bluuebunny/crossref_metadata_2025_split huggingface dataset:
The remarkable robustness of surrogate gradient learning for instilling complex function in spiking neural networks
Authors: Zenke Friedemann , Vogels Tim P. 
Published: June 2020

AbstractBrains process information in spiking neural networks. Their intricate connections shape the diverse functions these networks perform. In comparison, the functional capabilities of models of spiking networks are still rudimentary. This shortcoming is mainly due to the lack of insight and practical algorithms to construct the necessary connectivity. Any such algorithm typically attempts to build networks by iteratively reducing the error compared to a desired output. But assigning credit to hidden units in multi-layered spiking networks has remained challenging due to the non-differentiable nonlinearity of spikes. To avoid this issue, one can employ surrogate gradients to discover the required connectivity in spiking network models. However, the choice of a surrogate is not unique, raising the question of how its implementation influences the effectiveness of the method. Here, we use numerical simulations to systematically study how essential design parameters of surrogate gradients impact learning performance on a range of classification problems. We show that surrogate gradient learning is robust to different shapes of underlying surrogate derivatives, but the choice of the derivative’s scale can substantially affect learning performance. When we combine surrogate gradients with a suitable activity regularization technique, robust information processing can be achieved in spiking networks even at the sparse activity limit. Our study provides a systematic account of the remarkable robustness of surrogate gradient learning and serves as a practical guide to model functional spiking neural networks.
Mechanistic modeling of vascular tumor growth: an extension of Biot’s theory to hierarchical bi-compartment porous medium system
Authors: Sciumè Giuseppe 
Published: June 2020

AbstractExisting continuum multiphase tumor growth models typically do not include microvasculature, or if present, this is modeled as non-deformable. Vasculature behavior and blood flow are usually non-coupled with the underlying tumor phenomenology from the mechanical viewpoint; hence, phenomena as vessel compression/occlusion modifying microcirculation and oxygen supply cannot be taken into account.The tumor tissue is here modeled as a reactive bi-compartment porous medium: the extracellular matrix constitutes the solid scaffold; blood is in the vascular porosity whereas the extra-vascular porous compartment is saturated by two cell phases and interstitial fluid (mixture of water and nutrient species). The pressure difference between blood and the extra-vascular overall pressure is sustained by vessel walls and drives shrinkage or dilatation of the vascular porosity. Model closure is achieved thanks to a consistent non-conventional definition of the Biot’s effective stress tensor.Angiogenesis is modeled by introducing a vascularization state variable, and accounting for tumor angiogenic factors and endothelial cells. Closure relationships and mass exchange terms related to vessel formation are detailed in a numerical example reproducing the principal features of angiogenesis. This example is preceded by a first pedagogical numerical study on one-dimensional bio-consolidation. Results are exquisite to realize that the bi-compartment poromechanical model is fully coupled (the external loads impact fluid flow in both porous compartments) and to envision further applications as for instance modeling of drugs delivery and tissue ulceration.
A mobile genetic element in the SARS-CoV-2 genome is shared with multiple insect species
Authors: Tengs Torstein , Delwiche Charles F. , Jonassen Christine Monceyron 
Published: June 2020

ABSTRACTUnprecedented quantities of sequence data have been generated from the newly emergent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of COVID-19. We document here the presence of s2m, a highly conserved, mobile genetic element with unknown function, in both the SARS-CoV-2 genome and a large number of insect genomes. Although s2m is not universally present among coronaviruses and appears to undergo horizontal transfer, the high sequence conservation and universal presence of s2m among isolates of SARS-CoV-2 indicate that, when present, the element is essential for viral function.
Tissue distribution of ACE2 protein in Syrian golden hamster (Mesocricetus auratus) and its possible implications in SARS-CoV-2 related studies
Authors: Suresh Voddu , Parida Deepti , Minz Aliva P. , Senapati Shantibhusan 
Published: June 2020

AbstractRecently, the Syrian golden hamster (Mesocricetus auratus) has been demonstrated as a clinically relevant animal model for SARS-CoV-2 infection. However, lack of knowledge about the tissue-specific expression pattern of various proteins in these animals and the unavailability of reagents like antibodies against this species hampers optimal use of these models. The major objective of our current study was to analyze the tissue-specific expression pattern of angiotensin□converting enzyme 2 (ACE2), a proven functional receptor for SARS-CoV-2 in different organs of the hamster. We have adapted immunoblot analysis, immunohistochemistry, and immunofluorescence analysis techniques to evaluate the ACE2 expression pattern in different tissues of the Syrian golden hamster. We found that kidney, small intestine, esophagus, tongue, brain, and liver express ACE2. Epithelium of proximal tubules of kidney and surface epithelium of ileum expresses a very high amount of this protein. Surprisingly, analysis of stained tissue sections for ACE2 showed no detectable expression of ACE2 in the lung or tracheal epithelial cells. Similarly, all parts of the large intestine (caecum, colon, and rectum) were negative for ACE2 expression. Together, our findings corroborate some of the earlier reports related to ACE2 expression pattern in human tissues and also contradicts some others. We believe that the findings of this study will enable the appropriate use of the Syrian golden hamster to carryout SARS-CoV-2 related studies.
Manipulable object and human contact: preferences and modulation of emotional states in weaned piglets
Authors: Villain Avelyne S. , Lanthony Mathilde , Guérin Carole , Noûs Camille , Tallet Céline 
Published: June 2020

