bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leveraging Fungal Calcineurin-Inhibitor Structures, Biophysics and Dynamics to Design Selective and Non-Immunosuppressive FK506 Analogs
Authors: Gobeil Sophie M.-C. , Bobay Benjamin G. , Juvvadi Praveen R. , Cole D. Christopher , Heitman Joseph , Steinbach William J. , Venters Ronald A. , Spicer Leonard D. 
Published: April 2020

AbstractCalcineurin is a critical enzyme in fungal pathogenesis and antifungal drug tolerance and, therefore, an attractive antifungal target. Current clinically-accessible calcineurin inhibitors, such as FK506, are immunosuppressive to humans, so exploiting calcineurin inhibition as an antifungal strategy necessitates fungal-specificity in order to avoid inhibiting the human pathway. Harnessing fungal calcineurin-inhibitor crystal structures, we recently developed a less immunosuppressive FK506 analog, APX879, with broad-spectrum antifungal activity and demonstrable efficacy in a murine model of invasive fungal infection. Our overarching goal is to better understand, at a molecular level, the interaction determinants of the human and fungal FK506-binding proteins (FKBP12) required for calcineurin inhibition in order to guide the design of fungal-selective, non-immunosuppressive FK506 analogs. To this end, we characterized high-resolution structures of theM. circinelloidesFKBP12 bound to FK506, and of theA. fumigatus, M. circinelloidesand human FKBP12 proteins bound to the FK506 analog, APX879, which exhibits enhanced selectivity for fungal pathogens. Combining structural, genetic and biophysical methodologies with molecular dynamics simulations, we identify critical variations in these structurally similar FKBP12-ligand complexes that will guide the rational design of inhibitors with enhanced fungal-selectivity.Significance statementInvasive fungal infections are a leading cause of death in the immunocompromised patient population. The rise in drug resistance to current antifungals highlights the urgent need to develop more efficacious and highly selective agents. Numerous investigations of major fungal pathogens have confirmed the critical role of the calcineurin pathway for fungal virulence, making it an attractive target for antifungal development. Although FK506 inhibits calcineurin, it is immunosuppressive in humans and cannot be used as an antifungal. By combining structural, genetic, biophysical, andin silicomethodologies, we pinpoint regions of FK506 and a less immunosuppressive analog, APX879, that could be altered to enhance fungal selectivity. This work represents a significant advancement toward realizing calcineurin as a viable target for antifungal drug discovery.
Efficient phasing and imputation of low-coverage sequencing data using large reference panels
Authors: Rubinacci S. , Ribeiro D.M. , Hofmeister R. , Delaneau O. 
Published: April 2020

AbstractLow-coverage whole genome sequencing followed by imputation has been proposed as a cost-effective genotyping approach for disease and population genetics studies. However, its competitiveness against SNP arrays is undermined as current imputation methods are computationally expensive and unable to leverage large reference panels.Here, we describe a method, GLIMPSE, for phasing and imputation of low-coverage sequencing datasets from modern reference panels. We demonstrate its remarkable performance across different coverages and human populations. It achieves imputation of a full genome for less than $1, outperforming existing methods by orders of magnitude, with an increased accuracy of more than 20% at rare variants. We also show that 1x coverage enables effective association studies and is better suited than dense SNP arrays to access the impact of rare variations. Overall, this study demonstrates the promising potential of low-coverage imputation and suggests a paradigm shift in the design of future genomic studies.
Temporal ordering of omics and multiomic events inferred from time series data
Authors: Kaur Sandeep , Peters Timothy J. , Yang Pengyi , Luu Laurence Don Wai , Vuong Jenny , Krycer James R. , O’Donoghue Seán I. 
Published: April 2020

AbstractTemporal changes in omics events can now be routinely measured, however current analysis methods are often inadequate, especially for multiomics experiments. We report a novel analysis method that can infer event ordering at better temporal resolution than the experiment, and integrates omic events into two concise visualizations (event maps and sparklines). Testing our method gave results well-correlated with prior knowledge and indicated it streamlines analysis of time-series data.
Subtypes of functional connectivity associate robustly with ASD diagnosis
Authors: Urchs Sebastian G. , Tam Angela , Orban Pierre , Moreau Clara , Benhajali Yassine , Nguyen Hien Duy , Evans Alan C. , Bellec Pierre 
Published: April 2020

