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1
Soltani, Nader, Maxwel C. Oliveira, Guilherme S. Alves, Rodrigo Werle, Jason K. Norsworthy, Christy L. Sprague, Bryan G. Young, Daniel B. Reynolds, Ashli Brown, and Peter H. Sikkema. "Off-target movement assessment of dicamba in North America." Weed Technology 34, no. 3 (January 31, 2020): 318–30. http://dx.doi.org/10.1017/wet.2020.17.
Повний текст джерелаАнотація:
AbstractSix experiments were conducted in 2018 on field sites located in Arkansas, Indiana, Michigan, Nebraska, Ontario, and Wisconsin to evaluate the off-target movement (OTM) of dicamba under field-scale conditions. The highest estimated percentages of dicamba injury in non–dicamba-resistant (DR) soybean were 55%, 44%, 39%, 67%, 15%, and 44% injury for noncovered areas and 55%, 5%, 13%, 42%, 0%, and 41% injury for covered areas during dicamba application in Arkansas, Indiana, Michigan, Nebraska, Ontario, and Wisconsin, respectively. The level of injury generally decreased as the downwind distance increased under covered and noncovered areas at all sites. There was an estimated 10% injury in non-DR soybean at 113, 8, 11, 8, and 8 m; and estimated 1% injury at 293, 28, 71, 15, and 19 m from the edge of treated fields downwind when plants were not covered during dicamba application in Arkansas, Indiana, Michigan, Ontario, and Wisconsin, respectively. Assessment of filter-paper collectors placed from 4 to 137 m downwind from the edge of the sprayed area suggested the dicamba deposition reduced exponentially with distance. The greatest injury to non-DR soybean from dicamba OTM occurred at Nebraska and Arkansas (as far as 250 m). Non-DR soybean injury was greatest adjacent to the dicamba sprayed area, but injury decreased with no injury beyond 20 m downwind or in any other direction from the dicamba sprayed area in Indiana, Michigan, Ontario, and Wisconsin. The presence of soybean injury under covered and noncovered areas during the spray period for primary drift suggests that secondary movement of dicamba was evident at five sites. Additional research is needed to determine the exact forms of secondary movement of dicamba under different environmental conditions.
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Chaudhari, Hemangi G., Jon Penterman, Holly J. Whitton, Sarah J. Spencer, Nicole Flanagan, Maria C. Lei Zhang, Elaine Huang, et al. "Evaluation of Homology-Independent CRISPR-Cas9 Off-Target Assessment Methods." CRISPR Journal 3, no. 6 (December 1, 2020): 440–53. http://dx.doi.org/10.1089/crispr.2020.0053.
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Wang, Dan, Cuili Niu, Jingxin Han, Dejun Ma, and Zhen Xi. "Target DNA mutagenesis-based fluorescence assessment of off-target activity of the CRISPR-Cas9 system." RSC Advances 9, no. 16 (2019): 9067–74. http://dx.doi.org/10.1039/c8ra10017a.
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Corsi, Giulia I., Veerendra P. Gadekar, Jan Gorodkin, and Stefan E. Seemann. "CRISPRroots: on- and off-target assessment of RNA-seq data in CRISPR–Cas9 edited cells." Nucleic Acids Research 50, no. 4 (November 29, 2021): e20-e20. http://dx.doi.org/10.1093/nar/gkab1131.
Повний текст джерелаАнотація:
Abstract The CRISPR-Cas9 genome editing tool is used to study genomic variants and gene knockouts, and can be combined with transcriptomic analyses to measure the effects of such alterations on gene expression. But how can one be sure that differential gene expression is due to a successful intended edit and not to an off-target event, without performing an often resource-demanding genome-wide sequencing of the edited cell or strain? To address this question we developed CRISPRroots: CRISPR–Cas9-mediated edits with accompanying RNA-seq data assessed for on-target and off-target sites. Our method combines Cas9 and guide RNA binding properties, gene expression changes, and sequence variants between edited and non-edited cells to discover potential off-targets. Applied on seven public datasets, CRISPRroots identified critical off-target candidates that were overlooked in all of the corresponding previous studies. CRISPRroots is available via https://rth.dk/resources/crispr.
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Zhao, Hui, and Jeffrey D. Wolt. "Risk associated with off-target plant genome editing and methods for its limitation." Emerging Topics in Life Sciences 1, no. 2 (November 10, 2017): 231–40. http://dx.doi.org/10.1042/etls20170037.
Повний текст джерелаАнотація:
Assessment for potential adverse effects of plant genome editing logically focuses on the specific characteristics of the derived phenotype and its release environment. Genome-edited crops, depending on the editing objective, can be classified as either indistinguishable from crops developed through conventional plant breeding or as crops which are transgenic. Therefore, existing regulatory regimes and risk assessment procedures accommodate genome-edited crops. The ability for regulators and the public to accept a product focus in the evaluation of genome-edited crops will depend on research which clarifies the precision of the genome-editing process and evaluates unanticipated off-target edits from the process. Interpretation of genome-wide effects of genome editing should adhere to existing frameworks for comparative risk assessment where the nature and degree of effects are considered relative to a baseline of genome-wide mutations as found in crop varieties developed through conventional breeding methods. Research addressing current uncertainties regarding unintended changes from plant genome editing, and adopting procedures that clearly avoid the potential for gene drive initiation, will help to clarify anticipated public and regulatory questions regarding risk of crops derived through genome editing.
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Fischer, André, Manuel Sellner, Karolina Mitusińska, Maria Bzówka, Markus A. Lill, Artur Góra, and Martin Smieško. "Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2." International Journal of Molecular Sciences 22, no. 4 (February 19, 2021): 2065. http://dx.doi.org/10.3390/ijms22042065.
Повний текст джерелаАнотація:
The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious global health threat. Since no specific therapeutics are available, researchers around the world screened compounds to inhibit various molecular targets of SARS-CoV-2 including its main protease (Mpro) essential for viral replication. Due to the high urgency of these discovery efforts, off-target binding, which is one of the major reasons for drug-induced toxicity and safety-related drug attrition, was neglected. Here, we used molecular docking, toxicity profiling, and multiple molecular dynamics (MD) protocols to assess the selectivity of 33 reported non-covalent inhibitors of SARS-CoV-2 Mpro against eight proteases and 16 anti-targets. The panel of proteases included SARS-CoV Mpro, cathepsin G, caspase-3, ubiquitin carboxy-terminal hydrolase L1 (UCHL1), thrombin, factor Xa, chymase, and prostasin. Several of the assessed compounds presented considerable off-target binding towards the panel of proteases, as well as the selected anti-targets. Our results further suggest a high risk of off-target binding to chymase and cathepsin G. Thus, in future discovery projects, experimental selectivity assessment should be directed toward these proteases. A systematic selectivity assessment of SARS-CoV-2 Mpro inhibitors, as we report it, was not previously conducted.
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Zhang, Weiwei, Jianhang Yin, Zhengrong Zhang-Ding, Changchang Xin, Mengzhu Liu, Yuhong Wang, Chen Ai, and Jiazhi Hu. "In-depth assessment of the PAM compatibility and editing activities of Cas9 variants." Nucleic Acids Research 49, no. 15 (June 16, 2021): 8785–95. http://dx.doi.org/10.1093/nar/gkab507.
Повний текст джерелаАнотація:
Abstract A series of Cas9 variants have been developed to improve the editing fidelity or targeting range of CRISPR–Cas9. Here, we employ a high-throughput sequencing approach primer-extension-mediated sequencing to analyze the editing efficiency, specificity and protospacer adjacent motif (PAM) compatibility of a dozen of SpCas9 variants at multiple target sites in depth, and our findings validate the high fidelity or broad editing range of these SpCas9 variants. With regard to the PAM-flexible SpCas9 variants, we detect significantly increased levels of off-target activity and propose a trade-off between targeting range and editing specificity for them, especially for the near-PAM-less SpRY. Moreover, we use a deep learning model to verify the consistency and predictability of SpRY off-target sites. Furthermore, we combine high-fidelity SpCas9 variants with SpRY to generate three new SpCas9 variants with both high fidelity and broad editing range. Finally, we also find that the existing SpCas9 variants are not effective in suppressing genome instability elicited by CRISPR–Cas9 editing, raising an urgent issue to be addressed.
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Jefferts, Katharine, Janusz Burczynski, and William G. Pearcy. "Acoustical Assessment of Squid (Loligo opalescens) off the Central Oregon Coast." Canadian Journal of Fisheries and Aquatic Sciences 44, no. 6 (June 1, 1987): 1261–67. http://dx.doi.org/10.1139/f87-149.
