bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Accelerated Resolution Therapy (ART) for Post-Traumatic Stress Disorder (PTSD) Between Veterans With and Without Prior PTSD Treatment
Authors: Pang Tiantian , Murn Lindsay , Williams Dana , Lawental Maayan , Abhayakumar Anya , Kip Kevin E. 
Published: April 2021

AbstractBackgroundPost-traumatic stress disorder (PTSD) is a psychiatric disorder commonly caused by a traumatic event(s) and prevalent among service members and veterans. Accelerated Resolution Therapy (ART) is an emerging “mind-body” psychotherapy for PTSD that is generally briefer and less expensive than current first-line treatments, such as cognitive processing therapy (CPT) and prolonged exposure (PE) therapy.ObjectiveThis study aimed to examine the results of ART for treatment of military-related PTSD, with stratification by prior history of PTSD treatment, including refractory PTSD following receipt of guideline-driven first-line psychotherapy.MethodsThe study compares the PTSD treatment results of ART between (military service members and/or) veterans with a prior history of PTSD treatment (medication only, n=40; first-line psychotherapy, n=33; other psychotherapy, n=42) and a treatment-naïve group (n=33). Participants were assessed at baseline, post-treatment, and 3- or 6-month follow-up using PCL-M scores (PTSD checklist).ResultsMean age was 43.8 years, 95% male, 84% white race. The treatment completion rate was 72% with a mean of 3.5 treatment sessions. Within-group standardized effect sizes for pre-to-post changes in PTSD scores (PCL-M) were large at 1.11, 1.88, 1.03, and 1.48 for the medication only, first-line psychotherapy, other psychotherapy, and treatment-naïve groups, respectively (p=0.02 for between-group comparison). Similar results were observed for measures of depression and anxiety, and baseline to follow-up results was generally similar.ConclusionsIn a brief treatment period, ART appears to result in substantial reductions in symptoms of PTSD among veterans, including those previously treated (unsuccessfully) with first-line psychotherapies endorsed by the U.S. Department of Defense (DoD) and Veterans Affairs (VA). These results suggest that ART be considered as a treatment modality for veterans with refractory PTSD.HighlightsAccelerated Resolution Therapy (ART) is a potentially acceptable psychological intervention for treatment-refractory PTSD.
Evaluating Vaccine Efficacy Against SARS-CoV-2 Infection
Authors: Lin Dan-Yu , Gu Yu , Zeng Donglin , Janes Holly E. , Gilbert Peter B. 
Published: April 2021

AbstractAlthough interim results from several large placebo-controlled phase 3 trials demonstrated high vaccine efficacy (VE) against symptomatic COVID-19, it is unknown how effective the vaccines are in preventing people from becoming asymptomatically infected and potentially spreading the virus unwittingly. It is more difficult to evaluate VE against SARS-CoV-2 infection than against symptomatic COVID-19 because infection is not observed directly but rather is known to occur between two antibody or RT-PCR tests. Additional challenges arise as community transmission changes over time and as participants are vaccinated on different dates because of staggered enrollment or crossover before the end of the study. Here, we provide valid and efficient statistical methods for estimating potentially waning VE against SARS-CoV-2 infection with blood or nasal samples under time-varying community transmission, staggered enrollment, and blinded or unblinded crossover. We demonstrate the usefulness of the proposed methods through numerical studies mimicking the BNT162b2 phase 3 trial and the Prevent COVID U study. In addition, we assess how crossover and the frequency of diagnostic tests affect the precision of VE estimates.SummaryWe show how to estimate potentially waning efficacy of COVID-19 vaccines against SARS-CoV-2 infection using blood or nasal samples collected periodically from clinical trials with staggered enrollment of participants and crossover of placebo recipients.
Genomic Skimming and Nanopore Sequencing Uncover Cryptic Hybridization in One of World’s Most Threatened Primates
Authors: Malukiewicz Joanna , Cartwright Reed A , Dergam Jorge A , Igayara Claudia S , Nicola Patricia A , Pereira Luiz MC , Ruiz-Miranda Carlos R , Stone Anne C , Silva Daniel L , de Fátima Rodrigues da Silva Fernanda , Varsani Arvind , Walter Lutz , Wilson Melissa A , Zinner Dietmar , Roos Christian 
Published: April 2021

