bluuebunny/crossref_metadata_2025_split huggingface dataset:
The logic of recurrent circuits in the primary visual cortex
Authors: Oldenburg Ian Antón , Hendricks William D. , Handy Gregory , Shamardani Kiarash , Bounds Hayley A. , Doiron Brent , Adesnik Hillel 
Published: September 2022

AbstractRecurrent cortical activity sculpts visual perception by refining, amplifying, or suppressing incoming visual signals. Despite the importance of recurrent circuits for cortical processing, the basic rules that govern how nearby cortical neurons influence each other remains enigmatic. We used two-photon holographic optogenetics to activate ensembles of neurons in Layer 2/3 of the primary visual cortex (V1) in the absence of external stimuli to isolate the impact of local recurrence from external inputs. We find that the spatial arrangement and the stimulus feature preference of both the stimulated and the target ensemble jointly determine the net effect of recurrent activity, defining the cortical activity patterns that drive competition versus facilitation in L2/3 circuits. Computational modeling suggests that a combination of highly local recurrent excitatory connectivity and selective convergence onto inhibitory neurons give rise to these principles of recurrent activity. Our data and modeling reveal that recurrent activity can have varied impact, but a logic emerges through an understanding of the precise spatial distribution and feature preference of the multicellular pattern of activity.
Whole-genome sequencing and single acute toxicity of heavy metal to Photobacterium kishitanii FJ21
Authors: Yin Shuzheng , Yi Zilong , Liu Jia , Liu Gang , Fang Jun 
Published: September 2022

AbstractIn this study, the growth morphology of FJ21 strain was observed, and its 16S rRNA and whole genome were sequenced. Then, related software was used to make genome assembly, gene structure and function annotation, genome phylogenetic tree analysis, genome collinearity analysis and prediction of secondary metabolic gene cluster analysis. Finally, the single acute toxicity of five heavy metals to FJ21 strain was detected. There were luxC, luxD, luxA, luxB, luxF, luxE and luxG genes in FJ21, and the protein encoded by lux operon had certain hydrophilicity. The genome of this strain FJ21 contains a chromosome with a total length of 4853277bp and a GC content of 39.23%. The genome of FJ21 was compared with that of Photobacterium kishitanii ATCCBAA-1194, Photobacterium phosphoreum JCM21184, Photobacterium aquimaris LC2-065, Photobacterium malacitanum CECT9190, and Photobacterium carnosum TMW 2.2021. The average nucleotide identity(ANI), tetra nucleotide signatures (Tetra), comparative genome, and phylogenetic analysis proposed that FJ21 is a strain of Photobacterium kishitanii. In the acute toxicity test, the toxicity of heavy metals to the strain FJ21 is Pb(NO3)2 > ZnSO4·7H2O > CdCl2·2.5H2O > CuSO4·5H2O > K2Cr2O7.
Joint Likelihood-Free Inference of the Number of Selected SNPS and the Selection Coefficient in an Evolving Population
Authors: Xu Yuehao , Futschik Andreas , Dutta Ritabrata 
Published: September 2022

AbstractWith the exact likelihood often intractable, likelihood-free inference plays an important role in the field of population genetics. Indeed, several methodological developments in the context of Approximate Bayesian Computation (ABC) were inspired by population genetic applications. Here we explore a novel combination of recently proposed ABC tools that can deal with high dimensional summary statistics and apply it to infer selection strength and the number of selected loci for data from experimental evolution. While there are several methods to infer selection strength that operate on a single SNP level, our window based approach provides additional information about the selective architecture in terms of the number of selected positions. This is not trivial, since the spatial correlation introduced by genomic linkage leads to signals of selection also at neighboring SNPs. A further advantage of our approach is that we can easily provide an uncertainty quantification using the ABC posterior. Both on simulated and real data, we demonstrate a promising performance. This suggests that our ABC variant could also be interesting in other applications.
Does a history of co-occurrence predict plant performance, community productivity, or invasion resistance?
Authors: Agneray Alison C. , Forister Matthew L. , Parchman Thomas L. , Leger Elizabeth A. 
Published: September 2022

