bluuebunny/crossref_metadata_2025_split huggingface dataset:
WasR< 1 before the English lockdowns? On modelling mechanistic detail, causality and inference about Covid-19
Authors: Wood S. N. , Wit E. C. 
Published: February 2021

AbstractDetail is a double edged sword in epidemiological modelling. The inclusion of mechanistic detail in models of highly complex systems has the potential to increase realism, but it also increases the number of modelling assumptions, which become harder to check as their possible interactions multiply. In a major study of the Covid-19 epidemic in England, Knock et al. (2020) fit an age structured SEIR model with added health service compartments to data on deaths, hospitalization and test results from Covid-19 in seven English regions for the period March to December 2020. The simplest version of the model has 684 states per region. One main conclusion is that only full lockdowns brought the pathogen reproduction number,R, below one, withR≫ 1 in all regions on the eve of March 2020 lockdown. We critically evaluate the Knock et al. epidemiological model, and the semi-causal conclusions made using it, based on an independent reimplementation of the model designed to allow relaxation of some of its strong assumptions. In particular, Knock et al. model the effect on transmission of both non-pharmaceutical interventions and other effects, such as weather, using a piecewise linear function,b(t), with 12 breakpoints at selected government announcement or intervention dates. We replace this representation by a smoothing spline with time varying smoothness, thereby allowing the form ofb(t) to be substantially more data driven, and we check that the corresponding smoothness assumption is not driving our results. We also reset the mean incubation time and time from first symptoms to hospitalisation, used in the model, to values implied by the papers cited by Knock et al. as the source of these quantities. We conclude that there is no sound basis for using the Knock et al. model and their analysis to make counterfactual statements about the number of deaths that would have occurred with different lockdown timings. However, if fits of this epidemiological model structure are viewed as a reasonable basis for inference about the time course of incidence andR, then without very strong modelling assumptions, the pathogen reproduction number was probably below one, and incidence in substantial decline, some days before either of the first two English national lockdowns. This result coincides with that obtained by more direct attempts to reconstruct incidence. Of course it does not imply that lockdowns had no effect, but it does suggest that other non-pharmaceutical interventions (NPIs) may have been more effective than Knock et al. imply, and that full lockdowns were probably not the cause ofRdropping below one.
Human islet expression levels of Prostaglandin E2synthetic enzymes, but not prostaglandin EP3 receptor, are positively correlated with markers of β-cell function and mass in non-diabetic obesity
Authors: Truchan Nathan A. , Fenske Rachel J. , Sandhu Harpreet K. , Weeks Alicia M. , Patibandla Chinmai , Wancewicz Benjamin , Pabich Samantha , Reuter Austin , Harrington Jeffrey M. , Brill Allison L. , Peter Darby C. , Nall Randall , Daniels Michael , Punt Margaret , Kaiser Cecilia E. , Cox Elizabeth D. , Ge Ying , Davis Dawn B. , Kimple Michelle E. 
Published: February 2021

AbstractElevated islet production of prostaglandin E2(PGE2), an arachidonic acid metabolite, and expression of Prostaglandin E2Receptor subtype EP3 (EP3) are well-known contributors to the β-cell dysfunction of type 2 diabetes (T2D). Yet, many of the same pathophysiological conditions exist in obesity, and little is known about how the PGE2production and signaling pathway influences non-diabetic beta-cell function. In this work, plasma arachidonic acid and PGE2metabolite levels were quantified in a cohort of non-diabetic and T2D human subjects to identify their relationship with glycemic control, obesity, and systemic inflammation. In order to link these findings to processes happening at the islet level, cadaveric human islets were subject to gene expression and functional assays. Interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA levels, but not those of EP3, positively correlated with donor body mass index (BMI). IL-6 expression also strongly correlated with the expression of COX-2 and other PGE2synthetic pathway genes. Insulin secretion assays using an EP3-specific antagonist confirmed functionallyrelevant up-regulation of PGE2production. Yet, islets from obese donors were not dysfunctional, secreting just as much insulin in basal and stimulatory conditions as those from non-obese donors as a percent of content. Islet insulin content, on the other hand, was increased with both donor BMI and islet COX-2 expression, while EP3 expression was unaffected. We conclude up-regulated islet PGE2production may be part of the β-cell adaption response to obesity and insulin resistance that only becomes dysfunctional when both ligand and receptor are highly expressed in T2D.
Macroscopic quantities of collective brain activity during wakefulness and anesthesia
Authors: Ponce-Alvarez Adrián , Uhrig Lynn , Deco Nikolas , Signorelli Camilo M. , Kringelbach Morten L. , Jarraya Béchir , Deco Gustavo 
Published: February 2021

