bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid longitudinal SARS-CoV-2 intra-host emergence of novel haplotypes regardless of immune deficiencies
Authors: Manuto Laura , Grazioli Marco , Spitaleri Andrea , Fontana Paolo , Bianco Luca , Bertolotti Luigi , Bado Martina , Mazzotti Giorgia , Bianca Federico , Onelia Francesco , Lorenzin Giovanni , Simeoni Fabio , Lazarevic Dejan , Franchin Elisa , Del Vecchio Claudia , Dorigatti Ilaria , Tonon Giovanni , Cirillo Daniela , Lavezzo Enrico , Crisanti Andrea , Toppo Stefano 
Published: December 2021

ABSTRACTOn February 2020, the municipality of Vo’, a small town near Padua (Italy), was quarantined due to the first coronavirus disease 19 (COVID-19)-related death detected in Italy. The entire population was swab tested in two sequential surveys. Here we report the analysis of the viral genomes, which revealed that the unique ancestor haplotype introduced in Vo’ belongs to lineage B and, more specifically, to the subtype found at the end of January 2020 in two Chinese tourists visiting Rome and other Italian cities, carrying mutations G11083T and G26144T. The sequences, obtained for 87 samples, allowed us to investigate viral evolution while being transmitted within and across households and the effectiveness of the non-pharmaceutical interventions implemented in Vo’. We report, for the first time, evidence that novel viral haplotypes can naturally arise intra-host within an interval as short as two weeks, in approximately 30% of the infected individuals, regardless of symptoms severity or immune system deficiencies. Moreover, both phylogenetic and minimum spanning network analyses converge on the hypothesis that the viral sequences evolved from a unique common ancestor haplotype, carried by an index case. The lockdown extinguished both viral spread and the emergence of new variants, confirming the efficiency of this containment strategy. The information gathered from household was used to reconstructs possible transmission events.AUTHOR SUMMARYIt is of great interest and importance to understand SARS-CoV-2 ability to mutate generating new viral strains, and to assess the impact of containment strategies on viral transmission. In this study we highlight the rapid intra-host haplotype evolution regardless of symptom severity and immune deficiencies that we observed during the first wave of the pandemic in the municipality of Vo’ in Italy. The confirmation that all the haplotypes found in this small community derive from a common ancestor haplotype, has allowed us to track the rapid emergence of new variants but lockdown and mass testing efficiently prevented their spread elsewhere.
Sorghum Association Panel Whole-Genome Sequencing Establishes Pivotal Resource for Dissecting Genomic Diversity
Authors: Boatwright J. Lucas , Sapkota Sirjan , Jin Hongyu , Schnable James C. , Brenton Zachary , Boyles Richard , Kresovich Stephen 
Published: December 2021

AbstractAssociation mapping panels represent foundational resources for understanding the genetic basis of phenotypic diversity and serve to advance plant breeding by exploring genetic variation across diverse accessions with distinct histories of evolutionary divergence and local adaptation. We report the whole-genome sequencing (WGS) of 400 sorghum [Sorghum bicolor (L.) Moench] accessions from the Sorghum Association Panel (SAP) at an average coverage of 38X (25X-72X), enabling the development of a high-density genomic-marker set of 43,983,694 variants including SNPs (~ 38 million), indels (~ 5 million), and CNVs (170,000). We observe slightly more deletions among indels and a much higher prevalence of deletions among copy number variants compared to insertions. This new marker set enabled the identification of several putatively novel genomic associations for plant height and tannin content, which were not identified when using previous lower-density marker sets. WGS identified and scored variants in 5 kb bins where available genotyping-by-sequencing (GBS) data captured no variants, with half of all bins in the genome falling into this category. The predictive ability of genomic best unbiased linear predictor (GBLUP) models was increased by an average of 30% by using WGS markers rather than GBS markers. We identified 18 selection peaks across subpopulations that formed due to evolutionary divergence during domestication, and we found six Fst peaks resulting from comparisons between converted lines and breeding lines within the SAP that were distinct from the peaks associated with historic selection. This population has been and continues to serve as a significant public resource for sorghum research and demonstrates the value of improving upon existing genomic resources.Author summary
SARS-CoV-2 detection in multi-sample pools in a real pandemic scenario: a screening strategy of choice for active surveillance
Authors: Castellaro Andrés Marcos , Velez Pablo , Merlera Guillermo Giaj , Dueñas Juan Rondan , Condat Felix , Gallardo Jesica , Makhoul Aylen , Cinalli Camila , Cavaglieri Lorenzo Rosales , Cola Guadalupe Di , Sicilia Paola , López Laura ,   Facultad de Ciencias Químicas UNC Group, Bocco José Luis , Barbás María Gabriela , Pisano María Belén , Ré Viviana , Belaus Andrea , Castro Gonzalo 
Published: December 2021