1AbstractEnriching the life of farm animals is an obligation in intensive farming conditions. In pigs, manipulable materials are mandatory when no bedding is available. Like manipulable objects, positive human interactions might be considered as enrichment, as they provide the animals occasions to interact, increase their activity and lead to positive emotional states. In this study, we investigated how weaned piglets perceived a manipulable object, and a familiar human. After a similar familiarization to both stimuli, twenty-four weaned piglets were tested for a potential preference for one of the stimuli and submitted to isolation/reunion tests to evaluate the emotional value of the stimuli. We hypothesized that being reunited with a stimulus would attenuate the stress of social isolation and promote positive behaviors, and even more that the stimulus has a positive emotional value for piglets. Although our behavioural data did not allow to show a preference for one of the stimuli, piglets approached more often the human and were observed laying down only near the human. Using behavioural and bioacoustic data, we showed that reunion with the human decreased more the time spent in an attentive state and mobility of piglets than reunion with the object, and isolation. Vocalizations differed between reunions with the object and the human, and were different from vocalizations during isolation. The human presence led to higher frequency range, more noisy and shorter grunts. Finally, both stimuli decreased the isolation stress of piglets, and piglets seemed to be in a more positive emotional state with the human compared to the object. It confirms the potential need for positive human interactions to be used as pseudo-social enrichment in pigs.
Replication stress and FOXM1 drive radiation induced genomic instability and cell transformation
Authors: Li Zhentian , Yu David S. , Doetsch Paul W. , Werner Erica 
Published: June 2020

ABSTRACTIn contrast to the vast majority of research that has focused on the immediate effects of ionizing radiation, this work concentrates on the molecular mechanism driving delayed effects that emerge in the progeny of the exposed cells. We employed functional protein arrays to identify molecular changes induced in a human bronchial epithelial cell line (HBEC3-KT) and osteosarcoma cell line (U2OS) and evaluated their impact on outcomes associated with radiation induced genomic instability (RIGI) at day 5 and 7 post-exposure to a 2Gy X-ray dose, which revealed replication stress in the context of increased FOXM1 expression. Irradiated cells had reduced DNA replication rate detected by the DNA fiber assay and increased DNA resection detected by RPA foci and phosphorylation. Irradiated cells increased utilization of homologous recombination-dependent repair detected by a gene conversion assay and DNA damage at mitosis reflected by RPA positive chromosomal bridges, micronuclei formation and 53BP1 positive bodies in G1, all known outcomes of replication stress. Interference with the function of FOXM1, a transcription factor widely expressed in cancer, employing an aptamer, decreased radiation-induced micronuclei formation and cell transformation while plasmid-driven overexpression of FOXM1b was sufficient to induce replication stress, micronuclei formation and cell transformation.
TET1 interacts directly with NANOG via independent regions containing hydrophobic and aromatic residues
Authors: Pantier Raphaël , Mullin Nicholas , Hall-Ponsele Elisa , Chambers Ian 
Published: June 2020

AbstractThe DNA demethylase TET1 is highly expressed in embryonic stem cells. Knockout experiments indicate that TET1 is important for lineage commitment, and paradoxically, also for reprogramming to naïve pluripotency. TET1 binds to promoters through a CXXC domain which recognises unmethylated CpG dinucleotides. TET1 also binds to enhancers, presumably via interactions with partner proteins. The transcription factor NANOG interacts with TET1 and is predominantly localised at enhancers in ESCs. Therefore, NANOG may contribute to TET1 biological activity in pluripotent cells. However, the regions of TET1 involved in protein-protein interactions are mostly unknown. Here, we characterise the physical interaction between TET1 and NANOG using embryonic stem cells and bacterial expression systems. TET1 and NANOG interact through multiple binding sites that act independently. Critically, mutating conserved hydrophobic and aromatic residues within TET1 and NANOG abolishes the interaction. Comparative ChIP-seq analysis identifies genomic loci bound by both TET1 and NANOG, that correspond predominantly to pluripotency enhancers. Importantly, around half of NANOG transcriptional target genes are associated with TET1-NANOG co-bound sites. These results indicate a mechanism by which TET1 protein is targeted to specific sites of action at enhancers by direct interaction with a transcription factor.HighlightsNANOG and TET1 have regulatory roles in maintaining and reprogramming pluripotencyTET1 and NANOG interact via multiple independent binding regionsTET1 and NANOG interactions are mediated by aromatic and hydrophobic residuesTET1 residues that bind NANOG are highly conserved in mammalsCo-localisation of TET1 and NANOG on chromatin is enriched at NANOG target genes
Diverse Epithelial Cell Populations Contribute to Regeneration of Secretory Units in Injured Salivary Glands
Authors: Ninche Ninche , Kwak Mingyu , Ghazizadeh Soosan 
Published: June 2020