Повний текст джерелаАнотація:
Squid (Loligo opalescens) were surveyed acoustically in an area off the Oregon coast using dual-beam and echo integrator techniques. The method developed is shown to be feasible for in situ estimation of target strength, distribution, and abundance of midwater squids. Average target strength was estimated both while drifting with a squid school and cruising over one. The values derived, −58.6 to −58.7 dB, are much lower than previous estimates, but more realistic in relation to the target strength of fishes. Schools judged to be fish or squid showed little difference in depth or size, but varied significantly in geographic distribution. Density estimates ranged from 9.9 t/km2 in a known spawning area to 0.93 t/km2 in an adjacent area.
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Rao, D. D., N. Senzer, M. A. Cleary, and J. Nemunaitis. "Comparative assessment of siRNA and shRNA off target effects: what is slowing clinical development." Cancer Gene Therapy 16, no. 11 (August 28, 2009): 807–9. http://dx.doi.org/10.1038/cgt.2009.53.
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Ivanov, P. Yu, and O. G. Mikhailova. "By-catch in the specialized fishery of target crab species near Kamchatka." Researches of the aquatic biological resources of Kamchatka and the North-West Part of the Pacific Ocean 2, no. 64 (October 9, 2022): 35–54. http://dx.doi.org/10.15853/2072-8212.2022.64.35-54.
Повний текст джерелаАнотація:
Results of the assessment of by-catch in the specialized fishery of target crab species are presented. The studies covered three fishing areas: off Western Kamchatka (Kamchatka-Kuril and West Kamchatka sub- zones) and off the southeastern coast of Kamchatka (Petropavlovsk-Komandorskaya subzone). In addition to the target object, the catches included both non-target species of crabs and representatives of other groups of animals: fish and invertebrates. The by-catch of fish included representatives of several genera, the most common being Pacific cod (Gadus macrocephalus), Irish lords (Hemilepidothus sp.) and snailfishes (Careproctus sp.). Among invertebrate representatives in the by-catch, octopuses (Octopus sp.) most often prevailed by weight in the fishery of red king crab (Paralithodes camtschaticus) off Western Kamchatka and Tanner crab (Chionoecetes bairdi) off Eastern Kamchatka.
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Lin, Linda Yingqi, Samuele Cancellieri, Jing Zeng, Francesco Masillo, My Anh Nguyen, Nicola Bombieri, Stacy A. Maitland, et al. "Human Genetic Diversity Alters Therapeutic Gene Editing Off-Target Outcomes." Blood 138, Supplement 1 (November 5, 2021): 3993. http://dx.doi.org/10.1182/blood-2021-152429.
Повний текст джерелаАнотація:
Abstract CRISPR gene editing holds great promise to modify somatic genomes to ameliorate disease. In silico prediction of homologous sites coupled with biochemical evaluation of possible genomic off-targets may predict genotoxicity risk of individual gene editing reagents. However, standard computational and biochemical methods focus on reference genomes and do not consider the impact of genetic diversity on off-target potential. Here we developed a web application called CRISPRme that explicitly and efficiently integrates human genetic variant datasets with orthogonal genomic annotations to predict and prioritize off-target sites at scale. The method considers both single-nucleotide variants (SNVs) and indels, accounts for bona fide haplotypes, accepts spacer:protospacer mismatches and bulges, and is suitable for personal genome analyses. We tested the tool with a guide RNA (gRNA) targeting the BCL11A erythroid enhancer that has shown therapeutic promise in clinical trials for sickle cell disease (SCD) and β-thalassemia (Frangoul et al. NEJM 2021). We find that the top predicted off-target site is produced by a non-reference allele common in African-ancestry populations (rs114518452, minor allele frequency (MAF) = 4.5%) that introduces a protospacer adjacent motif (PAM) for SpCas9. We validate that SpCas9 generates indels (~9.6% frequency) and chr2 pericentric inversions in a strictly allele-specific manner in edited CD34+ hematopoietic stem/progenitor cells (HSPCs), although a high-fidelity Cas9 variant mitigates this off-target. This report illustrates how population and private genetic variants should be considered as modifiers of genome editing outcomes. We expect that variant-aware off-target assessment will be required for therapeutic genome editing efforts going forward, including both ongoing and future clinical trials, and we provide a powerful approach for comprehensive off-target prediction. CRISPRme is available at crisprme.di.univr.it. Disclosures No relevant conflicts of interest to declare.
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Lim, Ming Tsuey, Norazida Ab Rahman, Xin Rou Teh, Chee Lee Chan, Shantini Thevendran, Najwa Ahmad Hamdi, Ka Keat Lim, and Sheamini Sivasampu. "Optimal cut-off points for adherence measure among patients with type 2 diabetes in primary care clinics: a retrospective analysis." Therapeutic Advances in Chronic Disease 12 (January 2021): 204062232199026. http://dx.doi.org/10.1177/2040622321990264.
Повний текст джерелаАнотація:
Background: Medication adherence measures are often dichotomized to classify patients into those with good or poor adherence using a cut-off value ⩾80%, but this cut-off may not be universal across diseases or medication classes. This study aimed to examine the cut-off value that optimally distinguish good and poor adherence by using the medication possession ratio (MPR) and proportion of days covered (PDC) as adherence measures and glycated hemoglobin (HbA1c) as outcome measure among type 2 diabetes mellitus (T2DM) patients. Method: We used pharmacy dispensing data of 1461 eligible T2DM patients from public primary care clinics in Malaysia treated with oral antidiabetic drugs between January 2018 and May 2019. Adherence rates were calculated during the period preceding the HbA1c measurement. Adherence cut-off values for the following conditions were compared: adherence measure (MPR versus PDC), assessment period (90-day versus 180-day), and HbA1c target (⩽7.0% versus ⩽8.0%). Results: The optimal adherence cut-offs for MPR and PDC in predicting HbA1c ⩽7.0% ranged between 86.1% and 98.3% across the two assessment periods. In predicting HbA1c ⩽8.0%, the optimal adherence cut-offs ranged from 86.1% to 92.8%. The cut-off value was notably higher with PDC as the adherence measure, shorter assessment period, and a stricter HbA1c target (⩽7.0%) as outcome. Conclusion: We found that optimal adherence cut-off appeared to be slightly higher than the conventional value of 80%. The adherence thresholds may vary depending on the length of assessment period and outcome definition but a reasonably wise cut-off to distinguish good versus poor medication adherence to be clinically meaningful should be at 90%.
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Hall, F. R., J. Cooper, L. Kirchner, R. Downer, and R. Thacker. "Assessment of off-target movement of orchard pesticides: Capture efficiencies of synthetic and biological biomarkers." Journal of Environmental Science and Health, Part B 31, no. 4 (July 1996): 815–30. http://dx.doi.org/10.1080/03601239609373038.
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Garrood, William T., Nace Kranjc, Karl Petri, Daniel Y. Kim, Jimmy A. Guo, Andrew M. Hammond, Ioanna Morianou, et al. "Analysis of off-target effects in CRISPR-based gene drives in the human malaria mosquito." Proceedings of the National Academy of Sciences 118, no. 22 (April 30, 2021): e2004838117. http://dx.doi.org/10.1073/pnas.2004838117.
Повний текст джерелаАнотація:
CRISPR-Cas9 nuclease-based gene drives have been developed toward the aim of control of the human malaria vector Anopheles gambiae. Gene drives are based on an active source of Cas9 nuclease in the germline that promotes super-Mendelian inheritance of the transgene by homology-directed repair (“homing”). Understanding whether CRISPR-induced off-target mutations are generated in Anopheles mosquitoes is an important aspect of risk assessment before any potential field release of this technology. We compared the frequencies and the propensity of off-target events to occur in four different gene-drive strains, including a deliberately promiscuous set-up, using a nongermline restricted promoter for SpCas9 and a guide RNA with many closely related sites (two or more mismatches) across the mosquito genome. Under this scenario we observed off-target mutations at frequencies no greater than 1.42%. We witnessed no evidence that CRISPR-induced off-target mutations were able to accumulate (or drive) in a mosquito population, despite multiple generations’ exposure to the CRISPR-Cas9 nuclease construct. Furthermore, judicious design of the guide RNA used for homing of the CRISPR construct, combined with tight temporal constriction of Cas9 expression to the germline, rendered off-target mutations undetectable. The findings of this study represent an important milestone for the understanding and managing of CRISPR-Cas9 specificity in mosquitoes, and demonstrates that CRISPR off-target editing in the context of a mosquito gene drive can be reduced to minimal levels.
