Miracle-dz/UniFAR-FTUs huggingface dataset:
Ethanol antagonizes P2X4 receptors in ventral tegmental area neurons

P2X4 receptors are found throughout the central nervous system, and studies have shown that these purinergic receptors are important regulators of alcohol intake. The ventral tegmental area (VTA) is an important region for the rewarding and reinforcing properties of alcohol, but the role of P2X4 receptors in this region is unknown. Using both immunohistochemical and electrophysiological methods, we examined the interaction between P2X4 receptors and alcohol on VTA neurons. Incubation of brain slices containing the VTA for 2 h with siRNA targeting P2X4 receptors resulted in about a 25% reduction in P2X4 immunoreactivity in tyrosine hydroxylase positive VTA neurons. In electrophysiological experiments, ATP (0.5–3 mM) produced a reduction in the spontaneous firing rate, and ethanol significantly reduced this inhibition. Exposure to siP2X4 for 2 h via the recording micropipette resulted in a suppression of the response of VTA neurons to ATP, but no significant reduction in the ethanol inhibition of the ATP response was observed after this P2X4 downregulation. These results support the idea that VTA neurons are inhibited by ATP, ethanol antagonizes this inhibition, and the ethanol-sensitive component of ATP inhibition is mediated by P2X4 receptors. This interaction of ethanol with P2X4 receptors may be an important regulator of the rewarding effects of ethanol, making P2X4 receptors an intriguing target for the development of agents to treat alcohol use disorders.
Translating international guidelines for use in routine maternal and neonatal healthcare quality measurement

ABSTRACT Background Improving facility-based quality for maternal and neonatal care is the key to reducing morbidity and mortality rates in low- and middle-income countries. Recent guidance from WHO and others has produced a large number of indicators to choose from to track quality. Objective To explore how to translate complex global maternal and neonatal health standards into actionable application at the facility level. Methods We applied a two-step process as an example of how the 352 indicators in WHO’s 2016 Standards for Improving Quality of Maternal and Newborn Care in Health Facilities might be reduced to only those with the strongest evidence base, associated with outcomes, and actionable by facility managers. We applied Hill criteria and assessed whether indicators were within the control of facility managers. We next conducted a rapid review of supporting literature and applied GRADE analysis, retaining those with scores of ‘moderate’ or ‘high’. To understand the utility and barriers to measuring this limited set of indicators in practice, we undertook a case study of hypothetical measurement application in two districts in Bangladesh, interviewing 25 clinicians, managers, and other stakeholders. Results From the initial 352 indicators, 56 were retained. The 56 indicators were used as a base for interviews. Respondents emphasized the practical challenges to the use of complex guides and the need for parsimonious and actionable sets of quality indicators. Conclusions This work offers one way to move towards a reduced quality indicator set, beginning from current WHO guidance. Despite study limitations, this work provides evidence of the need for reduced and evidence-based sets of quality indicators if guides are to be used to improve quality in practice. We hope that future research will build on and refine our efforts. Measuring quality effectively so that evidence guides and improves practice is the first step to assuring safe maternal and neonatal care.
Chromatin network markers of leukemia

Abstract Motivation The structure of chromatin impacts gene expression. Its alteration has been shown to coincide with the occurrence of cancer. A key challenge is in understanding the role of chromatin structure (CS) in cellular processes and its implications in diseases. Results We propose a comparative pipeline to analyze CSs and apply it to study chronic lymphocytic leukemia (CLL). We model the chromatin of the affected and control cells as networks and analyze the network topology by state-of-the-art methods. Our results show that CSs are a rich source of new biological and functional information about DNA elements and cells that can complement protein–protein and co-expression data. Importantly, we show the existence of structural markers of cancer-related DNA elements in the chromatin. Surprisingly, CLL driver genes are characterized by specific local wiring patterns not only in the CS network of CLL cells, but also of healthy cells. This allows us to successfully predict new CLL-related DNA elements. Importantly, this shows that we can identify cancer-related DNA elements in other cancer types by investigating the CS network of the healthy cell of origin, a key new insight paving the road to new therapeutic strategies. This gives us an opportunity to exploit chromosome conformation data in healthy cells to predict new drivers. Availability and implementation Our predicted CLL genes and RNAs are provided as a free resource to the community at https://life.bsc. es/iconbi/chromatin/index.html. Supplementary information Supplementary data are available at Bioinformatics online.
Cellular and metabolic damage induced by desiccation in recalcitrant Araucaria angustifolia embryos

