Miracle-dz/UniFAR-FTUs huggingface dataset:
A discrete‐time survival model for porcine epidemic diarrhoea virus

Since the arrival of porcine epidemic diarrhea virus (PEDV) in the United States in 2013, elimination and control programs have had partial success. The dynamics of its spread are hard to quantify, though previous work has shown that local transmission and the transfer of pigs within production systems are most associated with the spread of PEDV. Our work relies on the history of PEDV infections in a region of the southeastern United States. This infection data is complemented by farm-level features and extensive industry data on the movement of both pigs and vehicles. We implement a discrete-time survival model and evaluate different approaches to modeling the local-transmission and network effects. We find strong evidence in that the local-transmission and pig-movement effects are associated with the spread of PEDV, even while controlling for seasonality, farm-level features, and the possible spread of disease by vehicles. Our fully Bayesian model permits full uncertainty quantification of these effects. Our farm-level out-of-sample predictions have a receiver-operating characteristic area under the curve (AUC) of 0.779 and a precision-recall AUC of 0.097. The quantification of these effects in a comprehensive model allows stakeholders to make more informed decisions about disease prevention efforts.
Motivational Dysregulation with Melanocortin 4 Receptor Haploinsufficiency

Obesity, by any standard, is a global health crisis. Both genetic and dietary contributions to the development and maintenance of obesity were integral factors of our experimental design. As mutations of the melanocortin 4 receptors (MC4R) are the leading monogenetic cause of obesity, MC4R haploinsufficient rats were fed a range of dietary fat (0-12%) in a longitudinal design. Physiological and motivational assessments were performed using a locomotor task, 5-choice sucrose preference task, an operant task with fixed and progressive ratios, as well as a distraction operant task. Dendritic spine morphology of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), cells with ample D1 and D2 receptors, was also assessed. The percentage of lipid deposits in the liver of each rat was also analyzed using the Area Fraction Fractionator probe for stereological measurements. MC4R haploinsufficiency resulted in a phenotypic resemblance for adult-onset obesity that was exacerbated by the consumption of a high-fat diet. Results from the operant tasks indicate that motivational deficits due to MC4R haploinsufficiency were apparent prior to the onset of obesity and exacerbated by dietary fat consumption after obesity was well established. Moreover, MSN morphology shifted to longer spines with smaller head diameters for the MC4R+/- animals under the high-fat diet, suggesting a potential mechanism for the dysregulation of motivation to work for food. Increasing our knowledge of the neural circuitry/mechanisms responsible for the rewarding properties of food has significant implications for understanding energy balance and the development of obesity.
Polar protein Wag31 both activates and inhibits cell wall metabolism at the poles and septum

Mycobacterial cell elongation occurs at the cell poles; however, it is not clear how cell wall insertion is restricted to the pole and organized. Wag31 is a pole-localized cytoplasmic protein that is essential for polar growth, but its molecular function has not been described. In this study we used alanine scanning mutagenesis to identify Wag31 residues involved in cell morphogenesis. Our data show that Wag31 has separate functions in not only new and old pole elongation, but also inhibition of both septation and new pole elongation. Our examination of phospho-ablative and phospho-mimetic mutants of Wag31 suggests that phosphorylation of Wag31 promotes old pole elongation, while the unphosphorylated form of Wag31 may promote resolution of the septum. This work establishes new regulatory functions of Wag31 in the mycobacterial cell cycle and clarifies the role of phosphorylation on Wag1. Importance Despite many previous studies, the molecular mechanisms of polar growth in mycobacteria is unclear. Wag31 is required for this polar elongation. In this work, we dissect Wag1 function by phenotyping wag31 point mutants. We find that Wag31 promotes elongation at both poles in different ways, and it can also inhibit cell wall metabolism at both the new pole and the septum. This work is important because it clarifies that Wag31 is doing several different things in the cell and gives us genetic tools to disentangle its functions.
The canonical PilT retraction ATPase promotes both extension and retraction of the MSHA type IVa pilus in Vibrio cholerae

