bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-Operative Kidney Biomarkers and Risks for Death, Cardiovascular and Chronic Kidney Disease Events: The TRIBE-AKI Study
Authors: Vasquez-Rios George , Moledina Dennis G. , Jia Yaqi , McArthur Eric , Mansour Sherry G. , Thiessen-Philbrook Heather , Shlipak Michael G. , Koyner Jay L. , Garg Amit X. , Parikh Chirag R. , Coca Steven G. ,   TRIBE-AKI Consortium
Published: December 2021

ABSTRACTBackgroundSoluble tumor necrosis factor receptor (sTNFR)1, sTNFR2, and plasma kidney injury molecule-1 (KIM-1) are associated with kidney events in patients with and without diabetes. However, their associations with clinical outcomes when obtained pre-operatively have not been explored.MethodsThe TRIBE-AKI cohort study is a prospective, multicenter, cohort study of high-risk adults undergoing cardiac surgery. We assessed the associations between pre-operative concentrations of plasma sTNFR1, sTNFR2, and KIM-1 and post-operative long-term outcomes including mortality, cardiovascular events, and chronic kidney disease (CKD) incidence or progression, ascertained after discharge.ResultsAmong 1378 participants included in the analysis with a median follow-up period was 6.7 (IQR 4.0-7.9), 434 (31%) patients died, 256 (19%) experienced cardiovascular events and out of 837 with available long-term kidney function data, 30% developed CKD. After adjustment for clinical covariates, each log increase in biomarker concentration was independently associated with mortality with 95%CI adjusted hazard ratios (aHRs) of 3.0 (2.3-4.0), 2.3 (1.8-2.9) and 2.0 (CI 1.6-2.4) for sTNFR1, sTNFR2 and KIM-1, respectively. For cardiovascular events, the 95%CI aHRs were 2.1 (1.5 – 3.1), 1.9 (1.4 – 2.6) and 1.6 (1.2 – 2.1) for sTNFR1, sTNFR2 and KIM-1, respectively. For CKD events, the aHRs were 2.2 (1.5 – 3.1) for sTNFR1, 1.9 (1.3 – 2.7) for sTNFR2, and 1.7 (1.3 – 2.3) for KIM-1. Despite the associations, each of the biomarkers alone or in combination failed to result in robust discrimination on an absolute basis or compared to a clinical model.ConclusionsTNFR1, sTNFR2, and KIM-1 were independently associated with longitudinal outcomes after discharge from a cardiac surgery hospitalization including death, cardiovascular and CKD events when obtained pre-operatively in high-risk individuals. Pre-operative plasma biomarkers could serve to assist during the evaluation of patients in whom cardiac surgery is planned.
Guiding ATR and PARP inhibitor combinations with chemogenomic screens
Authors: Zimmermann Michal , Bernier Cynthia , Kaiser Beatrice , Fournier Sara , Li Li , Desjardins Jessica , Skeldon Alexander , Rimkunas Victoria , Veloso Artur , Young Jordan T. F. , Roulston Anne , Zinda Michael 
Published: December 2021

SUMMARYCombinations of inhibitors of Ataxia Telangiectasia- and Rad3-related kinase (ATRi) and poly(ADP-ribose) polymerases (PARPi) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this we performed a genome-wide CRISPR/Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations or the Alternative Lengthening of Telomeres telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. Altogether, we present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.
Identifying long-range synaptic inputs using genetically encoded labels and volume electron microscopy
Authors: Ayuso-Jimeno Irene P. , Ronchi Paolo , Wang Tianzi , Gallori Catherine , Gross Cornelius T. 
Published: December 2021

