Miracle-dz/UniFAR-FTUs huggingface dataset:
Statistical structure of the trial-to-trial timing variability in synfire chains

Timing and its variability are crucial for behavior. Consequently, neural circuits that take part in the control of timing and in the measurement of temporal intervals have been the subject of much research. Here, we provide an analytical and computational account of the temporal variability in what is perhaps the most basic model of a timing circuit, the synfire chain. First, we study the statistical structure of trial-to-trial timing variability in a reduced but analytically tractable model: a chain of single integrate-and-fire neurons. We show that this circuit’s variability is well-described by a generative model consisting of local, global, and jitter components. We relate each of these components to distinct neural mechanisms in the model. Next, we establish in simulations that these results carry over to a noisy homogeneous synfire chain. Finally, motivated by the fact that a synfire chain is thought to underlie the circuit that takes part in the control and timing of zebra finch song, we present simulations of a biologically realistic synfire chain model of the zebra finch timekeeping circuit. We find the structure of trial-to-trial timing variability to be consistent with our previous findings, and to agree with experimental observations of the song’s temporal variability. Our study therefore provides a possible neuronal account of behavioral variability in zebra finches.
Ebola Virus Requires Phosphatidylserine Scrambling Activity for Efficient Budding and Optimal Infectivity

Within the last decade, countries in western and central Africa have experienced the most widespread and deadly Ebola outbreaks since Ebola virus was identified in 1976. While outbreaks are primarily attributed to zoonotic transfer events, new evidence is emerging outbreaks may be caused by a combination of spillover events and viral latency or persistence in survivors. ABSTRACT Ebola virus (EBOV) attaches to target cells using two categories of cell surface receptors: C-type lectins and phosphatidylserine (PS) receptors. PS receptors typically bind to apoptotic cell membrane PS and orchestrate the uptake and clearance of apoptotic debris. Many enveloped viruses also contain exposed PS and can therefore exploit these receptors for cell entry. Viral infection can induce PS externalization in host cells, resulting in increased outer PS levels on budding virions. Scramblase enzymes carry out cellular PS externalization; thus, we targeted these proteins in order to manipulate viral envelope PS levels. We investigated two scramblases previously identified to be involved in EBOV PS levels, transmembrane protein 16F and Xk-related protein 8 (XKR8), as possible mediators of cellular and viral envelope surface PS levels during the replication of recombinant vesicular stomatitis virus containing its native glycoprotein (rVSV/G) or the EBOV glycoprotein (rVSV/EBOV-GP). We found that rVSV/G and rVSV/EBOV-GP virions produced in XKR8 knockout cells contain decreased levels of PS on their surfaces, and the PS-deficient rVSV/EBOV-GP virions are 70% less efficient at infecting cells through PS receptors. We also observed reduced rVSV and EBOV virus-like particle (VLP) budding in ΔXKR8 cells. Deletion of XKR8 in HAP1 cells reduced rVSV/G and rVSV/EBOV-GP budding by 60 and 65%, respectively, and reduced Ebola VLP budding more than 60%. We further demonstrated that caspase cleavage of XKR8 is required to promote budding. This suggests that XKR8, in addition to mediating virion PS levels, may also be critical for enveloped virus budding at the plasma membrane. IMPORTANCE Within the last decade, countries in western and central Africa have experienced the most widespread and deadly Ebola outbreaks since Ebola virus was identified in 1976. While outbreaks are primarily attributed to zoonotic transfer events, new evidence is emerging outbreaks may be caused by a combination of spillover events and viral latency or persistence in survivors. The possibility that Ebola virus can remain dormant and then reemerge in survivors highlights the critical need to prevent the virus from entering and establishing infection in human cells. Thus far, host cell scramblases TMEM16F and XKR8 have been implicated in Ebola envelope surface phosphatidylserine (PS) and cell entry using PS receptors. We assessed the contributions of these proteins using CRISPR knockout cells and two EBOV models: rVSV/EBOV-GP and EBOV VLPs. We observed that XKR8 is required for optimal EBOV envelope PS levels and infectivity and particle budding across all viral models.
An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. Here we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis, psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis associated risk loci. For example, the variant rs10794648, which is generally assigned to IFNLR1, was linked to GRHL3 in our dataset, a gene essential in skin repair and development. Our findings, therefore, indicate a renewed importance of skin related factors in the risk of disease. Graphical Abstract In this article we take disease associated variants from 5 dermatological conditions and use cell type specific datasets to map genes that could be affected by these variants, providing insight into disease mechanisms.
Insights into the genetic basis of predator‐induced response in Daphnia galeata

