bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size
Authors: Siegel David A. , Thanh Cassandra , Wan Eunice , Hoh Rebecca , Hobbs Kristen , Pan Tony , Gibson Erica A. , Kroetz Deanna L. , Hunt Peter W. , Martin Jeffrey , Hecht Frederick , Pilcher Christopher , Milush Jeffrey , Martin Maureen , Carrington Mary , Pillai Satish , Busch Michael P. , Stone Mars , Levy Claire N. , Huang Meei-Li , Roychoudhury Pavitra , Hladik Florian , Jerome Keith R. , Kiem Hans-Peter , Henrich Timothy J. , Deeks Steven G. , Lee Sulggi 
Published: November 2021

AbstractObjectivePrior genomewide association studies have identified variation in MHC Class I alleles andCCR5Δ32as genetic predictors of viral control, especially in “elite” controllers, individuals who remain virally suppressed in the absence of therapy.DesignCross-sectional genomewide association study.MethodsWe analyzed custom whole exome sequencing and direct HLA typing from 202 ART-suppressed HIV+ non-controllers in relation to four measures of the peripheral CD4+ T cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression.ResultsPreviously reported “protective” host genetic mutations related to viral setpoint (e.g., among elite controllers) were found to predict smaller HIV reservoir size. The HLA “protective” B*57:01 was associated with significantly lower HIV usRNA (q=3.3×10−3), and among the largest subgroup, European ancestry individuals, theCCR5Δ32deletion was associated with smaller HIV tDNA (p=4.3×10−3) and usRNA (p=8.7×10−3). In addition, genomewide analysis identified several SNPs inMX1(an interferon stimulated gene) that were significantly associated with HIV tDNA (q=0.02), and the direction of these associations paralleledMX1gene eQTL expression.ConclusionsWe observed a significant association between previously reported “protective” MHC class I alleles andCCR5Δ32with the HIV reservoir size in non-controllers. We also found a novel association betweenMX1and HIV total DNA (in addition to other interferon signaling relevant genes,PPP1CB,DDX3X). These findings warrant further investigation in future validation studies.
A retinal circuit that vetoes optokinetic responses to fast visual motion
Authors: Mani Adam , Yang Xinzhu , Zhao Tiffany , Leyrer Megan L. , Schreck Daniel , Berson David M. 
Published: November 2021

AbstractOptokinetic nystagmus (OKN) complements the vestibulo-ocular reflex (VOR) to stabilize the retinal image during head rotation. OKN is driven by the ON direction-selective ganglion cells (ON DSGCs), a rare class of retinal output neuron that encodes both the direction and speed of global retinal slip. The cells and synaptic circuits that give ON DSGCs their directional tuning are well known, but those dictating their slow-speed preference (and thus OKN’s) remain enigmatic. Here, we probe this circuit through patch recordings, functional imaging, genetic manipulation, and serial electron microscopic reconstruction in mouse retina. We confirm earlier evidence that feedforward glycinergic inhibition is the main suppressor of ON DSGC responses to fast motion and reveal a surprising source for this inhibition ─ the VGluT3 amacrine cell, a retinal interneuron that releases both glycine and glutamate, exciting some neurons and inhibiting others. We find that VGluT3 cells respond robustly to fast global motion and that their output reaches most RGC types, as well as a diverse group of amacrine and bipolar cells. They enhance the response of ON-OFF DSGCs to fast motion, while suppressing it in ON DSGCs. Together, our results identify a novel role for VGluT3 cells, limiting the range of retinal slip speeds that drive image-stabilizing eye movements. More broadly, they suggest VGluT3 cells shape the response of many RGCs and amacrine cells to fast motion.
Cooperative electrolyte-PEG interactions drive the signal amplification in a solid-state nanopore
Authors: Chau Chalmers C. , Marcuccio Fabio , Soulias Dimitrios , Edwards Martin A. , Radford Sheena E. , Hewitt Eric W. , Actis Paolo 
Published: November 2021

ABSTRACTNanopore systems have emerged as a leading platform for the analysis of biomolecular complexes with single molecule resolution. However, the analysis of several analytes like short nucleic acids or proteins with nanopores represents a sensitivity challenge, because their translocation lead to small signals difficult to distinguish from the noise. Here, we report a simple method to enhance the signal to noise ratio in nanopore experiments by a simple modification of the solution used in nanopore sensing. The addition of poly-ethylene glycol (PEG) and the careful selection of the supporting electrolyte leads to large signal enhancement. We observed that the translocation dynamics are in good agreement with an established method that uses the lattice energy of an electrolyte to approximate the affinity of an ion to PEG. We identified CsBr as the optimal supporting electrolyte to complement PEG to enable the analysis of dsDNA at 500 kHz bandwidth, and the detection of dsDNA as short as 75 bp.
A vitamin D-RelB/NF-κB pathway limits Chandipura virus multiplication by rewiring the homeostatic state of autoregulatory type 1 interferon-IRF7 signaling
Authors: Ratra Yashika , Kumar Naveen , Saha Manti K. , Bharadwaj Chandrima , Chongtham Chen , Bais Sachendra S. , Medigeshi Guruprasad , Arimbasseri Gopalakrishnan A. , Basak Soumen 
Published: November 2021