AbstractEnzymes that facilitate the local deposition of electron dense reaction products have been widely used as labels in electron microscopy (EM). Peroxidases, in particular, can efficiently metabolize 3,3’-diaminobenzidine tetrahydrochloride hydrate (DAB) to produce precipitates with high contrast under EM following heavy metal staining, and can be genetically encoded to facilitate the labeling of specific cell-types or organelles. Nevertheless, the peroxidase/DAB method has so far not been reported to work in combination with 3D volume EM techniques (e.g. Serial blockface electron microscopy, SBEM; Focused ion beam electron microscopy, FIBSEM) because the surfactant treatment needed for efficient reagent penetration disrupts tissue ultrastructure and because these methods require the deposition of large amounts of heavy metals that can obscure DAB precipitates. However, a recently described peroxidase with enhanced enzymatic activity (dAPEX2) appears to successfully deposit EM-visible DAB products in thick tissue without surfactant treatment. Here we demonstrate that multiplexed dAPEX2/DAB tagging is compatible with both FIBSEM and SBEM volume EM approaches and use them to map long-range genetically identified synaptic inputs from the anterior cingulate cortex to the periaqueductal gray in the mouse brain.
PLaBAse: A comprehensive web resource for analyzing the plant growth-promoting potential of plant-associated bacteria
Authors: Patz S. , Gautam A. , Becker M. , Ruppel S. , Rodríguez-Palenzuela P. , Huson DH. 
Published: December 2021

ABSTRACTPlant-beneficial microorganisms are gaining importance for sustainable plant production and phytosanitary practices. Yet there is a lack of computational approaches targeting bacterial traits associated with plant growth-promotion (PGP), which hinders the in-silico identification, comparison, and selection of phytostimulatory bacterial strains. To address this problem, we have developed the new web resource PLaBAse (v1.01, http://plabase.informatik.uni-tuebingen.de/pb/plabase.php), which provides a number of services, including (i) a database for screening 5,565 plant-associated bacteria (PLaBA-db), (ii) a tool for predicting plant growth-promoting traits (PGPTs) of single bacterial genomes (PGPT-Pred), and (iii) a tool for the prediction of bacterial plant-association by marker gene identification (PIFAR-Pred). The latter was developed by Martínez-García et al. and is now hosted at University of Tuebingen. The PGPT-Pred tool is based on our new PGPT ontology, a literature- and OMICs-curated, comprehensive, and hierarchical collection of ∼6,900 PGPTs that are associated with 6,965,955 protein sequences. To study the distribution of the PGPTs across different environments, we applied it to 70,540 bacterial strains associated with (i) seven different environments (including plants), (iii) five different plant spheres (organs), and (iii) two bacteria-induced plant phenotypes. This analysis revealed that plant-symbiotic bacteria generally have a larger genome size and a higher count of PGPT-annotated protein encoding genes. Obviously, not all reported PGPTs are restricted to -or only enriched in-plant-associated and plant symbiotic bacteria. Some also occur in human- and animal-associated bacteria, perhaps due to the transmission of PGP bacteria (PGPBs) between environments, or because some functions are involved in adaption processes to various environments. Here we provide an easy-to-use approach for screening of PGPTs in bacterial genomes across various phyla and isolation sites, using PLaBA-db, and for standardized annotation, using PGPT-Pred. We believe that this resource will improve our understanding about the entire PGP processes and facilitate the prediction of PGPB as bio-inoculants and for biosafety strategies, so as to help to establish sustainable and targeted bacteria-incorporated plant production systems in the future.
A calibrated functional patch clamp assay to enhance clinical variant interpretation in KCNH2-related long QT syndrome
Authors: Jiang Connie , Richardson Ebony , Farr Jessica , Hill Adam P. , Ullah Rizwan , Kroncke Brett M. , Harrison Steven M. , Thomson Kate L. , Ingles Jodie , Vandenberg Jamie I. , Ng Chai-Ann 
Published: December 2021