ABSTRACTThe Brazilian buffy-tufted-ear marmoset (Callithrix aurita), one of the world’s most endangered primates, is threatened by anthropogenic hybridization with exotic, invasive marmoset species. As there are few genetic data available forC. aurita, we developed a PCR-free protocol with minimal technical requirements to rapidly generate genomic data with genomic skimming and portable nanopore sequencing. With this direct DNA sequencing approach, we successfully determined the complete mitogenome of a marmoset that we initially identified asC. aurita. The obtained nanopore-assembled sequence was highly concordant with a Sanger sequenced version of the same mitogenome. Phylogenetic analyses unexpectedly revealed that our specimen was a cryptic hybrid, with aC. auritaphenotype andC. penicillatamitogenome lineage. We also used publicly available mitogenome data to determine diversity estimates forC. auritaand three other marmoset species. Mitogenomics holds great potential to address deficiencies in genomic data for endangered, non-model species such asC. aurita. However, we discuss why mitogenomic approaches should be used in conjunction with other data for marmoset species identification. Finally, we discuss the utility and implications of our results and genomic skimming/nanopore approach for conservation and evolutionary studies ofC. auritaand other marmosets.
YhcB coordinates peptidoglycan and LPS biogenesis with phospholipid synthesis duringEscherichia colicell growth
Authors: Goodall Emily C. A. , Isom Georgia L. , Rooke Jessica L. , Icke Christopher , Pullela Karthik , Zhang Bing , Rae James , Tan Wee Boon , Winkle Matthias , Delhaye Antoine , Heinz Eva , Collet Jean-Francois , Cunningham Adam F. , Blaskovich Mark A. , Parton Robert G. , Cole Jeff A. , Chng Shu-Sin , Vollmer Waldemar , Bryant Jack A. , Henderson Ian R. 
Published: April 2021

AbstractThe cell envelope is essential for viability in all kingdoms of life. It retains enzymes and substrates within a confined space while providing a protective barrier to the external environment. Destabilising the envelope of bacterial pathogens is a common strategy employed by antimicrobial treatment. However, even in one of the most well studied organisms,Escherichia coli, there remain gaps in our understanding of how the synthesis of the successive layers of the cell envelope are coordinated during growth and cell division. Here, we used a whole genome phenotypic screen to identify mutants with a defective cell envelope. We report that loss ofyhcB, a conserved gene of unknown function, results in loss of envelope stability, increased cell permeability and dysregulated control of cell size. Using whole genome transposon mutagenesis strategies we report the complete genetic interaction network ofyhcB, revealing all genes with a synthetic negative and a synthetic positive relationship. These genes include those previously reported to have a role in cell envelope biogenesis. Surprisingly, we identified genes previously annotated as essential that became non-essential in a ΔyhcBbackground. Subsequent analyses suggest that YhcB sits at the junction of several envelope biosynthetic pathways coordinating the spatiotemporal growth of the cell, highlighting YhcB as an as yet unexplored antimicrobial target.
Generative AAV capsid diversification by latent interpolation
Authors: Sinai Sam , Jain Nina , Church George M , Kelsic Eric D 
Published: April 2021

SummaryAdeno-associated virus (AAV) capsids have shown clinical promise as delivery vectors for gene therapy. However, the high prevalence of pre-existing immunity against natural capsids poses a challenge for widespread treatment. The generation of diverse capsids that are potentially more capable of immune evasion is challenging because introducing multiple mutations often breaks capsid assembly. Here we target a representative, immunologically relevant 28-amino-acid segment of the AAV2 capsid and show that a low-complexity Variational Auto-encoder (VAE) can interpolate in sequence space to produce diverse and novel capsids capable of packaging their own genomes. We first train the VAE on a 564-sample Multiple-Sequence Alignment (MSA) of dependo-parvoviruses, and then further augment this dataset by adding 22,704 samples from a deep mutational exploration (DME) on the target region. In both cases the VAE generated viable variants with many mutations, which we validated experimentally. We propose that this simple approach can be used to optimize and diversify other proteins, as well as other capsid traits of interest for gene delivery.
Engineering single pan-specific ubiquibodies for targeted degradation of all forms of endogenous ERK protein kinase
Authors: Stephens Erin A. , Ludwicki Morgan B. , Meksiriporn Bunyarit , Li Mingji , Ye Tianzheng , Monticello Connor , Forsythe Katherine J. , Kummer Lutz , Plückthun Andreas , DeLisa Matthew P. 
Published: April 2021

