bluuebunny/crossref_metadata_2025_split huggingface dataset:
Noise source importance in linear stochastic models of biological systems that grow, shrink, wander, or persist
Authors: Strang Alexander , Huffmyer William , Rollins Hilary , Abbott Karen C. , Thomas Peter J. 
Published: January 2022

AbstractWhile noise is an important factor in biology, biological processes often involve multiple noise sources, whose relative importance can be unclear. Here we develop tools that quantify the importance of noise sources in a network based on their contributions to variability in a quantity of interest. We generalize the edge importance measures proposed by Schmidt and Thomas [1] for first-order reaction networks whose steady-state variance is a linear combination of variance produced by each directed edge. We show that the same additive property extends to a general family of stochastic processes subject to a set of linearity assumptions, whether in discrete or continuous state or time. Our analysis applies to both expanding and contracting populations, as well as populations obeying a martingale (“wandering”) at long times. We show that the original Schmidt-Thomas edge importance measure is a special case of our more general measure, and is recovered when the model satisfies a conservation constraint (“persists”). In the growing and wandering cases we show that the choice of observables (measurements) used to monitor the process does not influence which noise sources are important at long times. In contrast, in the shrinking or persisting case, which noise sources are important depends on what is measured. We also generalize our measures to admit models with affine moment update equations, which admit additional limiting scenarios, and arise naturally after linearization. We illustrate our results using examples from cell biology and ecology: (i) a model for the dynamics of the inositol trisphospate receptor, (ii) a model for an endangered population of white-tailed eagles, and (iii) a model for wood frog dispersal.Author summaryBiological processes are frequently subject to an ensemble of independent noise sources. Noise sources produce fluctuations that propagate through the system, driving fluctuations in quantities of interest such as population size or ion channel configuration. We introduce a measure that quantifies how much variability each noise source contributes to any given quantity of interest. Using these methods, we identify which binding events contribute significantly to fluctuations in the state of a molecular signalling channel, which life history events contribute the most variability to an eagle population before and after a successful conservation effort rescued the population from the brink of extinction, and which dispersal events, at what times, matter most to variability in the recolonization of a series of ponds by wood frogs after a drought.
Short periods of bipolar anodal TDCS induce no instantaneous dose-dependent increase in cerebral blood flow in the targeted human motor cortex
Authors: Liu Marie Louise , Karabanov Anke Ninija , Piek Marjolein , Petersen Esben Thade , Thielscher Axel , Siebner Hartwig Roman 
Published: January 2022

AbstractBackgroundAnodal transcranial direct current stimulation (aTDCS) of primary motor hand area (M1-HAND) can enhance corticomotor excitability. Yet, it is still unknown which current intensity produces the strongest effect on regional neural activity. Magnetic resonance imaging (MRI) combined with pseudo-continuous Arterial Spin Labeling (pc-ASL MRI) can map regional cortical blood flow (rCBF) and may thus be useful to probe the relationship between current intensity and neural response at the individual level.ObjectiveHere we employed pc-ASL MRI to map acute rCBF changes during short-duration aTDCS of left M1-HAND. Using the rCBF response as a proxy for regional neuronal activity, we investigated if short-duration aTDCS produces an instantaneous dose-dependent rCBF increase in the targeted M1-HAND that may be useful for individual dosing.MethodsNine healthy right-handed participants received 30 seconds of aTDCS at 0.5, 1.0, 1.5, and 2.0 mA with the anode placed over left M1-HAND and cathode over the right supraorbital region. Concurrent pc-ASL MRI at 3 T probed TDCS-related rCBF changes in the targeted M1-HAND. Movement-induced rCBF changes were also assessed.ResultsApart from a subtle increase in rCBF at 0.5 mA, short-duration aTDCS did not modulate rCBF in the M1-HAND relative to no-stimulation periods. None of the participants showed a dose-dependent increase in rCBF during aTDCS, even after accounting for individual differences in TDCS-induced electrical field strength. In contrast, finger movements led to robust activation of left M1-HAND before and after aTDCS.ConclusionShort-duration bipolar aTDCS does not produce instantaneous dose-dependent rCBF increases in the targeted M1-HAND at conventional intensity ranges.Therefore, the regional hemodynamic response profile to short-duration aTDCS may not be suited to inform individual dosing of TDCS intensity.HighlightsArterial spin labeling (ASL) MRI probed regional cerebral blood flow (rCBF) during anodal TDCS.Short-duration anodal TDCS was applied to left motor hand area (M1-HAND) at 0.5, 1.0, 1.5 and 2.0 mA.Anodal TDCS produced no instantaneous dose-dependent rCBF increase in left M1-HAND.Apart from a subtle increase at 0.5 mA, rCBF was not modified in M1-HAND during anodal TDCS.
Ecosystem size-induced environmental fluctuations affect the temporal dynamics of community assembly mechanisms
Authors: Bier Raven L. , Vass Máté , Székely Anna J. , Langenheder Silke 
Published: January 2022