ABSTRACTSalivary glands exert exocrine secretory function to provide saliva for lubrication and protection of the oral cavity. Its epithelium consists of several differentiated cell types including acinar, ductal and myoepithelial cells that are maintained in a lineage-restricted manner during homeostasis or after mild injuries. Glandular regeneration following a near complete loss of secretory cells, however, may involve cellular plasticity, although the mechanism and extent of such plasticity remain unclear. Here, by combining lineage-tracing experiments with a model of severe glandular injury in the mouse submandibular gland, we show thatde novoformation of secretory units involves induction of cellular plasticity in multiple non-acinar cell populations. Fate-mapping analysis revealed that although ductal stem cells marked by cytokeratin K14 and Axin2 undergo a multipotency switch, they do not make a significant contribution to acinar regeneration. Intriguingly, more than 80% of regenerated acini derive from differentiated cells including myoepithelial and ductal cells that dedifferentiate to a progenitor-like state before redifferentiation to acinar cells. The potential of diverse cell populations serving as a reserve source for acini widens the therapeutic options for hyposalivation.SummarySalivary glands rely in recruitment of committed and fully differentiated cell populations as well as stem cells to ensure rapid regeneration and recovery of secretory cells.
A single cellArabidopsisroot atlas reveals developmental trajectories in wild type and cell identity mutants
Authors: Shahan Rachel , Hsu Che-Wei , Nolan Trevor M. , Cole Benjamin J. , Taylor Isaiah W. , Vlot Anna Hendrika Cornelia , Benfey Philip N. , Ohler Uwe 
Published: June 2020

SummaryCell fate acquisition is a fundamental developmental process in all multicellular organisms. Yet, much is unknown regarding how a cell traverses the pathway from stem cell to terminal differentiation. Advances in single cell genomics1hold promise for unraveling developmental mechanisms2–3in tissues4, organs5–6, and organisms7–8. However, lineage tracing can be challenging for some tissues9and integration of high-quality datasets is often necessary to detect rare cell populations and developmental states10,11. Here, we harmonized single cell mRNA sequencing data from over 110,000 cells to construct a comprehensive atlas for a stereotypically developing organ with indeterminate growth, theArabidopsisroot. To test the utility of the atlas to interpret new datasets, we profiled mutants for two key transcriptional regulators at single cell resolution,shortrootandscarecrow. Although both transcription factors are required for early specification of cell identity12, our results suggest the existence of an alternative pathway acting in mature cells to specify endodermal identity, for whichSHORTROOTis required. Uncovering the architecture of this pathway will provide insight into specification and stabilization of the endodermis, a tissue analogous to the mammalian epithelium. Thus, the atlas is a pivotal advance for unraveling the transcriptional programs that specify and maintain cell identity to regulate organ development in space and time.
The transcriptome ofBalamuthia mandrillaristrophozoites for structure-based drug design
Authors: Phan Isabelle Q. , Rice Christopher A. , Craig Justin , Noorai Rooksana E. , McDonald Jacquelyn , Subramanian Sandhya , Tillery Logan , Barrett Lynn K. , Shankar Vijay , Morris James C. , Van Voorhis Wesley C. , Kyle Dennis E. , Myler Peter J. 
Published: June 2020

AbstractBalamuthia mandrillaris, a pathogenic free-living amoeba (FLA), causes cutaneous skin lesions as well as the brain-eating disease:Balamuthiagranulomatous amoebic encephalitis (GAE). These diseases, and diseases caused by other pathogenic FLA,Naegleria fowleriorAcanthamoebaspecies, are minimally studied from a drug discovery perspective; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Chemotherapies for CNS disease caused byB. mandrillarisrequire vast improvement. Current therapeutics are limited to a small number of drugs that were previously discovered in the last century throughin vitrotesting or identified after use in the small pool of surviving reports.Using our recently published methodology to identify potentially useful therapeutics, we screened a collection of 85 compounds that have previously been reported to have antiparasitic activity. We identified 59 compounds that impacted growth at concentrations below 220 μM. Since there is no fully annotated genome or proteome, we used RNA-Seq to reconstruct the transcriptome ofB. mandrillarisand locate the coding sequences of the specific genes potentially targeted by the compounds identified to inhibit trophozoite growth. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing.
Increased serum peripheral C-reactive protein is associated with reduced small-molecule brain perfusion in healthy volunteers and subjects with major depressive disorder
Authors: Turkheimer Federico E. , Althubaity Noha , Schubert Julia , Nettis Maria A. , Cousins Oliver , Dima Danai , Mondelli Valeria , Bullmore Edward T. , Pariante Carmine , Veronese Mattia 
Published: June 2020

