Bcl11b and Atoh8 Coordinate Cellular Plasticity for Reprogramming and Transformation

By dissecting and comparing the transcriptional trajectories and epigenomic traits of reprogramming and transforming cells at the single-cell resolution, Huyghe et al discovered Bcl11b and Atoh8, two key transcription factors controlling cell plasticity during pluripotent reprogramming and oncogenic transformation

Differentiable Vertex Fitting for Jet Flavour Tagging

We propose a differentiable vertex fitting algorithm that can be used for secondary vertex fitting, and that can be seamlessly integrated into neural networks for jet flavour tagging. Vertex fitting is formulated as an optimization problem where gradients of the optimized solution vertex are defined through implicit differentiation and can be passed to upstream or downstream neural network components for network training. More broadly, this is an application of differentiable programming to integrate physics knowledge into neural network models in high energy physics. We demonstrate how differentiable secondary vertex fitting can be integrated into larger transformer-based models for flavour tagging and improve heavy flavour jet classification.Comment: 11 page

Systematic Transcriptome Profiling of hPSC-Derived Osteoblasts Unveils CORIN’s Mastery in Governing Osteogenesis Through CEBPD Modulation

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin immunoprecipitation enrichment and mechanistic studies show that p38 MAPK-mediated CCAAT enhancer binding protein delta (CEBPD) upregulation is required for CORIN-modulated osteogenesis. Contrastingly, the type I transmembrane heparan sulfate proteoglycan SDC1 enriched in mesenchymal stem cells exerts a negative regulatory effect on osteogenesis through a similar mechanism. Chromatin immunoprecipitation-seq, bulk and single-cell transcriptomes, and functional validations indicated that CEBPD plays a critical role in controlling osteogenesis. In summary, our findings uncover previously unrecognized CORIN-mediated CEBPD transcriptomic networks in driving human osteoblast lineage commitment

A dual-tag microarray platform for high-performance nucleic acid and protein analyses

DNA microarrays serve to monitor a wide range of molecular events, but emerging applications like measurements of weakly expressed genes or of proteins and their interaction patterns will require enhanced performance to improve specificity of detection and dynamic range. To further extend the utility of DNA microarray-based approaches we present a high-performance tag microarray procedure that enables probe-based analysis of as little as 100 target cDNA molecules, and with a linear dynamic range close to 105. Furthermore, the protocol radically decreases the risk of cross-hybridization on microarrays compared to current approaches, and it also allows for quantification by single-molecule analysis and real-time on-chip monitoring of rolling-circle amplification. We provide proof of concept for microarray-based measurement of both mRNA molecules and of proteins, converted to tag DNA sequences by padlock and proximity probe ligation, respectively

Leishmanicidal Metabolites from Cochliobolus sp., an Endophytic Fungus Isolated from Piptadenia adiantoides (Fabaceae)

Protozoan parasites belonging to genera Leishmania and Trypanosoma are the etiological agents of severe neglected tropical diseases (NTDs) that cause enormous social and economic impact in many countries of tropical and sub-tropical areas of the world. In our screening program for new drug leads from natural sources, we found that the crude extract of the endophytic fungus Cochliobolus sp. (UFMGCB-555) could kill 90% of the amastigote-like forms of Leishmania amazonensis and inhibit by 100% Ellman's reagent reduction in the trypanothione reductase (TryR) assay, when tested at 20 µg mL−1. UFMGCB-555 was isolated from the plant Piptadenia adiantoides J.F. Macbr (Fabaceae) and identified based on the sequence of the internally transcribed spacer (ITS) regions of its ribosomal DNA. The chromatographic fractionation of the extract was guided by the TryR assay and resulted in the isolation of cochlioquinone A and isocochlioquinone A. Both compounds were active in the assay with L. amazonensis, disclosing EC50 values (effective concentrations required to kill 50% of the parasite) of 1.7 µM (95% confidence interval = 1.6 to 1.9 µM) and 4.1 µM (95% confidence interval = 3.6 to 4.7 µM), respectively. These compounds were not active against three human cancer cell lines (MCF-7, TK-10, and UACC-62), indicating some degree of selectivity towards the parasites. These results suggest that cochlioquinones are attractive lead compounds that deserve further investigation aiming at developing new drugs to treat leishmaniasis. The findings also reinforce the role of endophytic fungi as an important source of compounds with potential to enter the pipeline for drug development against NTDs

Comparative ICE Genomics: Insights into the Evolution of the SXT/R391 Family of ICEs