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He-Hua, Wang, Zhu Jian-Jun, Gu Xiao-Yan, and Chen Ye. "A Multiple Criteria Decision Analysis Method for Alternative Assessment Results Obeying a Particular Distribution and Application." Mathematical Problems in Engineering 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/2108726.
Повний текст джерелаАнотація:
A multiple criteria decision analysis (MCDA) problem is studied in this paper, for which the evaluation results obey a particular distribution. First, when solving a multiple criteria decision analysis (MCDA) problem, a grey target decision analysis framework is proposed to determine uncertain parameters and criteria weights. A measurement for comprehensive off-target distance is defined, which includes the undetermined parameters. Second, to satisfy the requirements of a specific distribution (such as a normal distribution) in the assessment results, an optimization model that incorporates the off-target distance constraints is proposed by considering the skewness and kurtosis test method. Third, a particle swarm optimization (PSO) algorithm is extended to solve the proposed model by seeking the appropriate parameters and weights. Fourth, a numerical example is applied to demonstrate the feasibility and application of the proposed method. In the end, the proposed model is extended to other distribution requirements.
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Fan, Cuiqing, Xiongwei Cai, Feng Zhang, Cindy Hochstetler, Xiaoyi Chen, Fukun Guo, Weidong Tian, and Yi Zheng. "Precision Assessment of on- and Off-Target Effects of mTOR Kinase Inhibitors in a Mouse Model." Blood 132, Supplement 1 (November 29, 2018): 2632. http://dx.doi.org/10.1182/blood-2018-99-115225.
Повний текст джерелаАнотація:
Abstract mTOR plays a critical role in controlling cell growth, survival and metabolism and is an important anti-cancer target. There are over 2,000 clinical trials involving mTOR inhibitors as single or combo-agent. The first gen mTOR inhibitors, i.e. rapamycin and rapalogs, are only effective towards mTORC1 and have shown limited efficacy in multiple clinical settings. The second gen mTOR inhibitors target mTOR kinase domain with significantly stronger antineoplastic potency, and over 30 clinical trials of various mTOR kinase inhibitors including AZD2014 are under way. While the new mTOR inhibitors are promising in effectiveness to suppress both mTORC1 and mTORC2 signaling mediated through the mTOR kinase activity, their safety and toxicity features remain a major concern. To precisely determine the on-/off-target effects of mTOR kinase inhibitors, we have generated the conditional Mx1-Cre;mTORflox/flox and Mx1-Cre;mTORflox/knockin D2338Amice that can inducibly yield the mTOR-/- (KO) and the mTOR kinase-activity deficient D2338A mutant knockin (KI) blood genotypes, respectively, upon poly I:C induction. Our previous studies have shown that mTOR KO in blood cells causes hematopoietic failure, with a remarkable reduction in bone marrow cellularity and a transient expansion but long-term exhaustion of hematopoietic stem cells (HSCs). mTOR KO HSCs displayed a loss of quiescence and increased proliferation but normal survival activity. In the current study, we found that the mTOR kinase-deficient D2338A KI mice show several similar phenotypes as mTOR KO, including a drastic inhibition of the mTORC1/mTORC2 downstream effectors p-S6K, p-4E-BP1 and p-AKT (S473) and transient increase in HSC number and proliferation. mTOR kinase deficiency leads to defective engraftment of HSCs in transplantation and failure of colony-formation by progenitors. RNA-seq analysis of the HSC (Lin-Sca-1+c-Kit+CD135-) population reveals that loss of mTOR and loss of mTOR kinase activity share similar changes in over a thousand genes which are enriched in functional clusters including ribosome biogenesis, cell cycle, MAPK pathway, PI3K-Akt pathway, Jak-Stat pathway, and NFkB pathway. Upon mTOR knockout or knockin, several key compensatory genes involved in cell proliferation and survival, including c-myc, Ccnd1, Fos, Jun, and Dusp1 are upregulated. RT-PCR and Western blot further validated that mTOR KO or KI leads to elevated mRNA and protein expression of these compensatory genes. Our RNA-seq analysis also identified ~1000 upregulated genes (such as Ocln, Itgal, and Dlg5) and ~700 downregulated genes (such as Lipg, Cndp2, and Ndst2) in KI vs. KO HSCs: the upregulated genes were enriched in several pathways such as cell adhesion, tight junction, TNF and Ras pathways, while the metabolic pathways were significantly enriched among the downregulated genes. These differential gene expressions underlie the difference in survival between mTOR KI and KO mice, with the median survival for KI mice at 29 days compared to 14 days for KO mice. These results indicate that while the mTOR kinase activity mediates a majority of mTOR regulator pathways, mTOR also confers kinase-independent roles. We next examined gene expression changes of mTOR WT and mTOR KI in response to 200 nM AZD2014. Further examination of differentially expressed (DE) genes between WT+AZD2014 and WT found around 200 DE genes, in which 150 genes (75% changes) overlapped with those DE genes between KI and WT. These overlapped 150 genes shared between WT HSCs treated with AZD2014 and mTOR KI are enriched in a number of important GO and Pathways, such as signal transduction, metabolic pathway, and PI3K-Akt pathway, and they represent on-target effects by the kinase inhibitor AZD2014. On the other hand, less than 40 DE genes between KI+AZD2014 and KI were detected, including Lilrb4, Nptx1 and Ahnak2, which represent off-target genes induced by AZD2014 treatment. Interestingly, the off-target gene set is not enriched in any GO or Pathway. Taken together, our inducible mTOR D2338A KI mouse presents an excellent model for precisely assessing mTOR kinase inhibitor efficacy and specificity. Our studies provide valuable information for the on- and off-target effects by the AZD2014 class of mTOR kinase inhibitors at a therapeutic dose, and reveal several potential biomarkers that can be useful in predicting the off-target effect of mTOR targeted therapies. Disclosures No relevant conflicts of interest to declare.
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Feng, Joseph C., Dean G. Thompson, and Philip E. Reynolds. "Fate of glyphosate in a Canadian forest watershed. 1. Aquatic residues and off-target deposit assessment." Journal of Agricultural and Food Chemistry 38, no. 4 (April 1990): 1110–18. http://dx.doi.org/10.1021/jf00094a045.
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Russo, Monia Teresa, Riccardo Aiese Cigliano, Walter Sanseverino, and Maria Immacolata Ferrante. "Assessment of genomic changes in a CRISPR/Cas9 Phaeodactylum tricornutum mutant through whole genome resequencing." PeerJ 6 (October 5, 2018): e5507. http://dx.doi.org/10.7717/peerj.5507.
Повний текст джерелаАнотація:
The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system, co-opted from a bacterial defense natural mechanism, is the cutting edge technology to carry out genome editing in a revolutionary fashion. It has been shown to work in many different model organisms, from human to microbes, including two diatom species, Phaeodactylum tricornutum and Thalassiosira pseudonana. Transforming P. tricornutum by bacterial conjugation, we have performed CRISPR/Cas9-based mutagenesis delivering the nuclease as an episome; this allowed for avoiding unwanted perturbations due to random integration in the genome and for excluding the Cas9 activity when it was no longer required, reducing the probability of obtaining off-target mutations, a major drawback of the technology. Since there are no reports on off-target occurrence at the genome level in microalgae, we performed whole-genome Illumina sequencing and found a number of different unspecific changes in both the wild type and mutant strains, while we did not observe any preferential mutation in the genomic regions in which off-targets were predicted. Our results confirm that the CRISPR/Cas9 technology can be efficiently applied to diatoms, showing that the choice of the conjugation method is advantageous for minimizing unwanted changes in the genome of P. tricornutum.
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Ahmad, Fiaz, Songchao Zhang, Baijing Qiu, Jing Ma, Huang Xin, Wei Qiu, Shibbir Ahmed, Farman Ali Chandio, and Aftab Khaliq. "Comparison of Water Sensitive Paper and Glass Strip Sampling Approaches to Access Spray Deposit by UAV Sprayers." Agronomy 12, no. 6 (May 29, 2022): 1302. http://dx.doi.org/10.3390/agronomy12061302.
