bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Association Study in a Rat Model of Temperament Identifies Multiple Loci for Exploratory Locomotion and Anxiety-Like Traits
Authors: Chitre Apurva S. , Hebda-Bauer Elaine K. , Blandino Peter , Bimschleger Hannah , Nguyen Khai-Minh , Maras Pamela , Li Fei , Ozel A. Bilge , Polysskaya Oksana , Cheng Riyan , Flagel Shelly B. , Watson Stanley J. , Li Jun , Akil Huda , Palmer Abraham A 
Published: July 2022

AbstractCommon genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment (bred High Responders (bHR) vs. Low Responders (bLR)). To identify genes underlying the response to selection, we phenotyped and genotyped 558 rats from an F2cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait.Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which thePik3c3gene is located. There were no significant loci for PavCA. We identified a missense variant in thePlekhf1gene on the chromosome 1:95 Mb QTL andFancfandGas2as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing thePkhd1l1andTrhrgenes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats.The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders.
Noncovalent antibody catenation on a target surface drastically increases the antigen-binding avidity
Authors: Song Jinyeop , Jeong Bo-Seong , Kim Seong-Woo , Im Seong-Bin , Cho Wonki , Ahn Myung-Ju , Oh Byung-Ha 
Published: July 2022

ABSTRACTImmunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface where target antigen molecules are abundant, and that it could be an effective way to greatly enhance the antigen-binding avidity. A thermodynamic simulation shows that quite low homodimerization affinity of a catenator, e.g. dissociation constant of 100 μM, can enhance nanomolar antigen-binding avidity to a picomolar level, and that the fold enhancement sharply depends on the density of the antigen. In a proof-of-concept experiment where antigen molecules are immobilized on a biosensor tip, C-terminal fusion of a weakly homodimerizing protein to two different antibodies enhanced the antigen-binding avidity by at least 210 to 5,120 folds from the intrinsic binding avidity. Thus, the homodimerization-induced antibody catenation would be a simple, powerful and general approach to improve many antibody applications, including the detection of scarce biomarkers and targeted anticancer therapies.
Study on endogenous inhibitors against PD-L1: cAMP as a potential candidate
Authors: Huang Qiuyang , Zang Xiaoling , Zhang Zhiwei , Zhang Xin , Ali Mustafa R. K. , Lv Zhihua 
Published: July 2022

AbstractThe discovery of new anticancer drugs targeting the PD-1/PD-L1 pathway has been research hotspots. In this study, a combination of biological affinity ultrafiltration (BAU), UPLC-HRMS, molecular dynamic (MD) simulations and molecular docking methods were applied to search for endogenous active compounds that can inhibit the binding of PD-L1 and PD-1. We screened dozens of potential cancer related endogenous compounds. The results showed that cyclic adenosine monophosphate (cAMP) had a direct inhibition effect on the PD-1/PD-L1 binding with an in vitro IC50 value of about 2.7 µM determined by homogeneous time-resolved fluorescence (HTRF) assay. The binding mode analyses for the cAMP - dimeric/monomeric PD-L1 complex indicated that cAMP was likely to bind to the dimeric PD-L1, since the binding free energies of the cAMP - dimeric and monomeric PD-L1 complex were about 23.6 and 15.1 kcal/mol, respectively, from MD simulations. The direct binding assay using surface plasmon resonance (SPR) method showed that cAMP could also bind to monomeric PD-L1 fixed on the sensor chip surface with a KD value of about 1.72 mM. Our findings suggested that cAMP may directly inhibit the PD-1/PD-L1 interaction.
Interpreting the molecular mechanisms of disease variants in human transmembrane proteins
Authors: Tiemann Johanna Katarina Sofie , Zschach Henrike , Lindorff-Larsen Kresten , Stein Amelie 
Published: July 2022

