bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning perturbation-inducible cell states of novel compounds from observability analysis of transcriptome dynamics
Authors: Hasnain Aqib , Balakrishnan Shara , Joshy Dennis M. , Smith Jen , Haase Steven B. , Yeung Enoch 
Published: May 2022

AbstractA major challenge in biotechnology and biomanufacturing is the identification of a set of biomarkers for perturbations and metabolites of interest. Here, we develop a data-driven, transcriptome-wide approach to rank perturbation-inducible genes from time-series RNA sequencing data for the discovery of analyte-responsive promoters. This provides a set of biomarkers that act as a proxy for the transcriptional state referred to as cell state. We construct low-dimensional models of gene expression dynamics and rank genes by their ability to capture the perturbation-specific cell state using a novel observability analysis. Using this ranking, we extract 15 analyte-responsive promoters for the organophosphate malathion in the underutilized host organismPseudomonas fluorescensSBW25. We develop synthetic genetic reporters from each analyte-responsive promoter and characterize their response to malathion. Furthermore, we enhance malathion reporting through the aggregation of the response of individual reporters with a synthetic consortium approach, and we exemplify the library’s ability to be useful outside the lab by detecting malathion in the environment. The library of living malathion sensors can be optimized for use in environmental diagnostics while the developed machine learning tool can be applied to discover perturbation-inducible gene expression systems in the compendium of host organisms.
Surrounding Traffic Matters: Increases in Traffic Volume Are Related to Changes in EEG Rhythms in Urban Cyclists
Authors: Robles Daniel , Kuziek Jonathan W. P. , Lai Jingyi , Mazumder Robin , Scanlon Joanna E. M. , Mathewson Kyle E. 
Published: May 2022

AbstractIn this study, we used an oddball EEG bicycle paradigm to study how changes in urban environments elicit changes in EEG markers. Participants completed an auditory oddball task while riding in three different cycling lane environments. A low traffic condition where participants rode in a fully separated bike lane alongside a quiet residential street, an intermediate traffic condition where participants rode alongside a busy residential street in a painted lane, and a heavy traffic condition where participants rode alongside fast/heavy traffic on a shared-use path. Relative to the low traffic, heavy traffic was associated with faster reaction time and a trend towards reduced accuracy, and increased N1 amplitude evoked by the standard tones. We attribute this difference in N1 amplitude to different attentional demands evoked by the different traffic conditions. In this fashion, heavy traffic requires greater auditory filtering. Furthermore, we found no differences in P3 amplitude associated with the traffic conditions. We discuss the implications of mobile paradigms to study attention in real-world settings.
Dynamic visualization of high-dimensional data
Authors: Sun Eric D. , Ma Rong , Zou James 
Published: May 2022

AbstractDimensionality reduction (DR) is commonly used to project highdimensional data into lower dimensions for visualization, which could then generate new insights and hypotheses. However, DR algorithms necessarily introduce distortions in the visualization and cannot faithfully represent all relations in the data. As such, there is a need for methods to assess the reliability of DR visualizations. Here we present DynamicViz, a framework for generating dynamic visualizations that capture the sensitivity of DR visualizations to perturbations in the data. DynamicVic can be applied to all commonly used DR methods. We show the utility of dynamic visualizations in diagnosing common interpretative pitfalls of static visualizations and extending existing single-cell analyses. We introduce the variance score to quantify the dynamic variability of observations in these visualizations. The variance score characterizes natural variability in the data and can be used to optimize DR algorithm implementations. We have made DynamicViz freely available to assist with the evaluation of DR visualizations.
Syntaxin1 Ser14 Phosphorylation is Required for Non-Vesicular Dopamine Release
Authors: Shekar A , Mabry SJ , Cheng MH , Aguilar JI , Patel S , Zanella D , Saleeby DP , Zhu Y , Romanazzi T , Ulery-Reynolds P , Bahar I , Carter AM , Matthies HJ , Galli A 
Published: May 2022