Повний текст джерелаАнотація:
Target and off-target spray depositions determine the spray’s effectiveness and impact on the environment. A decisive stage in the measurement of spray deposition and drift is selecting an appropriate sampling approach under field conditions. There are various approaches available for sampling spray deposition and drift, during the evaluation of ground sprayers used for the UAV sprayer assessment, under field conditions. In this study, two sampling approaches (water-sensitive paper, and glass strip collectors) were compared to analyze spray deposition in target and off-target zones. The results showed a variation in the estimation of the spray deposits among the two applied sampling methods. The results showed that the water-sensitive paper recorded the droplet deposition in the target zone with a range from 0.049 to 4.866 µLcm−2, whereas the glass strip recorded from 0.11 to 0.793 µLcm−2. The results also showed the water sensitive paper recorded an 80.3% higher deposition than that of the glass strip at zero position during the driving flight height 2 m and flight speed 2 ms−1 (T1 treatment). It can be concluded that variation in recorded depositing is due to the sampling material. It is recommended that the confident deposition results, measurement methods and sampling approaches must be standardized for UAV sprayers according to the field conditions and controlled within artificial assessments.
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Mogren, Christina L., and Jonathan Gary Lundgren. "In silico identification of off-target pesticidal dsRNA binding in honey bees (Apis mellifera)." PeerJ 5 (December 13, 2017): e4131. http://dx.doi.org/10.7717/peerj.4131.
Повний текст джерелаАнотація:
Background Pesticidal RNAs that silence critical gene function have great potential in pest management, but the benefits of this technology must be weighed against non-target organism risks. Methods Published studies that developed pesticidal double stranded RNAs (dsRNAs) were collated into a database. The target gene sequences for these pesticidal RNAs were determined, and the degree of similarity with sequences in the honey bee genome were evaluated statistically. Results We identified 101 insecticidal RNAs sharing high sequence similarity with genomic regions in honey bees. The likelihood that off-target sequences were similar increased with the number of nucleotides in the dsRNA molecule. The similarities of non-target genes to the pesticidal RNA was unaffected by taxonomic relatedness of the target insect to honey bees, contrary to previous assertions. Gene groups active during honey bee development had disproportionately high sequence similarity with pesticidal RNAs relative to other areas of the genome. Discussion Although sequence similarity does not itself guarantee a significant phenotypic effect in honey bees by the primary dsRNA, in silico screening may help to identify appropriate experimental endpoints within a risk assessment framework for pesticidal RNAi.
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Bae, Taegeun, Hanseop Kim, Jeong Hee Kim, Yong Jun Kim, Seung Hwan Lee, Byung-Joo Ham, and Junho K. Hur. "Specificity Assessment of CRISPR Genome Editing of Oncogenic EGFR Point Mutation with Single-Base Differences." Molecules 25, no. 1 (December 22, 2019): 52. http://dx.doi.org/10.3390/molecules25010052.
Повний текст джерелаАнотація:
In CRISPR genome editing, CRISPR proteins form ribonucleoprotein complexes with guide RNAs to bind and cleave the target DNAs with complete sequence complementarity. CRISPR genome editing has a high potential for use in precision gene therapy for various diseases, including cancer and genetic disorders, which are caused by DNA mutations within the genome. However, several studies have shown that targeting the DNA via sequence complementarity is imperfect and subject to unintended genome editing of other genomic loci with similar sequences. These off-target problems pose critical safety issues in the therapeutic applications of CRISPR technology, with particular concerns in terms of the genome editing of pathogenic point mutations, where non-mutant alleles can become an off-target with only a one-base difference. In this study, we sought to assess a novel CRISPR genome editing technique that has been proposed to achieve a high specificity by positioning the mismatches within the protospacer adjacent motif (PAM) sequence. To this end, we compared the genome editing specificities of the PAM-based and conventional methods on an oncogenic single-base mutation in the endothelial growth factor receptor (EGFR). The results indicated that the PAM-based method provided a significantly increased genome editing specificity for pathogenic mutant alleles with single-base precision.
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Patel, Bhavinkumar B., Carlos A. Barrero, Alan Braverman, Phillip D. Kim, Kelly A. Jones, Dian Er Chen, Russell P. Bowler, Salim Merali, Steven G. Kelsen, and Anthony T. Yeung. "Assessment of Two Immunodepletion Methods: Off-Target Effects and Variations in Immunodepletion Efficiency May Confound Plasma Proteomics." Journal of Proteome Research 11, no. 12 (October 29, 2012): 5947–58. http://dx.doi.org/10.1021/pr300686k.
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Ahmed, Firoz, Muthappa Senthil-Kumar, Xinbin Dai, Vemanna S. Ramu, Seonghee Lee, Kirankumar S. Mysore, and Patrick Xuechun Zhao. "pssRNAit: A Web Server for Designing Effective and Specific Plant siRNAs with Genome-Wide Off-Target Assessment." Plant Physiology 184, no. 1 (July 10, 2020): 65–81. http://dx.doi.org/10.1104/pp.20.00293.
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Pimentel, Helly, Helen Jarnagin, Hailing Zong, Courtney Todorov, Courtney M. Anderson, Bingqing Zhang, Christopher Bunker, and Xiao-Jun Ma. "Preclinical CAR-T cell target safety, biodistribution, and tumor infiltration analysis using in situ hybridization technology." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 112. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.112.
Повний текст джерелаАнотація:
112 Background: Chimeric antigen receptor (CAR) T cell therapy is highly effective in treating hematologic malignancies, and major efforts are being made to achieve similar efficacy in solid tumors. The greater potency of CAR-T cells compared to antibody therapeutics demands a more stringent CAR-T target safety assessment to avoid adverse events resulting from “on-target/off-tumor” activity. Furthermore, it is critical to track and monitor CAR+ T cells within intact tissue and tumor to understand the mechanisms underlying off-tumor toxicity and efficacy in tumor killing. Methods: We employed the RNAscope in situ hybridization (ISH) technology to assess target expression specificity and to track CAR-T cell distribution and activation in xenograft and host tissues using the RPMI-8226 xenograft mouse model. Results: For the CAR-T target candidates, Target X and Target Y, RNA ISH revealed that Target X was only expressed in the xenograft tumor and in no mouse organs, while Target Y was found to be expressed at low levels in mouse lung and liver, as well as in the xenograft tumor. Duplex RNA ISH assays with probes targeting the CAR 3’ UTR and either IFNG or GZMB allowed for highly sensitive and specific detection of CAR-T cells and their activation state in both tumor and normal tissues from vehicle, Target X CAR-T cell, or Target Y CAR-T cell treated mice. Activated Target X CAR-T cells expressing GZMB and IFNG were found only in the xenograft tumor, where Target X was expressed. In contrast, activated Target Y CAR-T cells were found almost exclusively in mouse lung and liver, with very few Target Y CAR-T cells being found in the xenograft tumor. Lastly, a multiplex ISH-IHC approach confirmed the presence of activated Target X CAR-T cells in the xenograft tumor through simultaneous detection of the Target X CAR 3’ UTR, IFNG, GZMB, and CD3. Conclusions: These data demonstrate how the RNAscope assay can be utilized for CAR-T cell efficacy and safety/toxicity assessment in preclinical models by detecting very low levels of target antigen expression in off-tumor tissues and monitoring CAR-T cell pharmacodynamics and activation in tumor models and can also be applied for assessing TCR-T cell activity in tumors.
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Vaillant, Andrew. "Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects." Viruses 14, no. 9 (September 16, 2022): 2052. http://dx.doi.org/10.3390/v14092052.
Повний текст джерелаАнотація:
Three types of oligonucleotide-based medicines are under clinical development for the treatment of chronic HBV infection. Antisense oligonucleotides (ASOs) and synthetic interfering RNA (siRNA) are designed to degrade HBV mRNA, and nucleic acid polymers (NAPs) stop the assembly and secretion of HBV subviral particles. Extensive clinical development of ASOs and siRNA for a variety of liver diseases has established a solid understanding of their pharmacodynamics, accumulation in different tissue types in the liver, pharmacological effects, off-target effects and how chemical modifications and delivery approaches affect these parameters. These effects are highly conserved for all ASO and siRNA used in human studies to date. The clinical assessment of several ASO and siRNA compounds in chronic HBV infection in recent years is complicated by the different delivery approaches used. Moreover, these assessments have not considered the large clinical database of ASO/siRNA function in other liver diseases and known off target effects in other viral infections. The goal of this review is to summarize the current understanding of ASO/siRNA/NAP pharmacology and integrate these concepts into current clinical results for these compounds in the treatment of chronic HBV infection.
