Conjugado Não-Linear; sendo esse, um caso particular do Método do Gradiente Conjugado, proposto para soluções de problemas não-lineares. O modelo matemático proposto atendeu às restrições preconizados na fertirrigação para o cálculo da quantidade de fertilizantes, à um baixo custo, tornando-o mais completo e eficiente. Dessa maneira, a metodologia proposta e o aplicativo desenvolvido são ferramentas importantes e acessíveis que podem auxiliar os produtores no manejo da fertirrigação. Palavras-chave: adubação, condutividade elétrica, custo, modelagem, programação não-linear. MOTA, F. D.; SÁNCHEZ-ROMÁN, R. M.; SILVA, H. O. F. MATHEMATICAL MODEL APPLIED TO FERTIGATION 2 ABSTRACT The objective of this work was to develop a mathematical model to assist farms in the determination of an optimal mixture of fertilizers in order to minimize the cost of nutritive solutions. This way, we developed a methodology that allows to identify an optimal mixture of fertilizers capable to assist farms in the management of fertigation. The methodology consisted of the development of an optimization mathematical model to assist in the determination of the optimal amount of fertilizers to be insert in the mixture in order to meet the nutritional needs of the crop at a minimum cost. In order to assist the user of this model, a mobile application was developed. Thus, this mobile application is a decision support tool to farms. Among the nonlinear programming methods, we opted for the Nonlinear Conjugate Gradient Method, this method is a particular case of the Conjugate Gradient Method, proposed to provide solutions of nonlinear problems. The proposed mathematical model complied with the restrictions recommended in fertigation regarding the calculation of the amount of fertilizer at a low cost; making it more efficient and complete. Therefore, the proposed methodology and the developed mobile application are important and accessible tools that could assist farms in the management of fertigation. Keywords: fertilization, electrical conductivity, cost, modeling, nonlinear programming.
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Betts, Keith A., Federico Felizzi, Ibou Dieye, Jia Li, Mathias Schulz, Samuel J. Hong, and Anthony S. Masaquel. "Cost-Effectiveness of Polatuzumab Vedotin Plus Bendamustine-Rituximab for Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma in the United States." Blood 136, Supplement 1 (November 5, 2020): 3. http://dx.doi.org/10.1182/blood-2020-136273.
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Introduction Polatuzumab vedotin (pola), a first-in-class CD79b-targeted antibody-drug conjugate, was recently approved by the United States (US) Food and Drug Administration (June 2019) in combination with bendamustine-rituximab (BR) for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) after at least two prior therapies. Approval was based on the results of a randomized Phase II trial (GO29365/NCT02257567) in which pola+BR demonstrated clinically meaningful improvements in complete response (CR) rates (40.0% vs 17.5%, respectively), progression-free survival (PFS; hazard ratio [HR], 0.36; 95% confidence interval [CI]: 0.21-0.63) and overall survival (OS; HR, 0.42; 95% CI: 0.24-0.75) versus BR alone in transplant-ineligible R/R DLBCL (Sehn et al. J Clin Oncol 2020). Objective To evaluate the cost-effectiveness of pola+BR in R/R DLBCL from a US payer's perspective, using 140mg and 30mg single-dose vials of pola and GO29365/NCT02257567 study data. Methods A partitioned survival model was developed to estimate the economic and health-related quality of life impact of pola+BR versus BR alone in transplant-ineligible R/R DLBCL. A lifetime horizon and 3% discount rate were considered for costs and outcomes. Clinical data (PFS, OS, drug utilization, treatment duration and adverse events [AEs]) were sourced from the GO29365/NCT02257567 study. Costs included drug acquisition/administration, AE management, PFS routine care, progressive disease (PD) medical care and end-of-life care. Quality-adjusted life-years (QALYs) were calculated using published utility estimates (Tisagenlecleucel, NICE Report 2019). The base-case analysis assumed OS was informed by PFS (extrapolated) and used a mixture cure rate model to estimate the proportion of putative long-term survivors (pola+BR: 21%; BR: 0% [Sehn et al. ICML 2019]). Deterministic and probabilistic sensitivity analyses (PSA) and scenario analyses (mixture cure rate model with OS modelled separately from PFS, and standard parametric survival models) were performed to assess uncertainty. Results The total cost of pola+BR ($210,418) was $92,329 higher than BR ($118,089), primarily due to higher drug/administration costs ($139,717 vs $47,944, respectively). Pola+BR reflected cost-savings for PD medical care (-$4,849) and end-of-life care (-$2,248) versus BR. Costs due to AE management were $6,484 higher for pola+BR ($21,989) than BR ($15,505). Treatment with pola+BR was associated with an additional 2.57 QALYs versus BR. The incremental cost-effectiveness ratio (ICER) was $35,864/QALY gained. The ICER was most sensitive to survival modelling assumptions, the discount rate considered for effectiveness, and utility in PFS. Results of the PSA showed that pola+BR was cost-effective versus BR in 68% and 97% of cases using a willingness-to-pay threshold of $50,000 and $100,000, respectively. Scenario analyses resulted in ICERs ranging from $41,442/QALY (mixture cure with OS modelled separately from PFS) to $72,166/QALY (standard parametric). Conclusions This updated cost-effectiveness analysis includes 30mg single-dose vials of pola in addition to the original 140mg vials, allowing more precise weight-based dosing. Driven predominantly by higher PFS/OS and the higher estimated proportion of long-term survivors, results suggest that in the US, pola+BR versus BR is cost-effective for the treatment of adults with transplant-ineligible R/R DLBCL. Disclosures Betts: Genentech, Inc.: Research Funding. Felizzi:F. Hoffmann-La Roche Ltd: Current Employment. Dieye:Analysis Group: Current Employment. Li:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech Inc.: Current Employment. Schulz:F. Hoffmann-La Roche Ltd: Current equity holder in private company; Genentech, Inc.: Current Employment. Hong:Genentech, Inc.: Current Employment; Karuna Therapeutics: Current equity holder in publicly-traded company; Y-mAbs Therapeutics: Current equity holder in publicly-traded company; Astellas Pharma: Ended employment in the past 24 months. Masaquel:Analysis Group: Current Employment.
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Mitchell, Patricia L., and Roger S. McLeod. "Conjugated linoleic acid and atherosclerosis: studies in animal models." Biochemistry and Cell Biology 86, no. 4 (August 2008): 293–301. http://dx.doi.org/10.1139/o08-070.