Diverse bacterial species use type IVa pili (T4aP) to interact with their environments. The dynamic extension and retraction of T4aP is critical for their function, but the mechanisms that regulate this dynamic activity remain poorly understood. T4aP are typically extended via the activity of a dedicated extension motor ATPase and retracted via the action of an antagonistic retraction motor ATPase called PilT. These motors are generally functionally independent, and loss of PilT commonly results in T4aP hyperpiliation due to undeterred pilus extension. However, for the mannose-sensitive hemagglutinin (MSHA) T4aP of Vibrio cholerae, the loss of PilT results in a loss of surface piliation, which is unexpected based on our current understanding of T4aP dynamics. Here, we employ a combination of genetic and cell biological approaches to dissect the underlying mechanism. Our results demonstrate that PilT is necessary for MSHA pilus extension in addition to its well-established role in promoting MSHA pilus retraction. Through a suppressor screen, we also provide genetic evidence that the structure of the MshA major pilin contributes to pilus extension. Together, these findings contribute to our understanding of the factors that regulate pilus extension and describe a previously uncharacterized function for the PilT motor ATPase. AUTHOR SUMMARY Many bacteria use filamentous appendages called pili to interact with their environment. These fibers dynamically extend and retract through the activity of ATPase motor proteins. In most pilus systems, deletion of the retraction motor results in uninterrupted pilus extension, leading to hyperpiliation. However, in the MSHA pilus system of V. cholerae, deletion of the retraction motor, pilT, results in a decrease in the number of surface pili. Here, we show that PilT is unexpectedly required for MSHA pilus extension in addition to its defined role in promoting pilus retraction. These results extend our understanding of the complex mechanisms underlying the dynamic activity of these broadly conserved filamentous appendages.
Multiomic deep delve of synthesis and secretion processes in a model peptidergic system

The cell bodies of hypothalamic magnocellular neurones are densely packed in the hypothalamic supraoptic nucleus (SON) whereas their axons project to the anatomically discrete posterior pituitary gland. We have taken advantage of this unique anatomical structure to establish proteome and phosphoproteome dynamics in neuronal cell bodies and axonal terminals in response to physiological stimulation. We have found that proteome and phosphoproteome responses are very different between somatic and axonal neuronal compartments, indicating the need of each cell domain to differentially adapt. In particular, changes in the phosphoproteome in the cell body are involved in the reorganisation of the cytoskeleton and in axonal terminals the regulation of synaptic and secretory processes. We have identified that prohormone precursors including vasopressin and oxytocin are phosphorylated in axonal terminals and become hyperphosphorylated following stimulation. By multi-omic integration of transcriptome and proteomic data we identify changes to proteins present in afferent inputs to this nucleus. Graphical abstract
OmicSelector: automatic feature selection and deep learning modeling for omic experiments

A crucial phase of modern biomarker discovery studies is selecting the most promising features from high-throughput screening assays. Here, we present the OmicSelector - Docker-based web application and R package that facilitates the analysis of such experiments. OmicSelector provides a consistent and overfitting-resilient pipeline that integrates 94 feature selection approaches based on 25 distinct variable selection methods. It identifies and then ranks the best feature sets using 11 modeling techniques with hyperparameter optimization in hold-out or cross-validation. OmicSelector provides classification performance metrics for proposed feature sets, allowing researchers to choose the overfitting-resistant biomarker set with the highest diagnostic potential. Finally, it performs GPU-accelerated development, validation, and implementation of deep learning feedforward neural networks (up to 3 hidden layers, with or without autoencoders) on selected signatures. The application performs an extensive grid search of hyperparameters, including balancing and preprocessing of next-generation sequencing (e.g. RNA-seq, miRNA-seq) oraz qPCR data. The pipeline is applicable for determining candidate circulating or tissue miRNAs, gene expression data and methylomic, metabolomic or proteomic analyses. As a case study, we use OmicSelector to develop a diagnostic test for pancreatic and biliary tract cancer based on serum small RNA next-generation sequencing (miRNA-seq) data. The tool is open-source and available at https://biostat.umed. pl/OmicSelector/
Comprehensive characterization of the transcriptional response to COVID-19 in multiple organs reveals shared signatures across tissues

Infection by Coronavirus SARS-CoV2 is a severe and often deadly disease that has implications for the respiratory system and multiple organs across the human body. While the effects in the lung have been extensively studied, less is known about COVID-19’s cellular impact across other organs. Here we contribute a single-nuclei RNA sequencing atlas comprising six human organs across 20 autopsies where we analyzed the transcriptional changes due to COVID-19 in multiple cell types. Computational cross-organ analysis for endothelial cells and macrophages identified systemic transcriptional changes in these cell types in COVID-19 samples. In addition, analysis of signaling pathways from multiple datasets showed several systemic dysregulations of signaling interaction in different cell types. Altogether, the COVID Tissue Atlas enables the investigation of both cell type-specific and cross-organ transcriptional responses to COVID-19, providing insights into the molecular networks affected by the disease and highlighting novel potential targets for therapies and drug development.
The histone variant H2A.W cooperates with chromatin modifications and linker histone H1 to maintain transcriptional silencing of transposons in Arabidopsis