AbstractOur understanding of the changes in functional brain organization in autism is hampered by the extensive heterogeneity that characterizes this neurodevelopmental disorder. Data driven clustering offers a straightforward way to decompose this heterogeneity into subtypes of distinguishable connectivity types and promises an unbiased framework to investigate behavioural symptoms and causative genetic factors. Yet the robustness and generalizability of these imaging subtypes is unknown. Here, we show that unsupervised functional connectivity subtypes are moderately associated with the clinical diagnosis of autism, and that these associations generalize to independent replication data. We found that subtypes identified robust patterns of functional connectivity, but that a discrete assignment of individuals to these subtypes was not supported by the data. Our results support the use of data driven subtyping as a data dimensionality reduction technique, rather than to establish clinical categories.
Substrate binding and turnover modulate the affinity landscape of dihydrofolate reductase to increase its catalytic efficiency
Authors: Galenkamp Nicole Stéphanie , Maglia Giovanni 
Published: April 2020

AbstractIt is generally accepted that enzymes structures evolved to stabilize the transition-state of a catalyzed reaction. Here, observing single molecules with a multi-turnover resolution, we provide experimental evidence for a more sophisticated narrative. We found that the binding of the NADPH cofactor to DHFR induces a first allosteric change that increases the affinity of the enzyme for the substrate. Then the enthalpy generated by the chemical step provides a power stroke that switches the enzyme to the product-bound conformations and promotes the release of the oxidized cofactor NADP+. The subsequent binding of NADPH to the vacated site provides the free energy for the recovery stroke, which induces the allosteric release of the product and resets the initial configuration. Intriguingly, the cycle is not perfect. Occasionally, DHFR undergoes second-long catalytic pauses, most likely reflecting the occupancy of an off-path conformation induced by excess energy liberated by the chemical step. This catalytic remodeling of the affinity landscape of DHFR is likely to have evolved to improve the efficiency of the reaction to cope with the high concentration of NADP+ inE. coli.And might be a general feature for complex enzymatic reaction where the binding and release of the products must be tightly controlled.
Two-dimensional reward evaluation in mice
Authors: Nachev Vladislav , Rivalan Marion , Winter York 
Published: April 2020

AbstractWhen choosing among multi-attribute options, integrating the full information may be computationally costly and time-consuming. So-called non-compensatory decision rules only rely on partial information, for example when a difference on a single attribute overrides all others. Such rules may be ecologically more advantageous, despite being economically suboptimal. Here we present a study that investigates to what extent animals rely on integrative rules (using the full information) versus non-compensatory rules when choosing where to forage. Groups of mice were trained to obtain water from dispensers varying along two reward dimensions: volume and probability. The mice’s choices over the course of the experiment suggested an initial reliance on integrative rules, later displaced by a sequential rule, in which volume was evaluated before probability. Our results also demonstrate that while the evaluation of probability differences may depend on the reward volumes, the evaluation of volume differences is seemingly unaffected by the reward probabilities.
Gait analysis of healthy rhesus monkeys using a pressure-sensing walkway system
Authors: Won Jinyoung , Kim Keonwoo , Yeo Hyeon-Gu , Park Junghyung , Seo Jincheol , Kim Yu Gyeong , Park Sung-Hyun , Choi Won Seok , Jeon Chang-Yeop , Lim Kyung Seob , Huh Jae-Won , Kim Young-Hyun , Jeong Jinwoo , Choi Ji-Woong , Lee Youngjeon 
Published: April 2020

