bluuebunny/crossref_metadata_2025_split huggingface dataset:
A quantitative landscape of cell fate transitions identifies principles of cellular decision-making
Authors: Sáez M. , Blassberg R. , Camacho-Aguilar E. , Siggia E. D. , Rand D. , Briscoe J. 
Published: March 2021

AbstractFate decisions in developing tissues involve cells transitioning between a set of discrete cell states, each defined by a distinct gene expression profile. Geometric models, often referred to as Waddington landscapes, in which developmental paths are given by the gradient and cell states by the minima of the model, are an appealing way to describe differentiation dynamics and developmental decisions. To construct and validate accurate dynamical landscapes, quantitative methods based on experimental data are necessary. To this end we took advantage of the differentiation of neural and mesodermal cells from pluripotent mouse embryonic stem cells exposed to different combinations and durations of signalling factors. We developed a principled statistical approach using flow cytometry data to quantify differentiating cell states. Then, using a framework based on Catastrophe Theory and approximate Bayesian computation, we constructed the corresponding dynamical landscape. The result was a quantitative model that accurately predicted the proportions of neural and mesodermal cells differentiating in response to specific signalling regimes. Analysis of the geometry of the landscape revealed two distinct ways in which cells make a binary choice between one of two fates. We discuss the biological relevance of these mechanisms and suggest that they represent general archetypal designs for developmental decisions. Taken together, the approach we describe is broadly applicable for the quantitative analysis of differentiation dynamics and for determining the logic of developmental cell fate decisions.
Complementary evolution of coding and noncoding sequence underlies mammalian hairlessness
Authors: Kowalczyk Amanda , Chikina Maria , Clark Nathan 
Published: March 2021

AbstractBody hair is a defining mammalian characteristic, but several mammals, such as whales, naked mole-rats, and humans, have notably less hair than others. To find the genetic basis of reduced hair quantity, we used our evolutionary-rates-based method, RERconverge, to identify coding and noncoding sequences that evolve at significantly different rates in so-called hairless mammals compared to hairy mammals. Using RERconverge, we performed an unbiased, genome-wide scan over 62 mammal species using 19,149 genes and 343,598 conserved noncoding regions to find genetic elements that evolve at significantly different rates in hairless mammals compared to hairy mammals. We show that these rate shifts resulted from relaxation of evolutionary constraint on hair-related sequences in hairless species. In addition to detecting known and potential novel hair-related genes, we also discovered hundreds of putative hair-related regulatory elements. Computational investigation revealed that genes and their associated noncoding regions show different evolutionary patterns and influence different aspects of hair growth and development. Many genes under accelerated evolution are associated with the structure of the hair shaft itself, while evolutionary rate shifts in noncoding regions also included the dermal papilla and matrix regions of the hair follicle that contribute to hair growth and cycling. Genes that were top-ranked for coding sequence acceleration included known hair and skin genesKRT2, KRT35, PKP1, andPTPRMthat surprisingly showed no signals of evolutionary rate shifts in nearby noncoding regions. Conversely, accelerated noncoding regions are most strongly enriched near regulatory hair-related genes and microRNAs, such asmir205, ELF3, andFOXC1, that themselves do not show rate shifts in their protein-coding sequences. Such dichotomy highlights the interplay between the evolution of protein sequence and regulatory sequence to contribute to the emergence of a convergent phenotype.
Characterization of a haplotype-reference panel for genotyping by low-pass sequencing in Swiss Large White pigs
Authors: Nosková Adéla , Bhati Meenu , Kadri Naveen Kumar , Crysnanto Danang , Neuenschwander Stefan , Hofer Andreas , Pausch Hubert 
Published: March 2021