AbstractUnderstanding processes that determine community membership and abundance is important for many fields from theoretical community ecology to conservation. However, spatial community studies are often conducted only at a single timepoint despite the known influence of temporal variability on community assembly processes. Here we used a spatiotemporal study to determine how environmental fluctuation differences induced by mesocosm volumes (larger volumes were more stable) influence assembly processes of aquatic bacterial metacommunities along a press disturbance gradient. By combining path analysis and network approaches, we found mesocosm size categories had distinct relative influences of assembly process and environmental factors that determined spatiotemporal bacterial community composition, including dispersal and species sorting by conductivity. These processes depended on, but were not affected proportionately by, mesocosm size. Low fluctuation, large mesocosms primarily developed through the interplay of species sorting that became more important over time and transient priority effects as evidenced by more time-delayed associations. High fluctuation, small mesocosms had regular disruptions to species sorting and greater importance of ecological drift and dispersal limitation indicated by lower richness and higher taxa replacement. Together, these results emphasize that environmental fluctuations influence ecosystems over time and its impacts are modified by biotic properties intrinsic to ecosystem size.
Optimal experimental designs for estimating genetic and non-genetic effects underlying infectious disease transmission
Authors: Pooley Christopher , Marion Glenn , Bishop Stephen , Doeschl-Wilson Andrea 
Published: January 2022

AbstractBackgroundInfectious disease spread in populations is controlled by individuals’ susceptibility (propensity to acquire infection), infectivity (propensity to pass on infection to others) and recoverability (propensity to recover/die). Estimating the effects of genetic risk factors on these host epidemiological traits can help reduce disease spread through genetic control strategies. However, the effects of previously identified ‘disease resistance SNPs’ on these epidemiological traits are usually unknown. Recent advances in computational statistics make it now possible to estimate the effects of single nucleotide polymorphisms (SNPs) on these traits from longitudinal epidemic data (e.g. infection and/or recovery times of individuals or diagnostic test results). However, little is known how to optimally design disease transmission experiments or field studies to maximise the precision at which pleiotropic SNP effects estimates for susceptibility, infectivity and recoverability can be estimated.ResultsWe develop and validate analytical expressions for the precision of SNP effects estimates on the three host traits assuming a disease transmission experiment with one or more non-interacting contact groups. Maximising these leads to three distinct ‘experimental’ designs, each specifying a different set of ideal SNP genotype compositions across groups: a) appropriate for a single contact-group, b) a multi-group design termed “pure”, and c) a multi-group design termed “mixed”, where ‘pure’ and ‘mixed’ refer to contact groups consisting of individuals with the same or different SNP genotypes, respectively. Precision estimates for susceptibility and recoverability were found to be less sensitive to the experimental design than infectivity. Data from multiple groups were found more informative about infectivity effects than from a single group containing the same number of individuals. Whilst the analytical expressions suggest that the multi-group pure and mixed designs estimate SNP effects with similar precision, the mixed design is preferable because it uses information from naturally occurring infections rather than those artificially induced. The same optimal design principles apply to estimating other categorical fixed effects, such as vaccinations status, helping to more effectively quantify their epidemiological impact.An onlinesoftware toolSIRE-PChas been developed which calculates the precision of estimated substitution and dominance effects of a single SNP (or vaccine status) associated with all three traits depending on experimental design parameters.ConclusionsThe developed methodology and software tool can be used to aid the design of disease transmission experiments for estimating the effect of individual SNPs and other categorical variables underlying host susceptibility, infectivity and recoverability.
Model-based hearing-enhancement strategies for cochlear synaptopathy pathologies
Authors: Drakopoulos Fotios , Vasilkov Viacheslav , Osses Vecchi Alejandro , Wartenberg Tijmen , Verhulst Sarah 
Published: January 2022