AbstractGait analysis in non-human primate models has been performed to elucidate the neural systems involved in controlling quadrupedal locomotor behavior. This study aimed to use a pressure-sensing walkway to identify characteristics of species-specific quadrupedal locomotion in rhesus monkeys. A total of nine healthy adult female rhesus monkeys(Macaca mulatta)were used for gait analysis. We measured the temporo-spatial and kinetic parameters of quadrupedal gait using a custom-built pressure-sensing walkway and compared the left- and right-side parameters to assess the symmetry of the gait pattern. All temporo-spatial and kinetic parameter values showed no significant differences among the nine rhesus monkeys for both the forelimbs and hindlimbs. However, significant differences were observed between forelimb and hindlimb kinetic parameters such as peak vertical force, vertical impulse, and the percentage of body weight distribution. All kinetic parameter values were higher for the forelimbs than for the hindlimbs. These data indicated that the center of gravity in healthy rhesus monkeys is located at the forelimbs rather than at the hindlimbs while walking. Furthermore, the symmetry indices considered for symmetric gait pattern showed a low variability. Most median symmetry index values were nearly zero, indicating no difference between the right and left sides. This study described valid methods for assessing gait parameters and demonstrated rhesus-specific characteristics of quadrupedal locomotion, providing a basis for the assessment of gait normality in rhesus monkeys.
Rapid and robust antibody Fab fragment crystallization utilizing edge-to-edge beta-sheet packing
Authors: Lieu Ricky , Antonysamy Stephen , Druzina Zhanna , Ho Carolyn , Kang Rebecca , Pustilnik Anna , Wang Jing , Atwell Shane 
Published: April 2020

AbstractAntibody therapeutics are one of the most important classes of drugs. Antibody structures have become an integral part of predicting the behavior of potential therapeutics, either directly or as the basis of modeling. Structures of Fab:antigen complexes have even greater value. While the crystallization and structure determination of Fabs is easy relative to many other protein classes, especially membrane proteins, broad screening and optimization of crystalline hits is still necessary. Through a comprehensive review of rabbit Fab crystal contacts and their incompatibility with human Fab structures, we identified a small secondary structural element from the rabbit light chain constant domain potentially responsible for hindering the crystallization of human Fabs. Upon replacing the human kappa constant domain FG loop (HQGLSSP) with the two residue shorter rabbit loop (QGTTS), we dramatically improved the crystallization of human Fabs and Fab:antigen complexes. Our design, which we call “Crystal Kappa”, enables rapid crystallization of human fabs and fab complexes in a broad range of conditions, with less material in smaller screens or from dilute solutions.
A Deep Learning Pipeline for Nucleus Segmentation
Authors: Zaki George , Gudla Prabhakar R. , Lee Kyunghun , Kim Justin , Ozbun Laurent , Shachar Sigal , Gadkari Manasi , Sun Jing , Fraser Iain D.C. , Franco Luis M. , Misteli Tom , Pegoraro Gianluca 
Published: April 2020

AbstractDeep learning is rapidly becoming the technique of choice for automated segmentation of nuclei in biological image analysis workflows. In order to evaluate the feasibility of training nuclear segmentation models on small, custom annotated image datasets that have been augmented, we have designed a computational pipeline to systematically compare different nuclear segmentation model architectures and model training strategies. Using this approach, we demonstrate that transfer learning and tuning of training parameters, such as the composition, size and pre-processing of the training image dataset, can lead to robust nuclear segmentation models, which match, and often exceed, the performance of existing, off-the-shelf deep learning models pre-trained on large image datasets. We envision a practical scenario where deep learning nuclear segmentation models trained in this way can be shared across a laboratory, facility, or institution, and continuously improved by training them on progressively larger and varied image datasets. Our work provides computational tools and a practical framework for deep learning-based biological image segmentation using small annotated image datasets.
Causes and consequences of bacteriophage diversification via genetic exchanges across lifestyles and bacterial taxa
Authors: Moura de Sousa Jorge A. , Pfeifer Eugen , Touchon Marie , Rocha Eduardo P.C. 
Published: April 2020

