bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core
Authors: Pak Alexander J. , Yu Alvin , Ke Zunlong , Briggs John A. G. , Voth Gregory A. 
Published: May 2021

AbstractThe molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind, fuse, and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes the preparation of the fusion machinery by dissociation of the S1 domains. We report the development of bottom-up coarse-grained (CG) models validated with cryo-electron tomography (cryo-ET) data, and the use of CG molecular dynamics simulations to investigate the dynamical mechanisms involved in viral binding and exposure of the S2 trimeric core. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces. The multivalent interaction cyclically and processively induces S1 dissociation, thereby exposing the S2 core containing the fusion machinery. Our simulations thus reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.
Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets
Authors: Guo Michael H. , Sama Prashanth , LaBarre Brenna A. , Lokhande Hrishikesh , Balibalos John , Chu Ci , Du Xiaomi , Kheradpour Pouya , Kim Charles C , Oniskey Taylor , Snyder Thomas , Soghoian Damien Z , Weiner Howard L. , Chitnis Tanuja , Patsopoulos Nikolaos A. 
Published: May 2021

AbstractMultiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. We utilized chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We found that CD4 T and B cells were independently enriched for MS genetics and further refined the driver subsets to Th17 and memory B cells, respectively. We replicated our findings in data from untreated and treated MS patients and found that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominated numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease.
A UAV-based high-throughput phenotyping approach to assess time-series nitrogen responses and identify traits associated genetic components in maize
Authors: Rodene Eric , Xu Gen , Delen Semra Palali , Smith Christine , Ge Yufeng , Schnable James , Yang Jinliang 
Published: May 2021

ABSTRACTAdvancements in the use of genome-wide markers have provided new opportunities for dissecting the genetic components that control phenotypic trait variation. However, cost-effectively characterizing agronomically important phenotypic traits on a large scale remains a bottleneck. Unmanned aerial vehicle (UAV)-based high-throughput phenotyping has recently become a prominent method, as it allows large numbers of plants to be analyzed in a time-series manner. In this experiment, 233 inbred lines from the maize diversity panel were grown in a replicated incomplete block under both nitrogen-limited conditions and following conventional agronomic practices. UAV images were collected during different plant developmental stages throughout the growing season. A pipeline for extracting plot-level images, filtering images to remove non-foliage elements, and calculating canopy coverage and greenness ratings based on vegetation indices (VIs) was developed. After applying the pipeline, about half a million plot-level image clips were obtained for 12 different time points. High correlations were detected between VIs and ground truth physiological and yield-related traits collected from the same plots, i.e., Vegetative Index (VEG) vs. leaf nitrogen levels (Pearson correlation coefficient, R = 0.73), Woebbecke index vs. leaf area (R = -0.52), and Visible Atmospherically Resistant Index (VARI) vs. 20 kernel weight – a yield component trait (R = 0.40). The genome-wide association study was performed using canopy coverage and each of the VIs at each date, resulting in N = 29 unique genomic regions associated with image extracted traits from three or more of the 12 total time points. A candidate gene Zm00001d031997, a maize homolog of the Arabidopsis HCF244 (high chlorophyll fluorescence 244), located underneath the leading SNPs of the canopy coverage associated signals that were repeatedly detected under both nitrogen conditions. The plot-level time-series phenotypic data and the trait-associated genes provide great opportunities to advance plant science and to facilitate plant breeding.
Towards a Mechanical Model for anisotropic Glioma Spread using Darcy’s law
Authors: Reséndiz Margarita 
Published: May 2021

The growth of a tumor within a finite domain (skull) generates mechanical forces that alter the physical interactions among cells. The relationship between these forces and the tumor architecture remains an open problem subjected to extensive research. Recently, it has been determined that those regions of high mechanical compression can accelerate and intensify the invasive capacity of the malignant cells, forming an irregular tumor whose full extent and edges are difficult to identify.In the present paper, we propose a one-dimensional mathematical model that describes the process of proliferation and diffusion of glioma cells taking into account the mechanical compression generated during its expansion. Supported on the mixture theory, we model the brain-tumor system as a multiphase mixture of cancer cells, healthy cells, biological fluids and extracellular matrix whose densities determine the mechanical loads generated during the volumetric growth. Our model provides a detailed understanding of the pressure distribution on the interface boundary between healthy and cancer cells. It validates the hypothesis that the conferred ability of cancer cells to proliferate depends strongly on the mechanical pressure sensed. Through the analysis of the mechanical pressure, we determine that the anisotropic loads promote cancer cells to grow preferentially in the directions of low mechanical compression.
Island-specific evolution of a sex-primed autosome in the planarianSchmidtea mediterranea
Authors: Guo Longhua , Bloom Joshua , Serrate Daniel Dols , David Eyal Ben , Schubert Olga T. , Kazuma Kaiya , Ho Katarina , Wei Yubao , Leighton Daniel , Boocock James , Vergara Tzitziki Lemus , Riutort Marta , Alvarado Alejandro Sánchez , Kruglyak Leonid 
Published: May 2021