AbstractPurposeModern sequencing technologies have revolutionised our detection of gene variants. In most genes, including KCNH2, the majority of missense variants are currently classified as variants of uncertain significance (VUS). The aim of this study is to investigate the utility of an automated patch-clamp assay for aiding clinical variant classification in the KCNH2 gene.MethodsThe assay was designed according to recommendations of the ClinGen sequence variant interpretation framework. Thirty-one control variants of known clinical significance (17 pathogenic/likely pathogenic, 14 benign/likely benign) were heterozygously expressed in Flp-In HEK293 cells. Variants were analysed for effects on current density and channel gating. A panel of 44 VUS was then assessed for reclassification.ResultsAll 17 pathogenic variant controls had reduced current density and 13/14 benign variant controls had normal current density, which enabled determination of normal and abnormal ranges for applying moderate or supporting evidence strength for variant classification. Inclusion of KCNH2 functional assay evidence enabled us to reclassify 6 out of 44 VUS as likely pathogenic.ConclusionThe high-throughput patch clamp assay can provide moderate strength evidence for clinical interpretation of clinical KCNH2 variants and demonstrates the value proposition for developing automated patch clamp assays for other ion channel genes.
The Geometry of Representational Drift in Natural and Artificial Neural Networks
Authors: Aitken Kyle , Garrett Marina , Olsen Shawn , Mihalas Stefan 
Published: December 2021

AbstractNeurons in sensory areas encode/represent stimuli. Surprisingly, recent studies have suggested that, even during persistent performance, these representations are not stable and change over the course of days and weeks. We examine stimulus representations from fluorescence recordings across hundreds of neurons in the visual cortex using in vivo two-photon calcium imaging and we corroborate previous studies finding that such representations change as experimental trials are repeated across days. This phenomenon has been termed “representational drift”. In this study we geometrically characterize the properties of representational drift in the primary visual cortex of mice in two open datasets from the Allen Institute and propose a potential mechanism behind such drift. We observe representational drift both for passively presented stimuli, as well as for stimuli which are behaviorally relevant. Across experiments, the drift most often occurs along directions that have the most variance, leading to a significant turnover in the neurons used for a given representation. Interestingly, despite this significant change due to drift, linear classifiers trained to distinguish neuronal representations show little to no degradation in performance across days. The features we observe in the neural data are similar to properties of artificial neural networks where representations are updated by continual learning in the presence of dropout, i.e. a random masking of nodes/weights, but not other types of noise. Therefore, we conclude that a potential reason for the representational drift in biological networks is driven by an underlying dropout-like noise while continuously learning and that such a mechanism may be computational advantageous for the brain in the same way it is for artificial neural networks, e.g. preventing overfitting.
Structure-guided optimization of light-activated chimeric G-protein coupled receptors
Authors: Tichy Alexandra-Madelaine , So Wang Lok , Gerrard Elliot J. , Janovjak Harald 
Published: December 2021

ABSTRACTG-protein coupled receptors (GPCRs) are the largest human receptor family and involved in virtually every physiological process. One hallmark of GPCR function is the specific coupling of activated receptors to selected downstream signaling pathways. The ability to tune this coupling would permit the development of receptors with new capabilities. GPCRs and G-proteins have been recently resolved structurally at high resolution, but this information was in only very few cases harnessed for a rational engineering of these protein complexes. Here, we demonstrate the structure-guided optimization of coupling in chimeric light-activated GPCRs (OptoXRs). Our hypothesis was that the incorporation of structural GPCR-Gα contacts will lead to improved receptor activity. We first evaluated structure-based alignments as complements to existing sequence-based methods for generation of chimeric receptors. We then show in a prototypical light-activated β2AR that inclusion of α-helical residues forming structural contacts to Gα resulted in receptors with 7- to 20-fold increased function compared to other design strategies. In turn, elimination of GPCR-Gα contacts diminished function. Finally, the efficient receptor design served as a platform for the optimization of a further light-activated receptor and spectral tuning of the photoreceptor core domain. Our work exemplifies how increased OptoXR potency and new functionalities can be achieved through structure-based design towards targeted inputs into cells and cellular networks.
Multiple phage resistance systems inhibit infection via SIR2-dependent NAD+ depletion
Authors: Garb Jeremy , Lopatina Anna , Bernheim Aude , Zaremba Mindaugas , Siksnys Virginijus , Melamed Sarah , Leavitt Azita , Millman Adi , Amitai Gil , Sorek Rotem 
Published: December 2021