ABSTRACTBacteriophages (phages) evolve rapidly by acquiring genes from other phages leading to mosaic genomes. Here, we identify numerous genetic transfers between distantly related phages and aim at understanding their frequency, consequences and the conditions favoring them. Gene flow tends to occur between phages that are enriched for recombinases, transposases and non-homologous end joining, suggesting that both homologous and illegitimate recombination contribute to gene flow. Phage family and host phyla are strong barriers to gene exchange, but phage lifestyle is not. We observe more exchanges between temperate phages even if they tend to have smaller genomes. These acquisitions often include transcription regulators and lysins. Yet, there is also extensive gene flow between temperate and virulent phages, or between the latter. These predominantly involve virulent phages with large genomes previously classed as low gene flux, and lead to the preferential transfer of genes encoding functions involved in cell energetics, nucleotide metabolism, DNA packaging and injection, and virion assembly. Such exchanges may explain the acquisition of genes in virulent phages, which tend to have the largest genomes. We used genetic transfers, which occur upon co-infection of a host, to compare phage host range. We found that virulent phages have broader host ranges and mediate genetic exchanges between narrow host range temperate phages infecting distant bacterial hosts, thus contributing to gene flow between virulent phages, as well as between temperate phages. This gene flow drastically expands the gene repertoires available for phage and bacterial evolution, including the transfer of functional innovations across taxa.
Prevention and Treatment of SHIVAD8 Infection in Rhesus Macaques by a Potent D-peptide HIV Entry Inhibitor
Authors: Nishimura Y. , Francis J.N. , Donau O. , Jesteadt E. , Sadjadpour R. , Smith A.R. , Seaman M.S. , Welch B.D. , Martin M.A. , Kay M.S. 
Published: April 2020

AbstractCholesterol-PIE12-trimer (CPT31) is a potent D-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a SHIV macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ~2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising new candidate for HIV prevention and treatment.
α-catenin switches between a slip and an asymmetric catch bond with F-actin to cooperatively regulate cell junction fluidity
Authors: Arbore C. , Sergides M , Gardini L. , Bianchi G. , Kashchuk A.V. , Pertici I. , Bianco P. , Pavone F.S. , Capitanio M. 
Published: April 2020

α-catenin is a crucial protein at cell junctions that provides connection between the actin cytoskeleton and the cell membrane. At adherens junctions (AJs), α-catenin forms heterodimers with β-catenin that are believed to resist force on F-actin. Outside AJs, α-catenin forms homodimers that directly connect the cell membrane to the actin cytoskeleton, but their mechanosensitive properties are inherently unknown.Surprisingly, by using ultra-fast laser tweezers we found that a single α-β-catenin heterodimer does not resist force but instead slips along F-actin in the direction of force. Conversely, the action of 5 to 10 α-β-catenin heterodimers together with force applied toward F-actin pointed end engaged a molecular switch in α-catenin, which unfolded and strongly bound F-actin as a cooperative catch bond. Similarly, an α-catenin homodimer formed an asymmetric catch bond with F-actin triggered by protein unfolding under force. Our data suggest that α-catenin clustering together with intracellular tension engage a fluid-to-solid phase transition at the membrane-cytoskeleton interface.
Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption
Authors: Karabegović Irma , Portilla-Fernandez Eliana , Li Yang , Ma Jiantao , Maas Silvana C.E. , Sun Daokun , Hu Emily A. , Kühnel Brigitte , Zhang Yan , Ambatipudi Srikant , Fiorito Giovanni , Huang Jian , Castillo-Fernandez Juan E. , Wiggins Kerri L. , de Klein Niek , Grioni Sara , Swenson Brenton R. , Polidoro Silvia , Treur Jorien L. , Cuenin Cyrille , Tsai Pei-Chien , Costeira Ricardo , Chajes Veronique , Braun Kim , Verweij Niek , Kretschmer Anja , Franke Lude , van Meurs Joyce B.J. , Uitterlinden André G. , de Knegt Robert J. , Ikram M. Arfan , Dehghan Abbas , Peters Annette , Schöttker Ben , Gharib Sina A. , Sotoodehnia Nona , Bell Jordana T. , Elliott Paul , Vineis Paolo , Relton Caroline , Herceg Zdenko , Brenner Hermann , Waldenberger Melanie , Rebholz Casey M. , Voortman Trudy , Pan Qiuwei , Fornage Myriam , Levy Daniel , Kayser Manfred , Ghanbari Mohsen 
Published: April 2020