ABSTRACTThe relationship between peripheral and central immunity and how these ultimately may cause depressed behaviour has been the focus of a number of imaging studies conducted with Positron Emission Tomography (PET). These studies aimed at testing the immune-mediated model of depression that proposes a direct effect of peripheral cytokines and immune cells on the brain to elicit a neuroinflammatory response via a leaky blood-brain barrier and ultimately depressive behaviour. However, studies conducted so far using PET radioligands targeting the neuroinflammatory marker 18 kDa translocator protein (TSPO) in patient cohorts with depression have demonstrated mild inflammatory brain status but no correlation between central and peripheral immunity.To gain a better insight into the relationship between heightened peripheral immunity and neuroinflammation, we estimated blood-to-brain and blood-to-CSF perfusion rates for two TSPO radiotracers collected in two separate studies, one large cross-sectional study of neuroinflammation in normal and depressed cohorts and a second study where peripheral inflammation in healthy controls was induced via subcutaneous injection of interferon (IFN)-α. In both studies we observed a consistent negative association between peripheral inflammation, measured with c-reactive protein P (CRP), and radiotracer perfusion into and from the brain parenchyma and CSF. Importantly, there was no association of this effect with the marker of BBB leakage S100β, that was unchanged, but there was an association between the reduction of tracer perfusion in volunteers injected with interferon (IFN)-α and VEGF, a potent vascular permeability factor.These results support a different model of peripheral-to-central immunity interaction whereas peripheral inflammation causes a “stiffening” of the healthy BBB with consequent reduction of small molecule trafficking to and from the blood into the brain and CSF. This effect, on the long term, is likely to disrupt brain homeostasis and induce depressive behavioural symptoms. Moreover, given the molecular similarity between the TSPO ligands and antidepressant, this phenomenon may underlie treatment resistance in depressive cohorts with heightened peripheral status.
Assessment of a Diagnostic Strategy Based on Chest Computed Tomography in Patients Hospitalized for COVID-19 Pneumonia: an observational study
Authors: Thieux Marine , Kalenderian Anne-Charlotte , Chabrol Aurélie , Gendt Laurent , Giraudier Emma , Lelievre Hervé , Lounis Samir , Mataix Yves , Moderni Emeline , Paradisi Laetitia , Ranchon Guillaume , Khoury Carlos El 
Published: June 2020

AbstractObjectivesTo assess the relevance of a diagnostic strategy for COVID-19 based on chest computed tomography (CT) in patients with hospitalization criteria.SettingObservational study with retrospective analysis in a French emergency department (ED).Participants and interventionFrom March 3 to April 2, 2020, 385 adult patients presenting to the ED for suspected COVID-19 underwent an evaluation that included history, physical examination, blood tests, real-time reverse transcription-polymerase chain reaction (RT-PCR) and chest CT. When the time-interval between chest CT and RT-PCR assays was longer than 7 days, patients were excluded from the study. Only patients with hospitalization criteria were included. Diagnosis accuracy was assessed using the sensitivity and specificity of RT-PCR.OutcomesSensitivity and specificity of RT-PCR, chest CT (also accompanied by lymphopenia) were measured and were also analyzed by subgroups of age and sex.ResultsAmong 377 included subjects, RT-PCR was positive in 36%, while chest CT was compatible with a COVID-19 diagnosis in 59%. In the population with positive RT-PCR, there were more men (55% vs 37%, p=0.015), a higher frequency of reticular and, or, interlobular septal thickening (53% vs 31%, p=0.02) as well as a higher frequency of bilateral lesion distribution (98% vs 86%, p=0.01) compared to the population with negative RT-PCR. The proportion of lymphopenia was higher in men vs women (47% vs 39%, p=0.03) and varies between patients >80 versus 50-80 and p<0.001).Using CT as reference, RT-PCR obtained a sensitivity of 61%, specificity of 93%. There was a significant difference between CT and RT-PCR diagnosis performance (p<0.001). When CT was accompanied by lymphopenia, sensitivity and specificity of RT-PCR were respectively 71% and 94%. CT abnormalities and lymphopenia provided diagnosis in 29% of patients with negative PCR.ConclusionsChest CT had a superior yield than RT-PCR in COVID-19 hospitalized patients, especially when accompanied by lymphopenia.