AbstractNext-generation sequencing of human genomes reveals millions of missense variants, some of which may lead to loss of protein function and ultimately disease. We here investigate missense variants in membrane proteins — key drivers in cell signaling and recognition. We find enrichment of pathogenic variants in the transmembrane region across 19,000 functionally classified variants in human membrane proteins. To accurately predict variant consequences, one fundamentally needs to understand the reasons for pathogenicity. A key mechanism underlying pathogenicity in missense variants of soluble proteins has been shown to be loss of stability. Membrane proteins though are widely understudied. We here interpret for the first time on a larger scale variant effects by performing structure-based estimations of changes in thermodynamic stability under the usage of a membrane-specific force-field and evolutionary conservation analyses of 15 transmembrane proteins. We find evidence for loss of stability being the cause of pathogenicity in more than half of the pathogenic variants, indicating that this is a driving factor also in membrane-protein-associated diseases. Our findings show how computational tools aid in gaining mechanistic insights into variant consequences for membrane proteins. To enable broader analyses of disease-related and population variants, we include variant mappings for the entire human proteome.SIGNIFICANCEGenome sequencing is revealing thousands of variants in each individual, some of which may increase disease risks. In soluble proteins, stability calculations have successfully been used to identify variants that are likely pathogenic due to loss of protein stability and subsequent degradation. This knowledge opens up potential treatment avenues. Membrane proteins form about 25% of the human proteome and are key to cellular function, however calculations for disease-associated variants have not systematically been tested on them. Here we present a new protocol for stability calculations on membrane proteins under the usage of a membrane specific force-field and its proof-of-principle application on 15 proteins with disease-associated variants. We integrate stability calculations with evolutionary sequence analysis, allowing us to separate variants where loss of stability is the most likely mechanism from those where other protein properties such as ligand binding are affected.
Soil chemistry and soil history significantly structure oomycete communities in Brassicaceae crop rotations
Authors: Blakney Andrew J.C. , Bainard Luke D. , St-Arnaud Marc , Hijri Mohamed 
Published: July 2022

AbstractOomycetes are critically important soil microbial communities, especially for agriculture where they are responsible for major declines in yields. Unfortunately, oomycetes are vastly understudied compared to bacteria and fungi. As such, our understanding of how oomycete biodiversity and community structure varies through time in the soil remains poor. Soil history established by previous crops is one factor known to structure other soil microbes, but has not been investigated for its influence on oomycetes. In this study, we established three different soil histories in field trials; the following year these plots were planted with five different Brassicaceae crops. We hypothesized that the previously established soil histories would structure different oomycete communities, regardless of their current Brassicaceae crop host, in both the roots and rhizosphere. We used a nested-ITS amplicon strategy incorporated with MiSeq metabarcoding, where the sequencing data was used to infer amplicon sequence variants (ASVs) of the oomycetes present in each sample. This allowed us to determine the impact of different soil histories on the structure and biodiversity of the oomycete root and rhizosphere communities from the five different Brassicaceae crops. We found that each soil history structured distinct oomycete rhizosphere communities, regardless of different Brassicaceae crop hosts, while soil chemistry structured the oomycete communities more during a dry year. Interestingly, soil history appeared specific to oomycetes, but was less influential for bacterial communities previously identified from the same samples. These results advance our understanding of how different agricultural practices and inputs can alter edaphic factors to impact future oomycete communities. Examining how different soil histories endure and impact oomycete biodiversity will help clarify how these important communities may be assembled in agricultural soils.HighlightsCrop rotations model how soil history impacts subsequent microbial communitiesBrassicaceae oilseed crops might mitigate pathogenic oomycetesSoil history significantly structures oomycete communitiesOomycetes are significantly affected by soil chemistryBrassicaceae crop hosts weakly influence oomycete communities
RGG motif-containing Scd6/LSM14A proteins regulate the translation of specific mRNAs in response to hydroxyurea-induced genotoxic stress
Authors: Mohanan Gayatri , Roy Raju , Malka-Mahieu Hélène , Lamba Swati , Fabbri Lucilla , Biswas Anusmita , Martineau Sylvain , Labbé Céline M. , Vagner Stéphan , Rajyaguru Purusharth I 
Published: July 2022

AbstractGenotoxic stress response (GSR) mediated by mRNA translation and decay regulation remains poorly explored. Here, we identify a unique role of yeast RGG-motif protein Scd6 and its human ortholog LSM14A in mRNA translation control upon hydroxyurea (HU)-mediated GSR. Scd6/LSM14A, but not all tested RGG-containing proteins, localize to HU-induced cytoplasmic puncta in an RGG-dependent manner. The absence of Scd6 increases HU tolerance but sensitizes the cells to HU upon overexpression of SRS2, a known dampener of the DNA- damage response. Scd6 bindsSRS2mRNA to repress its translation in cytoplasmic granules upon HU stress. Scd6-SRS2 interaction is modulated by arginine methylation (AM) and the LSm-domain, which acts as acis-regulator of Scd6 AM. Polysome-profiling experiments indicate that LSM14A regulates the translation of NHEJ factor mRNAs such asLIG4(DNL4 homolog) andRTEL1(SRS2 functional homolog), and the NHEJ activity in response to HU. Overall, this report unveils the role of AM and Scd6/LSM14A in the GSR by determining the translation status of specific mRNAs.
Protein Structure Prediction with Expectation Reflection
Authors: Cresswell-Clay Evan , Hoang Danh-Tai , McKenna Joe , Yang Chris , Zhang Eric , Periwal Vipul 
Published: July 2022