Transposable elements (TEs) are marked by a complex array of chromatin modifications, but a central unifying mechanism for how they are silenced remains elusive. Histone H3 Lysine 9 methylation (H3K9me) is an important component of heterochromatin in most eukaryotes, including plants. In flowering plants, the specialized histone variant H2A.W occupies nucleosomes found at TE sequences. This variant is deposited by the chromatin remodeler DDM1 and confers specific biophysical properties to the nucleosomes. Here we use genetic and genomic strategies to evaluate the role of H2A.W in transposon silencing in Arabidopsis. Compared with mutants lacking either H2A.W or H3K9me, the combined loss of both H2A.W and H3K9me causes a dramatic increase in both the number of expressed TEs and their expression levels. Synergistic effects are also observed when H2A.W is lost in combination with histone H1 or CH methylation. Collectively, these TEs are also upregulated in mutants lacking DDM1, which are impaired in H2A.W deposition and lose heterochromatic marks. We conclude that H2A.W acts in combination with different elements of heterochromatin to maintain silencing across a large spectrum of TEs present primarily in pericentric heterochromatin in Arabidopsis. In mammals, the DDM1 ortholog LSH deposits macroH2A to heterochromatin and silences TEs. We thus propose that specialized H2A variants localized to heterochromatin interact with a complex array of histone modifications to silence TEs in eukaryotes.
A product involving the $\beta$-family in stable homotopy theory

In the stable homotopy groups $\pi_{q(p^n+p^m+1)-3}(S)$ of the sphere spectrum $S$ localized at the prime $p$ greater than three, J. Lin constructed an essential family $\xi_{m,n}$ for $n \geq m + 2 >5$. In this paper, the authors show that the composite $\xi_{m,n}\beta_{s}\in \pi_{q(p^n+p^m+sp+s)-5}(S)$ for $2 \leq s < p$ is non-trivial, where $q=2(p-1)$ and $\beta_s \in \pi_{q(sp+s-1)-2}(S)$ is the known $\beta$-family. We show our result by explicit combinatorial analysis of the (modified) May spectral sequence.
The ER Protein Translocation Channel Subunit Sbh1 Controls Virulence of Cryptococcus neoformans

Cryptococcus neoformans is a yeast that causes almost 200,000 deaths worldwide each year, mainly of immunocompromised individuals. The surface structures of this pathogen, a protective cell wall surrounded by a polysaccharide capsule, are made and maintained by proteins that are synthesized inside the cell and travel outwards through the secretory pathway. ABSTRACT The fungal pathogen Cryptococcus neoformans is distinguished by a cell-wall-anchored polysaccharide capsule that is critical for virulence. Biogenesis of both cell wall and capsule relies on the secretory pathway. Protein secretion begins with polypeptide translocation across the endoplasmic reticulum (ER) membrane through a highly conserved channel formed by three proteins: Sec61, Sbh1, and Sss1. Sbh1, the most divergent, contains multiple phosphorylation sites, which may allow it to regulate entry into the secretory pathway in a species- and protein-specific manner. Absence of SBH1 causes a cell-wall defect in both Saccharomyces cerevisiae and C. neoformans, although other phenotypes differ. Notably, proteomic analysis showed that when cryptococci are grown in conditions that mimic aspects of the mammalian host environment (tissue culture medium, 37°C, 5% CO2), a set of secretory and transmembrane proteins is upregulated in wild-type, but not in Δsbh1 mutant cells. The Sbh1-dependent proteins show specific features of their ER targeting sequences that likely cause them to transit less efficiently into the secretory pathway. Many also act in cell-wall biogenesis, while several are known virulence factors. Consistent with these observations, the C. neoformans Δsbh1 mutant is avirulent in a mouse infection model. We conclude that, in the context of conditions encountered during infection, Sbh1 controls the entry of virulence factors into the secretory pathway of C. neoformans, and thereby regulates fungal pathogenicity. IMPORTANCE Cryptococcus neoformans is a yeast that causes almost 200,000 deaths worldwide each year, mainly of immunocompromised individuals. The surface structures of this pathogen, a protective cell wall surrounded by a polysaccharide capsule, are made and maintained by proteins that are synthesized inside the cell and travel outwards through the secretory pathway. A protein called Sbh1 is part of the machinery that determines which polypeptides enter this export pathway. We found that when Sbh1 is absent, both C. neoformans and the model yeast S. cerevisiae show cell-wall defects. Lack of Sbh1 also changes the pattern of secretion of both transmembrane and soluble proteins, in a manner that depends on characteristics of their sequences. Notably, multiple proteins that are normally upregulated in conditions similar to those encountered during infection, including several needed for cryptococcal virulence, are no longer increased. Sbh1 thereby regulates the ability of this important pathogen to cause disease.
A comprehensive map of preferentially located motifs reveals distinct proximal cis-regulatory elements in plants