AbstractThe study of states of arousal is key to understand the principles of consciousness. Yet, how different brain states emerge from the collective activity of brain regions remains unknown. Here, we studied the fMRI brain activity of monkeys during wakefulness and anesthesia-induced loss of consciousness. Using maximum entropy models, we derived collective, macroscopic properties that quantify the system’s capabilities to produce work, to contain information and to transmit it, and that indicate a phase transition from critical awake dynamics to supercritical anesthetized states. Moreover, information-theoretic measures identified those parameters that impacted the most the network dynamics. We found that changes in brain state and in state of consciousness primarily depended on changes in network couplings of insular, cingulate, and parietal cortices. Our findings suggest that the brain state transition underlying the loss of consciousness is predominantly driven by the uncoupling of specific brain regions from the rest of the network.
Phencyclidine-induced psychosis causes hypersynchronization and disruption of connectivity within prefrontal-hippocampal circuits that is rescued by antipsychotic drugs
Authors: Delgado-Sallent Cristina , Nebot Pau , Gener Thomas , Timplalexi Melina , Fath Amanda B , Puig M Victoria 
Published: February 2021

ABSTRACTNeural synchrony and functional connectivity are disrupted in neuropsychiatric disorders such as schizophrenia. However, these alterations and how they are affected by commonly prescribed neuropsychiatric medication have not been characterized in depth. Here, we investigated changes in neural dynamics of circuits involving the prefrontal cortex and the hippocampus during psychosis induced by the NMDAR antagonist phencyclidine and subsequent recovery by three different antipsychotic drugs (APDs), the classical APD haloperidol and two atypical APDs, clozapine and risperidone, in freely moving mice. We found that the psychotomimetic effects of phencyclidine were associated with hypersynchronization and disrupted communication of prefrontal-hippocampal pathways. Major alterations occurred in the prefrontal cortex, where phencyclidine increased oscillatory power at delta, high gamma and high frequencies (<100 Hz) and generated aberrant cross-frequency coupling, suggesting the presence of hypersynchronous cortical microcircuits. Cross-regional coupling and phase coherence were also enhanced, further reflecting that the circuit’s functional connectivity was increased. Phencyclidine also redirected the intrinsic flow of information at theta frequencies that traveled from the hippocampus to the prefrontal cortex into delta rhythms that traveled in the opposite direction. The three APDs rescued most phencyclidine-induced changes in power, coupling, phase coherence, and directionality, suggesting common cellular mechanisms of antipsychotic action. However, some differential effects were identified, likely resulting from the distinct affinity the three APDs have for dopamine and serotonin receptors. We therefore investigated how serotonin 1A (5-HT1AR) and 2A receptors (5-HT2AR) compare to the actions of the APDs. 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT rescued phencyclidine-induced increased power, coupling and phase coherence but were unable to normalize the circuit’s theta directionality. This suggests that other targets of the AAPDs working in tandem with 5-HT1ARs and 5-HT2ARs are required to ameliorate this key feature of the circuit.
Connection Failure: Differences in White Matter Microstructure are associated with5-HTTLPRbut not with Risk-Seeking for Losses
Authors: Neukam Philipp T. , Müller Dirk K. , Deza-Araujo Yacila I. , Pooseh Shakoor , Witt Stephanie H. , Rietschel Marcella , Smolka Michael N. 
Published: February 2021