AbstractUbiquibodies (uAbs) are a customizable proteome editing technology that utilizes E3 ubiquitin ligases genetically fused to synthetic binding proteins to steer otherwise stable proteins of interest (POIs) to the proteasome for degradation. The ability of engineered uAbs to accelerate the turnover of exogenous or endogenous POIs in a posttranslational manner offers a simple yet robust tool for dissecting diverse functional properties of cellular proteins as well as for expanding the druggable proteome to include tumorigenic protein families that have yet-to-be successfully drugged by conventional inhibitors. Here, we describe the engineering of uAbs comprised of a highly modular human E3 ubiquitin ligase, human carboxyl terminus of Hsc70-interacting protein (CHIP), tethered to different designed ankyrin repeat proteins (DARPins) that bind to nonphosphorylated (inactive) and/or doubly phosphorylated (active) forms of extracellular signal-regulated kinase 1 and 2 (ERK1/2). Two of the resulting uAbs were found to be global ERK degraders, pan-specifically capturing all endogenous ERK1/2 protein forms and redirecting them to the proteasome for degradation in different cell lines, including MCF7 breast cancer cells. Taken together, these results demonstrate how the substrate specificity of an E3 ubiquitin ligase can be reprogrammed to generate designer uAbs against difficult-to-drug targets, enabling a modular platform for remodeling the mammalian proteome.
Genomic Stability and Genetic Defense Systems inDolosigranulum pigruma Candidate Beneficial Bacterium from the Human Microbiome
Authors: Ramos Stephany Flores , Brugger Silvio D. , Escapa Isabel Fernandez , Skeete Chelsey A. , Cotton Sean L. , Eslami Sara M. , Gao Wei , Bomar Lindsey , Tran Tommy H. , Jones Dakota S. , Minot Samuel , Roberts Richard J. , Johnston Christopher D. , Lemon Katherine P. 
Published: April 2021

ABSTRACTDolosigranulum pigrumis positively associated with indicators of health in multiple epidemiological studies of human nasal microbiota. Knowledge of the basic biology ofD. pigrumis a prerequisite for evaluating its potential for future therapeutic use; however, such data are very limited. To gain insight intoD. pigrum’s chromosomal structure, pangenome and genomic stability, we compared the genomes of 28D. pigrumstrains that were collected across 20 years. Phylogenomic analysis showed closely related strains circulating over this period and closure of 19 genomes revealed highly conserved chromosomal synteny. Gene clusters involved in the mobilome and in defense against mobile genetic elements (MGEs) were enriched in the accessory genome versus the core genome. A systematic analysis for MGEs identified the first candidateD. pigrumprophage and insertion sequence. A systematic analysis for genetic elements that limit the spread of MGEs, including restriction modification (RM), CRISPR-Cas, and deity-named defense systems, revealed strain-level diversity in host defense systems that localized to specific genomic sites including one RM system hotspot. Analysis of CRISPR spacers pointed to a wealth of MGEs against whichD. pigrumdefends itself. These results reveal a role for horizontal gene transfer and mobile genetic elements in strain diversification while highlighting that inD. pigrumthis occurs within the context of a highly stable chromosomal organization protected by a variety of defense mechanisms.IMPORTANCEDolosigranulum pigrumis a candidate beneficial bacterium with potential for future therapeutic use. This is based on its positive associations with characteristics of health in multiple studies of human nasal microbiota across the span of human life. For example, high levels ofD. pigrumnasal colonization in adults predicts the absence ofStaphylococcus aureusnasal colonization. Also,D. pigrumnasal colonization in young children is associated with healthy control groups in studies of middle ear infections. Our analysis of 28 genomes revealed a remarkable stability ofD. pigrumstrains colonizing people in the U.S. across a 20-year span. We subsequently identified factors that can influence this stability, including genomic stability, phage predators, the role of MGEs in strain-level variation and defenses against MGEs. Finally, theseD. pigrumstrains also lacked predicted virulence factors. Overall, these findings add additional support to the potential forD. pigrumas a therapeutic bacterium.
A fastMyhsuper enhancer dictates adult muscle fiber phenotype through competitive interactions with the fastMyhgenes
Authors: Santos Matthieu Dos , Backer Stéphanie , Auradé Frédéric , Wong Matthew , Wurmser Maud , Pierre Rémi , Langa Francina , Cruzeiro Marcio Do , Schmitt Alain , Concordet Jean-Paul , Sotiropoulos Athanassia , Dilworth Jeffrey , Noordermeer Daan , Relaix Frédéric , Sakakibara Iori , Maire Pascal 
Published: April 2021