AbstractDefense-associated sirtuins (DSR) comprise a family of proteins that defend bacteria from phage infection via an unknown mechanism. These proteins are common in bacteria and harbor an N-terminal sirtuin (SIR2) domain. In this study we report that DSR proteins degrade nicotinamide adenine dinucleotide (NAD+) during infection, depleting the cell of this essential molecule and aborting phage propagation. Our data show that one of these proteins, DSR2, directly identifies phage tail tube proteins and then becomes an active NADase in Bacillus subtilis. Using a phage mating methodology that promotes genetic exchange between pairs of DSR2-sensitive and DSR2–resistant phages, we further show that some phages express anti-DSR2 proteins that bind and repress DSR2. Finally, we demonstrate that the SIR2 domain serves as an effector NADase in a diverse set of phage defense systems outside the DSR family. Our results establish the general role of SIR2 domains in bacterial immunity against phages.
Key features of inhibitor binding to the human mitochondrial pyruvate carrier hetero-dimer
Authors: Tavoulari Sotiria , Schirris Tom J.J. , Mavridou Vasiliki , Thangaratnarajah Chancievan , King Martin S. , Jones Daniel T.D. , Ding Shujing , Fearnley Ian M. , Kunji Edmund R.S. 
Published: December 2021

ABSTRACTThe mitochondrial pyruvate carrier (MPC) has emerged as a promising drug target for metabolic disorders, including non-alcoholic steatohepatitis and diabetes, metabolically dependent cancers and neurodegenerative diseases. Human MPC is a protein complex, but the composition of its active form is debated and the mechanisms of transport and inhibition are not resolved. We have recombinantly expressed and purified the human hetero-complex MPC1L/MPC2 and demonstrate that it is a functional hetero-dimer, like the yeast MPC hetero-dimers. Unlike the latter, human MPC1L/MPC2 binds the known inhibitors with high potencies. We identify the essential chemical features shared between these structurally diverse inhibitors and demonstrate that high affinity binding is not attributed to covalent bond formation with MPC cysteines, as previously thought. We also identify 14 new inhibitors of MPC, one outperforming the most potent compound UK5099 by tenfold. Two of them are the commonly prescribed drugs entacapone and nitrofurantoin, suggesting possible off-target mechanisms associated with their adverse effects. This work advances our understanding of MPC inhibition and will accelerate the development of clinically relevant MPC modulators.
Control of G2 phase duration by CDC25B modulates the switch from direct to indirect neurogenesis in the neocortex
Authors: Roussat Mélanie , Jungas Thomas , Audouard Christophe , Medevielle Francois , Davy Alice , Pituello Fabienne , Bel-Vialar Sophie 
Published: December 2021

AbstractDuring development, cortical neurons are produced in a temporally regulated sequence from apical progenitors, directly, or indirectly through the production of intermediate basal progenitors. The balance between these major progenitors’ types is determinant for the production of the proper number and types of neurons and it is thus important to decipher the cellular and molecular cues controlling this equilibrium. Here we address the role of a cell cycle regulator, the CDC25B phosphatase, in this process. We show that deleting CDC25B in apical progenitors leads to a transient increase of the production of TBR1+ neurons at the expense of TBR2+ basal progenitors in mouse neocortex. This phenotype is associated with lengthening of the G2 phase of the cell cycle, the total cell cycle length being unaffected. Using in utero electroporation and cortical slice cultures, we demonstrate that the defect in TBR2+ basal progenitor production requires interaction with CDK1 and is due to the G2 phase lengthening in CDC25B mutants. Altogether, this study identifies a new role for CDC25B and the length of the G2 phase in direct versus indirect neurogenesis at early stages of the cortical development.
The role of initiative climate as a resource caravan passageway in developing proactive service performance
Authors: Aslam Muhammad Zia , Fateh Adnan , Omar Safiah , Nazri Mohammad 
Published: December 2021