The identification of cis-regulatory elements controlling gene expression is an arduous challenge that is being actively explored to discover the key genetic factors responsible for traits of agronomic interest. Here, we have used a de novo and genome-wide approach for preferentially located motif (PLM) detection to investigate the proximal cis-regulatory landscape of Arabidopsis thaliana and Zea mays. We report three groups of PLMs in each gene-proximal region and emphasize conserved PLMs in both species, particularly in the 3’-gene-proximal region. Comparison with resources of transcription factor and microRNA binding sites indicates that 79% of the identified PLMs are unassigned, although some are supported by MNase-defined cistrome occupancy analysis. Enrichment analyses further reveal that unassigned PLMs provide functional predictions distinct from those inferred by transcription factor and microRNA binding sites. Our study provides a comprehensive map of PLMs and points at their potential utility for future characterization of orphan genes in plants.
Internally Controlled and Dynamic Optical Measures of Functional Tumor Biology

Imaging defined aspects of functional tumor biology with bioluminescent reporter transgenes is a popular approach amongst the research community in drug development, as it is sensitive, relatively high-throughput and low cost. However, the lack of internal controls subject functional bioluminescence to a number of unpredictable variables that reduce this powerful tool to semi-quantitative interpretation of large-scale effects. Here we report the generation of sensitive and quantitative live reporters for two key measures of functional cancer biology and pharmacologic stress: the cell cycle and oxidative stress. We developed a two-colored readout, where two independent enzymes convert a common imaging substrate into spectrally distinguishable light. The signal intensity of one color is dependent upon biological state, whereas the other color is constitutively expressed. The ratio of emitted colored light corrects the functional signal for independent procedural variables, substantially improving the robustness and interpretation of relatively low-fold changes in functional signal intensity after drug treatment. The application of these readouts in vitro is highly advantageous, as peak cell response to therapy can now be readily visualized for single or combination treatments and not simply assessed at an arbitrary and destructive timepoint. Spectral imaging in vivo can be challenging, but we also present evidence to show that the reporters can work in this context as well. Collectively, the development and validation of these internally controlled reporters allow researchers to robustly and dynamically visualize tumor cell biology in response to treatment. Given the prevalence of bioluminescence imaging, this presents significant and much needed opportunities for preclinical therapeutic development.
Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS). Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic MPC-ablation in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify a novel pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation. Highlights • Quiescent NSPCs have high levels of MPC and an active mitochondrial network • The import of pyruvate into mitochondria is necessary to maintain quiescence of NSPCs • MPC inhibition increases intracellular aspartate levels and triggers the activation of quiescent NSPCs • MPC-knockout NSPCs generate mature newborn neurons, leading to overall increased neurogenesis in adult and advanced age mice Graphical abstract
Investigation of nano- and micro-domains formed by ceramide-1-phosphate in freestanding lipid bilayers

Biological membranes are known for their complex nature and formation of domains is crucial for proper execution of multiple cellular processes. Such domains, mostly due to their nanoscale character, are rarely studied since implementation of techniques for their quantitative investigation is difficult. In this article we introduce spot-variation z-scan FCS implemented for the first time for artificial lipid vesicles of defined lipid composition. We used this approach to investigate behaviour of different species of ceramide-1-phosphate within membranes. We were able to provide quantitative description of lipid domains generated by ceramide-1-phosphate in nano and microscale. Aligning these results with in silico studies helped us to validate the approach and draw conclusions on complex behaviour of signalling lipids within biological membranes.
Perception of self- and externally-generated visual stimuli: Evidence from EEG and behaviour

Efference copy-based forward model mechanisms may help us to distinguish between self- and externally-generated sensory consequences. Previous studies have shown that neural activity and perception associated with self-initiated sensory consequences are reduced (sensory suppression). For example, event-related potentials (ERPs) elicited by tones that follow a button press are reduced in amplitude relative to ERPs elicited by passively attended tones. However, previous EEG studies investigating visual stimuli in this context are rare, provide inconclusive results, and lack adequate control conditions with passive movements. Furthermore, although self-initiation is known to modulate behavioural responses, it is not known whether differences in the amplitude of ERPs also reflect differences in perception of sensory outcomes. In this study, we presented to participants visual stimuli consisting of grey discs following either active button presses, or passive button presses, in which an electromagnet moved the participant’s finger. Two discs presented visually 500-1250 ms apart followed each button press, and participants judged which of the two was more intense. Early components of the primary visual response (N1 and P2) over the occipital electrodes were suppressed in the active condition. Interestingly, suppression in the intensity judgement task was only correlated with suppression of the visual P2 component. These data support the notion of efference copy-based forward model predictions in the visual sensory modality, but especially later processes (P2) seem to be perceptually relevant. Taken together, the results challenge the assumption that N1 differences reflect perceptual suppression and emphasise the relevance of the P2 ERP component.