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Conjugated linoleic acids (CLA) are isomeric forms of linoleic acid (LA) containing two conjugated sites of unsaturation. The most abundant dietary form of CLA is the cis-9,trans-11 (c-9,t-11) isomer that is found in the fatty tissues and milk of ruminant animals. CLA can also be acquired by ingestion of supplements, which are usually equimolar mixtures of the c-9,t-11 and t-10,c-12 CLA. For more than a decade, the potential for CLA to modify atherosclerosis in animal models has been examined. However, to date, the studies have failed to reach consensus on whether CLA can be effective in reducing the incidence or severity of atherosclerotic lesions, or whether or not plasma lipid and lipoprotein levels can be improved with CLA supplementation. This review will examine the evidence for and against a role for CLA in atherosclerosis, with a focus on the rabbit, the hamster, and the apoE-deficient mouse.
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Pacifico, Antonio. "Structural Compressed Panel VAR with Stochastic Volatility: A Robust Bayesian Model Averaging Procedure." Econometrics 10, no. 3 (July 12, 2022): 28. http://dx.doi.org/10.3390/econometrics10030028.
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This paper improves the existing literature on the shrinkage of high dimensional model and parameter spaces through Bayesian priors and Markov Chains algorithms. A hierarchical semiparametric Bayes approach is developed to overtake limits and misspecificity involved in compressed regression models. Methodologically, a multicountry large structural Panel Vector Autoregression is compressed through a robust model averaging to select the best subset across all possible combinations of predictors, where robust stands for the use of mixtures of proper conjugate priors. Concerning dynamic analysis, volatility changes and conditional density forecasts are addressed ensuring accurate predictive performance and capability. An empirical and simulated experiment are developed to highlight and discuss the functioning of the estimating procedure and forecasting accuracy.
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Mishra, S. K., S. N. Tripathi, S. G. Aggarwal, and A. Arola. "Effects of particle shape, hematite content and semi-external mixing with carbonaceous components on the optical properties of accumulation mode mineral dust." Atmospheric Chemistry and Physics Discussions 10, no. 12 (December 23, 2010): 31253–300. http://dx.doi.org/10.5194/acpd-10-31253-2010.
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Abstract. The radiative forcing estimation of the polluted mineral dust is limited due to lack of morphological analysis, mixing state with the carbonaceous components and the hematite content in the pure dust. The accumulation mode mineral dust has been found to mix with anthropogenically produced black carbon, organic carbon and brown carbon during long range transport. The above features of the polluted dust are not well accounted in the optical models and lead the uncertainty in the numerical estimation of their radiative impact. The Semi-external mixing being a prominent mixing of dust and carbonaceous components has not been studied in details so for compared to core-shell, internal and external mixing studies. In present study, we consider the pure mineral dust composed of non-metallic components (such as Quartz, Feldspar, Mica and Calcite) and metalic component like hematite (Fe2O3). The hematite percentage in the pure mineral dust governs its absorbance. Based on this hematite variation, the hematite fraction in pure mineral dust has been constrained between 0–8%. The morphological and mineralogical characterization of the polluted dust led to consider the three sphere, two sphere and two spheroid model shapes for polluted dust particle system. The pollution gives rise to various light absorbing aerosol components like black carbon, brown carbon and organic carbon (comprising of HUmic-Like Substances, HULIS) in the atmosphere. The entire above discussed model shapes have been considered for the mineral dust getting polluted with (1) organic carbon (especially HULIS component) (2) Brown carbon and (3) black carbon by making a semi-external mixture with pure mineral dust. The optical properties (like Single Scattering Albedo, SSA; Asymmetry parameter, g and Extinction efficiency, Qext) of above model shapes for the polluted dust have been computed using Discrete Dipole Approximation, DDA code. For above model shapes, the SSA was found to vary depending on hematite content (0–8%) and model shape composition. For the two sphere BC-mineral dust cluster, hematite was found to be dominating absorber compared to that of black carbon as the RBC/Rdust decreases. (i.e. with increase of dust sphere size compared to black carbon sphere in the composite 2-sphere cluster). SSA was found to be very sensitivity for the hematite content when both of the spheres (i.e. mineral dust and BC) are nearly of same size. The two spheroid system composed of organic carbon and dust with 0% hematite (OCD'-0) showed the maximum deviation of SSA (i.e.~5%) compared to the two sphere system of same composition and hematite content (OCD-0 ). Increase in hematite from 0 to 8% caused maximum SSA deviation of ~20% for two sphere organic carbon-dust system (OCD) while the same has been observed to be ~18% for two spheroid organic carbon-dust system (OCD'). SSA was found to be more sensitive to hematite content than that of particle shape. Compared to SSA, Asymmetry parameter, g was found to be more sensitive towards particle shape. For three-sphere model shapes with 0% hematite composed of black carbon-dust-dust (BCDD-0), brown carbon-dust-dust (BrCDD-0 ) and organic carbon-dust-dust (OCDD-0), the deviation of SSA and g relative to conjugate black carbon (BC), brown carbon (BrC) and organic carbon (OC) spheres are ~68% and ~31%, ~83% and ~31% and ~70% and ~33%, respectively. Thus modeled polluted dust optics will provide a better basis for radiative forcing estimation and many sensitivity studies.
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Corino, C., D. Magistrelli, V. Bontempo, and F. Rosi. "The influence of dietary conjugated linoleic acid (CLA) on serum leptin concentration in lactating sows." Proceedings of the British Society of Animal Science 2002 (2002): 95. http://dx.doi.org/10.1017/s1752756200007511.
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Conjugated linoleic acid (CLA) is a mixture of geometrical and positional isomers of linoleic acid. Health-promoting properties of CLA, which include antioxidant, anti-obesity and anticarcinogenic activities, have been demonstrated in a wide range of animal models (Pariza et al., 2001). Recent studies indicated the CLA has a favorable effect on immune competence in nursery (Bassaganya-Riera et al., 2001) and weaned pigs (Corino et al., 2001). For this reason CLA may be useful in sow nutrition to increase CLA content in colostrum and milk (Bee, 2000). However CLA-fed animals displayed also significantly reduced body fat (Pariza et al., 2001) and this effect may be detrimental to reproductive efficiency in sows per se and for the effects on metabolic hormones as well. Moreover some CLA isomers has been reported to influence leptin gene expression (Houseknacht et al., 1998). The present study examined the effects of dietary supplement of CLA on serum leptin in lactating sows.
