Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

Emergency crisis resource management: a simulation-based course developed by the Spanish Society of Emergency Medicine (SEMES) for health sciences students. / Emergency Crisis Resource Management de la Sociedad Española de Medicina de Urgencias y Emergencias: curso de gestión en crisis basado en simulación para estudiantes de ciencias de la salud.

OBJECTIVES: Educational programs based on high-fidelity simulation training aim to promote students' acquisition of nontechnical competencies such as understanding crisis resource management (CRM). This study evaluated the efficacy of a CRM course for students in their last year of university studies in health sciences. The course was developed by the Spanish Society of Emergency Medicine (SEMES). MATERIAL AND METHODS: Quasi-experimental study of a high-fidelity simulation course to teach emergency CRM (E-CRM) using preand postcourse measures of achievement in a single student cohort. A total of 209 students completed 2 selfadministered self-efficacy evaluations of their acquisition of nontechnical competencies and resilience. External observers also assessed the students' nontechnical competencies with objective measurement scales. RESULTS: Scores on resilience and self-efficacy assessments improved through the intervention (F = 25.90 and F = 68.02, respectively; P .001, for both pre-post comparisons). Statistically significant differences were found between students in different health sciences at baseline (t = 2.67; P = .008). Scores improved significantly on the Mayo High Performance Teamwork Scale (F = 6.18, P .001, eta2 = 0.20) and the Ottawa CRM Global Rating Scale (F = 5.58; P .005, eta2 = 0.19). CONCLUSION: The E-CRM course developed by a coordinated multiprofessional team based on high-fidelity simulations improved self-efficacy assessments of resilience and all nontechnical competencies.

OBJETIVO: Los programas educativos dirigidos a la adquisición de competencias no técnicas, tales como el Crisis Resource Management (CRM), basado en simulación de alta fidelidad, implican un aumento de las competencias del alumno en el manejo de situaciones de crisis. El objetivo del presente trabajo es evaluar la eficacia del programa Emergency CRM (E-CRM) de la Sociedad Española de Medicina de Urgencias y Emergencias, dirigido a estudiantes de último año de los grados de ciencias de la salud. METODO: Se llevó a cabo un estudio cuasiexperimental con medidas pre y posintervención, que consistió en un programa de E-CRM con simulación de alta fidelidad, en un único grupo. Participaron un total de 209 estudiantes que completaron dos instrumentos autoadministrados sobre la autoeficacia hacia las competencias no técnicas y la resiliencia. Además, a través de observadores externos se evaluó sus competencias no técnicas con instrumentos de evaluación objetivos. RESULTADOS: El alumnado mejoró las puntuaciones de resiliencia (F = 25,90; p < 0,001) y autoeficacia (F = 68,02; p 0,001) tras la intervención, con diferencias estadísticamente significativas para la resiliencia en la línea basal en función del grupo de estudios (t = 2,67; p = 0,008). Por otro lado, se encontraron mejoras de las puntuaciones obtenidas tanto para el instrumento Mayo High Performance Teamwork Scale (F = 6,18; p 0,001; eta2 = 0,20) como para el Ottawa Global Rating Scale Crisis Resource Management (F = 5,58; p 0,005; eta2 = 0,19). CONCLUSIONES: El programa de E-CRM, basado en simulación de alta fidelidad, con un equipo interprofesional coordinado, mejora la autoeficacia en todas las competencias no técnicas medidas y aumenta la resiliencia.

Indicators sand flies and environment associated to spatial landscaping change in Choco Biosphere Reserve UNESCO.

BACKGROUND OBJECTIVES: Sand flies are insects vector associated with terrestrial forest ecosystems; in the Ecuadorian Andes, they participate in the transmission of human cutaneous leishmaniasis. This geographical area is an opportunity to evaluate the role of sand flies as bioindicators od the degree of intervention of a tropical humid forest ecosystems (THF) associated with changes in the ecology of the local landscape. METHODS: CDC-light traps were used for collecting adults' sand flies in February 2020 in a humid tropical forest within Choco Biosphere Reserve. All species were identified using morphological keys. Analysis data about abundance, richness, species accumulation, diversity index, species composition communities, species sex proportion, spatial sand flies environmental, Renyi's Diversity Profile were performed to compare six spatial habitats in Mashpi locality, Ecuador. RESULTS: Sand flies were collected (n-1435); the main species are represented by Th. reburra Ny. trapidoi, Pa. aclydifera, Py. panamensis and Lu. hartmanni. Only Th. reburra is associated with not intervened forest, while the other 3 species are associated with intervened forest within Mashpi in the Choco Biosphere Reserve. The secondary forest has the major sandflies' richness, while the primary forest exhibits the major abundance. INTERPRETATION CONCLUSION: The results indicated that Th. reburra is a sandfly restricted to the Andean Forest and is a bioindicator of the high environmental health quality of the forest, while Ny. trapidoi and Pa. aclydifera are bioindicators of environmental disturbances in the forest. Additionally, Ps. panamensis, Lu. hartmanni and Ny. trapidoi are bioindicators of human impact and the risk of leishmaniasis.