Integrating and conjugative elements (ICEs) are one of the three principal types of self-transmissible mobile genetic elements in bacteria. ICEs, like plasmids, transfer via conjugation; but unlike plasmids and similar to many phages, these elements integrate into and replicate along with the host chromosome. Members of the SXT/R391 family of ICEs have been isolated from several species of gram-negative bacteria, including Vibrio cholerae, the cause of cholera, where they have been important vectors for disseminating genes conferring resistance to antibiotics. Here we developed a plasmid-based system to capture and isolate SXT/R391 ICEs for sequencing. Comparative analyses of the genomes of 13 SXT/R391 ICEs derived from diverse hosts and locations revealed that they contain 52 perfectly syntenic and nearly identical core genes that serve as a scaffold capable of mobilizing an array of variable DNA. Furthermore, selection pressure to maintain ICE mobility appears to have restricted insertions of variable DNA into intergenic sites that do not interrupt core functions. The variable genes confer diverse element-specific phenotypes, such as resistance to antibiotics. Functional analysis of a set of deletion mutants revealed that less than half of the conserved core genes are required for ICE mobility; the functions of most of the dispensable core genes are unknown. Several lines of evidence suggest that there has been extensive recombination between SXT/R391 ICEs, resulting in re-assortment of their respective variable gene content. Furthermore, our analyses suggest that there may be a network of phylogenetic relationships among sequences found in all types of mobile genetic elements

Risk factors associated with failing pre-transmission assessment surveys (pre-TAS) in lymphatic filariasis elimination programs: Results of a multi-country analysis.

Achieving elimination of lymphatic filariasis (LF) as a public health problem requires a minimum of five effective rounds of mass drug administration (MDA) and demonstrating low prevalence in subsequent assessments. The first assessments recommended by the World Health Organization (WHO) are sentinel and spot-check sites-referred to as pre-transmission assessment surveys (pre-TAS)-in each implementation unit after MDA. If pre-TAS shows that prevalence in each site has been lowered to less than 1% microfilaremia or less than 2% antigenemia, the implementation unit conducts a TAS to determine whether MDA can be stopped. Failure to pass pre-TAS means that further rounds of MDA are required. This study aims to understand factors influencing pre-TAS results using existing programmatic data from 554 implementation units, of which 74 (13%) failed, in 13 countries. Secondary data analysis was completed using existing data from Bangladesh, Benin, Burkina Faso, Cameroon, Ghana, Haiti, Indonesia, Mali, Nepal, Niger, Sierra Leone, Tanzania, and Uganda. Additional covariate data were obtained from spatial raster data sets. Bivariate analysis and multilinear regression were performed to establish potential relationships between variables and the pre-TAS result. Higher baseline prevalence and lower elevation were significant in the regression model. Variables statistically significantly associated with failure (p-value ≤0.05) in the bivariate analyses included baseline prevalence at or above 5% or 10%, use of Filariasis Test Strips (FTS), primary vector of Culex, treatment with diethylcarbamazine-albendazole, higher elevation, higher population density, higher enhanced vegetation index (EVI), higher annual rainfall, and 6 or more rounds of MDA. This paper reports for the first time factors associated with pre-TAS results from a multi-country analysis. This information can help countries more effectively forecast program activities, such as the potential need for more rounds of MDA, and prioritize resources to ensure adequate coverage of all persons in areas at highest risk of failing pre-TAS

An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis

Ribosome-associated mRNA quality control mechanisms ensure the fidelity of protein translation1,2. Although these mechanisms have been extensively studied in yeast, little is known about their role in mammalian tissues, despite emerging evidence that stem cell fate is controlled by translational mechanisms3,4. One evolutionarily conserved component of the quality control machinery, Dom34 (in higher eukaryotes known as Pelota (Pelo)), rescues stalled ribosomes 5 . Here we show that Pelo is required for mammalian epidermal homeostasis. Conditional deletion of Pelo in mouse epidermal stem cells that express Lrig1 results in hyperproliferation and abnormal differentiation of these cells. By contrast, deletion of Pelo in Lgr5-expressing stem cells has no effect and deletion in Lgr6-expressing stem cells induces only a mild phenotype. Loss of Pelo results in accumulation of short ribosome footprints and global upregulation of translation, rather than affecting the expression of specific genes. Translational inhibition by rapamycin-mediated downregulation of mTOR (mechanistic target of rapamycin kinase) rescues the epidermal phenotype. Our study reveals that the ribosome-rescue machinery is important for mammalian tissue homeostasis and that it has specific effects on different stem cell populations.</p