Abstract Embryos of Araucaria angustifolia seeds showed no dormancy; they germinated easily at temperatures ranging from 10° to 30°C, and the thermal optimum was about 25–30°C; they were recalcitrant. At harvest, their mean moisture content (dry weight basis) was about 120% and they completely lost viability when their moisture content fell to about 30%. The cotyledons were more sensitive to dehydration than the radicle. Dehydration induced deterioration of cell membranes as indicated by a high increase in leakage of solutes. It also resulted in damage in the nuclei, which was not repaired upon rehydration. During desiccation, respiratory activity decreased; however, O2 uptake was not an indication of germination ability, since it was significantly affected only when embryo moisture content reached the critical value of 30%. The decrease in the capacity to convert 1-aminocyclopropane 1-carboxylic acid to ethylene, which was observed at 30–60 min of dehydration, was a very early indicator of deterioration in embryos. Desiccation resulted also in a rapid decrease in the ability for protein synthesis as measured by [35S]methionine incorporation into total protein; 50% inhibition was observed after 30–60 min of desiccation for both axis and cotyledons.
Topological and kernel-based microbial phenotype prediction from MALDI-TOF mass spectra

Abstract Motivation Microbial species identification based on matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has become a standard tool in clinical microbiology. The resulting MALDI-TOF mass spectra also harbour the potential to deliver prediction results for other phenotypes, such as antibiotic resistance. However, the development of machine learning algorithms specifically tailored to MALDI-TOF MS-based phenotype prediction is still in its infancy. Moreover, current spectral pre-processing typically involves a parameter-heavy chain of operations without analyzing their influence on the prediction results. In addition, classification algorithms lack quantification of uncertainty, which is indispensable for predictions potentially influencing patient treatment. Results We present a novel prediction method for antimicrobial resistance based on MALDI-TOF mass spectra. First, we compare the complex conventional pre-processing to a new approach that exploits topological information and requires only a single parameter, namely the number of peaks of a spectrum to keep. Second, we introduce PIKE, the peak information kernel, a similarity measure specifically tailored to MALDI-TOF mass spectra which, combined with a Gaussian process classifier, provides well-calibrated uncertainty estimates about predictions. We demonstrate the utility of our approach by predicting antibiotic resistance of three clinically highly relevant bacterial species. Our method consistently outperforms competitor approaches, while demonstrating improved performance and security by rejecting out-of-distribution samples, such as bacterial species that are not represented in the training data. Ultimately, our method could contribute to an earlier and precise antimicrobial treatment in clinical patient care. Availability and implementation We make our code publicly available as an easy-to-use Python package under https://github.com/BorgwardtLab/maldi_PIKE.
Climate and phylogenetic history structure morphological and architectural trait variation among fine-root orders.

RATIONALE Fine roots mediate belowground resource acquisition, yet understanding of how fine-root functional traits vary along environmental gradients, within branching orders, and across phylogenetic scales remains limited. METHODS Morphological and architectural fine-root traits were measured on individual root orders of 20 oak species (genus Quercus) from divergent climates of origin that were harvested after three growing seasons in a glasshouse. These were then compared with similar measurements obtained from a phylogenetically diverse dataset of woody species from the Fine-Root Ecology Database (FRED). KEY RESULTS For the oaks, only precipitation seasonality and growing season moisture availability were correlated to aspects of root diameter and branching. Strong correlations among root diameters and architecture of different branch orders were common, while correlations between diameter and length were weakly negative. In contrast, the FRED dataset showed strong positive correlations between diameter and length and fewer correlations between root diameter and architectural traits. MAIN CONCLUSION Our findings suggest that seasonal patterns of availability are more important drivers of root adaptation in oaks than annual averages in precipitation and temperature. Furthermore, contrasting patterns of trait relationships between the oak and FRED datasets suggest that branching patterns are differentially constrained at narrow versus broad phylogenetic scales.
Inhibition of cathepsin S attenuates myocardial ischemia/reperfusion injury by suppressing inflammation and apoptosis