Improving fraud detection with semi-supervised topic modeling and keyword integration.

Fraud detection through auditors' manual review of accounting and financial records has traditionally relied on human experience and intuition. However, replicating this task using technological tools has represented a challenge for information security researchers. Natural language processing techniques, such as topic modeling, have been explored to extract information and categorize large sets of documents. Topic modeling, such as latent Dirichlet allocation (LDA) or non-negative matrix factorization (NMF), has recently gained popularity for discovering thematic structures in text collections. However, unsupervised topic modeling may not always produce the best results for specific tasks, such as fraud detection. Therefore, in the present work, we propose to use semi-supervised topic modeling, which allows the incorporation of specific knowledge of the study domain through the use of keywords to learn latent topics related to fraud. By leveraging relevant keywords, our proposed approach aims to identify patterns related to the vertices of the fraud triangle theory, providing more consistent and interpretable results for fraud detection. The model's performance was evaluated by training with several datasets and testing it with another one that did not intervene in its training. The results showed efficient performance averages with a 7% increase in performance compared to a previous job. Overall, the study emphasizes the importance of deepening the analysis of fraud behaviors and proposing strategies to identify them proactively.

Antimicrobial activities of Agave fructans against multi-resistant and biofilm-producing Staphylococcus aureus isolated from bovine mastitis.

Bovine mastitis is an emerging disease that causes large economic losses. Staphylococcus aureus its main etiological agent, is multi-resistant to antimicrobials and produces biofilm. The objective of this study was to investigate the effect of Agave fructans (AF), a type of prebiotic, on multi-resistant and biofilm-forming isolates of S. aureus. Ten isolates of S. aureus from bovine subclinical mastitis previously characterized as highly resistant to antimicrobials and biofilm formers were used in this study. The growth kinetics of S. aureus in the presence of AF was evaluated by the Baranyi and Roberts microbial growth model using the DMFit program. The antibacterial activity of AF against S. aureus was studied by the well-diffusion method and the effect on biofilm formation by the crystal violet method. All assays were performed in triplicate for each isolate and an ANOVA with Tukey's post hoc was performed considering p < 0.05 as significant. The AF showed a decrease in maximum growth rate (µmax) and OD max levels (Ymax) in all isolates with all concentrations. Also, zones of inhibition were observed due to the effect of all AF concentrations in all isolates in a dose-dependent manner. Interestingly, S. aureus biofilm formation was inhibited by all AF concentrations assessed in this study. More investigations are required to elucidate the mechanisms of action of AF on S. aureus as well as in vivo studies to evaluate its therapeutic efficacy for bovine mastitis.

Thioredoxin domain containing 5 is involved in the hepatic storage of squalene into lipid droplets in a sex-specific way.

Hepatic thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family found associated with anti-steatotic properties of squalene and located in the endoplasmic reticulum and in lipid droplets. Considering that the latter are involved in hepatic squalene accumulation, the present research was aimed to investigate the role of TXNDC5 on hepatic squalene management in mice and in the AML12 hepatic cell line. Wild-type and TXNDC5-deficient (KO) mice were fed Western diets with or without 1% squalene supplementation for 6 weeks. In males, but not in females, absence of TXNDC5 blocked hepatic, but not duodenal, squalene accumulation. Hepatic lipid droplets were isolated and characterized using label-free LC-MS/MS analysis. TXNDC5 accumulated in this subcellular compartment of mice receiving squalene and was absent in TXNDC5-KO male mice. The latter mice were unable to store squalene in lipid droplets. CALR and APMAP were some of the proteins that responded to the squalene administration in all studied conditions. CALR and APMAP were positively associated with lipid droplets in the presence of squalene and they were decreased by the absence of TXNDC5. The increased squalene content was reproduced in vitro using AML12 cells incubated with squalene-loaded nanoparticles and this effect was not observed in an engineered cell line lacking TXNDC5. The phenomenon was also present when incubated in the presence of a squalene epoxidase inhibitor, suggesting a mechanism of squalene exocytosis involving CALR and APMAP. In conclusion, squalene accumulation in hepatic lipid droplets is sex-dependent on TXNDC5 that blocks its secretion.

