Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid ...parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
Rice, a major food crop, is grown in a wide range of ecological conditions and suffers significant yield losses as it is constantly exposed to a wide range of environmental and biotic stresses. The ...prevalence of different biotypes/strains has necessitated assembling of numerous resistance genes/QTLs into elite genotypes to confer a broader scale of resistance. The current study reports successful pyramiding of genes/QTLs that confer tolerance/resistance to submergence (Sub1), salinity (Saltol), blast (Pi2, Pi9) and gall midge (Gm1, Gm4) to supplement the four bacterial blight resistance genes (Xa 4, xa5, xa13, Xa21) present in Improved Tapaswini, an elite cultivar. The precise transfer of genes/QTLs was accomplished through effective foreground selection and suitable gene pyramids were identified. Background selection was practiced using morphological and grain quality traits to enhance the recovery of the recurrent parental genome. In the bioassays, the pyramids exhibited higher levels of resistance/ tolerance against the target stresses. The novel feature of the study was successful pyramidization and demonstration of the function of ten genes/QTLs in a new genotype. This success can stimulate several such studies to realize the full potential of molecular plant breeding as the foundation for rice improvement.
The authors propose to estimate nonlinear small area population parameters by using the empirical Bayes (best) method, based on a nested error model. They focus on poverty indicators as particular ...nonlinear parameters of interest, but the proposed methodology is applicable to general nonlinear parameters. They use a parametric bootstrap method to estimate the mean squared error of the empirical best estimators. They also study small sample properties of these estimators by model-based and design-based simulation studies. Results show large reductions in mean squared error relative to direct area-specific estimators and other estimators obtained by "simulated" censuses. The authors also apply the proposed method to estimate poverty incidences and poverty gaps in Spanish provinces by gender with mean squared errors estimated by the mentioned parametric bootstrap method. For the Spanish data, results show a significant reduction in coefficient of variation of the proposed empirical best estimators over direct estimators for practically all domains. Les auteurs proposent d'estimer les paramètres non linéaires d'une population de petits domaines en utilisant une méthode bayésienne empirique. L'emphase est mise sur les indicateurs de pauvreté comme paramètres non linéaires d'intérêt particuliers, mais ils proposent une méthodologie qui s'applique à des paramètres non linéaires plus généraux. Ils utilisent une méthode de rééchantillonnage paramétrique pour estimer l'erreur quadratique moyenne du meilleur estimateur empirique. À l'aide de simulations basées sur le modèle et sur le plan de sondage, ils étudient les propriétés de ces estimateurs pour les petits échantillons. Les résultats obtenus montrent une grande réduction de l'erreur quadratique moyenne par rapport aux estimateurs propres aux régions et les autres estimateurs obtenus par recensements « simulés». Les auteurs ont aussi appliqué la méthodologie proposée à l'estimation des incidences de pauvreté et des disparités, en fonction du sexe, du niveau de la pauvreté des provinces espagnoles. Les erreurs quadratiques moyennes sont estimées en utilisant la méthode de rééchantillonnage paramétrique citée auparavant. Pour les données espagnoles, les résultats montrent une réduction substantielle du coefficient de variation des meilleurs estimateurs empiriques proposés par rapport aux estimateurs spécifiques pour pratiquement tous les domaines.
Standard statistical methods without taking proper account of the complexity of a survey design can lead to erroneous inferences when applied to survey data due to unequal selection probabilities, ...clustering, and other design features. In particular, the Type I error rates of hypotheses tests using standard methods can be much larger than the nominal significance level. Methods incorporating design features in testing hypotheses have been proposed, including Wald tests and quasi-score tests that involve estimated covariance matrices of parameter estimates. In this article, we present a unified approach to hypothesis testing without requiring estimated covariance matrices or design effects, by constructing bootstrap approximations to quasi-likelihood ratio statistics and quasi-score statistics and establishing its asymptotic validity. The proposed method can be easily implemented without a specific software designed for complex survey sampling. We also consider hypothesis testing for categorical data and present a bootstrap procedure for testing simple goodness of fit and independence in a two-way table. In simulation studies, the Type I error rates of the proposed approach are much closer to their nominal significance level compared with the naive likelihood ratio test and quasi-score test. An application to an educational survey under a logistic regression model is also presented.
