Miracle-dz/UniFAR-FTUs huggingface dataset:
Reconsidering the border between the visual and posterior parietal cortex of mice

The posterior parietal cortex (PPC) contributes to multisensory and sensory-motor integration, as well as spatial navigation. Based on studies in primates, the PPC is composed of several subdivisions with differing connection patterns, including areas that exhibit retinotopy. In mice the exact anatomical location and composition of the PPC is poorly understood. We present a revised delineation in which we classify the higher-order visual areas RL, AM and MMA as subregions of the mouse PPC. Retrograde and anterograde tracing revealed connectivity, characteristic for primate PPC, with sensory, retrosplenial, orbitofrontal, cingulate and motor cortex, as well as with several thalamic nuclei and the superior colliculus in the mouse. Regarding cortical input, RL receives major input from the somatosensory barrel field, while AM receives more input from the trunk, whereas MMA receives strong inputs from retrosplenial, cingulate and orbitofrontal cortices. These input differences suggest that each new PPC sub-region has a distinct function. Summarized, we put forward a new refined cortical map, including a mouse PPC that contains at least 6 sub-regions, RL, AM, MMA and PtP, MPta, LPta/A. These results will facilitate a more detailed understanding about the role that the PPC and its subdivisions play in multisensory integration-based behavior in mice. Highlights Higher-order visual areas RL, AM and MMA are part of the posterior parietal cortex (PPC) of the mouse based on connectivity. The mouse PPC contains at least 6 sub-regions, including RL, AM, MMA, PtP, LPtA/A and MPtA Specialized cortical input patterns to the new PPC subdivisions may reflect division of function. A new flattened map for mouse cortex represents refined auditory, visual, retrosplenial and PPC areas.
A new genetic method to predict the prognostic outcome of melanoma

Cutaneous melanoma is quite often encountered in dermato-oncology. This paper describes a new genetic method to predict the prognostic outcome of melanoma. Data were collected from the TCGA databases. According to tumor progression status, the data were divided into two groups to evaluate the significant biological processes and key genes influencing the outcome of melanoma using a bioinformatics method. By adopting a statistical regression analysis method, a novel score based on the contributing genes was developed. Cox regression analysis was used to validate the effectiveness of the genetic risk score in predicting the outcome. Seven biological processes associated with melanocytes were identified. A protein-protein interactions network showed that 27 functional genes were associated with the outcome of melanoma. Among these, three genes (COL17A1, ITGA6, and SPRR2F) were used to calculate the genetic risk score, which was regarded as an independent and effective risk factor for disease progression or overall survival in melanoma.
Exposons exploit cooperative changes in solvent exposure to detect cryptic allosteric sites and other functionally-relevant conformational transitions

Conformational changes can dramatically alter a protein’s function by changing the surfaces that are accessible to interact with binding partners. However, it is often difficult to hone in on the most relevant conformational changes from the cartesian coordinates of atoms on the protein’s surface. Instead, we describe a protein’s surface in terms of groups of residues that undergo cooperative changes in their solvent exposure. We term these groups exposons . We demonstrate that Markov state models (MSMs) elegantly identify the conformational transitions that give rise to an exposon, enabling users to rapidly find the most interesting conformational changes in their system. For example, this approach readily identifies previously-known cryptic allosteric sites and other functionally-relevant conformational transitions. Moreover, it predicts a cryptic allosteric site in an important target for combating antibiotic resistance that lacks known cryptic pockets. Experimental tests confirm that targeting this site reduces catalytic efficiency 15-fold.
Characterizing the Human Heart Rate Circadian Pacemaker through Widely Available Wearable Devices

The effects of real-world stimuli and how they vary across individuals remains largely unknown for lack of a continuous real-world circadian marker. Here, we show how an underlying circadian rhythm in heart rate (CRHR) can be extracted from several widely used wearables. Analysis of over 130,000 days of data from medical interns on rotating shifts shows how CRHR dynamics are distinct from those of sleep-wake timing and vary greatly among individuals. Analysis of circadian timekeeping in travelers in 5 continents shows how the circadian timekeeping more carefully controls wake time rather than sleep time. We determine a personalized phase response curve (PRC) of CRHR to activity for each individual, representing the first passive and personalized determination of how human circadian timekeeping continuously changes due to real-world stimuli. These results collectively establish CRHR as a practical method to study circadian rhythms in the real world. eTOC Blurb We show how the circadian rhythm in heart rate can be extracted from real world data collected by wearables. Studying data from a large cohort of medical interns working on shifts, we find very interesting dynamics of this circadian rhythm that are independent of the acute effects of activity or sleep-wake timing. These techniques can also determine personalized parameters of circadian timekeeping.
A Piezo1 Open State Reveals a Multi-fenestrated Ion Permeation Pathway