Optimal allocation of agriculture's public budget can improve transformation and healthy diets access in Ethiopia.

Agriculture is under transformation in sub-Saharan Africa where millions still do not have access to a healthy diet. Policy makers in this region should find ways to accelerate agricultural transformation while increasing access to healthy diets. Optimizing agriculture's public budget stands out as a handy option. By combining a dynamic computable general equilibrium model and a multi-criteria decision-making technique, and applying them in the context of Ethiopia, this paper points to an important trade-off that policy makers should keep in mind. An optimal allocation of agriculture's public budget aimed at increasing agri-food output, creating off-farm jobs and reducing rural poverty, which are agricultural transformation objectives, will help to reduce the cost of a healthy diet, allowing around 2 million more Ethiopians to afford it. This number could even be higher should policy makers allocate the budget optimally aiming at only lowering the cost of a healthy diet, but at the cost of reducing household income and slowing down transformation.

Endoplasmic Reticulum Protein TXNDC5 Interacts with PRDX6 and HSPA9 to Regulate Glutathione Metabolism and Lipid Peroxidation in the Hepatic AML12 Cell Line.

Non-alcoholic fatty liver disease or steatosis is an accumulation of fat in the liver. Increased amounts of non-esterified fatty acids, calcium deficiency, or insulin resistance may disturb endoplasmic reticulum (ER) homeostasis, which leads to the abnormal accumulation of misfolded proteins, activating the unfolded protein response. The ER is the primary location site for chaperones like thioredoxin domain-containing 5 (TXNDC5). Glutathione participates in cellular oxidative stress, and its interaction with TXNDC5 in the ER may decrease the disulfide bonds of this protein. In addition, glutathione is utilized by glutathione peroxidases to inactivate oxidized lipids. To characterize proteins interacting with TXNDC5, immunoprecipitation and liquid chromatography-mass spectrometry were used. Lipid peroxidation, reduced glutathione, inducible phospholipase A2 (iPLA2) and hepatic transcriptome were assessed in the AML12 and TXNDC5-deficient AML12 cell lines. The results showed that HSPA9 and PRDX6 interact with TXNDC5 in AML12 cells. In addition, TXNDC5 deficiency reduced the protein levels of PRDX6 and HSPA9 in AML12. Moreover, lipid peroxidation, glutathione and iPLA2 activities were significantly decreased in TXNDC5-deficient cells, and to find the cause of the PRDX6 protein reduction, proteasome suppression revealed no considerable effect on it. Finally, hepatic transcripts connected to PRDX6 and HSPA9 indicated an increase in the Dnaja3, Mfn2 and Prdx5 and a decrease in Npm1, Oplah, Gstp3, Gstm6, Gstt1, Serpina1a, Serpina1b, Serpina3m, Hsp90aa1 and Rps14 mRNA levels in AML12 KO cells. In conclusion, the lipid peroxidation system and glutathione mechanism in AML12 cells may be disrupted by the absence of TXNDC5, a novel protein-protein interacting partner of PRDX6 and HSPA9.

Common evolutionary origins of the bacterial glycyl tRNA synthetase and alanyl tRNA synthetase.