AbstractCoffee and tea are extensively consumed beverages worldwide. Observational studies have shown contradictory findings for the association between consumption of these beverages and different health outcomes. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. We conducted epigenome-wide association studies (EWAS) on coffee and tea consumptions in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis revealed 11 CpG sites significantly associated with coffee consumption (P-value <1.1×10-7), nine of them annotated to the genesAHRR, F2RL3, FLJ43663, HDAC4, GFI1andPHGDH, and two CpGs suggestively associated with tea consumption (P-value<5.0×10-6). Among these, cg14476101 was significantly associated with expression of its annotated genePHGDHand risk of fatty liver disease. Knockdown ofPHGDHexpression in liver cells showed a correlation with expression levels of lipid-associated genes, suggesting a role ofPHGDHin hepatic-lipid metabolism. Collectively, this study indicates that coffee consumption is associated with differential DNA methylation levels at multiple CpGs, and that coffee-associated epigenetic variations may explain the mechanism of action of coffee consumption in conferring disease risk.
When love becomes hate: how different consumer-brand relationships interact with crises to influence consumers' reactions
Authors: Ma Liang 
Published: April 2020

PurposeA well-accepted proposition in the literature of corporate strategic communication and public relations is that consumer-brand relationships (CBRs) affect corporate crisis communication. However, it is inconclusive whether CBRs protect or work against brands, because both buffering effects and love-becomes-hate effects have been found. This study attempts to explain and bridge the seemingly inconsistent findings by clarifying the effects of different types of CBRs in different brand transgressions.Design/methodology/approachRe-conceptualizing CBRs into non-identifying relationships and identifying relationships, this study examined the possible interaction effects of CBRs and crises on consumers' attitudes and emotions, which then influence their behavioral intentions. A three-step multi-group structural equation modeling (SEM) was used to analyze the data collected from an online experiment with nearly 900 consumers of two brands.FindingsAlthough non-identifying relationships offer buffering effects, identifying relationships primarily offer love-becomes-hate effects by intensifying negative emotions such as anger and disappointment, which in turn affect consumers' behavioral intentions. Such patterns hold regardless of whether a crisis directly threatens the core meaning of the brand.Originality/valueThis study clarifies the effects of different types of CBRs in crises and shows that deep psychological connections (i.e. identifying relationships) offer love-becomes-hate effects. It suggests that one promising future research direction for crisis communication and public relations scholars is to examine how to mitigate such love-becomes-hate effects so that brands can keep their loyal consumers.
Managerial control mechanisms and their influence on project performance: an investigation of the moderating role of complexity risk
Authors: Maqsoom Ahsen , Hamad Muhammad , Ashraf Hassan , Thaheem Muhammad Jamaluddin , Umer Muhammad 
Published: April 2020

PurposeDespite the efforts of project managers and the widespread use of project management methodologies, most of the projects remain unfulfilling in terms of delivering targeted performance. This for most part can be attributed to the inability of an organization to implement control mechanisms and ineffective management of complexity risk. Keeping in view the aforementioned problem, the objective of this study is to investigate the association between control modes and project performance. Moreover, this study also examines the moderating role of complexity risk on the association among various control modes and project performance.Design/methodology/approachThe data were collected from 171 construction projects through a postal questionnaire survey. Partial least squares structural equation modeling was utilized for testing the hypothesized relationships of the research model.FindingsThis study found significant positive relation between formal and informal control mechanisms and project performance. It is found that complexity risk significantly moderates the relationship between control modes and project performance. The results indicate that complexity risk positively moderates the relationship between outcome control and clan control with project performance. Furthermore, complexity risks negatively moderates the relationship between behavior control and project performance. However, the association between self-control and project performance is found insignificant in the presence of complexity risk.Originality/valueThis study is the first attempt to study the relationship of control mechanisms, complexity risk and project performance in the construction industry.