Force-sensing Piezo channels are essential to many aspects of vertebrate physiology. Activation of Piezo1 is facilitated by the presence of negative membrane lipids in the inner leaflet, such as phosphatidylinositol-4,5-bisphosphate (PIP2). Here, to study how Piezo1 opens, we performed molecular dynamics simulations of Piezo1 in membranes flattened by the periodic boundary effect and with or without PIP2 lipids. The Piezo1 pore spontaneously opens in the asymmetrical bilayer but not in the symmetric membrane or when PIP2 lipids are neutralized. Electrophysiological characterization of putative PIP2-interacting Piezo1 residues suggests the contribution of multiple PIP2 binding sites. Our Piezo1 open state recapitulates ionic selectivity, unitary conductance and mutant phenotypes obtained from numerous experimental studies. Tracking ion diffusion through the open pore reveals the presence of intracellular and extracellular fenestrations, delineating a multi-fenestrated permeation pathway. This open state sheds light on the mechanisms of lipid modulation, permeation, and selectivity in a Piezo channel.
Consensus-seeking and conflict-resolving ---an fMRI study on college couples’ shopping interaction

One of the typical campus scenes is the social interaction between college couples, and the lesson couples must keep learning is to adapt to each other. This fMRI study investigated the shopping interactions of 30 college couples, one lying inside and the other outside the scanner, beholding the same item from two connected PCs, making preference ratings and subsequent buy/not-buy decisions. The behavioral results showed the clear modulation of significant others’ preferences onto one’s own decisions, and the contrast of the “shop-together vs. shop-alone”, and the “congruent (both liked or disliked the item, 68%) vs. incongruent (one liked but the other disliked, and vice versa)” together trials, both revealed bilateral temporal parietal junction (TPJ) among other reward-related regions, likely reflecting mentalizing during preference harmony. Moreover, when contrasting “own-high/other-low vs. own-low/other-high” incongruent trials, left anterior inferior parietal lobule (l-aIPL) was parametrically mapped, and the “yield (e.g., own-high/not-buy) vs. insist (e.g., own-low/not-buy)” modulation further revealed left lateral-IPL (l-lIPL), together with left TPJ forming a local social decision network that was further constrained by the mediation analysis among left TPJ-lIPL-aIPL. In sum, these results exemplify, via the two-person fMRI, the neural substrate of shopping interactions between couples.
Nine Novel Cluster E Mycobacteriophages Isolated from Soil

Novel mycobacteriophages FireRed, MISSy, MPhalcon, Murica, Sassay, Terminus, Willez, YassJohnny, and Youngblood were isolated from soil samples on the host Mycobacterium smegmatis. Transmission electron microscopy revealed phage structures suggestive of the Siphoviridae family of phages. Phage genomes were sequenced and annotated, revealing that they belong to actinobacteriophage Cluster E. Here, we describe the features of these phage genomes and discuss their similarity to previously discovered cluster E phages.
Why is cancer not more common? A changing microenvironment may help to explain why, and suggests strategies for anti-cancer therapy

One of the great unsolved puzzles in cancer biology is not why cancers occur, but rather, explaining why so few cancers occur compared with the theoretical number that could occur given the number of progenitor cells in the body and the normal mutation rate. We hypothesised that a contributory explanation is that the tumour microenvironment (TME) is not fixed, and that this could impair the ability of neoplastic cells to retain a high enough fitness to become a cancer. The TME has implicitly been assumed to be static in most cancer evolution models, and we therefore developed a mathematical model of spatial cancer evolution assuming that the TME, and thus the optimum cancer phenotype, change over time. Based on simulations, we show how cancer cell populations adapt to diverse changing TME conditions and fitness landscapes. Compared with static TMEs which generate neutral dynamics, changing TMEs lead to complex adaptations with spatio-temporal heterogeneity involving variable sub-clonal fitness, mixing, competition and phylogeny patterns. In many cases, cancer cell populations fail to grow or undergo spontaneous regression, and even extinction. Our analyses predict that cancer evolution in a changing TME is challenging, and can help to explain why cancer is neither inevitable nor as common as expected. Should cancer driver mutations with effects dependent of the TME exist, they are likely to be selected. Anti-cancer prevention and treatment strategies based on changing the TME are feasible and potentially effective.
Bioinformatics analysis for L polymerase homology of arenaviruses