Abstract Phenotypic plastic responses allow organisms to rapidly adjust when facing environmental challenges—these responses comprise morphological, behavioral but also life‐history changes. Alteration of life‐history traits when exposed to predation risk have been reported often in the ecological and genomic model organism Daphnia. However, the molecular basis of this response is not well understood, especially in the context of fish predation. Here, we characterized the transcriptional profiles of two Daphnia galeata clonal lines with opposed life histories when exposed to fish kairomones. First, we conducted a differential gene expression, identifying a total of 125 candidate transcripts involved in the predator‐induced response, uncovering substantial intraspecific variation. Second, we applied a gene coexpression network analysis to find clusters of tightly linked transcripts revealing the functional relations of transcripts underlying the predator‐induced response. Our results showed that transcripts involved in remodeling of the cuticle, growth, and digestion correlated with the response to environmental change in D. galeata. Furthermore, we used an orthology‐based approach to gain functional information for transcripts lacking gene ontology (GO) information, as well as insights into the evolutionary conservation of transcripts. We could show that our candidate transcripts have orthologs in other Daphnia species but almost none in other arthropods. The unique combination of methods allowed us to identify candidate transcripts, their putative functions, and evolutionary history associated with predator‐induced responses in Daphnia. Our study opens up to the question as to whether the same molecular signature is associated with fish kairomones‐mediated life‐history changes in other Daphnia species.
Queryfuse is a sensitive algorithm for detection of gene-specific fusions

Recurrent chromosomal translocations, known as fusions, play important roles in carcinogenesis. They can serve as valuable diagnostic and therapeutic targets. RNA-seq is an ideal platform for detecting transcribed fusions, and computational methods have been developed to identify fusion transcripts from RNA-seq data. However, some transciptome realignment procedures for these methods are unnecessary, making this task computationally expensive and time consuming. Therefore, we have developed QueryFuse, a novel hypothesis-based algorithm that identifies gene-specific fusion from pre-aligned RNA-seq data. It is designed to help biologists quickly find and/or computationally validate fusions of interest, together with visualization and detailed properties of supporting reads. By aligning reads to Query genes at the pre-processing step with a more sensitive, memory intensive local aligner, QueryFuse can reduce alignment time and improve detection sensitivity. QueryFuse performed better or at comparable levels with two popular tools (deFuse and TopHatFusion) on both simulated and well-annotated cell-line datasets. Finally, using QueryFuse, we identified a novel fusion event with a potential therapeutic implication in clinical samples. Taken together, our results showed that QueryFuse is efficient and reliable for detecting gene-specific fusion events.
Investigating Population-scale Allele Specific Expression in Wild Populations of Oithona similis (Cyclopoida, Claus 1866)

Allele-specific expression (ASE) is a widely studied molecular mechanism at cell, tissue and organism levels. Here, we extrapolated the concept of ASE to the population-scale (psASE), aggregating ASEs detected at smaller scales. We developed a novel approach to detect psASE based on metagenomic and metatranscriptomic data of environmental samples containing communities of organisms. This approach which measures the deviation between the frequency and the relative expression of biallelic loci, was applied on samples collected during the Tara Oceans expedition (2009-2013), in combination to new Oithona similis transcriptomes, a widespread marine copepod. Among a total of 25,768 single nucleotide variants (SNVs) of O. similis, 587 (2.3%) were targeted by psASE in at least one population. The distribution of SNVs targeted by psASE in different populations is significantly shaped by population genomic differentiation (p-value = 9.3×10−9), supporting a partial genetic control of psASE. To investigate the link between evolution and psASE, loci under selection were compared to loci under psASE. A significant amount of SNVs (0.6%) were targeted by both selection and psASE (p-values < 9.89×10−3), supporting the hypothesis that natural selection and ASE may lead to the same phenotype. Population-scale ASE offers new insights into the gene regulation control in populations and its link with natural selection.
Chronic Interleukin-1 exposure triggers selective expansion of Cebpa-deficient multipotent hematopoietic progenitors

The early events that drive hematologic disorders like clonal hematopoiesis, myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia are not well understood. Most studies focus on the cell-intrinsic genetic changes that occur in these disorders and how they impact cell fate decisions. We consider how chronic exposure to the pro-inflammatory cytokine, interleukin-1β (IL-1β), impacts Cebpa-deficient hematopoietic stem and progenitor cells (HSPC) in competitive settings. We surprisingly found that Cebpa-deficient HSPC did not have a hematopoietic cell intrinsic competitive advantage; rather chronic IL-1β exposure engendered potent selection for Cebpa loss. Chronic IL-1β augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in a Cebpa-dependent manner. As a result, Cebpa-deficient HSPC are resistant to the pro-differentiative effects of chronic IL-1β, and competitively expand. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention. Summary Higa et al. show that chronic interleukin-1β exposure primes hematopoietic stem and progenitor cells for myelopoiesis by upregulating myeloid differentiation programs and repressing stem gene programs in a Cebpa-dependent manner. Consequently, interleukin-1 potently selects for Cebpa loss in hematopoietic stem and progenitor cells.
Differential TAM receptor regulation of hepatic physiology and injury