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Yagolovich, Anne, Andrey Kuskov, Pavel Kulikov, Leily Kurbanova, Dmitry Bagrov, Artem Artykov, Marine Gasparian, et al. "Amphiphilic Poly(N-vinylpyrrolidone) Nanoparticles Conjugated with DR5-Specific Antitumor Cytokine DR5-B for Targeted Delivery to Cancer Cells." Pharmaceutics 13, no. 9 (September 7, 2021): 1413. http://dx.doi.org/10.3390/pharmaceutics13091413.
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Nanoparticles based on the biocompatible amphiphilic poly(N-vinylpyrrolidone) (Amph-PVP) derivatives are promising for drug delivery. Amph-PVPs self-aggregate in aqueous solutions with the formation of micellar nanoscaled structures. Amph-PVP nanoparticles are able to immobilize therapeutic molecules under mild conditions. As is well known, many efforts have been made to exploit the DR5-dependent apoptosis induction for cancer treatment. The aim of the study was to fabricate Amph-PVP-based nanoparticles covalently conjugated with antitumor DR5-specific TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) variant DR5-B and to evaluate their in vitro cytotoxicity in 3D tumor spheroids. The Amph-PVP nanoparticles were obtained from a 1:1 mixture of unmodified and maleimide-modified polymeric chains, while DR5-B protein was modified by cysteine residue at the N-end for covalent conjugation with Amph-PVP. The nanoparticles were found to enhance cytotoxicity effects compared to those of free DR5-B in both 2D (monolayer culture) and 3D (tumor spheroids) in vitro models. The cytotoxicity of the nanoparticles was investigated in human cell lines, namely breast adenocarcinoma MCF-7 and colorectal carcinomas HCT116 and HT29. Notably, DR5-B conjugation with Amph-PVP nanoparticles sensitized resistant multicellular tumor spheroids from MCF-7 and HT29 cells. Taking into account the nanoparticles loading ability with a wide range of low-molecular-weight antitumor chemotherapeutics into hydrophobic core and feasibility of conjugation with hydrophilic therapeutic molecules by click chemistry, we suggest further development to obtain a versatile system for targeted drug delivery into tumor cells.
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Rad, T. A., M. V. Iksanov, V. M. Golod, and Yu Yu Malinkina. "Thermodynamic analysis of casting titanium alloys is the basis of information support in the optimal foundry technology development." Litiyo i Metallurgiya (FOUNDRY PRODUCTION AND METALLURGY), no. 1 (March 12, 2022): 25–31. http://dx.doi.org/10.21122/1683-6065-2022-1-25-31.
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The necessity of systematic formation of intellectual connections for integration into a single complex of currently fragmented software products for the technological analysis of the castings geometry, thermodynamic modeling of the titanium alloys properties, calculation of molding mixtures thermophysical characteristics for the purpose of conjugate implementation of a set of modeling procedures and casting processes diagnostics of is proved. Lack of such an integrated software package, computer analysis of modeling results in the existing manufacturing products practice demonstrates (by the example of the shrinkage defects distribution in a responsible casting of TL3 alloy) the need for radical technological design tools’ improvement.One of the key components of the “digital technology” being formed in the future is thermodynamic modeling of equilibrium phase transformations, which allows calculating the physico-chemical parameters, thermodynamic, thermophysical and casting parameters of titanium alloys and their evolution in the temperature range of crystallization. Based on thermodynamic simulation, experimental planning apparatus and the experience of statistical analysis carried out, a method for forming models for estimating equilibrium parameters used in modeling foundry processes has been developed, and it shows the possibility of applying it to various casting titanium alloys. For the standard composition of the TL3 alloy, a multifactor system of equations was obtained, reflecting the degree of influence of the components on the fluctuations of the alloy characteristics complex, which determine the development of a series of casting defects. The possibilities of using the obtained models for TL3 alloy and methods of obtaining them for use in computer modeling systems to increase the adequacy and accuracy of the results obtained are described.
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Barclay, L. Ross C., Jennifer K. Grandy, Heather D. MacKinnon, Heather C. Nichol, and Melinda R. Vinqvist. "Article." Canadian Journal of Chemistry 76, no. 12 (December 1, 1998): 1805–16. http://dx.doi.org/10.1139/v98-209.
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3,5-Di-tert-butyl-ortho-quinone, 6, and 1-(3,4-dimethoxyphenyl-2-(2-methoxyphenoxy)-1-propanone, 7, models for oxidized lignin and for lignin, were used as sensitizers of photo-oxidation. Product studies by HPLC from oxidation of methyl linoleate in solution sensitized by 6 or 7, and in sodium dodecyl sulfate (SDS) sensitized by 6, showed a product distribution of six hydroperoxides, the four conjugated 9- and 13-hydroperoxides of the geometrical isomers: trans-10, cis-12 (2), cis-9, trans-11 (3), trans-10, trans-12 (4), and trans-9, trans-11 (5)-octadecadienoates plus two nonconjugated hydroperoxides. The higher cis/trans to trans/trans (ct/tt) of geometrical isomers (2 + 3//4 + 5) compared to ct/tt from known thermal free-radical peroxidations (Type 1) indicate that singlet oxygen (Type 2) oxidation occurs in reactions sensitized by 6 or 7. Kinetic studies by oxygen uptake are reported on oxidations of hydrocarbons 1-phenyl-2-methylpropene,8, and trans-stilbene,9, sensitized by the quinone, 6, or by a dye, Rose Bengal. Quenching studies imply singlet oxygen reactions. Milled wood lignin undergoes self-initiated photo-oxidation in water, and oxygen uptake was quenched by sodium azide. Cellobiose, a cellulose model, undergoes sensitized photo-oxidation using model quinone, 6, in a mixture of tert-butyl alcohol and water or using the sensitizers benzophenone or the lignin model, 7, delivered on a solid support, silica gel, and these oxidations were quenched with sodium azide. These results implicate singlet oxygen in the photo-yellowing of high lignin content wood pulps.Key words: lignin models, ortho-quinone, photo-oxidation, singlet oxygen, lignin, cellobiose.
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Henriksen, Erik J., Mary K. Teachey, Zachary C. Taylor, Stephan Jacob, Arne Ptock, Klaus Krämer, and Oliver Hasselwander. "Isomer-specific actions of conjugated linoleic acid on muscle glucose transport in the obese Zucker rat." American Journal of Physiology-Endocrinology and Metabolism 285, no. 1 (July 2003): E98—E105. http://dx.doi.org/10.1152/ajpendo.00013.2003.