Many pathogenic viruses can transmit between humans and animals as zoonotic infectious often to cause dangerous disease with obvious clinical signs, sometimes globally. However, these outbreaks are generally only dealt with seriously when the viruses concerned have been confirmed and classified as zoonotic. Arenavirus haemorrhagic fever viruses can cause epidemics in some areas of the world. To assess the potential of similar viruses to become zoonotic in the future, bioinformatics of relatively conserved virus proteins, such as the L polymerase of arenaviruses, can be used to identify homology with viruses that might give future outbreaks. In this paper, new and archival metazoan transcriptome sequence data was used as a resource to identify similar sequences to known arenavirus sequences for the purpose of risk prediction. In essence, bioinformatics was utilized to provide a better understanding of the potential evolution and natural history of
Caenorhabditis elegans nematodes are not attracted to the terrestrial isopod Porcellio scaber

Phoresy is a behavior in which an organism, the phoront, travels from one location to another by ‘hitching a ride’ on the body of a host as it disperses. Some phoronts are generalists, taking advantage of any available host. Others are specialists and travel only when specific hosts are located using chemical cues to identify and move (chemotax) toward the preferred host. Free-living nematodes, like Caenorhabditis elegans, are often found in natural environments that contain terrestrial isopods and other invertebrates. Additionally, the C. elegans wild strain PB306 was isolated associated with the isopod Porcellio scaber. However, it is currently unclear if C. elegans is a phoront of terrestrial isopods, and if so, whether it is a specialist, generalist, or developmental stage-specific combination of both strategies. Because the relevant chemical stimuli might be secreted compounds or volatile odorants, we used different types of chemotaxis assays across diverse extractions of compounds or odorants to test whether C. elegans is attracted to P. scaber. We show that two different strains – the wild isolate PB306 and the laboratory-adapted strain N2 – are not attracted to P. scaber during either the dauer or adult life stages. Our results indicate that C. elegans was not attracted to chemical compounds or volatile odorants from P. scaber, providing valuable empirical evidence to suggest that any associations between these two species are likely opportunistic rather than specific phoresy.
Identification of viruses belonging to the family Partitiviridae from plant transcriptomes

Viruses in the family Partitiviridae consist of non-enveloped viruses with bisegmented double-stranded RNA genomes. Viruses in this family have been identified from plants and fungi. In this study, we identified several viruses belonging to the family Partitiviridae using plant transcriptomes. From 11 different plant species, we identified a total of 74 RNA segments representing 23 partitiviruses. Of 74 RNA segments, 28 RNA segments encode RNA-dependent RNA polymerases (RdRp) while 46 RNA segments encode coat proteins (CPs). According to ICTV demarcation for the family Partitiviridae, 25 RNAs encoding RdRp and 41 RNAs encoding CP were novel RNA segments. In addition, we identified eight RNA segments (three for RdRp and five for CP) belonging to the known partitivruses. Taken together, this study provides the largest number of partitiviruses from plant transcriptomes in a single study.
Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1

Ewing sarcoma breakpoint region 1 (EWSR1) encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of EWSR1, its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5’ EWSR1 isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5’ EWSR1 polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5’ EWSR1 isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the EWSR1 gene leading to early transcription termination and breakpoint formation.
SPEARS: Standard Performance Evaluation of Ancestral Reconstruction through Simulation

Ancestral haplotype maps provide useful information about genomic variation and biological processes. Reconstructing the descendent haplotype structure of homologous chromosomes, particularly for large numbers of individuals, can help with characterizing the recombination landscape, elucidating genotype-to-phenotype relationships, improving genomic predictions and more. Inferring haplotype maps from sparse genotype data is an efficient approach to whole-genome haplotyping, but this is a non-trivial problem. A standardized approach is needed to validate whether haplotype reconstruction software, conceived population designs and existing data for a given population provides accurate haplotype information for further inference. Results We introduce SPEARS, a pipeline for whole simulation-based appraisal of genome-wide ancestral haplotype inference. The pipeline generates virtual genotypes (truth data) with real-world missing data structure. It then proceeds to mimic analysis in practice, capturing sources of error due to imputation and reconstruction of ancestral haplotypes. Standard metrics allow researchers to assess which features of haplotype structure or regions of the genome are sufficiently accurate for analysis and reporting. Haplotype maps for 1,000 outcross progeny from a multi-parent population of maize is used to demonstrate SPEARS. Availability https://github.com/maizeatlas/spears
Cell Type Development in Chlamydia trachomatis Follows a Program Intrinsic to the Reticulate Body