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Tan, E‐Pien, Yilong Li, Martin Del Castillo Velasco‐Herrera, Kosuke Yusa, and Allan Bradley. "Off‐target assessment of CRISPR ‐ C as9 guiding RNA s in human i PS and mouse ES cells." genesis 53, no. 2 (December 10, 2014): 225–36. http://dx.doi.org/10.1002/dvg.22835.
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Ramaprasad, Jaya, Ming-Yi Tsai, Kai Elgethun, Vincent R. Hebert, Allan Felsot, Michael G. Yost, and Richard A. Fenske. "The Washington aerial spray drift study: assessment of off-target organophosphorus insecticide atmospheric movement by plant surface volatilization." Atmospheric Environment 38, no. 33 (October 2004): 5703–13. http://dx.doi.org/10.1016/j.atmosenv.2004.04.035.
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Cancellieri, Samuele, Matthew C. Canver, Nicola Bombieri, Rosalba Giugno, and Luca Pinello. "CRISPRitz: rapid, high-throughput and variant-aware in silico off-target site identification for CRISPR genome editing." Bioinformatics 36, no. 7 (November 25, 2019): 2001–8. http://dx.doi.org/10.1093/bioinformatics/btz867.
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ABSTRACT Motivation Clustered regularly interspaced short palindromic repeats (CRISPR) technologies allow for facile genomic modification in a site-specific manner. A key step in this process is the in silico design of single guide RNAs to efficiently and specifically target a site of interest. To this end, it is necessary to enumerate all potential off-target sites within a given genome that could be inadvertently altered by nuclease-mediated cleavage. Currently available software for this task is limited by computational efficiency, variant support or annotation, and assessment of the functional impact of potential off-target effects. Results To overcome these limitations, we have developed CRISPRitz, a suite of software tools to support the design and analysis of CRISPR/CRISPR-associated (Cas) experiments. Using efficient data structures combined with parallel computation, we offer a rapid, reliable, and exhaustive search mechanism to enumerate a comprehensive list of putative off-target sites. As proof-of-principle, we performed a head-to-head comparison with other available tools on several datasets. This analysis highlighted the unique features and superior computational performance of CRISPRitz including support for genomic searching with DNA/RNA bulges and mismatches of arbitrary size as specified by the user as well as consideration of genetic variants (variant-aware). In addition, graphical reports are offered for coding and non-coding regions that annotate the potential impact of putative off-target sites that lie within regions of functional genomic annotation (e.g. insulator and chromatin accessible sites from the ENCyclopedia Of DNA Elements [ENCODE] project). Availability and implementation The software is freely available at: https://github.com/pinellolab/CRISPRitzhttps://github.com/InfOmics/CRISPRitz. Supplementary information Supplementary data are available at Bioinformatics online.
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Fennell, Myles, Qing Xiang, Alexia Hwang, Chong Chen, Chun-Hao Huang, Chi-Chao Chen, Raphael Pelossof, and Ralph J. Garippa. "Impact of RNA-Guided Technologies for Target Identification and Deconvolution." Journal of Biomolecular Screening 19, no. 10 (August 27, 2014): 1327–37. http://dx.doi.org/10.1177/1087057114548414.
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For well over a decade, RNA interference (RNAi) has provided a powerful tool for investigators to query specific gene targets in an easily modulated loss-of-function setting, both in vitro and in vivo. Hundreds of publications have demonstrated the utility of RNAi in arrayed and pooled-based formats, in a wide variety of cell-based systems, including clonal, stem, transformed, and primary cells. Over the years, there have been significant improvements in the design of target-specific small-interfering RNA (siRNA) and short-hairpin RNA (shRNA), expression vectors, methods for mitigating off-target effects, and accurately interpreting screening results. Recent developments in RNAi technology include the Sensor assay, high-efficiency miR-E shRNAs, improved shRNA virus production with Pasha (DRGC8) knockdown, and assessment of RNAi off-target effects by using the C9-11 method. An exciting addition to the arsenal of RNA-mediated gene modulation is the clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas) system for genomic editing, allowing for gene functional knockout rather than knockdown.
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Goldmacher, Gregory V., Anuradha D. Khilnani, Robert H. I. Andtbacka, Jason J. Luke, F. Stephen Hodi, Aurelien Marabelle, Kevin Joseph Harrington, et al. "Response criteria for intratumoral immunotherapy in solid tumors: ItRECIST." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3141. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3141.
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3141 Background: The approval of intratumoral (IT) immunotherapy for metastatic melanoma and the active development of numerous novel IT drugs have created a need for standardized evaluation of response to this unique treatment strategy. The Response Evaluation Criteria in Solid Tumors (RECIST) is not suitable for assessing responses separately for injected and noninjected tumors. Building on RECIST concepts, we propose an IT immunotherapy RECIST (itRECIST) to capture data and assess local and systemic responses in a standardized fashion for clinical trials involving IT immunotherapies. Methods: itRECIST will address the unique needs of IT immunotherapy trials but, where possible, aligns with RECIST 1.1 and iRECIST. It does not dictate which lesions to inject but provides guidelines for collecting data and assessing response as treatment evolves. Results: itRECIST enables overall response assessment, separate response assessments in injected and noninjected lesions, and continued assessment following modifications of therapy at initial progression. At baseline, lesions are classified into 4 categories: target injected, target noninjected, nontarget injected, and nontarget noninjected. After baseline, lesions can be reclassified from noninjected to injected if the investigator decides to change the lesions to inject, but target and nontarget designations never change. Overall response at each assessment is based on target lesion response (injected and noninjected), nontarget lesion response, and absence/appearance of new lesions. Noninjected lesion response is determined by comparing tumor burden with baseline and nadir values. Injected lesion assessment is based on visit-to-visit changes in the lesions injected during treatment and on a combined assessment once the patient is off treatment. A new response category is defined to capture progression that would be “confirmed” per iRECIST even though injected lesions are responding and therapy continues. Multiple examples have been created to aid in training and adoption. Conclusions: itRECIST is an important step toward a standardized method of response assessment for this promising and evolving therapeutic modality. The proposed guidelines can be adopted into trial protocols and routine clinical practice without the need for complex additional assessments by treating physicians. Until there is evidence to support wider use, itRECIST is intended only to support standardized collection of data and to facilitate exploratory analysis. Authors G.V.G. and A.D.K. contributed equally to this work.
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Stover, Ed, Dominick Scotto, Chris Wilson, and Masoud Salyani. "Pesticide Spraying in Indian River Grapefruit: II. Overview of Factors Influencing Spray Efficacy and Off-target Deposition." HortTechnology 13, no. 1 (January 2003): 166–77. http://dx.doi.org/10.21273/horttech.13.1.0166.
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Foliar application of spray materials is an integral component of commercial citrus production. An intensive assessment of spray application practices has been stimulated by low fruit value and increased concern about potential surface water contamination in the Indian River citrus region of Florida. Many publications report research results regarding distribution of spray materials within orchards and off-target deposition, but interpretation is challenging because so many factors influence spray results, and integrating this information into practical recommendations is difficult. Canopy geometry and density are prominent factors contributing to variable deposition and spray drift. Environmental factors such as temperature, relative humidity, wind speed, and wind direction also greatly influence spray deposition and drift, and substantial changes can occur within seconds. In addition the physical and/or mechanical set up of the sprayer interact significantly with the other factors. A better understanding of these interactions should help growers optimize spray effectiveness and efficiency while reducing potential off-target effects.
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Nazari-Shafti, Timo Z., Sebastian Neuber, Ana G. Duran, Vasileios Exarchos, Christien M. Beez, Heike Meyborg, Katrin Krüger, et al. "MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells—Can They Predict Potential Off-Target Effects?" Biomolecules 10, no. 9 (September 22, 2020): 1353. http://dx.doi.org/10.3390/biom10091353.
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The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations.
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van Vollenhoven, Ronald, Alexandre Voskuyl, George Bertsias, Cynthia Aranow, Martin Aringer, Laurent Arnaud, Anca Askanase, et al. "A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS)." Annals of the Rheumatic Diseases 76, no. 3 (November 24, 2016): 554–61. http://dx.doi.org/10.1136/annrheumdis-2016-209519.
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ObjectivesTreat-to-target recommendations have identified ‘remission’ as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.MethodsAn international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%.ResultsThe task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life.ConclusionsThe work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.