AbstractAmphetamine (AMPH), a psychostimulant commonly prescribed for the treatment of neuropsychiatric and neurological disorders, has a high liability for abuse. The abuse and psychomotor stimulant properties of AMPH are primarily associated with its ability to increase dopamine (DA) neurotransmission. This increase is mediated, in large part, by non-vesicular DA release (DA efflux). DA efflux is the result of reversal of the DA transporter (DAT) promoted by AMPH. Syntaxin 1 (Stx1) is a SNARE protein that plays a pivotal role in vesicular release. Previously, we have shown that Stx1 also interacts with the distal DAT N-terminus, an event promoted by AMPH. Stx1 is phosphorylated at Ser14 by casein kinase II (CK2). Using Drosophila Melanogaster as an animal model, we show that this phosphorylation event is critical for non-vesicular DA release and regulates the expression of AMPH preference as well as the ability of AMPH to promote mating drive. We also show that reverse transport of DA mediated by DAT underlies these complex behaviors promoted by AMPH. Our molecular dynamics (MD) simulations of the phosphorylated DAT/Stx1 complex demonstrate that the phosphorylation state of these proteins plays a key role in allowing DAT to dwell in an efflux-willing state. This state also supports constitutive DA efflux (CDE), an event that occurs in the absence of AMPH. The DAT-Stx1 phosphorylated complex is characterized by the breakdown of two key salt bridges in DAT, K66-D345 and E428-R445, which are critical for the formation of the intracellular (IC) gate and for transport function. The breaking of these salt bridges leads to an opening and hydration of the DAT intracellular vestibule, allowing DA to bind from the cytosol, a mechanism that we hypothesize leads to CDE. We further determine the importance of Stx1 phosphorylation in CDE by pharmacologically inhibiting CK2 with CX-4945, a molecule currently in phase II clinical trials for cancer treatment. CX-4945 treatment prevented the expression of CDE in isolated Drosophila Melanogaster brains as well as behaviors associated with CDE. Thus, our results suggest that Stx1 phosphorylation is a possible pharmacological target for the treatment of AMPH abuse.
Modeling the effects of genetic and diet induced obesity on melanoma progression in zebrafish
Authors: Montal Emily , Lumaquin Dianne , Ma Yilun , Suresh Shruthy , White Richard M. 
Published: May 2022

AbstractObesity is a rising concern and associated with an increase in numerous cancers often in a sex-specific manner. Preclinical models are needed to deconvolute the intersection between obesity, sex, and cancer. We have generated a zebrafish system that can be used as a platform for studying these factors. We studied how germline overexpression of AgRP along with a high-fat diet (HFD) affects melanomas dependent on BRAFV600E. This revealed an increase in tumor incidence and area in male obese fish, but not females, consistent with the clinical literature. This is dependent on the somatic mutations, as male tumors generated with an RB1 mutation are sensitive to obesity, but this is not observed with PTEN. These data indicate that both germline and somatic mutations contribute to obesity related effects in melanoma. Given the rapid genetic tools available in the zebrafish, this provides a high-throughput system to dissect the interactions of genetics, diet, sex, and host factors in obesity-related cancers.Summary StatementDue to the rising incidence of obesity, there is a corresponding increased occurrence of obesity related cancers, which is often described to be dependent on sex. Here we developed a model to investigate the intersection between obesity, sex, and cancer.
Transmembrane protein 184B (TMEM184B) promotes expression of synaptic gene networks in the mouse hippocampus
Authors: Wright Elizabeth B. , Larsen Erik G. , Coloma-Roessle Cecilia M. , Hart Hannah R. , Bhattacharya Martha R.C. 
Published: May 2022

AbstractIn Alzheimer’s Disease (AD) and other dementias, hippocampal synaptic dysfunction and loss contribute to the progression of memory impairment. Recent analysis of human AD transcriptomes has provided a list of gene candidates that may serve as drivers of disease. One such candidate is the membrane protein TMEM184B. To evaluate whether TMEM184B contributes to neurological impairment, we asked whether loss of TMEM184B in mice causes gene expression or behavior alterations, focusing on the hippocampus. Because one major risk factor for AD is age, we compared young adult (5-month-old) and aged (15-month-old) wild type andTmem184b-mutant mice to assess the dual contributions of age and genotype. TMEM184B loss altered expression of pre- and post-synaptic transcripts by 5 months and continued through 15 months, specifically affecting genes involved in synapse assembly and neural development. Wnt-activated enhancer elements were enriched among differentially expressed genes, suggesting an intersection with this pathway. Few differences existed between young adult and aged mutants, suggesting that transcriptional effects of TMEM184B loss are relatively constant. To understand how TMEM184B disruption may impact behaviors, we evaluated memory using the novel object recognition test and anxiety using the elevated plus maze. Young adultTmem184b-mutant mice show normal object discrimination, suggesting a lack of memory impairment at this age. However, mutant mice showed decreased anxiety, a phenotype seen in some neurodevelopmental disorders. Taken together, our data suggest that TMEM184B is required for proper synaptic gene expression and anxiety-related behavior and is more likely to be linked to neurodevelopmental disorders than to dementia.
Improving Protein-Ligand Interaction Modeling with cryo-EM Data, Templates, and Deep Learning in 2021 Ligand Model Challenge
Authors: Giri Nabin , Cheng Jianlin 
Published: May 2022