The obligate intracellular bacterial pathogen Chlamydia trachomatis (Ctr) is reliant on an unusual developmental cycle consisting of two cell forms termed the elementary body (EB) and the reticulate body (RB). The EB is infectious and utilizes a type III secretion system and preformed effector proteins during invasion, but does not replicate. The RB replicates in the host cell but is non-infectious. This developmental cycle is central to chlamydial pathogenesis. In this study we developed mathematical models of the chlamydial developmental cycle that account for potential factors influencing the timing of RB to EB cell type switching during infection. Our models predicted that two broad categories of regulatory signals for RB to EB development could be differentiated experimentally; an “intrinsic” cell autonomous program inherent to each RB or an “extrinsic” environmental signal to which RBs respond. To experimentally differentiate between these hypotheses, we tracked the expression of Ctr developmental specific promoters using fluorescent reporters and live cell imaging. These experiments indicated that EB production was not influenced by increased MOI or by superinfection, suggesting the cycle follows an intrinsic program that is not influenced by environmental factors. Additionally, live cell imaging of these promoter constructs revealed that EB development is a multistep process linked to RB growth rate and cell division. The formation of EBs followed a cell type gene expression progression with the promoters for euo and ihtA active in RBs, while the promoter for hctA was active in early EBs/intermediate cells and finally the promoters for the true late genes, hctB, scc2, and tarp active in the maturing EB. Importance Chlamydia trachomatis is an obligate intracellular bacteria that can cause trachoma, cervicitis, urethritis, salpingitis, and pelvic inflammatory disease. To establish infection in host cells Chlamydia must complete a multi cell type developmental cycle. The developmental cycle consists of two specialized cells; the EB which mediates infection of new cells and the RB which replicates and eventually produces more EB cells to mediate the next round of infection. By developing and testing mathematical models to discriminate between two competing hypotheses for the nature of the signal controlling RB to EB cell type switching. We demonstrate that RB to EB development follows a cell autonomous program that does not respond to environmental cues. Additionally, we show that RB to EB development is a function of cell growth and cell division. This study serves to further our understanding of the chlamydial developmental cycle that is central to the bacterium’s pathogenesis.
Exact mapping of Illumina blind spots in the Mycobacterium tuberculosis genome reveals platform-wide and workflow-specific biases

Whole genome sequencing (WGS) is fundamental to M. tuberculosis basic research and many clinical applications. Coverage across Illumina-sequenced M. tuberculosis genomes is known to vary with sequence context, but this bias is poorly characterized. Here, through a novel application of phylogenomics that distinguishes genuine coverage bias from deletions, we discern Illumina “blind spots” in the M. tuberculosis reference genome for seven sequencing workflows. We find blind spots to be widespread, affecting 529 genes, and provide their exact coordinates, enabling salvage of unaffected regions. Fifty-seven PE/PPE genes (the primary families assumed to exhibit Illumina bias) lack blind spots entirely, while remaining PE/PPE genes account for 55.1% of blind spots. Surprisingly, we find coverage bias persists in homopolymers as short as 6 bp, shorter tracts than previously reported. While GC-rich regions challenge all Illumina sequencing workflows, a modified Nextera library preparation that amplifies DNA with a high-fidelity polymerase markedly attenuates coverage bias in GC-rich and homopolymeric sequences, expanding the “Illumina-sequencable” genome. Through these findings, and by defining workflow-specific exclusion criteria, we spotlight effective strategies for handling bias in M. tuberculosis Illumina WGS. This empirical analysis framework may be used to systematically evaluate coverage bias in other species using existing sequencing data.
High-throughput inverse toeprinting reveals the complete sequence dependence of ribosome-targeting antibiotics

It has recently become clear that various antibiotics block the translation of bacterial proteins in a sequence-specific manner. In order to understand how this specificity contributes to antibiotic potency and select better antimicrobial leads, new high-throughput tools are needed. Here, we present inverse toeprinting, a new method to map the position of ribosomes arrested on messenger RNAs during in vitro translation. Unlike ribosome profiling, our method protects the entire coding region upstream of a stalled ribosome, making it possible to work with transcript libraries that randomly sample the sequence space. We used inverse toeprinting to characterize the pausing landscape of free and drug-bound bacterial ribosomes engaged in translation. We obtained a comprehensive list of arrest motifs that could be validated in vivo, along with a quantitative measure of their pause strength. Thus, our method provides a highly parallel and scalable means to characterize the sequence specificity of translation inhibitors.
Measuring hospital spatial wingspan by using a discrete choice model with utility-threshold

Policy makers increasingly rely on hospital competition to incentivize patients to choose high-value care. Travel distance is one of the most important drivers of patients’ decision. The paper presents a method to numerically measure, for a given hospital, the distance beyond which no patient is expected to choose the hospital for treatment by using a new approach in discrete choice models. To illustrate, we compared 3 hospitals attractiveness related to this distance for asthma patients admissions in 2009 in Hérault (France), showing, as expected, CHU Montpellier is the one with the most important spatial wingspan. For estimation, Monte Carlo Markov Chain (MCMC) methods are used.