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The fatty acid-conjugated linoleic acid (CLA) enhances glucose tolerance and insulin action on skeletal muscle glucose transport in rodent models of insulin resistance. However, no study has directly compared the metabolic effects of the two primary CLA isomers, cis-9, trans-11-CLA (c9,t11-CLA) and trans-10, cis-12-CLA (t10,c12-CLA). Therefore, we assessed the effects of a 50:50 mixture of these two CLA isomers (M-CLA) and of preparations enriched in either c9,t11-CLA (76% enriched) or t10,c12-CLA (90% enriched) on glucose tolerance and insulin-stimulated glucose transport in skeletal muscle of the insulin-resistant obese Zucker ( fa/ fa) rat. Animals were treated daily by gavage with either vehicle (corn oil), M-CLA, c9,t11-CLA, or t10,c12-CLA (all CLA treatments at 1.5 g total CLA/kg body wt) for 21 consecutive days. During an oral glucose tolerance test, glucose responses were reduced ( P < 0.05) by 10 and 16%, respectively, in the M-CLA and t10,c12-CLA animals, respectively, whereas insulin responses were diminished by 21 and 19% in these same groups. There were no significant alterations in these responses in the c9,t11-CLA group. Insulin-mediated glucose transport activity was enhanced by M-CLA treatment in both type I soleus (32%) and type IIb epitrochlearis (58%) muscles and by 36 and 48%, respectively, with t10,c12-CLA. In the soleus, these increases were associated with decreases in protein carbonyls (index of oxidative stress, r = -0.616, P = 0.0038) and intramuscular triglycerides ( r = -0.631, P = 0.0028). Treatment with c9,t11-CLA was without effect on these variables. These results suggest that the ability of CLA treatment to improve glucose tolerance and insulin-stimulated glucose transport activity in insulin-resistant skeletal muscle of the obese Zucker rat are associated with a reduction in oxidative stress and muscle lipid levels and can be specifically ascribed to the actions of the t10,c12 isomer. In the obese Zucker rat, the c9,t11 isomer of CLA is metabolically neutral.
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Martins, Susana V., Paula A. Lopes, Cristina M. Alfaia, Pedro O. Rodrigues, Susana P. Alves, Rui M. A. Pinto, Matilde F. Castro, Rui J. B. Bessa, and José A. M. Prates. "Serum adipokine profile and fatty acid composition of adipose tissues are affected by conjugated linoleic acid and saturated fat diets in obese Zucker rats." British Journal of Nutrition 103, no. 6 (November 2, 2009): 869–78. http://dx.doi.org/10.1017/s000711450999256x.
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Conjugated linoleic acid (CLA) has been reported as having body fat lowering properties and the ability to modulate the inflammatory system in several models. In the present study, the effects of CLA added to saturated fat diets, from vegetable and animal origins, on the serum adipokine profile of obese Zucker rats were assessed. In addition, the fatty acid composition of epididymal and retroperitoneal adipose tissues was determined and a principal component analysis (PCA) was used to assess possible relationships between fatty acids and serum metabolites. Atherogenic diets (2 % cholesterol) were formulated with palm oil and ovine fat and supplemented or not with 1 % of a mixture (1:1) ofcis-9,trans-11 andtrans-10,cis-12-CLA isomers. CLA-fed animals exhibited lower daily feed intake, final body and liver weights, and hepatic lipids content. Total and LDL-cholesterol levels were increased in CLA-supplemented groups. CLA also promoted higher adiponectin and lower plasminogen activator inhibitor-1 (PAI-1) serum concentrations. In contrast to palm oil diets, ovine fat increased insulin resistance and serum levels of leptin, TNF-α and IL-1β. Epididymal and retroperitoneal adipose tissues had similar deposition of individual fatty acids. The PCA analysis showed that thetrans-10,cis-12-CLA isomer was highly associated with adiponectin and PAI-1 levels. Summing up, CLA added to vegetable saturated enriched diets, relative to those from animal origin, seems to improve the serum profile of adipokines and inflammatory markers in obese Zucker rats due to a more favourable fatty acid composition.
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Valeille, Karine, Jacqueline Férézou, Ghislaine Amsler, Annie Quignard-Boulangé, Michel Parquet, Daniel Gripois, Victoria Dorovska-Taran, and Jean-Charles Martin. "A cis-9,trans-11-conjugated linoleic acid-rich oil reduces the outcome of atherogenic process in hyperlipidemic hamster." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 2 (August 2005): H652—H659. http://dx.doi.org/10.1152/ajpheart.00130.2005.
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Conjugated linoleic acid (CLA) mixtures demonstrated antiatherogenic properties in several animal models, including hamsters, but the mechanism of action of the main food-derived CLA isomer is unknown in this species. This study thus focused on cis-9, trans-11-CLA (rumenic acid), and its effect was compared with that of fish oil, which is known to influence several aspects of atherogenesis. Syrian hamsters were fed (for 12 wk) diets containing 20% (wt/wt) butter fat (B diet) or the same diet augmented with either 1% (wt/wt) of a cis-9, trans-11-CLA-rich oil (BR diet) or 1% (wt/wt) fish oil (BF diet). The BR diet induced the lowest aortic lipid deposition (from −30% to −45%) among the butter oil-fed hamsters. In this group, plasma also displayed a reduced non-HDL-to-HDL-cholesterol ratio (21% less than in the butter oil group) and inflammatory serum amyloid A levels (70–80%) and an improvement of anti-oxidized LDL paraoxonase activity (all P < 0.05). Compared with the B group, the beneficial effects of the BR diet could be further explained in part by preventing the high VCAM-1 expression rate, increasing (30%) ATP-binding cassette subfamily A1 expression in the aorta, and downregulating expression of inflammatory-related genes (TNF-α, IL-1β, and cyclooxygenase 2, 2- to 2.8-fold, P < 0.05). This effect was partly associated with an activation of peroxisome proliferator-activating receptor (PPAR)/liver X receptor (LXR)-α signaling cascade. Interestingly, activation of PPAR/LXR-α signaling was not observed in hamsters fed the BF diet, in which the early signs of atherogenesis were increased. In conclusion, this study demonstrated that milk fat-rich cis-9, trans-11-CLA reduces the atherogenic process in hyperlipidemic hamsters.
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Vallera, DA, PA Taylor, A. Panoskaltsis-Mortari, and BR Blazar. "Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab')2-ricin toxin A chain immunotoxin." Blood 86, no. 11 (December 1, 1995): 4367–75. http://dx.doi.org/10.1182/blood.v86.11.4367.bloodjournal86114367.