AbstractElucidating protein-ligand interaction is crucial for studying the function of proteins and compounds in an organism and critical for drug discovery and design. The problem of protein-ligand interaction is traditionally tackled by molecular docking and simulation, which is based on physical forces and statistical potentials and cannot effectively leverage cryo-EM data and existing protein structural information in the protein-ligand modeling process. In this work, we developed a deep learning bioinformatics pipeline (DeepProLigand) to predict protein-ligand interactions from cryo-EM density maps of proteins and ligands.DeepProLigandfirst uses a deep learning method to predict the structure of proteins from cryo-EM maps, which is averaged with a reference (template) structure of the proteins to produce a combined structure to add ligands. The ligands are then identified and added into the structure to generate a protein-ligand complex structure, which is further refined. The method based on the deep learning prediction and template-based modeling was blindly tested in the 2021 EMDataResource Ligand Challenge and was ranked first in fitting ligands to cryo-EM density maps.This results demonstrate that the deep learning bioinformatics approach is a promising direction to model protein-ligand interaction on cryo-EM data using prior structural information. The source code, data, and instruction to reproduce the results are available on GitHub repository :https://github.com/jianlin-cheng/DeepProLigand
Large-scale whole-genome sequencing of migratory Bogong moths Agrotis infusa reveals genetic variants associated with migratory direction in a panmictic population
Authors: Wallace Jesse RA , Maleszka Ryszard , Warrant Eric J 
Published: May 2022

AbstractOne of the most interesting macroscopic phenomena in the animal world is seasonal migration. A central goal of research into animal migration is to better understand the mechanisms that evolved to solve the complex challenges which a migratory life history presents. Each year, and with a high degree of species-level site fidelity, the Australian Bogong moth makes a return migration of up to and over 1000 km between widely distributed breeding grounds and a specific set of aestivation sites in the Australian Alps. It does this without any opportunity to learn the migratory route or the location of the aestivation sites from either older generations or repeated migrations, meaning that the information required by the moth to navigate during its migration must be inherited. The migratory direction, and therefore the inherited navigational information in Bogong moths, varies with breeding site, providing us with an opportunity to search for the source of that heritability by comparing the genomes of moths collected from different breeding areas. We successfully sequenced whole nuclear genomes of 77 Bogong moths collected from across their breeding grounds and summer range, and found that the Bogong moth population contains a large amount of (mostly rare) variation. We found no evidence of population structure, indicating that Bogong moths are panmictic. A genome-wide scan for signals of selection indicate that the Bogong population has recently recovered from a past bottleneck, however genomic regions which have likely undergone balancing selection were also detected. Despite panmixia, four genetic variants in breeding-ground-caught Bogong moths were found to be significantly associated with geographic location, and therefore migratory direction, indicating promising future avenues of research into the molecular basis of long-distance navigation.
Genetic architectures of postmating isolation and morphology of two highly diverged rockfishes (genusSebastes)
Authors: Muto Nozomu , Kawasaki Takuma , Kakioka Ryo , Nagano Atsushi J. , Shimizu Yuta , Inose Shu , Shimizu Yohei , Takahashi Hiroshi 
Published: May 2022