AbstractA history of species co-occurrence in plant communities is hypothesized to lead to greater niche differentiation, more efficient resource partitioning, and more productive, resistant communities as a result of evolution in response to biotic interactions. We asked if individual species or community responses differed when communities were founded with species sharing a history of co-occurrence (sympatric) or with species originating from different locations (allopatric). Using shrub, grass, and forb species from six locations in the western Great Basin, USA, we compared establishment, productivity, reproduction, phenology, and resistance to invaders for experimental communities with either sympatric or allopatric associations. Each community type was planted with six taxa in outdoor mesocosms, measured over three growing seasons, and invaded with the annual grassBromus tectorumin the final season. For most populations, the allopatric or sympatric status of neighbors was not important. However, in some cases it was beneficial for some species from some locations to be planted with allopatric neighbors, while others benefited from sympatric neighbors, and some of these responses had large effects. For instance, theElymuspopulation that benefited the most from allopatry grew 50% larger with allopatric neighbors than in single origin mesocosms. This response affected invasion resistance, asB. tectorumbiomass was strongly affected by productivity and phenology ofElymusspp., as well asPoa secunda. Our results demonstrate that while community composition can in some cases affect plant performance in semi-arid plant communities, assembling sympatric communities is not sufficient to ensure high ecosystem services. Instead, we observed a potential interaction between sampling effects and evolutionary history that can create invasion resistant allopatric communities.
Single cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia
Authors: Robinson Troy M. , Bowman Robert L. , Persaud Sonali , Liu Ying , Gao Qi , Zhang Jingping , Sun Xiaotian , Miles Linde A. , Cai Sheng F. , Sciambi Adam , Llanso Aaron , Famulare Christopher , Goldberg Aaron , Dogan Ahmet , Roshal Mikhail , Levine Ross L. , Xiao Wenbin 
Published: September 2022

AbstractMeasurable residual disease (MRD), defined as the population of cancer cells which persists following therapy, serves as the critical reservoir for disease relapse in acute myeloid leukemia (AML) and other malignancies. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of more effective curative treatments. Discriminating between residual leukemic clones, preleukemic clones and normal precursors remains a challenge with current MRD tools. Herein, we developed a single cell (sc) MRD assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated scDNA sequencing and immunophenotyping. Our scMRD assay shows high sensitivity of approximately 0.01%, deconvolutes clonal architecture and provides clone-specific immunophenotypic data. In summary, our scMRD assay enhances MRD detection and simultaneously illuminates the clonal architecture of clonal hematopoiesis/pre-leukemic and leukemic cells surviving AML therapy.Statement of significanceScMRD assay integrates mutation and immunophenotype at single cell resolution and therefore distinguishes clonal hematopoiesis/preleukemic vs. leukemic clones. This study serves as a framework for identifying high-risk MRD clones and improving our understanding of both the molecular drivers and vulnerabilities of therapy resistant AML clones.
Do molecular fingerprints identify diverse active drugs in large-scale virtual screening? (no)
Authors: Venkatraman Vishwesh , Gaiser Jeremiah , Demekas Daphne , Roy Amitava , Xiong Rui , Wheeler Travis J. 
Published: September 2022