AbstractBackgroundThe key-ancestor approach has been frequently applied to prioritize individuals for whole-genome sequencing based on their marginal genetic contribution to current populations. Using this approach, we selected 70 key ancestors from two lines of the Swiss Large White breed that have been selected divergently for fertility and fattening traits and sequenced their genomes with short paired-end reads.ResultsUsing pedigree records, we estimated the effective population size of the dam and sire line to 72 and 44, respectively. In order to assess sequence variation in both lines, we sequenced the genomes of 70 boars at an average coverage of 16.69-fold. The boars explained 87.95 and 95.35% of the genetic diversity of the breeding populations of the dam and sire line, respectively. Reference-guided variant discovery using the GATK revealed 26,862,369 polymorphic sites. Principal component, admixture and FSTanalyses indicated considerable genetic differentiation between the lines. Genomic inbreeding quantified using runs of homozygosity was higher in the sire than dam line (0.28 vs 0.26). Using two complementary approaches (CLR and iHS), we detected 51 signatures of selection. However, only six signatures of selection overlapped between both lines. We used the sequenced haplotypes of the 70 key ancestors as a reference panel to call 22,618,811 genotypes in 175 pigs that had been sequenced at very low coverage (1.11-fold) using GLIMPSE. The genotype concordance, non-reference sensitivity and non-reference discrepancy between thus inferred and Illumina PorcineSNP60 BeadChip-called genotypes was 97.60, 98.73 and 3.24%, respectively. The low-pass sequencing-derived genomic relationship coefficients were highly correlated (r > 0.99) with those obtained from microarray genotyping.ConclusionsWe assessed genetic diversity within and between two lines of the Swiss Large White pig breed. Our analyses revealed considerable differentiation, even though the split into two populations occurred only few generations ago. The sequenced haplotypes of the key ancestor animals enabled us to implement genotyping by low-pass sequencing which offers an intriguing cost-effective approach to increase the variant density over current array-based genotyping by more than 350-fold.
Efficient high-resolution TMS mapping of the human motor cortex by nonlinear regression
Authors: Numssen Ole , Zier Anna-Leah , Thielscher Axel , Hartwigsen Gesa , Knösche Thomas R. , Weise Konstantin 
Published: March 2021

AbstractTranscranial magnetic stimulation (TMS) is a powerful tool to investigate causal structure-function relationships in the human brain. However, a precise delineation of the effectively stimulated neuronal populations is notoriously impeded by the widespread and complex distribution of the induced electric field.Here, we propose a method that allows rapid and feasible cortical localization at the individual subject level. The functional relationship between electric field and behavioral effect is quantified by combining experimental data with numerically modelled fields to identify the cortical origin of the modulated effect. Motor evoked potentials (MEPs) from three finger muscles were recorded for a set of random stimulations around the primary motor area. All induced electric fields were nonlinearly regressed against the elicited MEPs to identify their cortical origin.We could distinguish cortical muscle representation with high spatial resolution and localized them primarily on the crowns and rims of the precentral gyrus. A post-hoc analysis revealed exponential convergence of the method with the number of stimulations, yielding a minimum of about 180 random stimulations to obtain stable results.Establishing a functional link between the modulated effect and the underlying mode of action, the induced electric field, is a fundamental step to fully exploit the potential of TMS. In contrast to previous approaches, the presented protocol is particularly easy to implement, fast to apply, and very robust due to the random coil positioning and therefore is suitable for practical and clinical applications.
Quantifying the effects of intraspecific trait variation and interspecific trait correlations on interacting populations - a nonlinear averaging approach
Authors: van Benthem Koen J. , Bagawade Rishabh , Blüml Chantal , Nabutanyi Peter , Thon Frans M. , Wittmann Meike J. 
Published: March 2021