SummaryThe contractile properties of adult myofibers are shaped by their Myosin heavy chain (MYH) isoform content. We identify by snATAC-seq a 42kb super-enhancer (SE) at the locus regrouping the fastMyh(fMyh) genes. By 4C-seq we show that active fMyhpromoters interact with the SE by DNA looping, leading to the activation of a single promoter per nucleus. A rainbow mouse transgenic model of the locus including the SE recapitulates the endogenous spatio-temporal expression of adult fMyhgenes.In situdeletion of the SE by CRISPR/Cas9 editing demonstrates its major role in the control of associated fMyhgenes, and deletion of two fMyhgenes at the locus reveals an active competition of the promoters for the shared SE. Last, by disrupting the organization of fMyh, we uncover positional heterogeneity within limb skeletal muscles that may underlie selective muscle susceptibility to damage in certain myopathies.
Precision Genome and Base Editing by Regulating mRNA Nuclear Export Using Selective Inhibitors of Nuclear Export (SINEs)
Authors: Cui Yan-ru , Wang Shao-jie , Ma Tiancheng , Yu Peihong , Chen Jun , Guo Taijie , Meng Genyi , Jiang Biao , Dong Jiajia , Liu Jia 
Published: April 2021

AbstractCRISPR-based genome engineering tools are associated with off-target effects that constitutively active Cas9 protein may instigate. In the present study, we screened for irreversible small molecule off-switches of CRISPR-Cas9 and discovered that selective inhibitors of nuclear export (SINEs) could inhibit the cellular activity of CRISPR-Cas9 by interfering with the nuclear export of Cas9 mRNA. We subsequently found that SINEs, including an FDA-approved anticancer drug KPT330, could improve the specificities of CRISPR-Cas9-based genome and base editing tools in human cells.
NeuroMechFly, a neuromechanical model of adultDrosophila melanogaster
Authors: Ríos Victor Lobato , Ramalingasetty Shravan Tata , Özdil Pembe Gizem , Arreguit Jonathan , Ijspeert Auke Jan , Ramdya Pavan 
Published: April 2021

AbstractAnimal behavior emerges from a seamless interaction between neural network dynamics, musculoskeletal properties, and the physical environment. Accessing and understanding the interplay between these intertwined elements requires the development of integrative and morphologically realistic neuromechanical simulations. Until now, there has been no such simulation framework for the widely studied model organism,Drosophila melanogaster. Here we present NeuroMech-Fly, a data-driven model of the adult female fly within a physics-based simulation environment. NeuroMechFly combines a series of independent computational modules including a biomechanical exoskeleton with articulating body parts−legs, halteres, wings, abdominal segments, head, proboscis, and antennae−muscle models, and neural network controllers. To enable illustrative use cases, we first define minimal leg degrees-of-freedom by analyzing real 3D kinematic measurements during realDrosophilawalking and grooming. Then, we show how, by replaying these behaviors using NeuroMechFly’s biomechanical exoskeleton in its physics-based simulation environment, one can predict otherwise unmeasured torques and contact reaction forces. Finally, we leverage NeuroMechFly’s full neuromechanical capacity to discover neural networks and muscle parameters that enable locomotor gaits optimized for speed and stability. Thus, NeuroMechFly represents a powerful testbed for building an understanding of how behaviors emerge from interactions between complex neuromechanical systems and their physical surroundings.
Profiling the molecular signature of Satellite Glial Cells at the single cell level reveals high similarities between rodent and human
Authors: Avraham Oshri , Chamessian Alexander , Feng Rui , Yang Lite , Halevi Alexandra E. , Moore Amy M. , Gereau Robert W. , Cavalli Valeria 
Published: April 2021