AbstractIn a previous study (Neukam, Kroemer et al. 2018), we found for the5-HTTLPRgenotype higher risk-seeking for losses in S/S vs. L/L carrier, which could not be explained by acutely changed central serotonin levels. This finding alternatively may be the result of reduced top-down control from the frontal cortex due to altered signal pathways involving the amygdala and ventral striatum. The serotonergic system is known to be involved in neurodevelopment and neuroplasticity. Therefore, the aim of this study was to investigate whether structural differences in white matter can explain the differences in risk-seeking behaviour that we observed in our previous study and whether5-HTTLPRgroups differ in their white matter microstructure. These differences can be detected using diffusion-weighted imaging (DWI). We assumed lower structural connectivity in S/S compared to L/L carrier, and a negative relationship between risk-seeking for losses and connectivity. We used DWI to compute diffusion parameters for the frontostriatal and uncinate tract in 175 individuals (39 S/S, 80 S/L, 56 L/L). Results showed no significant relationship between diffusion parameters and risk-seeking for losses. Furthermore, we did not find significant differences in diffusion parameters of the S/S vs. L/L group. There were only group differences in the frontostriatal tract showing stronger structural connectivity in the S/L group, which is also reflected in the whole brain approach. Therefore, the data do not support our hypothesis that the association between5- HTTLPRand risk-seeking for losses is related to differences in white matter pathways implicated in decision-making.
CRISPR-Cas9 gene editing and rapid detection of gene-edited mutants using high-resolution melting in the apple scab fungus,Venturia inaequalis
Authors: Rocafort Mercedes , Arshed Saadiah , Hudson Debbie , Singh Jaspreet , Bowen Joanna K. , Plummer Kim M. , Bradshaw Rosie E. , Johnson Richard D. , Johnson Linda J. , Mesarich Carl H. 
Published: February 2021

AbstractBackgroundScab, or black spot, caused by the filamentous fungal pathogenVenturia inaequalis, is the most economically important disease of apple (Malusxdomestica) worldwide. To develop durable control strategies against this disease, a better understanding of the genetic mechanisms underlying the growth, reproduction, virulence and pathogenicity ofV. inaequalisis required. A major bottleneck for the genetic characterization ofV. inaequalisis the inability to easily delete or disrupt genes of interest using homologous recombination. Indeed, no gene deletions or disruptions inV. inaequalishave yet been published. Recently, CRISPR-Cas9 has emerged as an efficient tool for gene editing in filamentous fungi. With this in mind, we set out to establish CRISPR-Cas9 as a gene editing tool inV. inaequalis.ResultsWe showed that CRISPR-Cas9 can be used for gene inactivation in the apple scab fungus. As a proof of concept, we targeted the melanin biosynthesis pathway genetrihydroxynaphthalene reductase(THN), which has previously been shown to result in a light-brown colony phenotype when transcriptionally silenced using RNA interference. Using one of two CRISPR-Cas9 single guide RNAs (sgRNAs) targeted to theTHNgene, delivered by a single autonomously replicating Golden Gate-compatible plasmid, we were able to identify six of 36 stable transformants with a light-brown phenotype, indicating an~16.7% gene inactivation efficiency. Notably, of these sixTHNmutants, five had an independent mutation. As part of our pipeline, we also report a high-resolution melting (HRM) curve protocol for the rapid detection of CRISPR-Cas9 gene-edited mutants ofV. inaequalis. This protocol identified a single base pair deletion mutation in a sample containing only 5% mutant genomic DNA, indicating high sensitivity for mutant screening.ConclusionsIn establishing CRISPR-Cas9 as a tool for gene editing inV. inaequalis, we have provided a strong starting point for studies aiming to decipher the function of genes associated with the growth, reproduction, virulence and pathogenicity of this fungus. The associated HRM curve protocol will enable CRISPR-Cas9 transformants to be screened for gene inactivation in a high-throughput and low-cost manner, which will be particularly powerful in cases where the CRISPR-Cas9-mediated gene inactivation efficiency is low.
Evolution and connectivity influence the persistence and recovery of coral reefs under climate change in the Caribbean, Southwest Pacific, and Coral Triangle
Authors: McManus Lisa C. , Forrest Daniel L. , Tekwa Edward W. , Schindler Daniel E. , Colton Madhavi A. , Webster Michael M. , Essington Timothy E. , Palumbi Stephen R. , Mumby Peter J. , Pinsky Malin L. 
Published: February 2021