Supplementary materials
for this article are available online.
Things we can do because of learning are called outcomes of learning. Outcome based education (OBE) was propounded by William Spady in the 90s to bring the focus of formal education to what the ...students learn rather than what they were taught. OBE is a system of education giving priority to ends, purpose, accomplishments, and results. All decisions about the curriculum, assessment, and instruction are driven by the exit learning outcomes the students should display at the end of a program or a course. This paper presents a method of writing outcomes for General higher education programs. Outcomes for a higher education program are defined at three levels as program outcomes (POs), program specific outcomes (PSOs), and course outcomes (COs). The most important aspect of an outcome is that it should be observable and measurable. These are best written in a well-defined framework of taxonomy of learning. Bloom's taxonomy of learning identifies three domains of learning: Cognitive, affective and psychomotor. Revised Bloom taxonomy of cognitive domain has two dimensions cognitive levels and knowledge categories. It is proposed that CO statements be written within a well-defined structure: Action, knowledge elements, conditions, and criteria. Tagging COs with POs, PSOs, cognitive levels and the number of classroom hours associated facilitates the computation of attainment of COs, POs, and PSOs.
Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we ...reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the Leishmania tarentolae proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.
Soil microbial communities are important drivers of biogeochemical cycling of nutrients, organic matter decomposition, soil organic carbon, and Greenhouse gas emissions (GHGs: CO
, N
O, and CH
) and ...are influenced by crop and soil management practices. The knowledge on the impact of conservation agriculture (CA) on soil bacterial diversity, nutrient availability, and GHG emissions in semi-arid regions under rainfed conditions is vital to develop sustainable agricultural practices, but such information has not been systemically documented. Hence, studies were conducted for 10 years in rainfed pigeonpea (
L.)-castor bean (
L.) cropping system under semi-arid conditions to assess the effects of tillage and crop residue levels on the soil bacterial diversity, enzyme activity (Dehydrogenase, urease, acid phosphatase, and alkaline phosphatase), GHG emissions, and soil available nutrients (Nitrogen, phosphorus, and potassium). Sequencing of soil DNA through Illumina HiSeq-based 16S rRNA amplicon sequencing technology has revealed that bacterial community responded to both tillage and residue levels. The relative abundance of Actinobacteria in terms of Operational Taxonomic Unit (OTUs) at phyla, class as well as genera level was higher in CA (NTR1: No Tillage + 10 cm anchored residue and NTR2 NT + 30 cm anchored residue) over CT (conventional tillage without crop residues). CA resulted in higher enzyme activities (dehydrogenase, urease, acid phosphatase, and alkaline phosphatase) and reduction in GHG emissions over CT. CA recorded 34% higher and 3% lower OC, as compared to CT, and CTR1, respectively. CA recorded 10, 34, and 26% higher available nitrogen, phosphorus, and potassium over CT and CTR1, respectively. NTR1 recorded 25 and 38% lower N
O emissions as compared to CTR1 and CTR2, respectively. Whereas only NT recorded 12% higher N
O emissions as compared to CT. Overall, the results of the study indicate that CA improves the relative abundance of soil bacterial communities, nutrient availability, and enzyme activities, and may help to contribute to the mitigation of climate change, and sustainability in rainfed areas.
Breeding for resistance against Bacterial blight (BB), a destructive disease in rice, is a major challenge because of the rich diversity of the pathogen,
Xanthomonas oryzae
pv.
oryzae
. Three ...resistance genes i.e.
xa5
,
xa13
and
Xa21
were transferred from IRBB 60 through marker-assisted backcross breeding to supplement the
Xa4
gene present in Tapaswini, an elite cultivar having a wide coverage. The precise transfer was aided through effective foreground selection using STS markers RG 556, RG 136 and pTA248 linked to the three target genes, respectively. In the screening assays, the gene pyramids having four genes exhibited higher level of resistance against the disease. Background selection based on morphological and grain quality traits and SSR markers led to the recovery of 85–96 % of the recurrent parent genome in the gene pyramids. Multi location evaluation conducted over a two year period at several hotspot locations of bacterial blight in India has resulted in identification and release of CRMAS 2622-7-6 (IT-6), a promising gene pyramid as improved Tapaswini. The high levels of resistance exhibited in the improved genotype without any yield penalty and its similarity to the recurrent parent provides a successful demonstration of the potential of MAS in pyramiding genes as well as the recovery of the parental genome with high accuracy.