AbstractBackgroundThe current COVID-19 pandemic has overloaded the diagnostic capacity of laboratories by the gold standard method rRT-PCR. This disease has a high spread rate and almost a quarter of infected individuals never develop symptoms. In this scenario, active surveillance is crucial to stop the virus propagation.MethodsBetween July 2020 and April 2021, 11580 oropharyngeal swab samples collected in closed and semi-closed institutions were processed for SARS-CoV-2 detection in pools, implementing this strategy for the first time in Córdoba, Argentina. Five-sample pools were constituted before nucleic acid extraction and amplification by rRT-PCR. Comparative analysis of cycle threshold (Ct) values from positive pools and individual samples along with a cost-benefit report of the whole performance of the results was performed.ResultsFrom 2314 5-sample pools tested, 158 were classified as positive (6.8%), 2024 as negative (87.5%), and 132 were categorized as indeterminate (5.7%). The Ct value shift due to sample dilution showed an increase in Ct of 2.6±1.53 cycles for N gene and 2.6±1.78 for ORF1ab gene. Overall, 290 pools were disassembled and 1450 swabs were analyzed individually. This strategy allowed correctly identifying 99.8% of the samples as positive (7.6%) or negative (92.2%), avoiding the execution of 7,806 rRT-PCR reactions which represents a cost saving of 67.5%.ConclusionThis study demonstrates the feasibility of pooling samples to increase the number of tests performed, helping to maximize molecular diagnostic resources and reducing the work overload of specialized personnel during active surveillance of the COVID-19 pandemic.
COVID-19 Vaccines for Children with Developmental Disabilities: Parent Survey of Willingness and Concerns
Authors: Bonuck Karen , Iadarola Suzannah , Gao Qi , Siegel Joanne F. 
Published: December 2021

AbstractObjectiveWhile 1-in-6 US children has a developmental disability (DD), and such children are disproportionately affected by COVID-19, little is known about their vaccination status. We surveyed US parents of children with DDs to ascertain willingness and concerns regarding COVID-19 vaccines.MethodsAn online survey was distributed to national, statewide, and regional DD networks from June-September 2021. (Vaccines were authorized for adolescents in May 2021.) We report associations between vaccine willingness and concerns and: race/ethnicity, child age, in-person schooling, routine/flu vaccinations, and DD diagnoses. Willingness was categorized as Got /Will Get ASAP (high), Wait and See/Only if Required, or Definitely Not.Results393 parents (51.2% white) responded. Willingness differed by age (p<.001). High willingness was reported for 75.3%, 48.9%, and 38.1% of children aged 12-17, 6-11 and 0-5 years-old, respectively. Willingness differed by Autism diagnosis (p<.001) and routine and flu vaccination status (p<.01). Predominant concerns included side effects (89%) and children with disabilities not being in trials (79%). Less common concerns were: COVID not serious enough in children to warrant vaccine (22%) and misinformation (e.g., microchips, 5G, DNA changes) (24%). Concerns about vaccine safety differed by age (p<.05) and were highest for young children. In age-stratified adjusted models, Autism was positively associated with high willingness for 6-11year-olds (OR= 2.66, 95% CI= 1.12-6.35).ConclusionParents of children with DD are more willing for them to receive COVID-19 vaccines, compared to the general population. While few factors predicted willingness to vaccinate, addressing safety and developmental concerns regarding young children is warranted.
Excess interictal activity marks seizure prone cortical areas and mice in a genetic epilepsy model
Authors: Tobin William F. , Weston Matthew C. 
Published: December 2021