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Tirmenstein, Mark, Thomas E. Dorr, Evan B. Janovitz, Deborah Hagan, Lynn M. Abell, Joelle M. Onorato, Jean M. Whaley, Michael J. Graziano, and Timothy P. Reilly. "Nonclinical Toxicology Assessments Support the Chronic Safety of Dapagliflozin, a First-in-Class Sodium-Glucose Cotransporter 2 Inhibitor." International Journal of Toxicology 32, no. 5 (September 2013): 336–50. http://dx.doi.org/10.1177/1091581813505331.
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Dapagliflozin, a first-in-class, selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), promotes urinary glucose excretion to reduce hyperglycemia for the treatment of type 2 diabetes. A series of nonclinical studies were undertaken to evaluate dapagliflozin in species where it was shown to have pharmacologic activity comparable with that in humans at doses that resulted in supratherapeutic exposures. In vitro screening (>300 targets; 10 μmol/L) indicated no significant off-target activities for dapagliflozin or its primary human metabolite. Once daily, orally administered dapagliflozin was evaluated in Sprague-Dawley rats (≤6 months) and in beagle dogs (≤1 year) at exposures >5000-fold those observed at the maximum recommended human clinical dose (MRHD; 10 mg). Anticipated, pharmacologically mediated effects of glucosuria, osmotic diuresis, and mild electrolyte loss were observed, but there were no adverse effects at clinically relevant exposures, including in the kidneys or urogenital tract. The SGLT2−/− mice, which show chronic glucosuria, and dapagliflozin-treated, wild-type mice exhibited similar safety profiles. In rats but not dogs, dapagliflozin at >2000-fold MRHD exposures resulted in tissue mineralization and trabecular bone accretion. Investigative studies suggested that the effect was not relevant to human safety, since it was partially related to off-target inhibition of SGLT1, which was observed only at high doses of dapagliflozin and resulted in intestinal glucose malabsorption and increased intestinal calcium absorption. The rigorous assessment of supra- and off-target dapagliflozin pharmacology in nonclinical species allowed for a thorough evaluation of potential toxicity, providing us with confidence in its safety in patients with diabetes.
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Mensali, Nadia, Marit Renée Myhre, Pierre Dillard, Sylvie Pollmann, Gustav Gaudernack, Gunnar Kvalheim, Sébastien Wälchli, and Else Marit Inderberg. "Preclinical assessment of transiently TCR redirected T cells for solid tumour immunotherapy." Cancer Immunology, Immunotherapy 68, no. 8 (June 18, 2019): 1235–43. http://dx.doi.org/10.1007/s00262-019-02356-2.
Повний текст джерелаАнотація:
Abstract Off-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks. There is, therefore, a clear unmet need for assessing the safety of a therapeutic TCR in a more controllable manner than by the injection of permanently modified cellular products. Using transiently modified T cells combined with dose escalation has already been shown feasible for chimeric antigen receptor (CAR)-engineered T cells, but nothing is yet reported for TCR. We performed a preclinical evaluation of a therapeutic TCR transiently expressed in T cells by mRNA electroporation. We analyzed if the construct was active in vitro, how long it was detectable for and if this expression format was adapted to in vivo efficacy assessment. Our data demonstrate the potential of mRNA engineered T cells, although less powerful than permanent redirection, to induce a significant response. Thus, these findings support the development of mRNA based TCR-therapy strategies as a feasible and efficacious method for evaluating TCR safety and efficacy in first-in-man testing.
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Miyake, Rina, and Hiroko Itoh. "Design and Safety Assessment of Recommended Route off the Western Coast of Izu O Shima Island." Journal of Marine Science and Engineering 10, no. 8 (August 2, 2022): 1060. http://dx.doi.org/10.3390/jmse10081060.
Повний текст джерелаАнотація:
Ship routeing systems (e.g., traffic separation schemes) have been established worldwide to ensure ship traffic safety. There are no specific measures to establish an effective ship route. We have previously proposed a method to design and assess the route comparison with the present traffic flow in the interest to establish an effective ship routeing system, particularly for recommended routes. The method consists mainly of the following procedures: understanding the existing phenomena and the issues in the target area by analyzing target traffic flow; designing safety measures; assessing the safety measures; and determining the optimal safety measure. This method was used to design and assess the recommended route off the western coast of Izu O Shima Island. This route has been in service since January 2018. The purpose of this study is to validate the proposed method. First, the technical details of the method are described. An automatic identification system (AIS) observation was conducted before and after the implementation to validate the effectiveness of the recommended route for reducing collisions. The results show that the recommended route effectively reduces the risk of collisions. More specifically, the proposed method was found to be useful when establishing an effective recommended route.
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Graham, Scott. "The Non-combatant Casualty Cut-off Value: Assessment of a Novel Targeting Technique in Operation Inherent Resolve." International Criminal Law Review 18, no. 4 (November 10, 2018): 655–85. http://dx.doi.org/10.1163/15718123-01804002.
Повний текст джерелаАнотація:
A tension exists between treaty protections afforded to civilians in non-international armed conflicts from becoming objects of attacks and the International Criminal Court’s jurisdiction to punish commanders who recklessly cause such casualties. Yet, media and human rights organizations’ criticism that the non-combatant casualty cut-off value (NCV) constitutes a war crime cannot survive rational examination of the mens rea requirement in the Rome Statute. Coalition commanders and targeteers must ensure the NCV is neither presumptively nor conclusively applied in target engagement, whilst taking constant care to focus proportionality assessments to spare civilians.
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Roberts, M., S. Allen, E. Marsh, J. Clarke, and D. Coley. "Consequential impacts of a net-zero carbon design: life cycle assessment of an active building." IOP Conference Series: Earth and Environmental Science 1078, no. 1 (September 1, 2022): 012091. http://dx.doi.org/10.1088/1755-1315/1078/1/012091.
Повний текст джерелаАнотація:
Abstract Life Cycle Assessment (LCA) is becoming the predominant means for determining if a building design meets a carbon emission target. These target values are set to help building designers meet aspirational net-zero carbon targets. Within LCA, there are two modelling frameworks. Attributional LCA (ALCA) assigns a portion of global emissions to a specific product or process. Consequential LCA (CLCA) assesses the impacts from a market’s response to a change in demand for a product or process. A case study building, located in Swansea, UK, has been assessed to investigate the differences between ALCA and CLCA. The case study building employs: a modular off-site construction building fabric; on-site energy generation; and, on-site energy storage – all strategies that may be adopted at large scale to decarbonise the built environment. Based on global warming potential assessed over a 100-year time horizon (GWP100), the total upfront embodied impacts from CLCA are 19% higher than that from ALCA. Three differences exist within the rank order of building elements. The Frame presented the highest contribution to the GWP100 within the CLCA results, whereas External Walls contributed the most within the ALCA results. The differences arise mostly from how electricity production is modelled within attributional and consequential datasets and whether substitution or cut-off are used within the background processes. CLCA can capture the environmental impacts of decisions taken to create a net-zero built environment. However, CLCA should not be directly compared to ALCA without appreciating and recognising how the methods and scopes differ.
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Oropilla, Jean Q. L., Cid C. E. Diesta, Parunut Itthimathin, Oksana Suchowersky, and Zelma H. T. Kiss. "Both thalamic and pallidal deep brain stimulation for myoclonic dystonia." Journal of Neurosurgery 112, no. 6 (June 2010): 1267–70. http://dx.doi.org/10.3171/2009.10.jns091062.
Повний текст джерелаАнотація:
Myoclonic dystonia is poorly managed with medication and may be severe enough to warrant surgical intervention. Surgery has targeted either the globus pallidus pars interna (GPi) or the thalamus, but there is no accepted target for this condition. The authors present the case of a 23-year-old man treated with unilateral deep brain stimulation in both the thalamus and GPi. His movement disorder improved dramatically with stimulation. Two years postoperatively, the authors performed a double-blind assessment of the effects of each stimulator together, separately, and off stimulation. Videotape assessment, using tremor, dystonia, and myoclonus rating scales, showed that most of the benefit could be attributed to pallidal stimulation, although there was some advantage to stimulation at both sites. These results suggest that while GPi stimulation may be the better target for this condition, thalamic stimulation may be added in cases in which the benefit is insufficient.
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WINTER, SIDNEY G. "Problems at the Foundation? Comments on Felin and Foss." Journal of Institutional Economics 7, no. 2 (January 28, 2011): 257–77. http://dx.doi.org/10.1017/s1744137410000470.