Myocardial ischemia/reperfusion (I/R) injury leads to high mortality and morbidity due to the incomplete understanding of the underlying mechanism and the consequent lack of effective therapy. The present study revealed and validated key candidate genes in relation to inflammation and apoptosis pathways underlying myocardial I/R injury. Cathepsin S was identified as the top hub protein based on the protein–protein interaction analysis, and, thus, its role during myocardial I/R injury was further investigated. Myocardial I/R in mice resulted in significantly increased levels of myocardial injury biomarkers (cardiac troponin I, lactic dehydrogenase, and creatinine kinase‐MB) and inflammatory cytokines (interleukin‐1β [IL‐1β], IL‐6, and tumor necrosis factor‐α), elevated apoptosis rate, and upregulated protein expression of cleaved caspase‐8, cleaved caspase‐3, and cleaved poly ADP‐ribose polymerase. These abovementioned changes were blocked by two different selective cathepsin S inhibitors, LY3000328 or MIV‐247. Moreover, Kaplan–Meier survival plot showed that cathepsin S inhibition improved 21‐day survival rate following myocardial I/R injury. This study demonstrated that the inhibition of cathepsin S alleviated myocardial I/R‐induced injury by suppressing inflammation and apoptosis, which may be used in clinical applications of cardioprotection.
Characterization of midgut microbiome of Anopheles stephensi Liston

Background & objectives: Anopheles stephensi is an important vector of malaria in South East Asia. The abundance and diversity of gut microbiota in the disease vectors affect their development, digestion, metabolism and immunity. The immatures of An. stephensi engulf microbes from their aquatic environment. The present study investigates midgut microbiota of wild and laboratory populations and compares it with their habitat bacterial diversity to study transstadial transmissibility. Methods: The gut microbes from immatures, adults and water samples were cultured at ambient conditions on different media. The colony and biochemical characteristics, and 16S rRNA gene sequencing of gut microbes were studied. Results: Altogether, 298 bacterial isolates were characterized as 21 genera belonging to four major Phyla viz., Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria. In the field population-1, Proteobacteria and Firmicutes accounted for 49% and Actinobacteria constituted 51% of the bacterial isolates. In field population-2, Bacteroidetes and Firmicutes accounted for 99% of the isolates. In the laboratory populations, Firmicutes constituted 77%, while Proteobacteria 23% of the isolates. Additionally, 9 genera occurred in the breeding habitats, 13 in the larval midgut, 6 in pupal midgut, 9 in male midgut and 10 in the female midgut. Interpretation & conclusion: This is a unique study on diversity of microbiota of An. stephensi from breeding water, developmental stages and adults. Different culture media used enhanced the isolation of diverse bacteria. The presence of Micrococcus and Leucobacter in different life stages indicates their adaptation in An. stephensi as symbionts which need further evaluation for their role in paratransgenesis.
MHCAttnNet: predicting MHC-peptide bindings for MHC alleles classes I and II using an attention-based deep neural model