AbstractBesides its functions in the skeletomuscular system, vitamin D also promotes protective immunity against viral pathogens. Viral sensing by mammalian cells triggers nuclear activation of RelA/NF-κB and IRF3 factors, which collaborate in mediating the early induction of antiviral type 1 interferons (T1-IFNs). Autocrine T1-IFN signaling further accumulates otherwise negligibly expressed IRF7 in virus-infected cells that then sustains T1-IFN production in a positive feedback. Surprisingly, prior cell-culture studies revealed that vitamin D actually suppresses signal-induced RelA activation. Indeed, it remains unclear how vitamin D limits viral multiplication in a cell-autonomous manner. Here, we examined the role of vitamin D in controlling cellular infections by the Chandipura virus (CHPV), a cytoplasmic RNA virus implicated in human epidemics. We found that vitamin D conditioning produced an altered cell state less permissive for CHPV multiplication because of the heightened expression of T1-IFNs. It is thought that viruses also induce a distinct RelB/NF-κB activity, which counteracts RelA-driven T1-IFN expressions in infected cells. Our analyses instead characterized a basal nuclear RelB activity, which was downregulated upon vitamin D-mediated suppression of RelB synthesis. Interestingly, this vitamin D-RelB pathway provoked IRF7-mediated positive autoregulation augmenting constitutive T1-IFN expressions even in the absence of viral infections. Accordingly, RelB deficiency rendered redundant, while IRF7 depletion abrogated antiviral vitamin D actions. In sum, our study suggests that the homeostatic state of the signaling circuitry comprising of the NF-κB and T1-IFN pathways connects micronutrients to antiviral immunity at the cellular level.Significance statementVitamin D limits viral infections, but the underlying mechanism remains unclear. Linking micronutrients to antiviral immunity, Ratra et al. characterize an immune signaling circuitry engaged by vitamin D that generates a cellular state less permissive to infections by Chandipura virus, a pathogen of public health importance.
Act Natural: Functional Connectivity from Naturalistic Stimuli fMRI Outperforms Resting-State in Predicting Brain Activity
Authors: Gal Shachar , Coldham Yael , Tik Niv , Bernstein-Eliav Michal , Tavor Ido 
Published: November 2021

AbstractThe search for an ‘ideal’ approach to investigate the functional connections in the human brain is an ongoing challenge for the neuroscience community. While resting-state functional magnetic resonance imaging (fMRI) has been widely used to study individual functional connectivity patterns, recent work has highlighted the benefits of collecting functional connectivity data while participants are exposed to naturalistic stimuli, such as watching a movie or listening to a story. For example, functional connectivity data collected during movie-watching were shown to predict cognitive and emotional scores more accurately than resting-state-derived functional connectivity. We have previously reported a tight link between resting-state functional connectivity and task-derived neural activity, such that the former successfully predicts the latter. In the current work we use data from the Human Connectome Project to demonstrate that naturalistic-stimulus-derived functional connectivity predicts task-induced brain activation maps more accurately than resting-state-derived functional connectivity. We then show that activation maps predicted using naturalistic stimuli are better predictors of individual intelligence scores than activation maps predicted using resting-state. We additionally examine the influence of naturalistic-stimulus type on prediction accuracy. Our findings emphasize the potential of naturalistic stimuli as a promising alternative to resting-state fMRI for connectome-based predictive modelling of individual brain activity and cognitive traits.
Experimental evolution reveals the synergistic genomic mechanisms of adaptation to ocean warming and acidification in a marine copepod
Authors: Brennan Reid S. , deMayo James A. , Dam Hans G. , Finiguerra Michael , Baumann Hannes , Buffalo Vince , Pespeni Melissa H. 
Published: November 2021