AbstractComputational approaches for small-molecule drug discovery now regularly scale to consideration of libraries containing billions of candidate small molecules. One promising approach to increased speed in evaluating billion-molecule libraries is to develop succinct representations of each molecule that enable rapid identification of molecules with similar properties. Molecular fingerprints are thought to provide a mechanism for producing such representations. Here, we explore the utility of commonly-used fingerprints in the context of predicting similar molecular activity. We show that fingerprint similarity provides little discriminative power between active and inactive molecules for a target protein based on a known active – while they may sometimes provide some enrichment for active molecules in a drug screen, a screened dataset will still be dominated by inactive molecules. We also demonstrate that high-similarity actives appear to share a scaffold with the query active, meaning that they could more easily be identified by structural enumeration. Furthermore, even when limited to only active molecules, fingerprint similarity values do not correlate with compound potency. In sum, these results highlight the need for a new wave of molecular representations that will improve the capacity to detect biologically active molecules based on similarity to other such molecules.
The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change
Authors: Rehm Heidi L , Alaimo Joseph T , Aradhya Swaroop , Bayrak-Toydemir Pinar , Best Hunter , Brandon Rhonda , Buchan Jillian G , Chao Elizabeth C. , Chen Elaine , Clifford Jacob , Cohen Ana S A , Conlin Laura K , Das Soma , Davis Kyle W , Gaudio Daniela del , Viso Florencia Del , DiVincenzo Christina , Eisenberg Marcia , Guidugli Lucia , Hammer Monia B , Harrison Steven M , Hatchell Kathryn E , Dyer Lindsay Havens , Hoang Lily U , Holt James M. , Jobanputra Vaidehi , Karbassi Izabela D , Kearney Hutton M , Kelly Melissa A. , Kelly Jacob M. , Kluge Michelle L , Komala Timothy , Kruszka Paul , Lau Lynette , Lebo Matthew S. , Marshall Christian R , McKnight Dianalee , McWalter Kirsty , Meng Yan , Nagan Narasimhan , Neckelmann Christian S , Neerman Nir , Niu Zhiyv , Paolillo Vitoria K , Paolucci Sarah A , Perry Denise , Pesaran Tina , Radtke Kelly , Rasmussen Kristen J , Retterer Kyle , Saunders Carol J , Spiteri Elizabeth , Stanley Christine , Szuto Anna , Taft Ryan J , Thiffault Isabelle , Thomas Brittany C , Thomas-Wilson Amanda , Thorpe Erin , Tidwell Timothy J , Towne Meghan C , Zouk Hana 
Published: September 2022

AbstractPURPOSEVariants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.METHODSRates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 - 2021.RESULTSWe found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared to MGPs (32.6%; p<0.0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; p<0.001) whereas the use of GS compared to ES had no impact (22.2% vs 22.6%; p=ns).CONCLUSIONThe high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources towards important VUS follow-up.
Allelic Transcription Factor binding shape transcriptional kinetics observed with scRNA-seq in human cell lines
Authors: Jin Bowen , Feng Hao , Bush William S. 
Published: September 2022

AbstractGene expression from bulk RNA-seq studies is an average measurement between two chromosomes and across cell populations. Both allelic and cell-to-cell heterogeneity in gene expression results from promoter bursting patterns that repeatedly alternate between an activated and inactivated state. Increased cell-to-cell heterogeneity in gene expression has been associated with aging and stem cell pluripotency. However, studies of bursting kinetics and their molecular mechanism are relatively limited in human cells compared to other species due to laborious single-molecule experiments. Here, we systematically investigate the regulatory effect of genetic variants and transcription factor (TF) binding on transcriptional kinetics at the single chromosome level with GM12878. We found that the transcription initiation rate and burst frequency correlate most with eQTL effect sizes among transcriptional kinetics, which suggests that eQTLs affect average gene expression mainly through altering burst kinetics. We further found that ∼90% of the variance of burst frequency can be explained by TF occupancy in phase with the core promoter. We identified and replicated several examples where eQTL or GWAS catalog loci perturb TF binding affinity and are consequently associated with the change of burst kinetics.
Conserved allosteric inhibition mechanism in SLC1 transporters
Authors: Dong Yang , Wang Jiali , Garibsingh Rachel-Ann , Hutchinson Keino , Shi Yueyue , Eisenberg Gilad , Yu Xiaozhen , Schlessinger Avner , Grewer Christof 
Published: September 2022