The TAM receptor tyrosine kinases (RTK) Mer and Axl have been implicated in liver disease, yet our understanding of their roles in liver homeostasis and injury is limited. We therefore examined the performance of Mer and Axl mutant mice during aging, and in four models of liver injury. We find that Mer and Axl are most prominently expressed in Kupffer and hepatic endothelial cells, and that as Axl-/-Mertk-/- mice normally age, they develop profound liver disease. We further find that Mer signaling is critical to the phagocytosis of apoptotic hepatocytes that are generated during acute hepatic injury, and that Mer and Axl act in concert to inhibit injury-triggered cytokine production. TAM expression in Kupffer cells is crucial for these effects. In contrast, we show that Axl is uniquely important in mitigating liver damage during acute acetaminophen intoxication. Finally, we demonstrate that Axl exacerbates the fibrosis that develops in a model of chronic hepatic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that target these RTKs in the liver.
Vpr Co-assembles with Gag during HIV-1 Assembly

The HIV-1 accessory protein Vpr is packaged into new virions at a 7:1 ratio of Gag/Vpr. Previous biochemical and genetic analysis has shown that Vpr gets packaged into virions via an LXXLF motif on the p6 domain of the Gag structural polyprotein. The kinetics of Vpr packaging compared to Gag assembly was previously unknown. Here, we confirm via biochemistry and imaging that fluorescently tagged Vpr gets packaged into virus-like particles only when the LXXLF motif is intact. When the LXXLF motif is mutated, Vpr is no longer recruited to Gag assemblies. When Vpr and Gag assembly are imaged together, we see that Vpr co-assembles with a slight delay compared to Gag suggesting that Vpr is not being recruited to the membrane with Gag but is instead being recruited to actively assembling Gag. Importance HIV-1 affects over 30 million people around the globe, and although we have good treatments, there is still no cure. The virus encodes 15 distinct proteins, and four of those proteins are known as accessory proteins. Vpr is one of the accessory proteins that is packaged into HIV-1 by interacting with the Gag structural protein. Without Vpr, HIV-1 is not as infectious. Our research shows that Vpr is packaged into new viruses as the virus is being formed rather than being put in towards the end of the assembly of a virus. Getting a clearer view of each step in the process of assembling each virion will help inform future treatments and help with overall comparisons between the assembly of different viruses.
Study of neck shaft angle of femur in population of Bihar

Background: Neck shaft angle is the angle formed between the long axis of shaft and long axis of neck. Neck shaft angle of femur is an important parameter considering the biomechanics of hip joint. Neck shaft angle gives important information regarding race to which they belong. Normal neck shaft angle is in the range of 120 -140. Objective of the study was to find out the neck shaft angle of femur and correlate with the previous study. Methods: present study was conducted on 60 dry femur collected from different medical colleges of Bihar. The neck shaft angle was measured by Goniometer. Results: In this study the neck shaft angle of femur was 130.82, in male neck shaft angle of femur was 130.28 and in females it was 131.42. Conclusions: There is no significance difference between the male and female neck shaft angle. Orthopaedists use the normal range and mean of the neck shaft angle in diagnosis and treatment of the disease of hip. The angle is increased in poliomyelitis, congenital subluxation and dislocation of hip and decreased in congenital coxa vara.
A prática clínica odontológica = análise ergonômica da postura sentada = The dental clinical practice: ergonomic analysis of the sitting posture