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A new pharmacologic agent, anti-CD3F(ab')2-ricin toxin A chain (RTA), was synthesized for the purpose of targeting T cells and as a means of treating established graft-versus-host disease (GVHD). The Fc region of anti-CD3 monoclonal antibody (MoAb) was removed to prevent its ability to activate T cells. The resulting F(ab')2 fragments were conjugated to deglycosylated RTA (dgRTA), a catalytic and potent phytotoxin. The resulting immunotoxin (IT) was potent (greater than 95% inhibition) and selective in inhibiting T-cell mitogenesis in vitro. In vivo, the IT depleted 80% of T cells in mice receiving bone marrow (BM) transplants. Transplantation in an aggressive acute GVHD model using C57BL/6 donor cells and H-2 disparate B10.BR recipients resulted in an infiltration of CD3-expressing cells and a median survival time (MST) of 20 to 30 days. A 5-day course of anti-CD3F(ab')2-RTA (30 micrograms/d intraperitoneally) beginning 7 days after GVHD induction was beneficial in treating established GVHD in these mice, as evidenced by significantly prolonged survival (MST, greater than 80 days), superior mean weight values, and improved clinical appearance. Neither intact anti-CD3, unconjugated anti-CD3 F(ab')2 fragments, nor a mixture of anti-CD4 and anti-CD8 MoAbs (which are highly effective in prophylactic models) were as effective. F(ab')2 fragments made from anti-Lyt-1 (the murine homologue of human anti-CD5) linked to RTA were also not effective, despite the fact that both anti-CD3F(ab')2-RTA and anti-Lyt- 1F(ab')2-RTA had similar half-lives of about 9 hours. The IT also increased MST in two aggressive models of GVHD across non-H-2 minor histocompatibility barriers, indicating that the usefulness of anti- CD3F(ab')2-dgRTA is not limited to a single-strain combination. This agent should be further investigated as an alternative to current strategies for treating steroid refractory GVHD.
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Dua, R., P. Nhonthachit, C. Rinehart, C. L. Arteaga, R. Nahta, F. J. Esteva, J. Winslow, M. Bates, and C. Petropoulos. "Patterns of HER-family receptor dimerization in trastuzumab susceptible and trastuzumab resistant cell lines." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2533. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2533.
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2533 Background: HER2 overexpression is associated with accelerated disease progression and poor prognosis in breast cancer. Trastuzumab, a monoclonal antibody targeting the extracellular domain of HER2, is effective in the treatment of metastatic breast cancer. However, most patients treated with trastuzumab eventually develop clinical resistance. To investigate the role of HER-family receptors in trastuzumab resistance, we measured HER-family receptor expression, dimerization, and phosphorylation in trastuzumab susceptible and resistant cell lines. Methods: Cell lysates from trastuzumab susceptible and resistant BT474 and SKBR3 cell lines were obtained from the Arteaga and Esteva laboratories. Proximity-based, multiplexed assays were used to detect and quantify HER1, HER2, and HER3 expression and phosphorylation levels, as well as HER1/HER1, HER1/HER2, HER1/HER3, HER2/HER2, and HER2/HER3 dimers. Samples were incubated with a mixture of HER specific antibodies conjugated either with fluorescent reporter tags (eTags), or biotin, which binds a reporter tag releasing agent (chemical scissor). Reporter molecules are released based on proximity to the scissor in a photochemical reaction and separated by capillary gel electrophoresis. Results: In comparison to trastuzumab susceptible parental cell lines, both SKBR3 and BT474 trastuzumab-resistant cell lines displayed upregulated HER1 expression. Resistant BT474 cell lines exhibited markedly increased levels of HER1/HER2 heterodimers. Increases in HER2 phosphorylation in the trastuzumab resistant SKBR3 cell line were observed, consistent with previous studies implicating trastuzumab in the induction of HER2 phosphorylation. Total HER2 and HER3 levels were similar in trastuzumab susceptible and resistant BT474 cell lines. Conclusions: The development of trastuzumab resistance in these cell line models correlated with HER1 expression and the appearance of HER1:HER2 dimers. Since signaling initiated by such heterodimers is ineffectively antagonized by trastuzumab, these data suggest that selection for proliferative signaling mediated by HER1:HER2 dimers may represent a mechanism of trastuzumab resistance in breast cancer. No significant financial relationships to disclose.
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Hammett, Kirsten M., Gary K. Felton, Daniel J. Fisher, Lance T. Yonkos, Elizabeth J. Mullin, and Diana S. Aga. "Integrated Assessment of Aqueously Extractable Estrogens in Municipal Biosolids after Pilot-Scale Composting." Transactions of the ASABE 60, no. 5 (2017): 1645–58. http://dx.doi.org/10.13031/trans.12241.
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Abstract. Municipal biosolids contain natural estrogens, e.g., 17ß-estradiol (E2) and estrone (E1), and synthetic estrogens, e.g., 17a-ethinylestradiol (EE2), which can be transported to receiving waters via runoff when land-applied as fertilizer. Previous studies have investigated estrogens in runoff from biosolids-amended fields but have not tracked changes in estrogenicity within this water over time. Microbial conversion of conjugated estrogens (a major portion of water-extractable estrogens) to parent forms may result in temporary increases in estrogenicity in natural water bodies. The present study measured aqueously extractable estrogens in simulated runoff generated using biosolids sourced from four municipal wastewater treatment facilities in Maryland. Estrogen analytes (E2 and E1) were quantified over 10 d periods in 80 L static simulated runoff mixtures (0.5 g biosolids L-1) by LC-MS/MS, and estrogenic activity was estimated using the bioluminescent yeast estrogen screen (BLYES) assay and the fathead minnow () vitellogenin (VTG) induction model. The effectiveness of pilot-scale in-vessel, aerated, turned (IVAT) composting to reduce or eliminate aqueously extractable estrogens in biosolids was also investigated. On arrival, only one of four biosolids had environmentally meaningful levels of aqueously extractable estrogens. Results indicate that estrogens/estrogenicity increased >6.5-fold during the first 6 d in an aqueous extract generated with that sample, as indicated both by BLYES quantitation of estrogenicity (0.8 to 5.6 ng EEQ L-1) and LC-MS/MS quantitation of estrone (13.8 to 93.0 ng L-1). Results also indicate that IVAT composting was effective at reducing or eliminating aqueously extractible estrogens in that biosolids sample. This study demonstrates the need for low-level detection of estrogens/estrogenicity in complex environmental media and validates the benefits of screening assays and fish models as complementary sensitive tools for environmental monitoring. Keywords: Biosolids, Compost, Estrogenicity, Fathead minnow, Microbial deconjugation, Vitellogenin.