AbstractCorals are experiencing unprecedented decline from climate change-induced mass bleaching events. Dispersal not only contributes to coral reef persistence through demographic rescue but can also hinder or facilitate evolutionary adaptation. Locations of reefs that are likely to survive future warming therefore remain largely unknown, particularly within the context of both ecological and evolutionary processes across complex seascapes that differ in temperature range, strength of connectivity, network size, and other characteristics. Here, we used eco-evolutionary simulations to examine coral adaptation to warming across reef networks in the Caribbean, the Southwest Pacific, and the Coral Triangle. We assessed the factors associated with coral persistence in multiple reef systems to understand which results are general and which are sensitive to particular geographic contexts. We found that evolution can be critical in preventing extinction and facilitating the long-term recovery of coral communities in all regions. Furthermore, the strength of immigration to a reef (destination strength) and current sea surface temperature robustly predicted reef persistence across all reef networks and across temperature projections. However, we found higher initial coral cover, slower recovery, and more evolutionary lag in the Coral Triangle, which has a greater number of reefs and more larval settlement than the other regions. We also found the lowest projected future coral cover in the Caribbean. These findings suggest that coral reef persistence depends on ecology, evolution, and habitat network characteristics, and that, under an emissions stabilization scenario (RCP 4.5), recovery may be possible over multiple centuries.
Sublingual allergen immunotherapy with recombinant dog allergens prevents airway hyperresponsiveness in a model of asthma marked by vigorous TH2 and TH17 cell responses
Authors: Stark Julian M. , Liu Jielu , Tibbitt Christopher A. , Christian Murray , Ma Junjie , Wintersand Anna , Murrell Ben , Adner Mikael , Grönlund Hans , Gafvelin Guro , Coquet Jonathan M. 
Published: February 2021

AbstractAllergy to dogs affects around ten percent of the population in developed countries. Immune therapy of allergic patients with dog allergen extracts has shown limited therapeutic benefit. Herein, we established a mouse model of dog allergy and tested the efficacy of a recombinant protein containing Can f 1, f 2, f 4 and f 6 as a sublingual immune therapy (SLIT). Repeated inhalation of dog extracts induced infiltration of the airways by TH2 cells, eosinophils and goblet cells, reminiscent of the house dust mite (HDM) model of asthma. However, dog allergen extracts also induced robust TH17 cell responses, which was associated with a high neutrophilic infiltration of the airways and promoted airway hyperresponsiveness more potently than HDM allergens. scRNA-Seq analysis of T helper cells responding to dog allergens identified several unique clusters with TH17 cells being hallmarked by the expression of several receptors including IL-17RE. Analysis of T cell receptors also depicted a high frequency of clones that were shared between TH17, TH2 and suppressive Treg cells, indicative of the plasticity of T helper cells in this model. Importantly, prophylactic SLIT reduced airway hyperresponsiveness and type 2-mediated inflammation in this model supporting the use of recombinant allergens in immune therapy.
Phylogenetic reconstruction of ancestral ecological networks through time for pierid butterflies and their host plants
Authors: Braga Mariana P , Janz Niklas , Nylin Sören , Ronquist Fredrik , Landis Michael J 
Published: February 2021

AbstractThe study of herbivorous insects underpins much of the theory that concerns the evolution of species interactions. In particular, Pieridae butterflies and their host plants have served as a model system for studying evolutionary arms-races. To learn more about the coevolution of these two clades, we reconstructed ancestral ecological networks using stochastic mappings that were generated by a phylogenetic model of host-repertoire evolution. We then measured if, when, and how two ecologically important structural features of the ancestral networks (modularity and nestedness) evolved over time. Our study shows that as pierids gained new hosts and formed new modules, a subset of them retained or recolonized the ancestral host(s), preserving connectivity to the original modules. Together, host-range expansions and recolonizations promoted a phase transition in network structure. Our results demonstrate the power of combining network analysis with Bayesian inference of host-repertoire evolution to understand changes in complex species interactions over time.
GRAFIMO: variant and haplotype aware motif scanning on pangenome graphs
Authors: Tognon Manuel , Bonnici Vincenzo , Garrison Erik , Giugno Rosalba , Pinello Luca 
Published: February 2021