AbstractExcitatory Amino Acid Transporter 1 (EAAT1) is a plasma-membrane glutamate transporter belonging to the SLC1 family of solute carriers. It plays a key role in neurotransmitter transport and contributes to the regulation of the extracellular glutamate concentration in the mammalian brain. The structure of EAAT1 was determined using cryo-EM, in complex with UCPH-101, a highly potent and non-competitive inhibitor of EAAT1. Alanine Serine Cysteine Transporter 2 (ASCT2) is a neutral amino acid transporter, which regulates pools of amino acids such as glutamine, serine and alanine between intracellular and extracellular compartments in a Na+dependent manner. ASCT2 also belongs to the SLC1 family and shares 58% sequence similarity with EAAT1. However, allosteric modulation of ASCT2 via non-competitive inhibitors is unknown. Here we explore the UCPH-101 inhibitory mechanisms of EAAT1 and ASCT2 by using rapid kinetic experiments. Our results show that UCPH-101 slows substrate translocation rather than substrate or Na+binding, confirming a non-competitive inhibitory mechanism, but only partially inhibits wild-type ASCT2 with relatively low affinity. Guided by computational modeling using ligand docking and molecular dynamics (MD) simulations, we selected two residues involved in UCPH-101/EAAT1 interaction, which were mutated in ASCT2 (F136Y, I237M, F136Y/I237M) in the corresponding positions. We show that in the F136Y/I237M double mutant transporter, 100% of the inhibitory effect of UCPH-101 on anion current could be restored, and the apparent affinity was increased (Ki= 9.3 μM), much closer to the EAAT1 value of 0.6 μM. Finally, we identify a novel non-competitive ASCT2 inhibitor, identified through virtual screening and experimental testing against the allosteric site, further supporting its localization. Together, these data indicate that the mechanism of allosteric modulation is conserved between EAAT1 and ASCT2. Due to the difference in binding site residues between ASCT2 and EAAT1, these results raise the possibility that more potent, and potentially selective inhibitors can be designed that target the ASCT2 allosteric binding site.
FDA-approved drug screening identified micafungin as an antiviral agent against bat-borne emerging zoonotic Pteropine orthoreovirus
Authors: Katta Tetsufumi , Sato Ayato , Kadofusa Naoya , Ishibashi Tomoki , Shimoda Hiroshi , Iida Atsuo , Hondo Eiichi 
Published: September 2022

AbstractBat-borne emerging zoonotic viruses cause major outbreaks, such as the Ebola virus, Nipah virus, severe acute respiratory syndrome (SARS) coronavirus, and SARS-CoV-2. Pteropine orthoreovirus (PRV), which spillover event occurred from fruit bats to humans, causes respiratory syndrome in humans widely in South East Asia. Repurposing approved drugs against PRV is a critical tool to confront future PRV pandemics. We screened 2,943 compounds in an FDA-approved drug library and identified eight hit compounds that reduce viral cytopathic effects on cultured Vero cells. Real-time quantitative PCR analysis revealed that six of eight hit compounds significantly inhibited PRV replication. Among them, micafungin used clinically as an antifungal drug, displayed a prominent antiviral effect on PRV.HighlightsA library of 2,943 FDA-approved drugs was screened to find potential antiviral drugs of Pteropine orthoreovirus.Six hit compounds dramatically inhibited viral replication in vitro.Micafungin possessed antiviral activity to multiple strains of PRV.
Noncanonical inflammasome assembly requires caspase-11 catalytic activity and intra-molecular autoprocessing
Authors: Akuma Daniel C. , Grubaugh Daniel , Odunze Chukwuma E. , Shin Sunny , Taabazuing Cornelius Y. , Brodsky Igor E. 
Published: September 2022

ABSTRACTInflammatory caspases are cysteine protease zymogens whose activation following infection or cellular damage occurs within supramolecular organizing centers (SMOCs) known as inflammsasomes. Inflammasomes are large oligomeric complexes that recruit caspases to undergo proximity-induced autoprocessing, leading to formation of the enzymatically active form that cleaves downstream targets. Binding of bacterial LPS to its cytosolic sensor, caspase-11 (Casp11), promotes Casp11 aggregation within a high molecular weight complex known as the noncanonical inflammasome, where it is activated to cleave gasdermin D and induce pyroptosis. However, the cellular correlates of Casp11 oligomerization and whether Casp11 forms an LPS-induced SMOC within cells remain unknown. Using fluorescently labeled Casp11, we found that LPS transfection of macrophages induced Casp11 speck formation, providing direct evidence that Casp11 forms LPS-induced specks in macrophages. Unexpectedly, we found that catalytic activity was required for Casp11 to form LPS-induced specks in macrophages. Importantly, both catalytic activity and autoprocessing were required for Casp11 speck formation in an ectopic expression system, and Casp11 processing via an exogenous protease was sufficient to induce Casp11 speck formation. These data reveal a previously-undescribed role for Casp11 catalytic activity and self-cleavage in non-canonical inflammasome assembly and indicate that Casp11 catalytic activity and autoprocessing occur upstream of, and mediate, Casp11 oligomerization. Our data provide new insight into the molecular requirements for assembly of Casp11 noncanonical inflammasome complexes.
PepGM: A probabilistic graphical model for taxonomic inference of viral proteome samples with associated confidence scores
Authors: Holstein Tanja , Kistner Franziska , Martens Lennart , Muth Thilo 
Published: September 2022