Aminoacyl-tRNA synthetases (aaRSs) establish the genetic code. Each aaRS covalently links a given canonical amino acid to a cognate set of tRNA isoacceptors. Glycyl tRNA aminoacylation is unusual in that it is catalyzed by different aaRSs in different lineages of the Tree of Life. We have investigated the phylogenetic distribution and evolutionary history of bacterial glycyl tRNA synthetase (bacGlyRS). This enzyme is found in early diverging bacterial phyla such as Firmicutes, Acidobacteria, and Proteobacteria, but not in archaea or eukarya. We observe relationships between each of six domains of bacGlyRS and six domains of four different RNA-modifying proteins. Component domains of bacGlyRS show common ancestry with (i) the catalytic domain of class II tRNA synthetases; (ii) the HD domain of the bacterial RNase Y; (iii) the body and tail domains of the archaeal CCA-adding enzyme; (iv) the anti-codon binding domain of the arginyl tRNA synthetase; and (v) a previously unrecognized domain that we call ATL (Ancient tRNA latch). The ATL domain has been found thus far only in bacGlyRS and in the universal alanyl tRNA synthetase (uniAlaRS). Further, the catalytic domain of bacGlyRS is more closely related to the catalytic domain of uniAlaRS than to any other aminoacyl tRNA synthetase. The combined results suggest that the ATL and catalytic domains of these two enzymes are ancestral to bacGlyRS and uniAlaRS, which emerged from common protein ancestors by bricolage, stepwise accumulation of protein domains, before the last universal common ancestor of life.

Changes in diversity and species composition in the assemblage of live and dead bats at wind farms in a highly diverse region.

Besides direct mortality, wind farms also affect aerial fauna by modifying their communities, reducing species diversity and richness through disturbance. During three consecutive years, we used mist nets and acoustic recorders, and conducted carcass searches, to characterize the assemblage of bat species and to estimate bat mortality at two nearby wind farms sited <5 km apart in a highly biodiverse region. We asked whether the diversity, richness and evenness of the assemblages varied yearly, predicting it would decrease through time. Richness and evenness did not change, but the diversity of species recorded acoustically, 96% being aerial insectivores, was significantly lower the third year. We estimate 4 - 15.7 fatalities/MW/year by wind farm, with 63% of species found as carcasses being aerial insectivores. We found >40% of dissimilarity in the species composition of bat assemblages between wind farms despite the short distance between them, with species turnover accounting for more than half of the dissimilarity every year. Similarly, species turnover accounted for >15% of the dissimilarity in the composition of the assemblage of live bats (captured and recorded acoustically) and the assemblage obtained through carcass searches. Our findings suggest that nearby wind farms impact bat communities differentially and aerial insectivores disproportionally. Long term, multi-method surveys are needed to characterize bat communities in highly diverse regions and to evaluate the post-construction effects that wind farms have on them.

Dietary proteins modulate high-density lipoprotein characteristics in a sex-specific way in Apoe-deficient mice.

OBJECTIVES: The type and amount of dietary protein have become a topic of renewed interest, considering their involvement in several diseases. However, little attention has been devoted to the effect of avian proteins despite their wide human consumption. In a previous study, we saw that compared with soybean protein, the consumption of avian proteins, depending on sex, resulted in similar or lower atherosclerosis with a higher paraoxonase 1 activity, an antioxidant enzyme carried by high-density lipoproteins (HDL). This suggests that under these conditions, the HDL lipoproteins may undergo important changes. The aim of this research was to study the influence of soybean, chicken, and turkey proteins on the characteristics of HDL. METHODS: Male and female Apoe-deficient mice were fed purified Western diets based on the AIN-93 diet, differing only in the protein source, for 12 wk. After this period, blood and liver samples were taken for analysis of HDL composition and hepatic expression of genes related to HDL metabolism (Abca1, Lcat, Pltp, Pon1, and Scarb1). Depending on sex, these genes define a different network of interactions. Females consuming the turkey protein-containing diet showed decreased atherosclerotic foci, which can be due to larger very-low-density lipoproteins (VLDLs) calculated by molar ratio triacylglycerols/VLDL cholesterol and higher expression of Lcat. In contrast, in males, a higher ratio of paraoxonase1 to apolipoprotein A1 decreased the oxidative status of the different lipoproteins, and augmented Abca1 expression was observed. CONCLUSIONS: The source of protein has an effect on the development of atherosclerosis depending on sex by modifying HDL characteristics and the expression of genes involved in their properties.

Phylogeographic relationships and morphological evolution between cave and surface Astyanax mexicanus populations (De Filippi 1853) (Actinopterygii, Characidae).