AbstractMetazoan adaptation to global change will rely on selection of standing genetic variation. Determining the extent to which this variation exists in natural populations, particularly for responses to simultaneous stressors, is therefore essential to make accurate predictions for persistence in future conditions. Here, we identify the genetic variation enabling the copepod Acartia tonsa to adapt to experimental ocean warming, acidification, and combined ocean warming and acidification (OWA) conditions over 25 generations. Replicate populations showed a strong and consistent polygenic response to each condition, targeting an array of adaptive mechanisms including cellular homeostasis, development, and stress response. We used a genome-wide covariance approach to partition the genomic changes into selection, drift, and lab adaptation and found that the majority of allele frequency change in warming (56%) and OWA (63%) was driven by selection but acidification was dominated by drift (66%). OWA and warming shared 37% of their response to selection but OWA and acidification shared just 1%. Accounting for lab adaptation was essential for not inflating a shared response to selection between all treatments. Finally, the mechanisms of adaptation in the multiple-stressor OWA conditions were not an additive product of warming and acidification, but rather a synergistic response where 47% of the allelic responses to selection were unique. These results are among the first to disentangle how the genomic targets of selection differ between single and multiple stressors and to demonstrate the complexity that non-additive multiple stressors will contribute to attempts to predict adaptive responses to complex environments.
Prophylactic Treatment of Undernourished Mice with Cotrimoxazole Induces a Different Profile of Dysbiosis with Functional Metabolic Alterations
Authors: Budziarek Eslabão Lívia , Gubert Gabriela Farias , Beltrame Lucas C. , de Mello Isis M. A. , Bruna-Romero Oscar , Zárate-Bladés Carlos R. 
Published: November 2021

1.AbstractChildhood malnutrition affects physiology and development, it increases infection rate which may not present clinical signs in severe cases. To overcome this issue, the World Health Organization recommends prophylactic treatment with Cotrimoxazole (SXT) along with nutritional recovery. This treatment is controversial since evidence of reduction in morbidity and mortality is not a consensus and could induce the development of antibiotic resistant bacteria. Moreover, the impact of the use of this wide-spectrum antibiotic on gut microbiota, in a critical period of development and weakness, is unknown. To understand how SXT prophylaxis could affect gut microbiota in undernutrition, we induced protein-energy undernutrition in weaning C57BL/6 mice for three weeks and treated animals with SXT for two weeks. Using 16S rRNA gene sequencing we compared the taxonomic composition and metabolic pathways of control mice, animals submitted to undernutrition (UND), treated with SXT, or undernourished and SXT treated (UND+SXT). Undernutrition protocol was responsible for increasing Bacteroidetes and decreasing Firmicutes abundance. We identified that UND mice had a significant increase in predicted pathways related to metabolic syndromes later in life. The prophylactic SXT treatment alone resulted in significant loss in community richness and beta diversity. In addition, we identified the reduction of 6 families in SXT treated mice, including the butyrate producers Lachnospiraceae and Ruminococcaceae. The double challenge (UND+SXT) resulted in a reduction in Clostridiaceae family and in the urea cycle pathway, both related to the fermentation of amino acids, the intestinal epithelial permeability, and the healthy gut environment. Our results show that SXT prophylaxis during an undernourishment period in young mice did not re-establish the undernourished microbiota community composition similar to healthy controls, but induces a distinct dysbiotic profile, with functional metabolic consequences.
mRNA Vaccines Induce Rapid Antibody Responses in Mice
Authors: Gebre Makda S. , Rauch Susanne , Roth Nicole , Gergen Janina , Yu Jingyou , Liu Xiaowen , Cole Andrew C. , Mueller Stefan O. , Petsch Benjamin , Barouch Dan H. 
Published: November 2021

ABSTRACTmRNA vaccines can be developed and produced quickly, making them attractive for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. We sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first examined immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA, but not DNA, immunization. The mRNA vaccine also induced increased levels of IL-5, IL-6 and MCP-1. We then evaluated immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines with the same HIV-1 envelope antigen in mice. Induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Eliciting rapid humoral immunity may be an advantageous property of mRNA vaccines for controlling infectious disease outbreaks.IMPORTANCEmRNA vaccines can be developed and produced in record time. Here we demonstrate induction of rapid antibody responses by mRNA vaccines encoding two different viral antigens by day 5 following immunization in mice. The rapid immune kinetics of mRNA vaccines can be an advantageous property that makes them well suited for rapid control of infectious disease outbreaks.
Genetic support of a causal relationship between Iron status and atrial fibrillation: a Mendelian randomization study
Authors: Wang Tianyi , Cheng Jun , Wang Yanggan 
Published: November 2021