AbstractInteractions between two species, e.g. between a predator species and a prey species, can often be described as the sum of many individual-by-individual interactions whose outcomes depend on the traits of the interacting individuals. These traits often vary substantially among individuals in each species, and individuals do not always interact randomly, e.g. due to plastic responses to a shared environmental factor in a heterogeneous landscape. Here we investigate the impact of intraspecific trait variation (ITV) and such interspecific trait correlations on species interactions via nonlinear averaging. Building on past models that integrate over an interaction kernel to obtain the impacts of ITV, we develop a modeling framework that allows to model arbitrary species interactions, with interspecific trait correlations as novel feature. Based on two key ingredients, a joint trait distribution and a two-dimensional interaction function, the average interaction parameters (e.g. average predation rate) can be quantified numerically, approximated using an insightful Taylor approximation, and compared to cases without ITV. We highlight two applications of our framework. First, we study the quantitative and qualitative effects of ITV and trait correlations in a simple predator-prey model and show that even in the absence of evolution, variation and trait correlations among interacting individuals can make or break the coexistence between species. Second, we use simulated field data for a predator-prey system to show how the impact of ITV on an ecological interaction can be estimated from empirical data.HighlightsWe model how intraspecific trait variation in two species affects their interaction.Our framework allows correlations between the traits of interacting individuals.Trait variation and correlations can strongly affect ecological interactions.Trait variation and correlations can make or break coexistence.The effect of intraspecific trait variation can be estimated from data.
Identifying regions in prefrontal cortex related to working memory improvement: a novel meta-analytic method using electric field modeling
Authors: Wischnewski Miles , Mantell Kathleen E. , Opitz Alexander 
Published: March 2021

AbstractAltering cortical activity using transcranial direct current stimulation (tDCS) has been shown to improve working memory (WM) performance. Due to large inter-experimental variability in the tDCS montage configuration and strength of induced electric fields, results have been mixed. Here, we present a novel meta-analytic method relating behavioral effect sizes to electric field strength to identify brain regions underlying largest tDCS-induced WM improvement. Simulations on 69 studies targeting left prefrontal cortex showed that tDCS electric field strength in lower dorsolateral prefrontal cortex (Brodmann area 45/47) relates most strongly to improved WM performance. This region explained 7.8% of variance, equaling a medium effect. A similar region was identified when correlating WM performance and electric field strength of right prefrontal tDCS studies (n = 18). Maximum electric field strength of five previously used tDCS configurations were outside of this location. We thus propose a new tDCS montage which maximizes the tDCS electric field strength in that brain region. Our findings can benefit future tDCS studies that aim to affect WM function.Highlights-We summarize the effect of 87 tDCS studies on working memory performance-We introduce a new meta-analytic method correlating tDCS electric fields and performance-tDCS-induced electric fields in lower DLPFC correlate significantly with improved working memory-The lower DLPFC was not maximally targeted by most tDCS montages and we provide an optimized montage
DNA Preparation inVitis viniferaL. For Third Generation Sequencing
Authors: Androniki Bibi C. , Anastasios Kollias , Maria Astrinaki , Despoina Vassou , Dimitris Kafetzopoulos , Kriton Kalantidis , Panagiotis Moschou N. 
Published: March 2021

AbstractBackgroundThere have been several attempts to sequence the genome ofVitis viniferaL. (grapevine), utilizing low-resolution second-generation platforms. Nevertheless, the characterization of the grapevine genetic resources and its adaptation to vulnerable conditions could be better addressed through extensive and high-resolution genome sequencing.MinION is a third-generation sequencer preferred by many laboratories due to its relatively low cost, ease of use and small size. Even though this long-read technology has been rapidly improving, to reach its full potential requires high-quality DNA.ResultsHere we establish a workflow for DNA extraction suitable for MinION sequencing long reads from grapevine. This protocol was tested with leaf samples from different positions on annual growing branches of grapevine, Purified nuclei from fresh young leaves that led to high quality, long DNA fragments, suitable for long-read sequencing were successfully generated. It is evident that longer reads in grapevine associate with both fresh tissue and adjusted conditions used for nuclei purification.ConclusionsWe propose that this workflow presents a significant advancement for long-read quality DNA isolation for grapevine and likely other plant species.
Structurally Distributed Surface Sites Tune Allosteric Regulation
Authors: McCormick James W. , Russo Marielle A.X. , Thompson Samuel , Blevins Aubrie , Reynolds Kimberly A. 
Published: March 2021