ABSTRACTPeripheral sensory neurons located in dorsal root ganglia relay sensory information from the peripheral tissue to the brain. Satellite glial cells (SGC) are unique glial cells that form an envelope completely surrounding each sensory neuron soma. This organization allows for close bi-directional communication between the neuron and it surrounding glial coat. Morphological and molecular changes in SGC have been observed in multiple pathological conditions such as inflammation, chemotherapy-induced neuropathy, viral infection and nerve injuries. There is evidence that changes in SGC contribute to chronic pain by augmenting neuronal activity in various rodent pain models. SGC also play a critical role in axon regeneration. Whether findings made in rodent model systems are relevant to human physiology have not been investigated. Here we present a detailed characterization of the transcriptional profile of SGC in mouse, rat and human at the single cell level. Our findings suggest that key features of SGC in rodent models are conserved in human. Our study provides the potential to leverage rodent SGC properties and identify potential targets in humans for the treatment of nerve injuries and alleviation of painful conditions.
The ChvG–ChvI and NtrY–NtrX two-component systems coordinately regulate growth ofCaulobacter crescentus
Authors: Stein Benjamin J. , Fiebig Aretha , Crosson Sean 
Published: April 2021

AbstractTwo-component signaling systems (TCSs) are comprised of a sensory histidine kinase and a response regulator protein. In response to environmental changes, sensor kinases directly phosphorylate their cognate response regulator to affect gene expression. Bacteria typically express multiple TCSs that are insulated from one another and regulate distinct physiological processes. There are certainly examples of cross-regulation between TCSs, but this phenomenon remains relatively unexplored. We have identified regulatory links between the ChvG–ChvI (ChvGI) and NtrY–NtrX (NtrYX) TCSs, which control important and often overlapping processes in α-proteobacteria, including maintenance of the cell envelope. Deletion ofchvGandchvIinCaulobacter crescentuslimited growth in defined medium and a selection for genetic suppressors of this growth phenotype uncovered interactions amongchvGI, ntrYX, andntrZ, which encodes a previously uncharacterized periplasmic protein. Significant overlap in the experimentally-defined ChvI and NtrX transcriptional regulons provided support for the observed genetic connections betweenntrYXandchvGI. Moreover, we present evidence that the growth defect of strains lackingchvGIis influenced by the phosphorylation state of NtrX and, to some extent, by levels of the TonB-dependent receptor ChvT. Measurements of NtrX phosphorylationin vivoindicated that NtrZ is an upstream regulator of NtrY, and that NtrY primarily functions as an NtrX phosphatase. We propose a model in which NtrZ functions in the periplasm to inhibit NtrY phosphatase activity; regulation of phosphorylated NtrX levels by NtrZ and NtrY provides a mechanism to modulate and balance expression of the NtrX and ChvI regulons under different growth conditions.ImportanceTwo-component signaling systems (TCSs) enable bacteria to regulate gene expression in response to physiochemical changes in their environment. The ChvGI and NtrYX TCSs regulate diverse pathways associated with pathogenesis, growth, and cell envelope function in many α-proteobacteria. We usedCaulobacter crescentusas a model to investigate regulatory connections between ChvGI and NtrYX. Our work defined the ChvI transcriptional regulon inC. crescentusand revealed a genetic interaction between ChvGI and NtrYX, whereby modulation of NtrYX signaling affects the survival of cells lacking ChvGI. In addition, we identified NtrZ as a periplasmic inhibitor of NtrY phosphatase activityin vivo. Our work establishesC. crescentusas an excellent model to investigate multi-level regulatory connections between ChvGI and NtrYX in α-proteobacteria.
Evidence for a Nuclear Role forDrosophilaDlg as a Regulator of the NURF Complex
Authors: Sharp Katherine A. , Khoury Mark J. , Wirtz-Peitz Frederick , Bilder David 
Published: April 2021

AbstractScrib, Dlg, and Lgl are basolateral regulators of epithelial polarity and tumor suppressors whose molecular mechanisms of action remain unclear. We used proximity biotinylation to identify proteins localized near Dlg in theDrosophilawing imaginal disc epithelium. In addition to expected membrane- and cytoskeleton-associated protein classes, nuclear proteins were prevalent in the resulting mass spectrometry data set, including all four members of the NURF chromatin remodeling complex. Subcellular fractionation demonstrated a nuclear pool of Dlg and proximity ligation confirmed its position near the NURF complex. Genetic analysis showed that NURF activity is also required for the overgrowth ofdlgtumors, and this growth suppression correlated with a reduction in Hippo pathway gene expression. Together, these data suggest a nuclear role for Dlg in regulating chromatin and transcription through a more direct mechanism than previously thought.Highlight SummaryProximity proteomics is used as an entry point towards identifying partners of the polarity-regulating tumor suppressor Dlg. A nuclear pool of the protein associated with NURF chromatin remodelers is revealed, along with evidence of functional interactions during growth regulation.