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Ackerman, Shelley, Felix Hartmann, Cecelia Pearson, Joseph Gonzalez, Po Yi Ho, Samuel Kimmey, Andrew Luo, et al. "603 Covalent attachment of a TLR7/8 agonist to tumor-targeting antibodies drives potent anti-tumor efficacy by synergistically activating FcgR- and TLR- signaling and enables safe systemic administration." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A638. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0603.
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BackgroundImmune stimulating antibody conjugates (ISACs) covalently attach TLR7/8 immune stimulants to tumor-targeting antibodies. ISACs can be delivered systemically and act locally in the tumor microenvironment by requiring the following biological steps to elicit immune activation: 1) tumor antigen recognition, 2) Fc receptor mediated phagocytosis by myeloid antigen presenting cells (APCs), and 3) activation of endosomal TLR7 and TLR8. Here, we demonstrate that covalent attachment of our TLR7/8 agonist to tumor-targeting antibodies not only enables the resulting ISACs to be safely administered systemically in preclinical models, but also unexpectedly promotes synergy between the FcgR and TLR pathways that results in amplified anti-tumor immunity in mice and robust immune activation in human leukocytes as compared to the co-administration of the components.MethodsISAC activity and mechanistic studies were analyzed via flow cytometry, ELISA and CyTOF following in vitro coculture of human leukocytes with tumor cell lines. In vivo efficacy of HER2-targeting ISACs following systemic administration was assessed in a trastuzumab-resistant HER2+ human tumor xenograft model. Safety and tolerability were assessed in tumor-bearing mice and healthy non-human primates (NHP).ResultsWhile co-administration of intratumoral TLR7/8 agonist and intraperitoneal trastuzumab failed to control tumor growth, systemic administration of the same TLR7/8 agonist and trastuzumab in our ISAC format was efficacious and induced complete tumor regression in an Fc- and TLR-dependent manner. Analysis of primary human leukocytes stimulated with ISACs in tumor co-culture assays indicated that ISACs elicit amplified and sustained phosphorylation of Fc and TLR signaling pathways, such as pERK1/2 and pIRF-7, as compared to the unconjugated mixture of the same TLR7/8 agonist and tumor targeted antibody. ISAC stimulation was largely restricted to antigen presenting cells such as dendritic cells and plasmacytoid dendritic cells that express the relevant Fc receptors and TLR7 and/or TLR8. Modifications to the ISAC that reduce FcgR engagement (N297A/Q) or render the agonist inactive halted ISAC-mediated activation and in vivo anti-tumor efficacy. Lastly, our HER2-targeting ISACs were well-tolerated when delivered systemically in mice and NHPs.ConclusionsOur ISACs enable potent TLR agonists to be safely administered systemically in preclinical models. ISACs provide distinct and unexpected advantages over unconjugated TLR agonists, notably by driving synergy between FcgR and TLR pathways, leading to robust myeloid activation and anti-tumor efficacy. These data support the evaluation of BDC-1001, a HER2-targeted ISAC in the ongoing Phase 1/2 trial (NCT04278144).
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Sigurdsson, Valgardur, Hajime Takei, Svetlana Soboleva, Visnja Radulovic, Roman Galeev, Kavitha Siva, L. M. Fredrik Leeb-Lundberg, Takashi Iida, Hiroshi Nittono, and Kenichi Miharada. "Bile Acids Protect Expanding Hematopoietic Stem Cells from Unfolded Protein Stress in Fetal Liver." Blood 126, no. 23 (December 3, 2015): 897. http://dx.doi.org/10.1182/blood.v126.23.897.897.
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Abstract Hematopoietic stem cells (HSCs) are effectively expanded in fetal liver (FL), while they are maintained in a dormant state in adult bone marrow (BM). However, developmental mechanisms allowing this have not been fully explained. BM-HSCs have the lowest protein synthesis rate within the blood hierarchy, even under forced self-renewal divisions. In addition, HSCs are vulnerable to and quickly activate endoplasmic reticulum (ER) stress responses fueled by accumulation of unfolded / misfolded proteins (Miharada et al., Cell Rep. 2014). Of note, we have seen that FL-HSCs have low levels of ER stress related genes despite their high proliferation status without an increase in heat shock protein levels, strongly indicating that other factor(s) block ER stress elevation. This raises the question how HSCs deal with the higher protein-folding requirement during expansion in the FL. Here we demonstrate that bile acids (BAs) are required to eliminate ER stress in the FL and are essential for proper expansion of FL-HSCs. Measurement of protein synthesis rate using OP-puro incorporation revealed that protein synthesis was enhanced in FL-HSCs, whereas BM-HSCs have half the rate of other populations in BM. Mass spectrometry analyses showed that BAs in the FL were all taurine conjugated while 30% of BA in the adult liver was taurine-conjugated, and the main proportion was taurocholic acid (TCA) that is known for its low toxicity. In the FL we also detected secondary BAs (e.g. TDCA), requiring intestinal bacteria in the production process, suggesting that FL BAs are a mixture of fetal and maternal BAs. Reduction of BA levels using GW4064, a chemical inhibitor of BA synthesis, significantly decreased the number of HSCs (6.6 fold decrease compared to vehicle treatment). This decrease was due to increased apoptosis caused by elevated ER stress levels. Similarly, dual deletion of Cyp27a1, a key BA synthetic enzyme, in both mother and fetus severely decreased total cellularity (2.0 fold decrease compared to littermate heterozygotes) and number of HSCs (6.8 fold decrease) in FL due to increased ER stress and subsequent apoptosis. Interestingly, FL of homozygotes grown in heterozygous mothers did not show any significant differences compared to littermate heterozygotes, suggesting that the contribution of maternal BA in FL is critical for HSCs. In both models, ER stress-oriented apoptosis and reduction in cellularity were most pronounced within the HSC population, indicating that stem cells are particularly sensitive to BA levels during development in FL. Importantly, injection of TCA or Salubrinal, an ER stress inhibitor, rescued the effects of BA reduction in both models. These data strongly suggest that BAs are required to block ER stress elevation in expanding FL-HSCs. ER stress and protein aggregation are closely linked together in number of pathological diseases like AlzheimerÕs- and HuntingtonÕs disease. Quantification of aggregated proteins (aggresomes) revealed that Cyp27a1 KO FL-HSCs from homozygote mothers contained significantly higher amount of aggresomes (2.0 fold), while KO FL-HSCs from heterozygote mothers showed no increase. Higher levels of aggregated proteins were most pronounced within the HSC population and BA suppressed formation of aggresomes during in vitro culture. This leads to reduction of ER stress and the maintenance of functional HSCs. Finally, transplantation assay showed that TCA can support functional HSCs ex vivo for up to 14 days. These findings propose a novel role for BA as a critical part of fetal hematopoiesis supporting expansion of HSC. Maternal and fetal BA coordinately contribute to this natural chaperone regulation. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Lee, Ha Kyeong, Ruby Maharjan, Yeojin Jeon, Jeong Uk Choi, and Youngro Byun. "Abstract 339: Anti-doppel monoclonal antibody as a tumor endothelial cell-specific angiogenesis inhibitor." Cancer Research 82, no. 12_Supplement (June 15, 2022): 339. http://dx.doi.org/10.1158/1538-7445.am2022-339.