PurposeThe study aims to examine the role of initiative climate as a resource caravan passageway in engaging employees and developing a proactive frontline service workforce to identify the mechanisms whereby scarce resources efficiently yielding the desired outcomes can help organizations improve productivity and gain competitive advantage, thereby helping clarify the leadership–performance relationship in service organizations.Design/methodology/approachThe study employed a quantitative research design with a cross-sectional survey conducted among frontline hospitality employees in Malaysia. Partial least squares structural equation modeling (PLS-SEM) was used to examine the hypothesized relationships.FindingsThe initiative climate is significant as a resource caravan passageway to transmit the positive impact of interpersonal leadership onto the engagement and proactive performance of frontline hospitality employees in whom initiative climate and employee engagement sequentially mediated the relationship between interpersonal leadership and proactive service performance.Research limitations/implicationsThe online data collection procedure conducted through LinkedIn and Facebook and cross-sectional, self-reported survey method are significant limitations of the current study.Practical implicationsThe findings of the study will aid in developing organizational interventions for an engaged and proactive frontline service workforce, as interpersonal leadership can positively impact the engagement and proactive behavior of frontline service employees via initiative climate. Therefore, hospitality managers should value interpersonal leadership and initiative climate as coexisting organizational resources.Originality/valueThe study shows the significance of initiative climate in the relationships between interpersonal leadership, employee engagement and the proactive performance of frontline service employees.
Sensitivity analysis for automotive EMC measurements using quasistatic Darwin model
Authors: Bingler Arnold , Bilicz Sándor , Csörnyei Márk 
Published: December 2021

Purpose
The purpose of this paper is performing a global sensitivity analysis for automotive electromagnetic compatibility (EMC) measurements related to the CISPR 25 setup in order to examine the effect of the setup uncertainties on the resonance phenomenon.

Design/methodology/approach
An integral equation formulation is combined with Darwin model and special Green’s functions to model the configuration. The method of Sobol’ indices is used to gain sensitivity factors enhanced with a polynomial chaos metamodel.

Findings
The proposed model resulted in by orders of magnitude lower number of degrees of freedom and runtime compared to popular numerical methods, e.g. finite element method. The result of the sensitivity study is in good agreement with the underlying physical phenomena and improves the understanding of the resonances.

Practical implications
The fast model supplemented by the sensitivity factors can be used in EMC design and optimization.

Originality/value
The proposed method is original in the sense of combining a polynomial chaos metamodel with a low-cost integral equation model to reduce the computational demand for the sensitivity study.
A solution to the problem of brand definition
Authors: Avis Mark , Henderson Isaac Levi 
Published: December 2021

Purpose
This paper aims to critically evaluate the definition of the brand concept, support the critique with an empirical study and provide a definition to resolve the problems that have been identified.

Design/methodology/approach
This paper combines a conceptual critique with empirical research using a sample of 730 journal papers to analyse the scope and number of brand-related concepts in extant literature.

Findings
The brand concept has evolved to become problematic with no clarity of definition. There has been an explosion in the number of brand-related concepts that make the brand concept opaque and unwieldy. Based upon the findings, the authors argue that it is necessary to return to a “label and associations model” of the brand concept to ameliorate these issues.

Research limitations/implications
The empirical research presented examines only 730 papers from a much wider body of brand literature. Nonetheless, it illustrates the fact that researchers and theorists are not talking about the same concept when using the term “brand”.

Practical implications
Practitioners are not being served by academic branding literature because no two researchers appear to be studying the same entity. This prevents a body of research from being built to guide practitioners.

Originality/value
This paper makes an original contribution by combining a conceptual critique and empirical study to examine the problems arising from the absence of an agreed definition of the brand concept and uses this as a foundation for creating a resolution to the problems.