The Astyanax mexicanus complex includes two different morphs, a surface- and a cave-adapted ecotype, found at three mountain ranges in Northeastern Mexico: Sierra de El Abra, Sierra de Guatemala and Sierra de la Colmena (Micos). Since their discovery, multiple studies have attempted to characterize the timing and the number of events that gave rise to the evolution of these cave-adapted ecotypes. Here, using RADseq and genome-wide sequencing, we assessed the phylogenetic relationships, genetic structure and gene flow events between the cave and surface Astyanax mexicanus populations, to estimate the tempo and mode of evolution of the cave-adapted ecotypes. We also evaluated the body shape evolution across different cave lineages using geometric morphometrics to examine the role of phylogenetic signal versus environmental pressures. We found strong evidence of parallel evolution of cave-adapted ecotypes derived from two separate lineages of surface fish and hypothesize that there may be up to four independent invasions of caves from surface fish. Moreover, a strong congruence between the genetic structure and geographic distribution was observed across the cave populations, with the Sierra de Guatemala the region exhibiting most genetic drift among the cave populations analysed. Interestingly, we found no evidence of phylogenetic signal in body shape evolution, but we found support for parallel evolution in body shape across independent cave lineages, with cavefish from the Sierra de El Abra reflecting the most divergent morphology relative to surface and other cavefish populations.

Differentially Expressed Genes in Response to a Squalene-Supplemented Diet Are Accurate Discriminants of Porcine Non-Alcoholic Steatohepatitis.

Squalene is the major unsaponifiable component of virgin olive oil, the fat source of the Mediterranean diet. To evaluate its effect on the hepatic transcriptome, RNA sequencing was carried out in two groups of male Large White x Landrace pigs developing nonalcoholic steatohepatitis by feeding them a high fat/cholesterol/fructose and methionine and choline-deficient steatotic diet or the same diet with 0.5% squalene. Hepatic lipids, squalene content, steatosis, activity (ballooning + inflammation), and SAF (steatosis + activity + fibrosis) scores were analyzed. Pigs receiving the latter diet showed hepatic squalene accumulation and twelve significantly differentially expressed hepatic genes (log2 fold change < 1.5 or <1.5) correlating in a gene network. These pigs also had lower hepatic triglycerides and lipid droplet areas and higher cellular ballooning. Glutamyl aminopeptidase (ENPEP) was correlated with triglyceride content, while alpha-fetoprotein (AFP), neutralized E3 ubiquitin protein ligase 3 (NEURL3), 2'-5'-oligoadenylate synthase-like protein (OASL), and protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B) were correlated with activity reflecting inflammation and ballooning, and NEURL3 with the SAF score. AFP, ENPEP, and PPP1R1B exhibited a remarkably strong discriminant power compared to those pathological parameters in both experimental groups. Moreover, the expression of PPP1R1B, TMEM45B, AFP, and ENPEP followed the same pattern in vitro using human hepatoma (HEPG2) and mouse liver 12 (AML12) cell lines incubated with squalene, indicating a direct effect of squalene on these expressions. These findings suggest that squalene accumulated in the liver is able to modulate gene expression changes that may influence the progression of non-alcoholic steatohepatitis.

Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1.

Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated by Polycomb repressive deubiquitinase complex (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. The PR-DUB subunits (BAP1 and ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How PR-DUB establishes specificity for H2AK119Ub over other nucleosomal ubiquitination sites and how disease-associated mutations of the enzyme affect activity are unclear. Here, we determine a cryo-EM structure of human BAP1 and the ASXL1 DEUBAD in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for restructuring the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing insight into understanding cancer etiology.

Mitochondrial phylogeography and molecular evolution of the rhodopsin visual pigment in troglobitic populations of Astyanax mexicanus (De Filippi, 1853).