AbstractBackgroundAtrial fibrillation is the most common arrhythmia disease.Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and the risk of atrial fibrillation may be biased by confounding and reverse causality.The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely appied to estimate the causal effect,to reveal whether systemic iron status was causally related to atrial fibrillation.MethodsSingle nucleotide polymorphisms (SNPs) strongly associated (P < 5×10−8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium.Summary-level data for the genetic associations with atrial fibrillation were acquired from AFGen (Atrial Fibrillation Genetics) consortium study(including 65,446 atrial fibrillation cases and 522,744 controls). We used a two-sample MR analysis to obtain a causal estimate, and further verified credibility through sensitivity analysis.ResultsGenetically instrumented serum iron [OR:1.09;95%; confidence interval (CI)1.02-1.16; p=0.01], ferritin [OR:1.16;95%CI:1.02-1.33; p=0.02], and transferrin saturation [OR:1.05;95%CI:1.01-1.11; p=0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR:0.90;95%CI:0.86-0.97; p=0.006] was an inverse correlation with atrial fibrillation.ConclusionIn conclusion,our results strongly elucidated a causal link between genetically determined higher iron status and increased the risk of atrial fibrillation.This provided new ideas for clinical prevention and treatment of atrial fibrillation.
CRISPR-Csx28 forms a Cas13b-activated membrane pore required for robust CRISPR-Cas adaptive immunity
Authors: VanderWal Arica R. , Park Jung-Un , Polevoda Bogdan , Kellogg Elizabeth H. , O’Connell Mitchell R. 
Published: November 2021

AbstractType VI CRISPR-Cas systems use the RNA-guided RNase Cas13 to defend bacteria against viruses, and some of these systems encode putative membrane proteins that have unclear roles in Cas13-mediated defense. Here we show that Csx28, of Type VI-B2 systems, forms membrane pore structures to slow cellular metabolism upon viral infection, and this activity drastically increases anti-viral defense. High- resolution cryo-EM reveals that Csx28 exists unexpectedly as a detergent-encapsulated octameric pore, and we then show these Csx28 pores are membrane localized in vivo. Activation of Csx28 in vivo strictly requires sequence-specific recognition of viral mRNAs by Cas13b, and this activation results in Csx28-mediated membrane depolarization, slowed metabolism, and inhibition of sustained viral infection. Together, our work reveals an unprecedented mechanism by which Csx28 acts as a downstream, Cas13b-activated, effector protein that uses membrane perturbation as an anti-viral defense strategy.
Xist-mediated silencing requires additive functions of SPEN and Polycomb together with differentiation-dependent recruitment of SmcHD1
Authors: Bowness Joseph S. , Nesterova Tatyana B. , Wei Guifeng , Rodermund Lisa , Almeida Mafalda , Coker Heather , Carter Emma J. , Kadaster Artun , Brockdorff Neil 
Published: November 2021

SummaryX chromosome inactivation (XCI) is mediated by the non-coding RNA Xist which directs chromatin modification and gene silencing in cis. The RNA binding protein SPEN and associated corepressors have a central role in Xist-mediated gene silencing. Other silencing factors, notably the Polycomb system, have been reported to function downstream of SPEN. In recent work we found that SPEN has an additional role in correct localisation of Xist RNA in cis, indicating that its contribution to chromatin-mediated gene silencing needs to be reappraised. Making use of a SPEN separation-of-function mutation we show that SPEN and Polycomb pathways in fact function in parallel to establish gene silencing. Additionally, we find that differentiation-dependent recruitment of the chromosomal protein SmcHD1 is required for silencing many X-linked genes. Our results provide important insights into the mechanism of X inactivation and the coordination of chromatin-based gene regulation with cellular differentiation and development.
A tonic nicotinic brake controls spike timing in striatal spiny projection neurons
Authors: Matityahu Lior , Malgady Jeffrey M. , Schirelman Meital , Johansson Yvonne , Wilking Jennifer , Silberberg Gilad , Goldberg Joshua A. , Plotkin Joshua L. 
Published: November 2021

AbstractStriatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4β2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by “priming” feedforward inhibition, a process that may shape SPN spike timing, striatal processing and synaptic plasticity.Impact StatementA novel mechanism describing how tonic activation of nicotinic acetylcholine receptors can modulate the timing of striatal output by priming feed forward inhibition.
Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse
Authors: Richardson Amy , Ciampani Victoria , Stancu Mihai , Newton Sherylanne , Steinert Joern R. , Pilati Nadia , Graham Bruce P. , Kopp-Scheinpflug Conny , Forsythe Ian D. 
Published: November 2021

SummaryKv3 potassium currents mediate rapid repolarization of action potentials (AP), supporting fast spikes and high repetition rates. Of the four Kv3 gene family members, Kv3.1 and Kv3.3 are highly expressed in the auditory brainstem and we exploited this to test for subunit-specific roles at the calyx of Held presynaptic terminal. Deletion of Kv3.3 (but not Kv3.1) increased presynaptic AP duration and facilitated transmitter release, which in turn enhanced short-term depression during high frequency transmission. The response to sound was delayed in the Kv3.3KO, with higher spontaneous and lower evoked firing, thereby reducing signal-to-noise ratio. Computational modelling showed that the enhanced EPSC and short-term depression in the Kv3.3KO reflected increased vesicle release probability and accelerated activity-dependent vesicle replenishment. We conclude that Kv3.3 is the presynaptic ‘delayed rectifier’, enabling short duration, precisely timed APs to maintain transmission at high frequencies and during sustained synaptic activity.