Abstract Motivation Accurate prediction of binding between a major histocompatibility complex (MHC) allele and a peptide plays a major role in the synthesis of personalized cancer vaccines. The immune system struggles to distinguish between a cancerous and a healthy cell. In a patient suffering from cancer who has a particular MHC allele, only those peptides that bind with the MHC allele with high affinity, help the immune system recognize the cancerous cells. Results MHCAttnNet is a deep neural model that uses an attention mechanism to capture the relevant subsequences of the amino acid sequences of peptides and MHC alleles. It then uses this to accurately predict the MHC-peptide binding. MHCAttnNet achieves an AUC-PRC score of 94.18% with 161 class I MHC alleles, which outperforms the state-of-the-art models for this task. MHCAttnNet also achieves a better F1-score in comparison to the state-of-the-art models while covering a larger number of class II MHC alleles. The attention mechanism used by MHCAttnNet provides a heatmap over the amino acids thus indicating the important subsequences present in the amino acid sequence. This approach also allows us to focus on a much smaller number of relevant trigrams corresponding to the amino acid sequence of an MHC allele, from 9251 possible trigrams to about 258. This significantly reduces the number of amino acid subsequences that need to be clinically tested. Availability and implementation The data and source code are available at https://github.com/gopuvenkat/MHCAttnNet.
A NEW RAUISUCHIAN REPTILE (DIAPSIDA: ARCHOSAURIA) FROM THE LATE TRIASSIC OF POLAND

Abstract A crushed rauisuchian skull and several vertebrae belonging to a single individual have been found in the Upper Triassic strata at Krasiejów, Poland, probably corresponding in age to the Lehrberg Beds (late Carnian) of Baden-Württemberg, Germany. A maxilla of Teratosaurus suevicus from the early Norian (Stubensandstein at Heslach) is similar to that of the Krasiejów specimen. The dorsal process of the maxilla is more oblique than in T. suevicus, the medial anterior foramen is set on the medial side, contrary to being exposed anteriorly in T. suevicus, and foramina for replacement teeth are not connected by a dental groove and are set in straight line. A new species of Teratosaurus is proposed to accommodate the Polish material, and a more complete diagnosis of the genus is presented.
Efficacy of 1,3-Dichloropropene Plus Chloropicrin in Combination with Herbicides on Purple Nutsedge (Cyperus rotundus) Control in Tomato1

A study was conducted to compare the effect of 1,3-dichloropropene (1,3-D) + chloropicrin (Pic) in a 83:17 ratio (C-17) used alone or in combination with herbicides on tomato. Treatments evaluated included 1,3-D (325 kg ai/ha) plus Pic (67 kg ai/ha) used either alone or with pebulate (4.5 kg ai/ha), napropamide (4.5 kg ai/ha), metolachlor (1.1 and 2.3 kg ai/ha), lactofen (2.3 kg ai/ha), or flazasulfuron (0.4 kg ai/ha). Pebulate was consistently more effective in controlling purple nutsedge than the other herbicides tested. Purple nutsedge was more effectively controlled with C-17 in combination with pebulate than with the fumigant alone. Shallow incorporation of pebulate failed to improve weed control and tomato fruit yield. Nomenclature: Chloropicrin; 1,3-dichloropropene; flazasulfuron; lactofen; metolachlor; napropamide; pebulate; purple nutsedge, Cyperus rotundus L. #3 CYPRO; tomato, Lycopersicon esculentum Mill. ‘Solar Set’. Additional index words: Flazasulfuron, lactofen, methyl bromide, metolachlor, napropamide, pebulate, soil fumigant. Abbreviations: C-17, 1,3-D + Pic (87:13); 1,3-D, 1,3-dichloropropene; MBr, methyl bromide; Pic, chloropicrin; WAT, weeks after treatment.
Structural study of the transcriptional co-activator SAGA

The SAGA complex (Spt-Ada-Gcn5 acetyl transferase) is a transcriptional coactivator, highly conserved in eukaryotes, involved in the transcription of 10% of the genes in yeast, where it bridges the components of the pre-initiation complex such as the TATA-box Binding Protein (TBP) and activators, as well as modifies histones in the chromatin template (acetylation and deubiquitination). This work has revealed the molecular architecture of the complex observed by electron microscopy. We could (i) localize the deubiquitination module within the whole complex and thus (ii) define the interaction surface with the nucleosome; (iii) reveal the presence of two TBP-interacting surfaces localized at the tips of a molecular clamp; (iv) observe a functional link between the deubiquitination module, in particular the Sgf73 protein, and the conformation adopted by this clamp.
The evolution of genetic diversity in changing environments