AbstractOur ability to rationally optimize allosteric regulation is limited by incomplete knowledge of the mutations that tune allostery. Are these mutations few or abundant, structurally localized or distributed? To examine this, we conducted saturation mutagenesis of a synthetic allosteric switch in which Dihydrofolate reductase (DHFR) is regulated by a blue-light sensitive LOV2 domain. Using a high-throughput assay wherein DHFR catalytic activity is coupled toE. coligrowth, we assessed the impact of 1548 viable DHFR single mutations on allostery. Despite most mutations being deleterious to activity, fewer than 5% of mutations had a statistically significant influence on allostery. Most allostery disrupting mutations were proximal to the LOV2 insertion site. In contrast, allostery enhancing mutations were structurally distributed and enriched on the protein surface. Combining several allostery enhancing mutations yielded near-additive improvements to dynamic range. Our results indicate a path towards optimizing allosteric function through variation at surface sites.
Notch signaling via Hey1 and Id2b regulates Müller glia’s regenerative response to retinal injury
Authors: Sahu Aresh , Devi Sulochana , Jui Jonathan , Goldman Daniel 
Published: March 2021

AbstractZebrafish Müller glia (MG) respond to retinal injury by suppressing Notch signaling and producing progenitors for retinal repair. A certain threshold of injury-derived signal must be exceeded in order to engage MG in a regenerative response (MG’s injury-response threshold). Pan-retinal Notch inhibition expands the zone of injury-responsive MG at the site of focal injury, suggesting that Notch signaling regulates MG’s injury-response threshold. We found that Notch signaling enhanced chromatin accessibility and gene expression at a subset of regeneration-associated genes in the uninjured retina. Two Notch effector genes,hey1andid2b, were identified that reflect bifurcation of the Notch signaling pathway, and differentially regulate MG’s injury-response threshold and proliferation of MG-derived progenitors. Furthermore, Notch signaling component gene repression in the injured retina suggests a role for Dll4, Dlb, and Notch3 in regulating Notch signaling in MG and epistasis experiments confirm that the Dll4/Dlb-Notch3-Hey1/Id2b signaling pathway regulates MG’s injury-response threshold and proliferation.
Impact of Vaccine Prioritization Strategies on Mitigating COVID-19: An Agent-Based Simulation Study using an Urban Region in the United States
Authors: Tatapudi Hanisha , Das Rachita , Das Tapas K. 
Published: March 2021

ABSTRACTBackgroundApproval of novel vaccines for COVID-19 had brought hope and expectations, but not without additional challenges. One central challenge was understanding how to appropriately prioritize the use of limited supply of vaccines. This study examined the efficacy of the various vaccine prioritization strategies using the vaccination campaign underway in the U.S.MethodsThe study developed a granular agent-based simulation model for mimicking community spread of COVID-19 under various social interventions including full and partial closures, isolation and quarantine, use of face mask and contact tracing, and vaccination. The model was populated with parameters of disease natural history, as well as demographic and societal data for an urban community in the U.S. with 2.8 million residents. The model tracks daily numbers of infected, hospitalized, and deaths for all census age-groups. The model was calibrated using parameters for viral transmission and level of community circulation of individuals. Published data from the Florida COVID-19 dashboard was used to validate the model. Vaccination strategies were compared using a hypothesis test for pairwise comparisons.ResultsThree prioritization strategies were examined: a minor variant of CDC’s recommendation, an age-stratified strategy, and a random strategy. The impact of vaccination was also contrasted with a no vaccination scenario. The study showed that the campaign against COVID-19 in the U.S. using vaccines developed by Pfizer/BioNTech and Moderna 1) reduced the cumulative number of infections by 10% and 2) helped the pandemic to subside below a small threshold of 100 daily new reported cases sooner by approximately a month when compared to no vaccination. A comparison of the prioritization strategies showed no significant difference in their impacts on pandemic mitigation.ConclusionsEven though vaccines for COVID-19 were developed and approved much quicker than ever before, their impact on pandemic mitigation was small as the explosive spread of the virus had already infected a significant portion of the population, thus reducing the susceptible pool. A notable observation from the study is that instead of adhering strictly to a sequential prioritizing strategy, focus should perhaps be on distributing the vaccines among all eligible as quickly as possible, after providing for the most vulnerable. As much of the population worldwide is yet to be vaccinated, results from this study should aid public health decision makers in effectively allocating their limited vaccine supplies.
Cargo crowding, stationary clusters and dynamical reservoirs in axonal transport
Authors: Kumar Vinod , Vasudevan Amruta , Venkatesh Keertana , Maiya Reshma , Sood Parul , Murthy Kausalya , Koushika Sandhya P. , Menon Gautam I. 
Published: March 2021