AbstractSequence covariation in multiple sequence alignments of homologous proteins has been used extensively to obtain insights into protein structure. However, global statistical inference is required in order to ascertain direct relationships between amino acid positions in these sequences that are not simply secondary correlations induced by interactions with a third residue. Methods for statistical inference of such covariation have been developed to exploit the growing availability of sequence data. These hints about the folded protein structure provide critical a priori information for more detailed 3D predictions by neural networks. We present a novel method for protein structure inference using an iterative parameter-free model estimator which uses the formalism of statistical physics. With no tunable learning rate, our method scales to large system sizes while providing improved performance in the regime of small sample sizes. We apply this method to 40974 PDB structures and compare its performance to that of other methods. Our method outperforms existing methods for 76% of analysed proteins.
Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells
Authors: Romero-Moreno Ricardo , Czowski Brandon , Harris Lindsey , Kuehn Jessamine F. , White Katharine A. 
Published: July 2022

SummaryIntracellular pH (pHi) dynamics regulate normal cell function, and dysregulated pHi dynamics is an emerging hallmark of cancer (constitutively increased pHi) and neurodegeneration (constitutively decreased pHi). However, the molecular mechanisms by which pHi dynamics regulate cell biology are poorly understood. Here, we discovered that altering pHi in normal human breast epithelial cells triggers global transcriptional changes. We identified 176 genes differentially regulated by pHi, with pHi-dependent genes clustering in signaling and glycolytic pathways. Using various normal epithelial cell models, we showed pH-dependent Notch1 expression, with increased protein abundance at high pHi. This resulted in pH-dependent downstream signaling, with increased Notch1 signaling at high pHi. We also found that high pHi increased the expression of glycolytic enzymes and regulators of pyruvate fate, including lactate dehydrogenase and pyruvate dehydrogenase kinase. These transcriptional changes were sufficient to alter lactate production, with high pHi shifting these normal epithelial cells toward a glycolytic metabolism and increasing lactate production. Thus, pHi dynamics transcriptionally regulate signaling and metabolic pathways in normal epithelial cells. Our data reveal new molecular regulators of pHi-dependent biology and a role for increased pHi in driving the acquisition of cancer-associated signaling and metabolic changes in normal human epithelial cells.
Allosteric inhibition of Staphylococcus aureus MenD by 1,4-dihydroxy naphthoic acid: A feedback inhibition mechanism of the menaquinone biosynthesis pathway
Authors: Stanborough Tamsyn , Ho Ngoc Anh Thu , Bulloch Esther M. M. , Bashiri Ghader , Dawes Stephanie S. , Akazong Etheline W. , Titterington James , Allison Timothy M. , Jiao Wanting , Johnston Jodie M. 
Published: July 2022

SummaryMenaquinones (MKs) are electron carriers in bacterial respiratory chains. In Staphylococcus aureus (Sau), MKs are essential for aerobic and anaerobic respiration. As MKs are redox-active, their biosynthesis likely requires tight regulation to prevent disruption of cellular redox balance. We recently found that the Mycobacterium tuberculosis MenD, the first committed enzyme of the MK biosynthesis pathway, is allosterically inhibited by the downstream metabolite 1,4-dihydroxy-2-naphthoic acid (DHNA). To understand if this is a conserved mechanism in phylogenetically distant genera that also utilize MK, we investigated whether the Sau-MenD is allosterically inhibited by DHNA. Our results show that DHNA binds to and inhibits SEPHCHC synthase activity of Sau-MenD enzymes. We identified residues in the DHNA binding pocket that are important for catalysis (Arg98, Lys283, Lys309) and inhibition (Arg98, Lys283). Furthermore, we show that exogenous DHNA inhibits growth of Sau, an effect that can be rescued by supplementing the growth media with MK-4. Our results demonstrate that despite a lack of strict conservation of the DHNA-binding pocket between Mtb-MenD and Sau-MenD, feedback inhibition by DHNA is a conserved mechanism in Sau-MenD and hence the Sau MK biosynthesis pathway. These findings may have implications for the development of anti-staphylococcal agents targeting MK biosynthesis
Public relations ethics in the 21st century: a state-of-the-field review
Authors: Jackson Michaela , Chorazy Ella , Sison Marianne D. , Wise Deborah 
Published: July 2022

PurposeTo conduct a systematic review of public relations ethics (PRE) research and scholarship in the 21st century and suggest future research directions. The study is prompted by macro-level phenomena that have impacted societies since the beginning of the 21st century—notably globalisation 4.0 and the fourth industrial revolution.Design/methodology/approachA systematic review was used to search academic literature. Articles discussing PRE in nine leading English-language public relations and business ethics journals between 2000 and 2019 were reviewed. A code-frame facilitated data extraction and subsequent quantitative analysis; qualitative analysis identified key themes.FindingsThe review identified 288 articles, with discussions involving PRE increasing over time. Most works approached the topic generally, rather than from a specific sub-disciplinary perspective, and drew from professional settings. Works were dominated by authors from North American institutions and North American samples. Research became increasingly empirical and intra-disciplinary and discussion about ethics was broadly categorised as part of public relations practice or from the perspective of the “academy”. Overall, the field can be described as of notable size, maturing, yet unbalanced in some regards.Originality/valueThe review helps to identify whether PRE research reflects major changes in the 21st century and augments the sparse recent reviews of PRE research.
A bibliometric analysis and future research opportunities in Multinational Business Review
Authors: Jain Rajesh , Oh Chang Hoon , Shapiro Daniel 
Published: July 2022

Purpose
This paper aims to evaluate the past contributions of Multinational Business Review (MBR), identify research gaps and opportunities and provide a research agenda that addresses several sustainability-related and other contemporary challenges.