AbstractPostmating isolation is thought to be an important driver of the late stages of speciation. However, relatively little is empirically known about the process compared to other isolating mechanisms that drive the early stages of speciation, especially in non-model organisms. We characterized the genetic architecture of postmating isolation between two rockfishes,Sebastes schlegeliiandS. trivittatus, whose reproductive isolation is complete. We examined transmission ratio distortion (TRD) patterns of genetic markers in two reciprocal backcross populations. Markers showing either of the two types of TRD was widespread across the genome, with some of the distorted markers forming extensive clusters around the recombination coldspots. These suggest that the postmating isolation effectively prevents gene flow across the genome and the recombination landscape contributes to the genetic architecture. Comparisons between two backcross families and two developmental stages showed little similarity in the distorted markers, suggesting asymmetry and stage-specificity of the isolation. This may be due to hybrid incompatibility involving maternal factors or extrinsic selection. The lack of sex-ratio distortion in the mapping families suggested that Haldane’s rule in terms of hybrid inviability does not hold. Additionally, QTL mapping detected significant QTLs for sex and the morphological traits relevant to speciation and convergence of rockfishes, including body coloration. Genes in the melanocortin system, includingagouti-signaling protein 1(asip1) andmelanocortin 1 receptor(mc1r), might underlie the horizontal and vertical color patterns on the body, respectively. These findings constitute an essential step towards a comprehensive understanding of speciation and morphological diversification of rockfishes.
The outer surface protease, SepM, is required for blp locus activation in three of the four most common pherotypes of Streptococcus pneumoniae
Authors: Ratner Samantha , Bollinger Kevin , Richardson John , Dawid Suzanne 
Published: May 2022

AbstractStreptococcus pneumoniae (pneumococcus) is an important human pathogen that primarily resides in the nasopharynx. To persist in this polymicrobial environment, pneumococcus must compete with other members of the bacterial community. Competition is mediated in part by the action of the blp locus which encodes a variable array of bacteriocins and their associated immunity proteins. The locus is controlled by a two-component regulatory system that senses the extracellular concentration of the peptide pheromone, BlpC. There are four major pherotypes of BlpC that can be found in most pneumococcal genomes. Here, we show that the protease, SepM, is required for activation of three of the four major pherotypes. The only SepM independent BlpC type is 9AA shorter than the SepM-dependent peptides, consistent with a cleavage event at the C-terminal end. The processing event occurs following secretion and removal of the C terminal region is required for binding to the histidine kinase receptor. Synthetic truncated peptides or full-length peptides pre-incubated with SepM-expressing bacteria can upregulate the blp locus independent of SepM. We show that SepM-independent peptides accumulate in the supernatant of secreting cells at low levels suggesting a role for the tail in peptide secretion, stability or solubility and demonstrating a significant tradeoff for SepM-independence.ImportanceStreptococcus pneumoniae is an important cause of disease in humans that occurs when the bacteria in the nasopharynx bypasses host defenses to invade deeper tissues. Colonization fitness thus represents an important initial step in pathogenesis. S. pneumoniae produces antimicrobial peptides called bacteriocins which provide a competitive advantage over neighboring bacteria in the nasopharynx. The blp locus encodes a variable array of bacteriocins that participate in competition. Here, we demonstrate that activation of the blp locus requires a surface protease that activates the blp signal peptide. There are naturally occurring signal peptides that do not require cleavage, but these are characterized by poor secretion. We describe an additional, previously unappreciated activation step in the control of bacteriocin production in S. pneumoniae.
Multiple viral protein genome-linked proteins compensate viral translation in a +ssRNA virus infection
Authors: Warsaba Reid , Stoynov Nikolay , Moon Kyung-Mee , Flibotte Stephane , Foster Leonard , Jan Eric 
Published: May 2022