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Abstract Introduction: Approved angiogenesis inhibitors generally target certain growth factors or their receptors, which exist in both normal and cancerous cells; this results in suppression of cell-signaling pathways throughout the body and causes adverse effects. For this reason, there is a need for a new angiogenesis inhibitor that can specifically target the tumor vasculature. In our previous study, we revealed that doppel, a prion-like protein, was overexpressed specifically in the tumor vasculatures, but not in normal endothelium, and its expression enhanced blood vessel formation. To develop our new anti-angiogenic agent, we produced monoclonal antibodies which target doppel as the antigen. Methods: We evaluated whether the doppel antibody inhibits angiogenesis by a spheroid assay. We cultured human colonic tumor-associated endothelial cells (HCTEC) and collected the cells by a hanging drop method. After producing compact aggregates, the spheroids were collected and embedded into collagen-based 3D cultures. The culture media/growth factor/doppel antibody mixture was added to each well that contained 3D spheroid cultures. After 24 hours, the number of sprouts was counted and analyzed. Further, HCTECs were incubated with culture media, growth factor, and doppel antibodies for investigating the underlying mechanisms. Each well was lysed, and we conducted western blot and microarray experiments using the lysates. In addition, we injected fluorescent dye-conjugated doppel antibody into tumor xenograft mouse models and visualized the tumor-targeting efficacy using in vivo imaging system (IVIS). Results: In spheroid assays, we found that doppel antibody SNU-H01 and SNU-H02 inhibit angiogenesis (by 32% and 29%, respectively) compared to control. In anti-phosphorylation assays using western blot, the amount of phosphorylated VEGFR2 and phosphorylated FGFR1 was decreased in doppel antibody SNU-H01 and SNU-H02-treated groups. Also, when SNU-H02-treated lysate was added to the microarray kit, STAT5A and beta-catenin were inhibited. Inhibition of STAT5A may promote apoptosis and increase sensitivity to anticancer drugs, and inhibition of beta-catenin may further increase suppression of angiogenesis. In addition, doppel antibody SNU-H04 accumulates in the tumor significantly higher compared to IgG injected mouse group. Conclusion: Doppel antibodies in development, SNU-H01, -H02, -H03, -H04, will be screened and selected for their anti-angiogenic efficacy and favorable pharmacodynamic features. We hope that doppel antibody is expected to be a new and superior tumor vasculature-specific angiogenesis inhibitor that can overcome the limitations of existing anti-angiogenic agents. Citation Format: Ha Kyeong Lee, Ruby Maharjan, Yeojin Jeon, Jeong Uk Choi, Youngro Byun. Anti-doppel monoclonal antibody as a tumor endothelial cell-specific angiogenesis inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 339.
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Brill, Alexander, Tobias Fuchs, Janie Yang, Maria Köllnberger, Anil K. Chauhan, Steffen Massberg, and Denisa D. Wagner. "VWF-Mediated Platelet Adhesion is Required for Deep Vein Thrombosis in a Flow Restriction Model." Blood 114, no. 22 (November 20, 2009): 473. http://dx.doi.org/10.1182/blood.v114.22.473.473.
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Abstract Abstract 473 Deep vein thrombosis (DVT) and its life-threatening complication, pulmonary embolism, are wide-spread in the Western world. Disturbance of blood flow without substantial endothelial denudation is a leading pathogenic factor for non-cancer related DVT. Von Willebrand Factor (VWF), a large multimeric protein, facilitates hemostasis via two separate pathways by stabilizing coagulation Factor VIII (FVIII) and by recruiting platelets to injured vessel wall or thrombi through the interaction with GPIb-alpha. Whereas the role of FVIII in DVT has been suggested by clinical studies (Koster T et al., Lancet, 345(8943):152-5,1995), whether VWF-platelet interaction is implicated in venous thrombosis remains unclear. We utilized murine models of partial and complete flow restriction in the inferior vena cava (IVC) in mice to mimic clinical conditions in which thrombus develops in deep veins. In 8-10 week old C57BL/6 male mice anesthetized by isoflurane-oxygen mixture, IVC and two side branches were ligated by a polypropylene suture immediately below the renal veins to obtain complete blood stasis. For partial flow restriction (stenosis), IVC ligation was performed over a 30G needle and then the needle was removed. Mice were euthanized after 48 h and thrombi from the IVC were taken for analysis. Results were evaluated using the chi-square test. The VWF-/- mice were completely protected from thrombosis in the stenosis model: none of the 14 VWF-/- mice developed a thrombus compared to 6/6 wild-type (WT) mice (p<0.001). In the stasis model, a similar albeit less pronounced phenotype was observed (33% of VWF-/- mice with thrombus, n=9, versus 82% in WT mice, n=11; p<0.03). Stenosis-induced thrombi in WT mice contained abundant amounts of VWF, as was shown by immunostaining. To delineate the involvement of VWF-platelet interactions, we infused WT mice with GPG-290, a recombinant GPIb-alpha N-terminal domain conjugated with human IgG1 Fc fragment. This compound has been shown to inhibit VWF-GPIb-alpha interaction (Hennan JK et al., Thromb Haemost, 95(3):469-75, 2006), but does not interfere with FVIII binding and turnover. Infusion of GPG-290 markedly reduced thrombus development in the stenosis model (3/9 GPG-290-treated WT mice developed DVT versus 9/9 vehicle-treated control mice; p=0.003). Notably, in the absence of blood flow (stasis model), GPG-290 was less effective (83% thrombosis development in vehicle-treated WT, n=6, versus 55.6% thrombosis in GPG-290-treated WT group, n=9; p=0.26). We next addressed the events preceding thrombus formation in the DVT stenosis model using intravital microscopy on living mice. We observed accumulation of fluorescently labeled platelets and leukocytes in the IVC in the area below the suture 6 h after stenosis induction. The amount of both adhering platelets and leukocytes was substantially reduced in VWF-/- mice compared to WT (approx. 20-fold, p<0.005 and 11-fold, p<0.001, respectively). In conclusion, VWF mediates platelet and leukocyte recruitment to the vessel wall. This initiates thrombus development in the absence of major endothelial injury. Interference with the VWF-GPIb-alpha axis may be a potential target for prophylaxis of deep vein thrombosis. Disclosures: No relevant conflicts of interest to declare.