AbstractGenetic epilepsies are often caused by variants in widely expressed genes, potentially impacting numerous brain regions and functions. For instance, gain-of-function (GOF) variants in the widely expressed Na+-activated K+ channel gene KCNT1 alter basic neurophysiological and synaptic properties of cortical neurons, leading to developmental epileptic encephalopathy. Yet, aside from causing seizures, little is known about how such variants reshape interictal brain activity, and how this relates to epileptic activity and other disease symptoms.To address this knowledge gap, we monitored neural activity across the dorsal cortex in a mouse model of human KCNT1-related epilepsy using in vivo, awake widefield Ca2+ imaging. We observed 52 spontaneous seizures and 1700 interictal epileptiform discharges (IEDs) in homozygous mutant (Kcnt1m/m) mice, allowing us to map their appearance and spread at high spatial resolution. Outside of seizures and IEDs, we detected ~46,000 events, representing interictal cortical activity, in both Kcnt1m/m and wild-type (WT) mice, and we classified them according to their spatial profiles.Spontaneous seizures and IEDs emerged within a consistent set of susceptible cortical areas, and seizures propagated both contiguously and non-contiguously within these areas in a manner influenced, but not fully determined, by underlying synaptic connectivity. Seizure emergence was predicted by a progressive concentration of total cortical activity within the impending seizure emergence zone. Outside of seizures and IEDs, similar events were detected in WT and Kcnt1m/m mice, suggesting that the spatial structure of interictal activity was largely preserved. Several features of these events, however, were altered in Kcnt1m/m mice. Most event types were briefer, and their intensity more variable, across Kcnt1m/m mice; mice showing more intense activity spent more time in seizure. Furthermore, the rate of events whose spatial profile overlapped with where seizures and IEDs emerged was increased in Kcnt1m/m mice.Taken together, these results demonstrate that an epilepsy-causing K+ channel variant broadly alters physiology. Yet, outside of seizures and IEDs, it acts not to produce novel types of cortical activity, but rather to modulate its amount. The areas where seizures and IEDs emerge show excessively frequent and intense interictal activity and the mean intensity of an individual’s cortical activity predicts its seizure burden. These findings provide critical guidance for targeting future research and therapy development.
Early life exercise primes the neural epigenome to facilitate gene expression and hippocampal memory consolidation
Authors: Raus AM , Fuller TD , Nelson NE , Valientes DA , Bayat A , Ivy AS 
Published: December 2021

AbstractAerobic exercise is well known to promote neuroplasticity and hippocampal memory. In the developing brain, early-life exercise (ELE) can lead to lasting improvements in hippocampal function, yet molecular mechanisms underlying this phenomenon have not been fully explored. In this study, adolescent transgenic mice harboring the “NuTRAP” (Nuclear tagging and Translating Ribosome Affinity Purification) cassette in Emx1 expressing neurons (“Emx1-NuTRAP” mice) undergo ELE followed by a hippocampal learning task, in order to determine the molecular underpinnings of exercise contributing to improved hippocampal memory performance. We simultaneously isolate and sequence translating mRNA and nuclear chromatin from a single hippocampus in a cell-type specific manner (excitatory neurons), demonstrate validity of our new technical approach, and couple multi-omics sequencing data to evaluate histone modifications H4K8ac and H3K27me3 and their influence on gene expression after ELE. We then evaluate new gene expression – histone modification relationships specifically during hippocampal memory consolidation that may play a critical role in facilitated memory after ELE. Our data reveal novel candidate gene-histone modification interactions and implicate gene regulatory pathways involved in ELE’s impact on hippocampal learning and memory.
Accumulation and maintenance of information in evolution
Authors: Hledík Michal , Barton Nick , Tkačik Gašper 
Published: December 2021