Повний текст джерелаАнотація:
Abstract:This paper reviews the assessment of the routines and capabilities literature provided by T. Felin and N. J. Foss, ‘The Endogenous Origins of Experience, Routines and Organizational Capabilities: The Poverty of Stimulus’, published by theJournal of Institutional Economics. Although valuable points are raised, the assessment is largely off target because it is fixated on the implausible view that the literature assessed is strongly shaped by the tradition of behavioral psychology (B. F. Skinner and others). At the same time, important portions of the routines and capabilities literature that are highly relevant to the authors’ substantive concerns, and which are plainly inconsistent with the main interpretive claim, are not considered.
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Aghdeab, Shukry, Ahmed G. Abdulameer, Ahmed B. Abdulwahhab, and Majid H. Ismiel. "Improve the Surface Characteristics of the Electric Discharge Machining Employing a Method Burnishing Process." Engineering and Technology Journal 38, no. 4A (April 25, 2020): 545–51. http://dx.doi.org/10.30684/etj.v38i4a.308.
Повний текст джерелаАнотація:
Electrical Discharge Machining (EDM) applies the concept of material eradication by utilizing electric spark erosion. The target of this exploration concentrates to examine the ideal procedure parameters of EDM on Aluminum 6061-T6as a workpiece with copper as a tool electrode. The effect of various process operators 'on machining rendering was examined. Internal factors with current (10, 20, 30) Ampere, pulse on time (50, 100, 150) µs was used after which takes pulse off time (25, 50, 75) µs. All parameters applied for empirical acts with influence on Ra (surface roughness ). The result showed that MRR" Material Removal Rate” is increment by expanding in current and pulse on time and it declines by expanding in pulse off time. Optimal condition are gained when using " Using current 30 Ampere, pulse on time is 150 µs and minimize assessment of pulse off time is 25 µs.
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Coombs, Roger F., and Richard Barr. "In situ measurements of orange roughy (Hoplostethus atlanticus) target strength." ICES Journal of Marine Science 64, no. 6 (June 27, 2007): 1220–34. http://dx.doi.org/10.1093/icesjms/fsm084.
Повний текст джерелаАнотація:
Abstract Coombs, R. F., and Barr, R. 2007. In situ measurements of orange roughy (Hoplostethus atlanticus) target strength. – ICES Journal of Marine Science, 64: 1220–1234. Orange roughy (Hoplostethus atlanticus) support one of New Zealand's most valuable commercial fisheries, and its assessment poses many problems. Acoustic estimation using echo integration has become one of the main sources of biomass information, and for this an estimate of orange roughy target strength (TS) is needed. Its schooling characteristics together with patterns in the rate of change of phase vs. TS plots are used to identify ensembles of orange roughy targets from in situ TS data collected from a wide range of fishing areas off eastern New Zealand. The results suggest a TS of −49.3 dB for an orange roughy of 35 cm standard length.
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Jhawer, M., H. L. Kindler, Z. Wainberg, J. Ford, P. Kunz, L. Tang, S. McCallum, H. Kallender, and M. A. Shah. "Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 4502. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4502.
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4502 Background: GSK089 is an oral, small-molecule inhibitor of cMET and VEGFR2/KDR, and has potent antitumor activity in cMET-amplified cell lines and xenografts. cMET is reportedly amplified, overexpressed and/or activated in GC, making it an attractive therapeutic target. This phase II study examines the safety and efficacy of 2 dosing schedules of GSK089 as a single agent in patients (pts) with metastatic GC. Methods: Pts with distal esophagus, GE junction or stomach adenocarcinoma, 0–2 prior chemotherapy regimens, adequate organ function, measurable disease, and ECOG PS 0–2 are sequentially enrolled in 2 cohorts: 1) Intermittent 5 days on/9 off - GSK089 240 mg/d on D1–5 repeated every 14 days, and 2) Daily - 80 mg/d. Primary study endpoint (response) is assessed every 8 weeks. cMET amplification by FISH (≥2 copies of cMET per copy of chromosome 7) is not an entry criterion, but is determined on archival tissue for all pts. Pre- and on-treatment tumor biopsies in select pts and plasma samples in all pts are analyzed for GSK089 effects on direct and downstream drug targets. GSK089 pharmacokinetics (PK) are also evaluated. Results: As of 12/19/08, enrollment to the 5 on/9 off cohort is complete with 41 evaluable pts, and 14 evaluable pts have enrolled on the daily cohort. cMET amplification was seen in 3/43 (7%) pts tested; all 3 were in 5 on/9 off cohort. Best response of stable disease (SD), was noted in 6/41 (15%) pts in the 5 on/9 off cohort (none were cMET-amplified), with 2 pts SD >6 months, 1 ongoing; and in 3/14 (21%) pts in the daily cohort. Among all-enrolled pts (48 pts in 5 on/9 off, 16 pts in daily cohort), LFT abnormalities (9%), fatigue (5%), and venous thromboembolism (3%) were the most common GSK089 related grade 3- 4 adverse events (AE). Only 1 possibly related grade 5 AE, death due to unknown cause, was noted. Conclusions: GSK089 is well tolerated on both dosing schedules. cMET amplification in metastatic GC is rare. Single agent GSK089 demonstrates minimal antitumor activity in a cMET-unselected gastric population on the 5 on/9 off schedule. Enrollment on the daily dosing schedule continues, now with mandatory pre- and on-treatment biopsies to better define cMET pathway and target inhibition with GSK089. No significant financial relationships to disclose.
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Zhang, Yunpu, and Ganlin Shan. "A Risk-Based Multisensor Optimization Scheduling Method for Target Threat Assessment." Mathematical Problems in Engineering 2019 (August 4, 2019): 1–14. http://dx.doi.org/10.1155/2019/2043727.
Повний текст джерелаАнотація:
The reasonable scheduling of multisensor systems to maximize combat benefits has become a research hotspot in the field of sensor management. To minimize the uncertainty in the threat level of targets and improve the survivability of sensors, a risk-based multisensor scheduling method is proposed in this paper. In this scheduling problem, the best sensors are systematically selected to observe targets for the trade-off between the threat assessment risk and the emission risk. First, the scheduling problem is modelled as a partially observable Markov decision process (POMDP) for target threat assessment. Second, the calculation methods of the threat assessment risk and the emission risk are proposed to quantify the potential loss caused by the uncertainty in the threat level of targets and the emission of sensors. Then, a nonmyopic sensor scheduling objective function is built to minimize the total risk which is the weighted sum of the threat assessment risk and the emission risk. Furthermore, to solve the high complexity computational problem in optimization, a decision tree search algorithm based on branch pruning is designed. Finally, simulations are conducted, and the results show that the proposed algorithm can significantly reduce the searching time and memory consumption in optimization compared with those of traditional algorithms, and the proposed method has a better risk control effect than the existing sensor scheduling methods.
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Ciğerci, İbrahim Hakkı. "Genotoxic assessment of oxadiazon and pendimethalin herbicides on Eisenia hortensis by comet and micronucleus tests." Pakistan Journal of Agricultural Sciences 59, no. 02 (January 1, 2022): 207–11. http://dx.doi.org/10.21162/pakjas/22.9940.
Повний текст джерелаАнотація:
Herbicides are chemicals that are widely and unconsciously used to control unwanted weeds. Herbicides do not only damage the target animals, but they also damage the off-target soil fauna. In our study, it was aimed to determine the mutational genotoxic consequences of commonly used Oxadiazon (OD) and Pendimethalin (PM) herbicides in agriculture fields on Eisenia hortensis (E. hortensis) species by using Comet and Micronucleus tests. Consequently, the LD50values for OD and PM herbicides were estimated at0.25 ppm and 0.24 ppm, respectively. Concentration series of OD and PM herbicides, ½ LD50, LD50, and 2 × LD50 were applied to E. hortensis for 48 h. As a negative control group, distilled water was used for both herbicides. An increase inthe concentration of damaged DNA and chromosomal aberration of E. hortensis coelomocytes was observed by both herbicides. Highest DNA damage (32.33 ± 2.51; 15.33 ± 1.15) was observed by the highest concentrations of OD (0.51 ppm) and PM (0.48 ppm), respectively. The negative control group had shown the least genotoxic effects. There was statistically significant (p <0.05) difference among different concentration values of OD and PM herbicides.
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Urgessa, Megersso. "The Mini Nutritional Assessment tool’s applicability for the elderly in Ethiopia: validation study." PeerJ 10 (November 16, 2022): e14396. http://dx.doi.org/10.7717/peerj.14396.