Zn (II) is one the common pollutant among heavy metals found in industrial effluents. Removal of pollutant from industrial effluents can be accomplished by various techniques, out of which adsorption ...was found to be an efficient method. Applications of adsorption limits itself due to high cost of adsorbent. In this regard, a low cost adsorbent produced from palm oil kernel shell based agricultural waste is examined for its efficiency to remove Zn (II) from waste water and aqueous solution. The influence of independent process variables like initial concentration, pH, residence time, activated carbon (AC) dosage and process temperature on the removal of Zn (II) by palm kernel shell based AC from batch adsorption process are studied systematically. Based on the design of experimental matrix, 50 experimental runs are performed with each process variable in the experimental range. The optimal values of process variables to achieve maximum removal efficiency is studied using response surface methodology (RSM) and artificial neural network (ANN) approaches. A quadratic model, which consists of first order and second order degree regressive model is developed using the analysis of variance and RSM - CCD framework. The particle swarm optimization which is a meta-heuristic optimization is embedded on the ANN architecture to optimize the search space of neural network. The optimized trained neural network well depicts the testing data and validation data with R2 equal to 0.9106 and 0.9279 respectively. The outcomes indicates that the superiority of ANN-PSO based model predictions over the quadratic model predictions provided by RSM.
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•Palm oil kernels based activated carbon as low cost agricultural adsorbent for zinc removal•Particle Swarm Optimization (PSO) embedded with artificial neural network (ANN) algorithm for search space•Novel approach to model and optimize the pollutant removal by ANN-PSO integration•Optimization of process variables for maximum removal of pollutant by Response Surface methodology (RSM)
Based on its marked overexpression in multiple malignancies and its roles in promoting cell survival and proliferation, survivin is an attractive candidate for targeted therapy. Toward this end, a ...detailed understanding of the mechanisms regulating survivin expression in different cancer cells will be critical. We have previously shown that the RNA-binding protein (RBP) CUG-BP1 is overexpressed in esophageal cancer cells and post-transcriptionally regulates survivin in these cells. The objective of this study was to investigate the role of microRNAs (miRs) in regulating survivin expression in esophageal cancer cells. Using miR expression profiling analysis, we found that miR-214-3p is one of the most markedly downregulated miRs in two esophageal squamous cancer cell lines compared with esophageal epithelial cells. Interestingly, using miR target prediction programs, both survivin and CUG-BP1 mRNA were found to contain potential binding sites for miR-214-3p. Forced expression of miR-214-3p in esophageal cancer cells leads to a decrease in the mRNA and protein levels of both survivin and CUG-BP1. This effect is due to decreased mRNA stability of both targets. By contrast, silencing miR-214-3p in esophageal epithelial cells leads to an increase in both survivin and CUG-BP1 mRNA and protein. To determine whether the observed effect of miR-214-3p on survivin expression was direct, mediated through CUG-BP1, or both, binding studies utilizing biotin pull-down assays and heterologous luciferase reporter constructs were performed. These demonstrated that the mRNA of survivin and CUG-BP1 each contain two functional miR-214-3p-binding sites as confirmed by mutational analysis. Finally, forced expression of miR-214-3p enhances the sensitivity of esophageal cancer cells to cisplatin-induced apoptosis. This effect is abrogated with rescue expression of survivin or CUG-BP1. These findings suggest that miR-214-3p acts as a tumor suppressor and that its downregulation contributes to chemoresistance in esophageal cancer cells by targeting both survivin and CUG-BP1.
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