AbstractSelection accumulates information in the genome — it guides stochastically evolving populations towards states (geno-type frequencies) that would be unlikely under neutrality. This can be quantified as the Kullback-Leibler (KL) divergence between the actual distribution of genotype frequencies and the corresponding neutral distribution. First, we show that this population-level information sets an upper bound on the information at the level of genotype and phenotype, limiting how precisely they can be specified by selection. Next, we study how the accumulation and maintenance of information is limited by the cost of selection, measured as the genetic load or the relative fitness variance, both of which we connect to the control-theoretic KL cost of control. The information accumulation rate is upper bounded by the population size times the cost of selection. This bound is very general, and applies across models (Wright-Fisher, Moran, diffusion) and to arbitrary forms of selection, mutation and recombination. Finally, the cost of maintaining information depends on how it is encoded: specifying a single allele out of two is expensive, but one bit encoded among many weakly specified loci (as in a polygenic trait) is cheap.
Directing Min protein patterns with advective bulk flow
Authors: Meindlhumer Sabrina , Brauns Fridtjof , Finžgar Jernej Rudi , Kerssemakers Jacob , Dekker Cees , Frey Erwin 
Published: December 2021

AbstractThe Min proteins constitute the best-studied model system for pattern formation in cell biology. We theoretically predict and experimentally show that the propagation direction of in vitro Min protein patterns can be controlled by a hydrodynamic flow of the bulk solution. We find downstream propagation of Min wave patterns for low MinE:MinD concentration ratios, upstream propagation for large ratios, but multistability of both propagation directions in between. Whereas downstream propagation can be described by a minimal model that disregards MinE conformational switching, upstream propagation can be reproduced by a reduced switch model, where increased MinD bulk concentrations on the upstream side promote protein attachment. Our study demonstrates that a differential flow, where bulk flow advects protein concentrations in the bulk, but not on the surface, can control surface-pattern propagation. This suggests that flow can be used to probe these features and to constrain mathematical models for pattern-forming systems.
Small Molecules Targeting the Disordered Transactivation Domain of the Androgen Receptor Induce the Formation of Collapsed Helical States
Authors: Zhu Jiaqi , Salvatella Xavier , Robustelli Paul 
Published: December 2021

AbstractCastration-resistant prostate cancer (CRPC) is a lethal condition suffered by ∼35% of prostate cancer patients who become resistant to existing FDA-approved drugs. Small molecules that target the intrinsically disordered N-terminal domain of the androgen receptor (AR-NTD) have shown promise in circumventing CPRC drug-resistance. A prodrug of one such compound, EPI-002, entered human trials in 2015 but was discontinued after phase I due to poor potency. The compound EPI-7170 was subsequently found to have improved potency, and a related compound entered human trials in 2020. NMR measurements have localized the strongest effects of these compounds to a transiently helical region of the disordered AR-NTD but no detailed structural or mechanistic rationale exists to explain their affinity to this region or the comparative potency of EPI-7170. Here, we utilize all-atom molecular dynamics simulations to elucidate the binding mechanisms of the small molecules EPI-002 and EPI-7170 to the disordered AR-NTD. We observe that both compounds induce the formation of collapsed helical states in the Tau-5 transactivation domain and that these bound states consist of heterogenous ensembles of interconverting binding modes. We find that EPI-7170 has a higher affinity to Tau-5 than EPI-002 and that the EPI-7170 bound ensemble contains a substantially higher population of collapsed helical states than the bound ensemble of EPI-002. We identify a network of interactions in the EPI-7170 bound ensemble that stabilize collapsed helical conformations. Our results provide atomically detailed binding mechanisms for EPI compounds consistent with NMR experiments that will prove useful for drug discovery for CRPC.SummaryIntrinsically disordered proteins (IDPs), which do not fold into a well-defined three-dimensional structure under physiological conditions, are implicated in many human diseases. Such proteins are difficult to characterize at an atomic level and are extremely challenging drug targets. Small molecules that target a disordered domain of the androgen receptor have entered human trials for the treatment of castration-resistant prostate cancer, but no structural or mechanistic rationale exists to explain their inhibition mechanisms or relative potencies. Here, we utilize molecular dynamics computer simulations to elucidate atomically detailed binding mechanisms of these compounds and understand their inhibition mechanisms. Our results suggest strategies for developing more potent androgen receptor inhibitors and general strategies for IDP drug design.
Fast, high-throughput production of improved rabies viral vectors for specific, efficient and versatile transsynaptic retrograde labeling
Authors: Sumser Anton , Joesch Maximilian , Jonas Peter , Ben-Simon Yoav 
Published: December 2021