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Steltenpohl, Pavol, and Elena Graczová. "Application of extended NRTL equation for ternary liquid-liquid and vapor-liquid-liquid equilibria description." Chemical Papers 64, no. 3 (January 1, 2010). http://dx.doi.org/10.2478/s11696-010-0006-x.
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AbstractSimulation of a hydrocarbons mixture separation by extractive distillation was based on binary vapor-liquid as well as liquid-liquid equilibrium data. Sulfolane was considered as extractive solvent for the selective toluene separation from a model mixture with heptane. For simulation of the chosen hydrocarbons mixture separation in the presence of an extractive solvent, the NRTL model was considered. A set of temperature-dependent binary NRTL parameters was evaluated independently by fitting the experimental vapor-liquid and liquid-liquid equilibrium data of the respective binary subsystems. In order to improve the description of the ternary vapor-liquid equilibrium, original NRTL model extended by the ternary contribution term was used. Parameters of the ternary contribution were obtained by direct fitting of available ternary liquid-liquid equilibrium data while employing the original binary NRTL parameters. Quality of the ternary vapor-liquid-liquid equilibrium description using the original and the extended excess Gibbs energy models was assessed by comparing the calculated compositions of conjugate liquid phases with experimental data. Using the extended NRTL model, mean deviation of the computed mole fractions decreased by approximately four times (9.73 × 10−3) compared to the value obtained using the original NRTL model. Both original and extended NRTL models were employed for the simulation of a model mixture separation by extractive distillation. At chosen experimental conditions, high purity distillate (x 1 > 0.999) was obtained. Results of the aromatics extractive distillation in the presence of sulfolane were compared to those obtained with N-methylpyrrolidone as the extractive solvent.
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Paterniti, Irene, Alessia Filippone, Irina Naletova, Valentina Greco, Sebastiano Sciuto, Emanuela Esposito, Salvatore Cuzzocrea, and Enrico Rizzarelli. "Trehalose–Carnosine Prevents the Effects of Spinal Cord Injury Through Regulating Acute Inflammation and Zinc(II) Ion Homeostasis." Cellular and Molecular Neurobiology, September 19, 2022. http://dx.doi.org/10.1007/s10571-022-01273-w.
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AbstractSpinal cord injury (SCI) leads to long-term and permanent motor dysfunctions, and nervous system abnormalities. Injury to the spinal cord triggers a signaling cascade that results in activation of the inflammatory cascade, apoptosis, and Zn(II) ion homeostasis. Trehalose (Tre), a nonreducing disaccharide, and l-carnosine (Car), (β-alanyl-l-histidine), one of the endogenous histidine dipeptides have been recognized to suppress early inflammatory effects, oxidative stress and to possess neuroprotective effects. We report on the effects of the conjugation of Tre with Car (Tre–car) in reducing inflammation in in vitro and in vivo models. The in vitro study was performed using rat pheochromocytoma cells (PC12 cell line). After 24 h, Tre–car, Car, Tre, and Tre + Car mixture treatments, cells were collected and used to investigate Zn2+ homeostasis. The in vivo model of SCI was induced by extradural compression of the spinal cord at the T6–T8 levels. After treatments with Tre, Car and Tre–Car conjugate 1 and 6 h after SCI, spinal cord tissue was collected for analysis. In vitro results demonstrated the ionophore effect and chelating features of l-carnosine and its conjugate. In vivo, the Tre–car conjugate treatment counteracted the activation of the early inflammatory cascade, oxidative stress and apoptosis after SCI. The Tre–car conjugate stimulated neurotrophic factors release, and influenced Zn2+ homeostasis. We demonstrated that Tre–car, Tre and Car treatments improved tissue recovery after SCI. Tre–car decreased proinflammatory, oxidative stress mediators release, upregulated neurotrophic factors and restored Zn2+ homeostasis, suggesting that Tre–car may represent a promising therapeutic agent for counteracting the consequences of SCI.
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Alibakhshi, Mojdeh, Mahmoud Reza Sohrabi, and Mehran Davallo. "Chemometrics-assisted spectrophotometric method for simultaneous estimation of antipsychotic drugs in biological fluid." Current Pharmaceutical Analysis 16 (January 27, 2020). http://dx.doi.org/10.2174/1573412916666200127150554.
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Background: Haloperidol (HP) and Risperidone (RIS) are antipsychotic drugs and the simultaneous determination of these drugs is important. Estimation of HP and RIS alone or in combination with other drugs has been performed in a variety of ways. Objective: The aim of this paper was to propose a rapid, simple, accurate, and robust method for the simultaneous determination of HP and RIS using artificial neural networks (ANNs), partial least squares (PLS), and principal component regression (PCR) methods along with spectrophotometry technique. Methods: The simultaneous spectrophotometric determination of HP and RIS in synthetic mixtures and biological fluid was performed by applying ANNs containing feed forward backpropagation (FFBP) and radial basis function (RBF) networks as intelligent methods, as well as PLS, and principal component regression PCR as multivariate calibration methods. The Levenberg–Marquardt (LM), Scaled conjugate gradient (SCG), and Resilient Back-propagation (RP) algorithms with different layers and neurons were used in FFBP network and obtained results were compared with each other. Results: Among various algorithms of the FFBP network, the LM algorithm was selected as the best model with a lower mean square error (MSE). MSE of the RBF model was 1.46×10-25 and 1.62×10-23 for HP and RIS, respectively. On the other hand, the mean recovery of PLS and PCR was 99.91%, 100.01% and 98.60%, 101.90% for HP and RIS, respectively. Conclusion: The proposed models and high-performance liquid chromatography (HPLC) as a reference method were compared with each other by one-way analysis of variance (ANOVA) test at the 95 % confidence level for the urine sample. It was observed that the developed methods presented comparable results for the simultaneous determination of HP and RIS.