AbstractTranscription factors (TFs) are proteins that promote or reduce the expression of genes by binding short genomic DNA sequences known as transcription factor binding sites (TFBS). While several tools have been developed to scan for potential occurrences of TFBS in linear DNA sequences or reference genomes, no tool exists to find them in pangenome variation graphs (VGs). VGs are sequence-labelled graphs that can efficiently encode collections of genomes and their variants in a single, compact data structure. Because VGs can losslessly compress large pangenomes, TFBS scanning in VGs can efficiently capture how genomic variation affects the potential binding landscape of TFs in a population of individuals. Here we present GRAFIMO (GRAph-based Finding of Individual Motif Occurrences), a command-line tool for the scanning of known TF DNA motifs represented as Position Weight Matrices (PWMs) in VGs. GRAFIMO extends the standard PWM scanning procedure by considering variations and alternative haplotypes encoded in a VG. Using GRAFIMO on a VG based on individuals from the 1000 Genomes project we recover several potential binding sites that are enhanced, weakened or missed when scanning only the reference genome, and which could constitute individual-specific binding events. GRAFIMO is available as an open-source tool, under the MIT license, athttps://github.com/pinellolab/GRAFIMOandhttps://github.com/InfOmics/GRAFIMO.Author summaryTranscription factors (TFs) are key regulatory proteins and mutations occurring in their binding sites can alter the normal transcriptional landscape of a cell and lead to disease states. Pangenome variation graphs (VGs) efficiently encode genomes from a population of individuals and their genetic variations. GRAFIMO is an open-source tool that extends the traditional PWM scanning procedure to VGs. By scanning for potential TBFS in VGs, GRAFIMO can simultaneously search thousands of genomes while accounting for SNPs, indels, and structural variants. GRAFIMO reports motif occurrences, their statistical significance, frequency, and location within the reference or alternative haplotypes in a given VG. GRAFIMO makes it possible to study how genetic variation affects the binding landscape of known TFs within a population of individuals.
Machine learning for single cell genomics data analysis
Authors: Raimundo Félix , Papaxanthos Laetitia , Vallot Céline , Vert Jean-Philippe 
Published: February 2021

AbstractSingle-cell omics technologies produce large quantities of data describing the genomic, transcriptomic or epigenomic profiles of many individual cells in parallel. In order to infer biological knowledge and develop predictive models from these data, machine learning (ML)-based model are increasingly used due to their flexibility, scalability, and impressive success in other fields. In recent years, we have seen a surge of new ML-based method development for low-dimensional representations of single-cell omics data, batch normalization, cell type classification, trajectory inference, gene regulatory network inference or multimodal data integration. To help readers navigate this fast-moving literature, we survey in this review recent advances in ML approaches developed to analyze single-cell omics data, focusing mainly on peer-reviewed publications published in the last two years (2019-2020).
Bone Marrow-Derived AXL Tyrosine Kinase Promotes Mitogenic Crosstalk and Cardiac Allograft Vasculopathy
Authors: Glinton Kristofor , DeBerge Matthew , Fisher Emily , Schroth Samantha , Sinha Arjun , Wang Jiao-Jing , Wasserstrom J. Andrew , Ansari Mohammed Javeed , Zhang Zheng Jenny , Feinstein Matthew , Leventhal Joseph R. , Forbess Joseph M. , Lomasney Jon , Luo Xunrong , Thorp Edward B. 
Published: February 2021

ABSTRACTCardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derivedAxl gene, we report thatAxlantagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses ofAxl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions ofAxluncovered complementary cell-proliferative pathways by whichAxlpromotes CAV-associated inflammation. Specifically,Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered thatAxl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloidAxlin the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.