AbstractIt is well known that ageing and noise exposure are important causes of sensorineural hearing loss, and can result in damage of the outer hair cells or other structures of the inner ear, including synaptic damage to the auditory nerve (AN), i.e., cochlear synaptopathy (CS). Despite the suspected high prevalence of CS among people with self-reported hearing difficulties but seemingly normal hearing, conventional hearing-aid algorithms do not compensate for the functional deficits associated with CS. Here, we present and evaluate a number of auditory signal-processing strategies designed to maximally restore AN coding for listeners with CS pathologies. We evaluated our algorithms in subjects with and without suspected age-related CS to assess whether physiological and behavioural markers associated with CS can be improved. Our data show that after applying our algorithms, envelope-following responses and perceptual amplitude-modulation sensitivity were consistently enhanced in both young and older listeners. Speech-in-noise intelligibility showed small improvements after processing but mostly for young normal-hearing participants, with median improvements of up to 8.3%. Since our hearing-enhancement strategies were designed to optimally drive the AN fibres, they were able to improve temporal-envelope processing for listeners both with and without suspected CS. Our proposed algorithms can be rapidly executed and can thus extend the application range of current hearing aids and hearables, while leaving sound amplification unaffected.
Microstructural Impairments in a Topologically Distinct Prefrontal-Habenular Connection in Cocaine Addiction
Authors: King Sarah G. , Gaudreault Pierre-Olivier , Malaker Pias , Kim Joo-won , Alia-Klein Nelly , Xu Junqian , Goldstein Rita Z. 
Published: January 2022

AbstractDrug addiction is characterized by neuroadaptations in mesocorticolimbic networks regulating reward and inhibitory control. The habenula (Hb) is central to adaptive reward and aversion-driven behaviors, serving as a hub connecting emotion/cognitive processing regions including the prefrontal cortex (PFC). However, its role in human drug addiction has not been fully explored. Using diffusion tractography, we detailed PFC structural connectivity with three regions, namely the Hb, ventral tegmental area (VTA), and anterior thalamus (AT), and quantified the tract-specific microstructural integrity using diffusion tensor imaging within the anterior limb of the internal capsule (ALIC) in healthy and cocaine-addicted individuals. White matter microstructure in cocaine-addicted individuals was uniquely impaired in PFC-Hb projections in the ALIC, distinguishable from adjacent PFC-VTA and PFC-AT projections, with more pronounced abnormalities in short-term abstinence. These findings extend preclinical evidence of PFC-Hb circuit impairments in addiction and contextualize the plausible existence of a similar PFC-Hb connection in the human brain.
Differential Requirement of DICER1 Activity during Development of Mitral and Tricuspid Valves
Authors: Yan Shun , Peng Yin , Lu Jin , Shakil Saima , Shi Yang , Crossman David K. , Johnson Walter H , Liu Shanrun , Lincoln Joy , Wang Qin , Jiao Kai 
Published: January 2022

AbstractMitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. We specifically inactivatedDicer1in the endocardium during cardiogenesis, and unexpectedly found thatDicer1-deletion caused congenital mitral valve stenosis and regurgitation, while it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA Sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.Summary statementAlthough mitral and tricuspid heart valves are both derived from same cell sources in the atrioventricular region through similar initiation and remodeling processes, congenital dysplasia simultaneously affecting both valves is clinically uncommon. We show that DICER1 activity is only essential for mitral valve development whereas it is dispensable for other valves. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that is differentially required to regulate mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.
Parameterized syncmer schemes improve long-read mapping
Authors: Dutta Abhinav , Pellow David , Shamir Ron 
Published: January 2022

AbstractMotivationSequencing long reads presents novel challenges to mapping. One such challenge is low sequence similarity between the reads and the reference, due to high sequencing error and mutation rates. This occurs, e.g., in a cancer tumor, or due to differences between strains of viruses or bacteria. A key idea in mapping algorithms is to sketch sequences with their minimizers. Recently, syncmers were introduced as an alternative sketching method that is more robust to mutations and sequencing errors.ResultsWe introduce parameterized syncmer schemes, a generalization of syncmers, and provide a theoretical analysis for multi-parameter schemes. By combining these schemes with downsampling or minimizers we can achieve any desired compression and window guarantee. We implemented the use of parameterized syncmer schemes in the popular minimap2 and Winnowmap2 mappers. In tests on simulated and real long read data from a variety of genomes, the syncmer-based algorithms, with scheme parameters selected on the basis of the theoretical analysis, reduced unmapped reads by 20-60% at high compression while usually using less memory. The advantage was more pronounced at low sequence identity. At sequence identity of 75% and medium compression, syncmer-minimap had only 37% as many unmapped reads, and 8% fewer of the reads that did map were incorrectly mapped. Even at lower compression and error rates, parameterized syncmer based mapping mapped more reads than the original minimizer-based mappers as well as mappers using the original syncmer schemes. We conclude that using parameterized syncmer schemes can improve mapping of long reads in a wide range of settings.Availabilityhttps://github.com/Shamir-Lab/syncmer_mappingSupplementary informationSupplementary data are available at https://github.com/Shamir-Lab/syncmer_mapping.Author summaryPopular long read mappers use minimizers, the minimal hashed k-mers from overlapping windows, as alignment seeds. Recent work showed that syncmers, which select a fixed set of k-mers as seeds, are more likely to be conserved under errors or mutations than minimizers, making them potentially useful for mapping error-prone long reads. We introduce a framework for creating syncmers, that we call parameterized syncmer schemes, which generalize those introduced so far, and provide a theoretical analysis of their properties. We implemented parameterized syncmer schemes in the minimap2 and Winnowmap2 long read mappers. Using parameters selected on the basis of our theoretical analysis we demonstrate improved mapping performance, with fewer unmapped and incorrectly mapped reads on a variety of simulated and real datasets. The improvements are consistent across a broad range of compression rates and sequence identities, with the most significant improvements for lower sequence identity (high error or mutation rates) and high compression.
Single-molecule mapping of replisome progression
Authors: Claussin Clémence , Vazquez Jacob , Whitehouse Iestyn 
Published: January 2022