The main objective of this study was to perform a survey on the "state of the art", as well as to assess the influence of the saddle seat on the clinical practice of dental students and the satisfaction with the type of seat used. In article 1, the systematic review and metaanalysis aimed to verify whether the saddle seat provides lower ergonomic risk than conventional seats. In article 2, the randomized and controlled clinical trial aimed to assess, in dental students, the impact of saddle and conventional seats regarding the variables of center of gravity of frontal and lateral planes, functional impairment associated with the condition of cervical and low back pain, and seating satisfaction. In article 1, the search was performed in eight electronic databases and resulted in 3,147 records, from which two were considered eligible. The findings of this review indicate that the saddle seat provides lower ergonomic risk than the conventional seat. In article 2, 84 dental students were allocated in Group Control (GC) and Intervention (GI). The GC (n = 40) used the conventional seat for clinical care and the GI (n = 44) used the saddle seat. After ten months of follow-up, a statistically significant reduction was observed for the daily problems related to neck pain, as well as an improvement in the projection of the center of gravity of the lateral plane for GI (p < 0.05) and a significant worsening in the means of projection of the center of gravity of the lateral plane for GC (p ≤ 0.05). The saddle seat was better evaluated regarding seating satisfaction in all aspects (p < 0.001). The saddle seat presented higher satisfaction and had a positive impact on lateral body alignment and on the daily problems regarding the cervical region, while the conventional seat presented a negative impact on lateral body alignment. In conclusion, the impact of the saddle seat, when compared to the conventional one, was significantly positive regarding ergonomic risk, projection of the lateral center of gravity, daily problems related to the cervical region, and satisfaction. This thesis is original and contributed to the development of scientific knowledge from three main points. Primarily, it is the first systematic review in the literature to investigate the influence of the type of seat on the ergonomic risk among dentists and/or dental students. Second, it is the first randomized and controlled clinical trial to assess the influence of different types of seats on dental students over one academic year in the clinical practices with patients. Third, it provides a background for further studies related to this topic, so this work may be a reference target for research in numerous fields of study, and it helps to decrease the lack of literature on the topic of the saddle seat in the dental clinical practice.
THE SELF-QUANTIFICATION MOVEMENT – IMPLICATIONS FOR HEALTH CARE PROFESSIONALS - Selfcare Journal

The growing phenomenon of self-quantification – people who observe certain aspects of their lives in great detail, analyze this data, and conduct self-experiments in the interests of improving their lives – is something health care professionals (HCPs) should be aware of. Many self-quantifiers’ efforts are focused on health and HCPs may need to learn how best to interact with such deeply-engaged and knowledgeable patients. HCPs may also benefit from leveraging some of the tools and learnings that stem from the self-quantification movement. This paper examines the self-quantification phenomenon through the experiences of the Quantified Self, a leading organization in this movement, describes the key driving factors, and suggests some implications for HCPs.
Physical factors contributing to regulation of bacterial surface motility

Microbes routinely face the challenge of acquiring territory and resources on wet surfaces. Cells move in large groups inside thin, surface-bound water layers, often achieving speeds of 30 µm/s within this environment, where viscous forces dominate over inertial forces (low Reynolds number). The canonical Gram-positive bacterium Bacillus subtilis is a model organism for the study of collective migration over surfaces with groups exhibiting motility on length scales three orders of magnitude larger than themselves within a few doubling times. Genetic and chemical studies clearly show that the secretion of endogenous surfactants and availability of free surface water are required for this fast group motility. Here we show that: (i) water availability is a sensitive control parameter modulating an abiotic jamming-like transition that determines whether the group remains fluidized and therefore collectively motile, (ii) groups self-organize into discrete layers as they travel, (iii) group motility does not require proliferation, rather groups are pulled from the front, and (iv) flow within expanding groups is capable of moving material from the parent colony into the expanding tip of a cellular dendrite with implications for expansion into regions of varying nutrient content. Together, these findings illuminate the physical structure of surface-motile groups and demonstrate that physical properties, like cellular packing fraction and flow, regulate motion from the scale of individual cells up to length scales of centimeters.
DNA methylation is indispensable for leukemia inhibitory factor dependent embryonic stem cells reprogramming

Naïve pluripotency can be maintained by the 2i/LIF supplements (CHIR99021, PD0325901 and LIF), which primarily affect canonical WNT, FGF/ERK, and JAK/STAT3 signaling. However, whether one of these tripartite supplements alone is sufficient to maintain naïve self-renewal remain unclear. Here we show that LIF alone is sufficient to induce reprogramming of 2i/LIF cultured ESCs (2i/L-ESCs) to ESCs with hypermethylated state (L-ESCs). In vitro, upon withdrawal of 2i, 2i/L-ESCs overcome the epigenetic barrier and DNA hypermethylated, which accompanies transcriptional changes and subsequent establishment of epigenetic memory. Global transcriptome features also show that L-ESCs are close to 2i/L-ESCs and in a stable state between naïve and primed pluripotency. Notably, our results demonstrate that DNA methylation is indispensable for LIF-dependent mouse ESCs reprogramming and self-renew. LIF-dependent ESCs reprogramming efficiency is significantly increased in serum treatment and reduced in Dnmt3a or Dnmt3l knockout ESCs. Importantly, unlike epiblast and EpiSCs, L-ESCs contribute to somatic tissues and germ cells in chimaeras. Such simple culture system of ESCs is more conducive to clarify the molecular mechanism of ESCs in vitro culture. Highlights and novelty LIF alone supports ESCs self-renew and pluripotency in chemically defined media. L-ESCs re-establish the epigenetic memory in reprogramming. DNA methylation is indispensable for L-ESCs reprogramming. L-ESCs contribute to somatic tissues and germ cells in chimaeras.