AbstractMolecular motors drive the directed transport of presynaptic vesicles along the narrow axons of nerve cells. Stationary clusters of such vesicles are a prominent feature of axonal transport, but little is known about their physiological and functional relevance. Here, we develop a simulation model describing key features of axonal cargo transport with a view to addressing this question, benchmarking the model against our experiments in the touch neurons ofC. elegans. Our simulations provide for multiple microtubule tracks and varied cargo motion states while also incorporating cargo-cargo interactions. Our model also incorporates obstacles to vesicle transport in the form of microtubule ends, stalled vesicles, and stationary mitochondria. We devise computational methodologies to simulate both axonal bleaching and axotomy, showing that our results reproduce the properties of both moving as well as stationary cargo in vivo. Increasing vesicle numbers leads to larger and more long-lived stationary clusters of vesicular cargo. Vesicle clusters are dynamically stable, explaining why they are ubiquitously seen. Modulating the rates of cargo motion-state switching allows cluster lifetimes and flux to be tuned both in simulations and experiments. We demonstrate, both in simulations and in an experimental system, that suppressing reversals leads to larger stationary vesicle clusters being formed while also reducing flux. Our simulation results support the view that the physiological significance of clusters is located in their role as dynamic reservoirs of cargo vesicles, capable of being released or sequestered on demand.
Long-term cross-scale comparison of grazing and mowing on plant diversity and community composition in a salt-marsh system
Authors: Chen Qingqing , Bakker Jan P. , Alberti Juan , Bakker Elisabeth S. , Smit Christian , Olff Han 
Published: March 2021

AbstractLand abandonment is increasing in recent decades in Europe, usually accompanied by a decline in biodiversity. Whether livestock grazing and mowing can safeguard biodiversity across spatial scales in the long term is unclear.Using a 48-year experiment in a salt marsh, we compared land abandonment (without grazing and mowing) and seven management regimes including cattle grazing, early season mowing, late season mowing, both early and late season mowing, and grazing plus each of the mowing regimes on plant diversity at the local (i.e. plot) and landscape scales (i.e. across plots). Also, we compared their effects on community composition (both in identities and abundances) in time and space.Under land abandonment, plant diversity declined in the local communities and this decline became more apparent at the landscape scale, particularly for graminoids and halophytes. All management regimes, except the late season mowing, maintained plant diversity at these scales.Local plant communities under all treatments underwent different successional trajectories, in the end, diverged from their initial state except for that under grazing (a cyclic succession). Interannual composition change remained stable over time under land abandonment and grazing plus early season mowing. It increased over time under grazing and late season mowing, it increased in the second half of the experiment under other treatments. Vegetation homogenized in the landscape over time under land abandonment while vegetation was heterogeneous under all management regimes.Synthesis.Our experiment suggests that late season mowing may not be sustainable to conserve plant diversity in salt marshes. Other management regimes can maintain plant diversity across scales and vegetation heterogeneity in the landscape in the long term, but local community composition may change over time.