Cave-adapted animals provide a unique opportunity to study the evolutionary mechanisms underlying phenotypic, metabolic, behavioral, and genetic evolution in response to cave environments. The Mexican tetra ( Astyanax mexicanus) is considered a unique model system as it shows both surface and cave-dwelling morphs. To date, at least 33 different cave populations have been identified, with phylogenetic studies suggesting an origin from at least two independent surface lineages, thereby providing a unique opportunity to study parallel evolution. In the present study, we carried out the most exhaustive phylogeographic study of A. mexicanus to date, including cave and surface localities, using two mitochondrial markers (cytochrome b (cyt b) and cytochrome c oxidase subunit I ( COI)) and nuclear rhodopsin visual pigment ( rho). Additionally, we inferred the molecular evolution of rho within the two contrasting environments (cave and surface) and across three geographic regions (Sierra de El Abra, Sierra de Guatemala, and Micos). In total, 267 individuals were sequenced for the two mitochondrial fragments and 268 individuals were sequenced for the rho visual pigment from 22 cave and 46 surface populations. Phylogeographic results based on the mitochondrial data supported the two-lineage hypothesis, except for the Pachón and Chica caves, whose introgression has been largely documented. The Sierra de El Abra region depicted the largest genetic diversity, followed by the Sierra de Guatemala region. Regarding the phylogeographic patterns of rho, we recovered exclusive haplogroups for the Sierra de El Abra (Haplogroup I) and Sierra de Guatemala regions (Haplogroup IV). Moreover, a 544 bp deletion in the rho gene was observed in the Escondido cave population from Sierra de Guatemala, reducing the protein from seven to three intramembrane domains. This change may produce a loss-of-function (LOF) but requires further investigation. Regarding nonsynonymous ( dN) and synonymous ( dS) substitution rates (omega values ω), our results revealed the prevailing influence of purifying selection upon the rho pigment for both cave and surface populations (ω<1), but relaxation at the El Abra region. Notably, in contrast to the other two regions, we observed an increase in the number of dN mutations for Sierra de El Abra. However, given that a LOF was exclusively identified in the Sierra de Guatemala region, we cannot dismiss the possibility of a pleiotropic effect on the Rho protein.

Supervised Deep Learning Techniques for Image Description: A Systematic Review.

Automatic image description, also known as image captioning, aims to describe the elements included in an image and their relationships. This task involves two research fields: computer vision and natural language processing; thus, it has received much attention in computer science. In this review paper, we follow the Kitchenham review methodology to present the most relevant approaches to image description methodologies based on deep learning. We focused on works using convolutional neural networks (CNN) to extract the characteristics of images and recurrent neural networks (RNN) for automatic sentence generation. As a result, 53 research articles using the encoder-decoder approach were selected, focusing only on supervised learning. The main contributions of this systematic review are: (i) to describe the most relevant image description papers implementing an encoder-decoder approach from 2014 to 2022 and (ii) to determine the main architectures, datasets, and metrics that have been applied to image description.

Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.

Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

Effectiveness of a standardised patient simulation programme in undergraduate nursing students 6 months after implementation: A quasi-experimental study.

AIMS: The objectives were to evaluate the effectiveness of a standardised patient simulation programme and to analyse to what extent the students transferred the skills covered in the simulation to clinical practice 6 months after the intervention. DESIGN: A quasi-experimental study was carried out, with measurements taken pre-, post- and 6 months after the implementation of a standardised patient simulation programme in a single group. METHODS: Eligible to participate were all final year nursing undergraduates during the 2020-2021 academic year. In total, 41 undergraduate nursing students took part in all stages of the study. It was measured attitude towards communication, self-efficacy, communication skills and resilience. The degree to which communication skills were used in the real setting was also assessed. RESULTS: The students' scores for self-efficacy and perceived communication skills improved and were maintained after six months. Regarding to resilience, improvement was even evident six months following the intervention. In terms of the transfer to clinical practice, the students were making moderate to high use of the communication skills learned in the simulation.

Structural basis of histone H2A lysine 119 deubiquitination by Polycomb Repressive Deubiquitinase BAP1/ASXL1.

The maintenance of gene expression patterns during metazoan development is achieved by the actions of Polycomb group (PcG) complexes. An essential modification marking silenced genes is monoubiquitination of histone H2A lysine 119 (H2AK119Ub) deposited by the E3 ubiquitin ligase activity of the non-canonical Polycomb Repressive Complex 1. The Polycomb Repressive Deubiquitinase (PR-DUB) complex cleaves monoubiquitin from histone H2A lysine 119 (H2AK119Ub) to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. BAP1 and ASXL1, subunits that form active PR-DUB, are among the most frequently mutated epigenetic factors in human cancers, underscoring their biological importance. How PR-DUB achieves specificity for H2AK119Ub to regulate Polycomb silencing is unknown, and the mechanisms of most of the mutations in BAP1 and ASXL1 found in cancer have not been established. Here we determine a cryo-EM structure of human BAP1 bound to the ASXL1 DEUBAD domain in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for remodeling the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing new insight into understanding cancer etiology. One Sentence Summary: We reveal the molecular mechanism of nucleosomal H2AK119Ub deubiquitination by human BAP1/ASXL1.