Повний текст джерелаАнотація:
Background The Mini Nutrition Assessment (MNA) is a widely used and valid tool for screening and assessment of malnutrition among the elderly population worldwide. However, MNA has not been validated among the Ethiopian elderly population and this study assessed the validity of the tool for the target population. Methods Cross-sectional validation study design employed to validate MNA in Meki town, East Ethiopia. This study included 176 randomly selected elders living in the community, whereas amputated, bedridden, visible deformity, known liver and/or renal disorders were excluded. The original MNA questionnaires were translated to local language and administered to each participant after doing the pretest. The anthropometric, self-perception of nutritional status and serum albumin concentrations were measured. Reliability, validity, sensitivity, specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) were calculated. Receiver-operating characteristic (ROC) curve analysis was plotted to identify the area under the curve (AUC) and optimal cut-off value for the prediction of malnutrition. Result A total of one hundred and seventy-six elders participated in this study. Of the total participants, 78(44.3%) were males. The mean (SD) age of the participants was 67.6 (±5.8) years and ranged from 60 to 84 years. The prevalence of malnutrition based on the MNA criteria (MNA < 17 points) was 18.2%, and 13.1% based on serum albumin concentration (<3 g/dl).The MNA had an overall Internal consistency of Cronbach’s alpha 0.61. The tool also demonstrated significant criterion-related validity (0.75, p < 0.001) and concurrent validity (0.51, p < 0.001) with serum albumin concentration and self-perception of nutritional status respectively. Using the original cut-off point, the sensitivity, specificity, PPV and NPV of the tool were 93.5%, 44.6%, 65.4% and 86.0%, respectively. By modifying, the cut-off point to a value of <20.5, the sensitivity and specificity of the tool increases to 97.6% and 82.8% respectively. The AUC (95%CI) showed an overall accuracy of 92.7% (88.5, 96.9). Conclusion The MNA tool can be used as a valid malnutrition screening tool for the Ethiopian elderly population by modifying the original cut-off point.
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Punt, André E., Malcolm Haddon, L. Richard Little, and Geoffrey N. Tuck. "The effect of marine closures on a feedback control management strategy used in a spatially aggregated stock assessment: a case study based on pink ling in Australia." Canadian Journal of Fisheries and Aquatic Sciences 74, no. 11 (November 2017): 1960–73. http://dx.doi.org/10.1139/cjfas-2016-0017.
Повний текст джерелаАнотація:
Simulation is used to explore the effect of spatial heterogeneity and spatial closures on the ability of feedback-control management strategies to achieve goals relating to conservation and utilization of fishery resources. The operating model underlying the projections is based on pink ling, Genypterus blacodes, off southern Australia and assumes that animals are sedentary following settlement. The management strategies are able to move the resource towards the target level in the absence of spatial closures even though assessment results are biased. The probability of reducing the stock below its limit reference point is higher when growth rates vary spatially, but the effect is small. The probability of the stock being above its target reference point is lower when one of the smaller spatial areas is closed. However, performance is markedly different when a larger fraction of the total area is closed, with stock size being substantially larger than the target at the end of the projection period.
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Zhang, Wei, Zheng Lv, Yupeng Zhang, Subash C. B. Gopinath, Yi Yuan, Deyou Huang, and Liu Miao. "Targeted Diagnosis, Therapeutic Monitoring, and Assessment of Atherosclerosis Based on Mesoporous Silica Nanoparticles Coated with cRGD-Platelets." Oxidative Medicine and Cellular Longevity 2022 (September 29, 2022): 1–19. http://dx.doi.org/10.1155/2022/6006601.
Повний текст джерелаАнотація:
Objective. The off-target effects and severe side effects of PPARα and LXRα agonists greatly limit their application in atherosclerosis (AS). Therefore, this study intended to use mesoporous silica nanoparticles as carriers to generate MnO nanoparticles in situ with T1WI-MRI in mesoporous pores and simultaneously load PPARα and LXRα agonists. Afterward, cRGD-chelated platelet membranes can be used for coating to construct a new nanotheranostic agent. Methods. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles were synthesized by a chemical method. Dynamic light scattering (DLS) was utilized to detect the size distribution and polydispersity index (PDI) of the nanoparticles. The safety of the nanoparticles was detected by CCK8 in vitro and HE staining and kidney function in vivo. Cell apoptosis was detected by flow cytometry detection and TUNEL staining. Oxidative stress responses (ROS, SOD, MDA, and NOX levels) were tested via a DCFH-DA assay and commercial kits. Immunofluorescence and phagocytosis experiments were used to detect the targeting of nanoparticles. Magnetic resonance imaging (MRI) was used to detect the imaging performance of cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles. Using western blotting, the expression changes in LXRα and ABCA1 were identified. Results. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles were successfully established, with a particle size of approximately 150 nm and PDI less than 0.3, and showed high safety both in vitro and in vivo. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles showed good targeting properties and better MRI imaging performance in AS. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles showed better antioxidative capacities, MRI imaging performance, and diagnostic and therapeutic effects on AS by regulating the expression of LXRα and ABCA1. Conclusion. In the present study, cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles with high safety and the capacity to target vulnerable plaques of AS were successfully established. They showed better performance on MRI images and treatment effects on AS by promoting cholesterol efflux through the regulation of ABCA1. These findings might address the problems of off-target effects and side effects of nanoparticle-mediated drug delivery, which will enhance the efficiency of AS treatment and provide new ideas for the clinical treatment of AS.
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Goraj, Zdobyslaw Jan, Marek Malinowski, and Andrzej Frydrychewicz. "Design of novel aerial jet target." Aircraft Engineering and Aerospace Technology 89, no. 4 (July 3, 2017): 511–19. http://dx.doi.org/10.1108/aeat-10-2016-0174.
Повний текст джерелаАнотація:
Purpose This paper aims to present and discuss the requirements for flying targets which sometimes are contradictory to each other and to perform a trade-off analysis before the design activity is started. It also aims to demonstrate conceptual and preliminary design processes using a practical example of PW-61 configuration and to show how results of experimental flight tests using a scaled flying target will be described and analyzed before manufacturing the full scale flying target. Design/methodology/approach An important part of the paper consists of the selection of tailplane configuration of the flying target UAV to protect some expensive on-board systems against serious damages and to obtain a sufficient dynamic stability, independently of the amount of the petrol in fuel tank. Inverted V-tail, U-tail and H-tail configurations were considered and compared both, theoretically and in-flight experiments. Findings Flight dynamics models and associated computational procedures were useful both in a preliminary design phase and during the final assessment of the configuration after flight tests. Selection of the tailplane configuration for the flying target UAV is very important to protect some expensive on-board systems against serious damages and to obtain a sufficient dynamic stability, independent of the amount of the petrol in fuel tank. Practical implications Flying targets should be speedy, maneuverable, cheap, easy in deployment and multi-recoverable (if not destroyed by live ammunition), must have relatively low take-off weight and an endurance of at least 1 h. This paper can be useful for proper selection of requirements and preliminary design parameters to make the design process more economically effective. Originality/value This paper presents very efficient methods of assessing the design parameters of flying targets, especially in an early stage of the design process. Stability computations are performed based on equations of motion and are supplemented by flight tests using the scaled flying models. It can be considered as an original, not typical, but very practical approach because it delivers lots of data in the early design stages at relatively low cost.
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Wang, Ena, Alessandra Cesano, Lisa H. Butterfield, and Francesco Marincola. "Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy." Journal for ImmunoTherapy of Cancer 8, no. 2 (October 2020): e001619. http://dx.doi.org/10.1136/jitc-2020-001619.
Повний текст джерелаАнотація:
The therapeutic index (TI) is a quantitative assessment of a drug safety proportional to its effectiveness. The estimation is intuitive when the engagement of the product with its target is dependent on stable chemistry and predictable pharmacokinetics as is the case for small molecules or antibodies. But for therapeutics with complex biodistribution and context-dependent potency such as adoptive cell therapy (ACT) products, TI estimations need to consider a broader array of factors. These include product-dependent variability such as functional fitness, unpredictable pharmacokinetics due to non-specific trapping, sequestration and extravasation into normal tissues and variable rates of in vivo expansion. In the case of solid malignancies, additional modifiers dependent on individual tumor immune biology may affect pharmacodynamics, including differential trafficking to benign compared with cancer tissue, hampered engagement with target cells, immune suppression and cellular dysfunction due to unfavorable metabolic conditions. Here, we propose a patient-specific assessment of factors affecting on-tumor from off-tumor activity in disparate immunologic environments that impact ACT’s clinical efficacy and may favorably balance the TI. for ACT products.