ABSTRACTViral protein genome-linked (VPg) protein plays an essential role in protein-primed replication of plus stranded RNA viruses. VPg is covalently linked to the 5’ end of the viral RNA genome via a phosphodiester bond typically at a conserved amino acid. Whereas most viruses have a single VPg, some viruses encode multiple VPgs that are proposed to have redundant yet undefined roles in viral replication. Here, we use the dicistrovirus, cricket paralysis virus (CrPV), which encodes four non-identical copies of VPg, as a model to characterize the role of VPg copies in infection. Dicistroviruses encode two main open reading frames (ORFs) that are driven by distinct IRESs. We systematically generated single and combinatorial deletions and mutations of VPg1-4 within the CrPV infectious clone and monitored viral yield in Drosophila S2 cells. Deletion of one to three VPg copies progressively decreased viral yield and delayed viral replication, suggesting a threshold number of VPgs for productive infection. Mass spectrometry analysis of CrPV VPg-linked RNAs revealed viral RNA linkage to either a serine or threonine in VPg, from which mutations in all VPgs attenuated infection. Mutating serine 4 in a single VPg abolished viral infection, indicating a dominant-negative effect. Using viral minigenome reporters that monitor dicistrovirus 5’ untranslated (UTR) and intergenic internal ribosome entry site (IRES) translation revealed a relationship between VPg copy number and the ratio of distinct IRES translation. We uncover a novel viral strategy whereby VPg copies in dicistrovirus genomes compensate for the relative IRES translation efficiencies to promote infection.ImportanceGenetic duplication is exceedingly rare in small RNA viral genomes as there is selective pressure to prevent RNA genomes from expanding. However, some small RNA viruses encode multiple copies of a viral protein, most notably an unusual viral protein that is linked to the viral RNA genome. Here, we investigate a family of viruses that contains multiple viral protein genome-linked proteins and reveal a novel viral strategy whereby viral protein copy number counterbalances differences in viral protein synthesis mechanisms.
A robust, highly multiplexed mass spectrometry assay to identify SARS-CoV-2 variants
Authors: Hernandez Matthew M. , Banu Radhika , Shrestha Paras , Gonzalez-Reiche Ana S. , van de Guchte Adriana , Farrugia Keith , Sebra Robert ,   Mount Sinai PSP Study Group, Gitman Melissa R. , Nowak Michael D. , Cordon-Cardo Carlos , Simon Viviana , van Bakel Harm , Sordillo Emilia Mia , Luna Nicolas , Ramirez Angie , Castañeda Sergio Andres , Patiño Luz Helena , Ballesteros Nathalia , Muñoz Marina , Ramírez Juan David , Paniz-Mondolfi Alberto E. 
Published: May 2022

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are characterized by differences in transmissibility and response to therapeutics. Therefore, discriminating among them is vital for surveillance, infection prevention, and patient care. While whole viral genome sequencing (WGS) is the “gold standard” for variant identification, molecular variant panels have become increasingly available. Most, however, are based on limited targets and have not undergone comprehensive evaluation. We assessed the diagnostic performance of the highly multiplexed Agena MassARRAY® SARS-CoV-2 Variant Panel v3 to identify variants in a diverse set of 391 SARS-CoV-2 clinical RNA specimens collected across our health systems in New York City, USA as well as in Bogotá, Colombia (September 2, 2020 – March 2, 2022). We demonstrate almost perfect levels of interrater agreement between this assay and WGS for 9 of 11 variant calls (κ ≥ 0.856) and 25 of 30 targets (κ ≥ 0.820) tested on the panel. The assay had a high diagnostic sensitivity (≥93.67%) for contemporary variants (e.g., Iota, Alpha, Delta, Omicron [BA.1 sublineage]) and a high diagnostic specificity for all 11 variants (≥96.15%) and all 30 targets (≥94.34%) tested. Moreover, we highlight distinct target patterns that can be utilized to identify variants not yet defined on the panel including the Omicron BA.2 and other sublineages. These findings exemplify the power of highly multiplexed diagnostic panels to accurately call variants and the potential for target result signatures to elucidate new ones.ImportanceThe continued circulation of SARS-CoV-2 amidst limited surveillance efforts and inconsistent vaccination of populations has resulted in emergence of variants that uniquely impact public health systems. Thus, in conjunction with functional and clinical studies, continuous detection and identification are quintessential to inform diagnostic and public health measures. Furthermore, until WGS becomes more accessible in the clinical microbiology laboratory, the ideal assay for identifying variants must be robust, provide high resolution, and be adaptable to the evolving nature of viruses like SARS-CoV-2. Here, we highlight the diagnostic capabilities of a highly multiplexed commercial assay to identify diverse SARS-CoV-2 lineages that circulated at over September 2, 2020 – March 2, 2022 among patients seeking care at our health systems. This assay demonstrates variant-specific signatures of nucleotide/amino acid polymorphisms and underscores its utility for detection of contemporary and emerging SARS-CoV-2 variants of concern.