AbstractFundamental aspects of DNA replication, such as the anatomy of replication stall sites, how replisomes are influenced by gene transcription and whether the progression of sister replisomes is coordinated are poorly understood. Available techniques do not allow the precise mapping of the positions of individual replisomes on chromatin. We have developed a new method called Replicon-seq that entails the excision of full-length replicons by controlled nuclease cleavage at replication forks. Replicons are sequenced using Nanopore, which provides a single molecule readout of long DNA molecules. Using Replicon-seq, we have investigated replisome movement along chromatin. We found that sister replisomes progress with remarkable consistency from the origin of replication but function autonomously. Replication forks that encounter obstacles pause for a short duration but rapidly resume synthesis. The helicase Rrm3 plays a critical role both in mitigating the effect of protein barriers and facilitating efficient termination. Replicon-seq provides an unprecedented means of defining replisome movement across the genome.
UV-C light completely blocks highly contagious Delta SARS-CoV-2 aerosol transmission in hamsters
Authors: Fischer Robert J. , Port Julia R. , Holbrook Myndi G. , Yinda Kwe Claude , Creusen Martin , ter Stege Jeroen , de Samber Marc , Munster Vincent J. 
Published: January 2022

AbstractBehavioral and medical control measures are not effective in containing the spread of SARS-CoV-2. Here we report on the effectiveness of a preemptive environmental strategy using UV-C light to prevent airborne transmission of the virus in a hamster model and show that UV-C exposure completely prevents airborne transmission between individuals
Adeno-associated Virus Receptor-binding: Flexible Domains and Alternative Conformations through cryo-Electron Tomography of AAV2 and AAV5 complexes
Authors: Hu Guiqing , Silveria Mark A. , Chapman Michael S. , Stagg Scott M. 
Published: January 2022

AbstractRecombinant forms of adeno-associated virus (rAAV) are vectors of choice in the development of treatments for a number of genetic dispositions. Greater understanding of AAV’s molecular virology is needed to underpin needed improvements in efficiency and specificity. Recent advances have included identification of a near universal entry receptor, AAVR, and structures by cryo-electron microscopy (EM) single particle analysis (SPA) that revealed, at high resolution, only the domains of AAVR most tightly bound to AAV. Here, cryogenic electron tomography (cryo-ET) is applied to reveal the neighboring domains of the flexible receptor. For AAV5, where the PKD1 domain is bound strongly, PKD2 is seen in three configurations extending away from the virus. AAV2 binds tightly to the PKD2 domain at a distinct site, and cryo-ET now reveals four configurations of PKD1, all different from that seen in AAV5. The AAV2 receptor complex also shows unmodeled features on the inner surface that appear to be an equilibrium alternate configuration. Other AAV structures start near the 5-fold axis, but now β-strand A is the minor conformer and, for the major conformer, partially ordered N-termini near the 2-fold axis join the canonical capsid jellyroll fold at the βA-βB turn. The addition of cryo-ET is revealing unappreciated complexity that is likely relevant to viral entry and to the development of improved gene therapy vectors.IMPORTANCEWith 150 clinical trials for 30 diseases underway, AAV is a leading gene therapy vector. Immunotoxicity at high doses used to overcome inefficient transduction, has occasionally proven fatal and highlighted gaps in fundamental virology. AAV enters cells, interacting through distinct sites with different domains of the AAVR receptor, according to AAV clade. Single domains are resolved in structures by cryogenic electron microscopy. Here, the adjoining domains are revealed by cryo-electron tomography of AAV2 and AAV5 complexes. They are in flexible configurations interacting minimally with AAV, despite measurable dependence of AAV2 transduction on both domains.