AbstractMotivationInferring taxonomy in mass spectrometry-based shotgun proteomics is a complex task. In multi-species or viral samples of unknown taxonomic origin, the presence of proteins and corresponding taxa must be inferred from a list of identified peptides which is often complicated by protein homology: many proteins do not only share peptides within a taxon but also between taxa. However, correct taxonomic identification is crucial when identifying different viral strains with high sequence homology – considering, e.g., the different epidemiological characteristics of the various strains of SARS-CoV-2. Additionally, many viruses mutate frequently, further complicating the correct assignment of virus proteomic samples.ResultsWe present PepGM, a probabilistic graphical for the taxonomic assignment of virus proteomic samples with strain-level resolution and associated confidence scores. PepGM combines the results of a standard proteomic database search algorithm with belief propagation to calculate the marginal distributions, and thus confidence score, for potential taxonomic assignments. We demonstrate the performance of PepGM using several publicly available virus proteomic datasets, showing its strain-level resolution performance. In two out of eight cases, the taxonomic assignments were only correct on species level, which PepGM clearly indicates by lower confidence scores.Availability and ImplementationPepGM is written in Python and embedded into a Snakemake workflow. Its is available at https://github.com/BAMeScience/PepGM
Transpiration and water use efficiency of sorghum canopies have a large genetic variability and are positively related under naturally high evaporative demand
Authors: Pilloni Raphaël , Aparna Kakkera , Ghazzal Zineb El , Kar Soumyashree , Kumar A Ashok , Hajjarpoor Amir , Affortit Pablo , Ribière William , Kholova Jana , Tardieu François , Vadez Vincent 
Published: September 2022

AbstractIndoor experiments with individual plants often show that transpiration rate is restricted under high vapor pressure deficit (VPD), resulting in a plateau of transpiration that increases water use efficiency (WUE) of some genotypes. We tested this hypothesis outdoors during dry or rainy seasons of India and Senegal, based on the response of the transpiration of canopy-grown sorghum plants to the reference evapotranspiration that takes both light and VPD into account. This response showed no plateau at high evaporative demand in 47 genotypes, but a large genetic variability was observed for the slope of the relationship over the whole range of evaporative demand. Unexpectedly, this slope was genetically correlated with WUE in two experiments with high evaporative demand: genotypes that most transpired had the highest WUE. Conversely, a negative correlation was observed under low evaporative demand. Genotypes with high WUE and response to evaporative demand were also those allowing maximum light penetration into the canopy. We suggest that this caused the observed high WUE of these genotypes because leaves within the canopy had sufficient light for photosynthesis whereas we observed a lower VPD in the canopy than in open air when leaf area index reached 2.5-3, thereby decreasing transpiration.HighlightsThe transpiration response to evaporative demand was genetically variable and correlated to WUE: genotypes that most transpired had highest light penetration towards leaves subjected to lower VPD than in air.
Mortality without springing a leak: Locust gut epithelia do not become more permeable to fluorescent dextran and bacteria in the cold
Authors: El-Saadi Mahmoud I. , Brzezinski Kaylen , Hinz Aaron , Phillips Laura , Wong Alex , Gerber Lucie , Overgaard Johannes , MacMillan Heath A. 
Published: September 2022

AbstractThe insect gut, which plays a role in ion and water balance, has been shown to leak solutes in the cold. Cold stress can also activate insect immune systems, but it is unknown if the leak of the gut microbiome is a possible immune trigger in the cold. We developed a novel feeding protocol to load the gut of locusts (Locusta migratoria) with fluorescent bacteria before exposing them to -2°C for up to 48 h. No bacteria were recovered from the hemolymph of cold-exposed locusts, regardless of exposure duration. To examine this further, we used an ex vivo gut sac preparation to re-test cold-induced fluorescent FITC-dextran leak across the gut and found no increased rate of leak. These results question not only the validity of FITC-dextran as a marker of paracellular barrier permeability in the gut, but also to what extent the insect gut becomes leaky in the cold.