AbstractTo understand the function of neuronal circuits it is crucial to disentangle the connectivity patterns within the network. However, most tools currently used to explore connectivity have low-throughput, low-selectivity, or limited accessibility. Here, we report the development of an improved packaging system for the production of the highly neurotrophic RVdGenvA-CVS-N2c rabies viral vectors, yielding titers orders of magnitude higher with no background contamination, at a fraction of the production time, while preserving the efficiency of transsynaptic labeling. Along with the production pipeline, we developed suites of “starter” AAV and bicistronic RVdG-CVS-N2c vectors, enabling retrograde labeling from a wide range of neuronal populations, tailored for diverse experimental requirements. We demonstrate the power and flexibility of the new system by uncovering hidden local and distal inhibitory connections in the hippocampal formation and by imaging the functional properties of a cortical microcircuit across weeks. Our novel production pipeline provides a convenient approach to generate new rabies vectors, while our toolkit flexibly and efficiently expands the current capacity to label, manipulate and image the neuronal activity of interconnected neuronal circuits in vitro and in vivo.
Upstream charged and hydrophobic residues impact the timing of membrane insertion of transmembrane helices
Authors: Nicolaus Felix , Ibrahimi Fatima , den Besten Anne , von Heijne Gunnar 
Published: December 2021

AbstractDuring SecYEG-mediated cotranslational insertion of membrane proteins, transmembrane helices (TMHs) first make contact with the membrane when their N-terminal end is ~45 residues away from the peptidyl transferase center. However, we recently uncovered instances where the first contact is delayed by up to ~10 residues. Here, we recapitulate these effects using a model TMH fused to two short segments from the BtuC protein: a positively charged loop and a re-entrant loop. We show that the critical residues are two Arg residues in the positively charged loop and four hydrophobic residues in the re-entrant loop. Thus, both electrostatic and hydrophobic interactions involving sequence elements that are not part of a TMH can impact the way the latter behaves during membrane insertion.
Cerebellar acceleration of learning in an evidence-accumulation task
Authors: Oostland Marlies , Kislin Mikhail , Chen Yuhang , Chen Tiffany , Venditto Sarah Jo , Deverett Ben , Wang Samuel S.-H. 
Published: December 2021

AbstractPerturbation to the cerebellum can lead to motor dysfunction, cognitive deficits, and behavioral inflexibility. Here we report that a cerebellum-specific transgenic mouse model with disrupted Purkinje cell function shows unexpectedly accelerated learning on a sensory evidence-accumulation task, as well as enhanced sensory reactivity to touch and auditory cues. Computational latent-state analysis of behavior revealed that accelerated learning was associated with enhanced focus on current over past trials. Learning was also accelerated by providing cue-locked optogenetic stimulation of Purkinje cells, but unaffected by continuous optogenetic interference with Purkinje cell activity. Both transgenic and optogenetically-boosted mice showed prolonged electrophysiological activity in Purkinje-cell complex spikes and anterior cingulate cortex. We suggest that cerebellar activity may shape evidence-accumulation learning by enhancing task focus and neocortical processing of current experience.
Multiplex, translaminar imaging in the spinal cord of behaving mice
Authors: Shekhtmeyster Pavel , Carey Erin M. , Duarte Daniela , Ngo Alexander , Gao Grace , Nelson Nicholas A. , Clark Charles L. , Nimmerjahn Axel 
Published: December 2021

AbstractWhile the spinal cord is known to play critical roles in sensorimotor processing, including pain-related signaling, corresponding activity patterns in genetically defined cell types across spinal laminae have remained elusive. Calcium imaging has enabled cellular activity measurements in behaving rodents but is currently limited to superficial regions. Using chronically implanted microprisms, we imaged sensory and motor evoked activity in regions and at speeds inaccessible by other high-resolution imaging techniques. To enable translaminar imaging in freely behaving animals through implanted microprisms, we additionally developed wearable microscopes with custom-compound microlenses. This new integrated system addresses multiple challenges of previous wearable microscopes, including their limited working distance, resolution, contrast, and achromatic range. The combination of these innovations allowed us to uncover that dorsal horn astrocytes in behaving mice show somatosensory program-dependent and lamina-specific calcium excitation. Additionally, we show that tachykinin precursor 1 (Tac1)-expressing neurons exhibit upper laminae-restricted activity to acute mechanical pain but not locomotion.