The production and maintenance of genetic and phenotypic diversity under temporally fluctuating selection and the signatures of environmental and selective volatility in the patterns of genetic and phenotypic variation have been important areas of focus in population genetics. On one hand, stretches of constant selection pull the genetic makeup of populations towards local fitness optima. On the other, in order to cope with changes in the selection regime, populations may evolve mechanisms that create a diversity of genotypes. By tuning the rates at which variability is produced, such as the rates of recombination, mutation or migration, populations may increase their long-term adaptability. Here we use theoretical models to gain insight into how the rates of these three evolutionary forces are shaped by fluctuating selection. We compare and contrast the evolution of recombination, mutation and migration under similar patterns of environmental change and show that these three sources of phenotypic variation are surprisingly similar in their response to changing selection. We show that knowing the shape, size, variance and asymmetry of environmental runs is essential for accurate prediction of genetic evolutionary dynamics.
Synthesis and In vivo Studies of Protein C-loaded Nanoparticles with PEO Modified Surfaces

Protein C-loaded nanoparticles coated with monomethoxypoly (ethylene oxide) (MPEO) were prepared by double emulsion/solvent evaporation using water-soluble biocompatible copolymers of MPEO and polylactide, as surfactants of the secondary emulsion. The nanoparticle preparation was optimized to obtain the best yield of encapsulated protein C and provide the greatest retention of its biological activity. The nanoparticles were characterized in terms of size, zeta potential, and thickness of the MPEO external layer. Protein C-loaded nanoparticles were injected into the bloodstream of guinea pigs and the protein concentration in plasma is measured as a function of time. After a rapid release corresponding to 20% of the injected protein, the protein plasma concentration progressively decreased and reached a value close to zero after 5 h. Consequently, the in vivo fate of the fluorescent nanoparticles coated with or without MPEO is studied. The uncoated nanoparticles were rapidly captured by the circulating granulocytes while the coated ones were not. The histological analysis of the spleen, 1 hour after injection, showed that the MPEO-coated particles were retained in this organ, while the uncoated ones were not captured.
ENDANGERED MUTUALISMS: The Conservation of Plant-Pollinator Interactions

▪ Abstract The pollination of flowering plants by animals represents a critical ecosystem service of great value to humanity, both monetary and otherwise. However, the need for active conservation of pollination interactions is only now being appreciated. Pollination systems are under increasing threat from anthropogenic sources, including fragmentation of habitat, changes in land use, modern agricultural practices, use of chemicals such as pesticides and herbicides, and invasions of non-native plants and animals. Honeybees, which themselves are non-native pollinators on most continents, and which may harm native bees and other pollinators, are nonetheless critically important for crop pollination. Recent declines in honeybee numbers in the United States and Europe bring home the importance of healthy pollination systems, and the need to further develop native bees and other animals as crop pollinators. The “pollination crisis” that is evident in declines of honeybees and native bees, and in damage to web.
Experimental Illumination of Comprehensive Fitness Landscapes: A Dissertation

Evolution is the single cohesive logical framework in which all biological processes may exist simultaneously. Incremental changes in phenotype over imperceptibly large timescales have given rise to the enormous diversity of life we witness on earth both presently and through the natural record. The basic unit of evolution is mutation, and by perturbing biological processes, mutations may alter the fitness of an individual. However, the fitness effect of a mutation is difficult to infer from historical record, and complex to obtain experimentally in an efficient and accurate manner. We have recently developed a high throughput method to iteratively mutagenize regions of essential genes in yeast and subsequently analyze individual mutant fitness termed Exceedingly Methodical and Parallel Investigation of Randomized Individual Codons (EMPIRIC). Utilizing this technique as exemplified in Chapters II and III, it is possible to determine the fitness effects of all possible point mutations in parallel through growth competition followed by a high throughput sequencing readout. We have employed this technique to determine the distribution of fitness effects in a nine amino acid region of the Hsp90 gene of S. cerevisiae under elevated temperature, and found the bimodal distribution of fitness effects to be remarkably consistent with near-neutral theory. Comparing the measured fitness effects of mutants to the natural record, phylogenetic alignments appear to be a poor predictor of experimental fitness.