Design/methodology/approach
This study analyzes 400 papers published between 2003 and 2021 to map the MBR’s intellectual and conceptual structure using advanced bibliometric techniques.

Findings
The bibliographic coupling technique identifies core clusters in MBR papers, and subsequent content analysis of these clusters reveals the following five research fronts: internalization theory and the future of international business (IB) research; internationalization and firm performance; regionalization versus globalization debate; internationalization by emerging market firms; and global dynamic capabilities and firm internationalization.

Originality/value
To the best of the authors’ knowledge, this is the first comprehensive analysis of past contributions of MBR to research on IB and suggests a way for MBR to play a seminal role in addressing contemporary challenges in IB.
Examining sources of post‐acute care inequities with layered target matching
Authors: Niknam Bijan A. , Zubizarreta Jose R. 
Published: July 2022

AbstractObjectiveTo examine factors associated with racial inequities in discharge location, skilled nursing facility (SNF) utilization, and readmissions.Data SourcesA 20% sample of longitudinal Medicare claims from 2016 to 2018.Study DesignWe present layered target matching, a method for studying sources of inequities. Layered target matching examines a fixed target population profile representing any race, ethnicity, or vulnerable population, sequentially adjusting for sets of characteristics that may contribute to inequities these groups endure. We use the method to study racial inequities in post‐acute care use and readmissions.Data Collection/Extraction MethodsWe studied Black and non‐Hispanic White fee‐for‐service Medicare beneficiaries aged 66+ admitted to short‐term acute‐care hospitals for qualifying diagnoses or procedures between January 1, 2016 and November 30, 2018.Principal FindingsAdmitted Black patients tended to be younger, had significantly higher rates of risk factors such as diabetes, stroke, or renal disease, and were much more frequently admitted to large or academic hospitals. Relative to demographically similar White patients, Black patients were significantly more likely to be discharged to SNFs (21.8% vs. 19.3%, difference = 2.5%, p < 0.0001) and to receive any SNF care within 30 days of discharge (25.3% vs. 22.4%, difference = 2.9%, p < 0.0001). Black patients were also significantly more likely to experience 30‐day readmission (18.7% vs. 14.5%, difference = 4.2%, p < 0.0001). Differences in reasons for hospitalization and risk factors explained most of the differences in discharge location, post‐acute care use, and readmission rates, while additional adjustment for differences in hospital characteristics and complications made little difference for any of the measures studied.ConclusionsWe found significant Black–White differences in discharge to SNFs, SNF utilization, and readmission rates. Using layered target matching, we found that differences in risk factors and reasons for hospitalization explained most of these differences, while differences in hospitals did not materially impact the differences.
SNAP work requirements increase mental health care use
Authors: Allen Lindsay , Henry Diana , Atwood Alicia 
Published: July 2022

AbstractObjectiveWe measured the impact of Supplemental Nutrition Assistance Program (SNAP) work requirements on mental health care use.Data Sources and Study SettingWe used 2015–2018 West Virginia Medicaid and SNAP data.Study DesignNine counties were exposed to SNAP work requirements. Using an event study framework, we assessed how this changed the probability and number of visits for depression and anxiety in the treatment versus the control group.Data Collection/Extraction MethodsThe sample included individuals aged 18–49, enrolled in both SNAP and Medicaid at the start of the study. Dually eligible individuals were excluded.Principal FindingsAt baseline, the probability of having a mood disorder visit was 6.1% among women and 5.3% among men, rising by 0.9 percentage points (SE 0.4, relative change +14.1%) among women and 0.7 percentage points (SE 0.3, relative change +13.0%) among men after exposure to work requirements. The probability of having an anxiety visit rose by 1.0 (SE 0.4) percentage points among women, a 17.8% relative increase over the baseline of 5.8%. Among men, the likelihood of having an anxiety visit increased by 1.0 percentage points (SE 0.5), a relative change of 24.3% over a baseline probability of 5.0%, though this effect occurred much more gradually compared to women.ConclusionsExposure to SNAP work requirements was associated with increases in health care use for mood disorders and anxiety among enrollees. The policy's effect differed between men and women.