AbstractThe sexual biotype of the planarianSchmidtea mediterraneais a hermaphrodite indigenous to Tunisia and several Mediterranean islands. Here, we isolated individual chromosomes and used sequencing, Hi-C and linkage mapping to assemble a chromosome-scale genome reference. The linkage map revealed an extremely low rate of recombination on chromosome 1. We confirmed suppression of recombination on chromosome 1 by quantifying recombination events in individual sperm and oocytes. We showed that the extensive heterozygous regions, previously designated as J and V haplotypes, comprise essentially all of chromosome 1. Genome sequencing of individuals isolated in the wild indicated that this heterozygosity has evolved specifically in populations from Sardinia and Corsica. We found that chromosome 1 acquired many genes that determine the development of female and male reproductive systems, along with haplotype-specific expression of such sex specific genes. These molecular signatures and restricted recombination in a hermaphrodite led us to propose that chromosome 1 is a sex-primed autosome, providing direct molecular evidence for the traditional model of how sex chromosomes may have evolved from autosomes.
A method for single molecule localization microscopy of tissues reveals non-random distribution of nuclear pores in Drosophila
Authors: Cheng Jinmei , Allgeyer Edward S. , Richens Jennifer H. , Džafić Edo , Palandri Amandine , Lewkow Bohdan , Sirinakis George , Johnston Daniel St 
Published: May 2021

AbstractSingle Molecule Localisation Microscopy (SMLM) can provide nanoscale resolution in thin samples but has rarely been applied to tissues, because of high background from out of focus emitters. Here we describe a line scanning microscope that provides optical sectioning for SMLM in tissues. Imaging endogenously-tagged nucleoporins and F-actin on this system using DNA- and peptide-PAINT routinely gives 30nm resolution or better at depths greater than 20 µm. This revealed that the nuclear pores are nonrandomly distributed in most Drosophila tissues, in contrast to cultured cells. Lamin Dm0 shows a complementary localisation to the nuclear pores, suggesting that it corrals the pores. Furthermore, ectopic expression of the tissue-specific Lamin C distributes the nuclear pores more randomly, whereas lamin C mutants enhance nuclear pore clustering, particularly in muscle nuclei. Since nucleoporins interact with specific chromatin domains, nuclear pore clustering could regulate chromatin organisation locally and contribute to the disease phenotypes caused by human Lamin A/C laminopathies.
Species’ traits and exposure as a future lens for quantifying seabird bycatch vulnerability in global fisheries
Authors: Richards Cerren , Cooke Robert S. C. , Bowler Diana E. , Boerder Kristina , Bates Amanda E. 
Published: May 2021

AbstractFisheries bycatch, the incidental mortality of non-target species, is a global threat to seabirds and a major driver of their declines worldwide. Identifying the most vulnerable species is core to developing sustainable fisheries management strategies that aim to improve conservation outcomes. To advance this goal, we present a preliminary vulnerability framework that integrates dimensions of species’ exposure, sensitivity, and adaptive capacity to fisheries bycatch to classify species into five vulnerability classes. The framework combines species’ traits and distribution ranges for 341 seabirds, along with a spatially resolved fishing effort dataset. Overall, we find most species have high vulnerability scores for the sensitivity and adaptive capacity dimensions. By contrast, exposure is more variable across species, and thus the median scores calculated within seabird families is low. We further find 46 species have high exposure to fishing activities, but are not identified as vulnerable to bycatch, whilst 133 species have lower exposure, but are vulnerable to bycatch. Thus, the framework has been valuable for revealing patterns between and within the vulnerability dimensions. Still, further methodological development, additional traits, and greater availability of threat data are required to advance the framework and provide a new lens for quantifying seabird bycatch vulnerability that complements existing efforts, such as the International Union for Conservation of Nature (IUCN) Red List.
Entry Pathway for the Inverse Agonist Ligand in the G Protein-Coupled Receptor Rhodopsin
Authors: Tian He , Gunnison Kathryn M. , Kazmi Manija A. , Sakmar Thomas P. , Huber Thomas 
Published: May 2021

ABSTRACTWhile the number of high-resolution structures of ligand-bound G protein-coupled receptors (GPCRs) has been steadily climbing, ligand binding and unbinding pathways remain largely undefined. The visual photoreceptor rhodopsin (Rho) represents a curious case among GPCRs because its primary ligand 11-cis-retinal (11CR) is an inverse agonist, which partitions into the bilayer and is likely to enter its orthosteric binding pocket through an intermembranous pathway. Light activates Rho by converting 11CR to all-trans-retinal (ATR), which serves as an agonist ligand. The light-triggered switch from the inactive to the active conformation creates two openings in the transmembrane region, suggesting pathways for exit of ATR and subsequent entry of 11CR to regenerate Rho. However, stabilization of an active ligand-free opsin conformation has been found to inhibit 11CR binding. Here we address this paradox of opsin regeneration with 11CR. We used genetic code expansion to engineer Rho mutants that serve as fluorescence sensors for measuring 11CR binding kinetics and energetics. We found mutations that alter a channel between transmembrane helices 5 and 6 (TM5/6) dramatically affect 11CR binding kinetics, but not ATR release kinetics. Our data provide direct experimental evidence for 11CR entry between TM5/6 in Rho that involves dynamic allosteric control of the ligand entry channel. Our findings can be extended to other visual pigments and a wide range of GPCRs with hydrophobic ligands that are hypothesized to enter their binding pockets through transmembrane pores.
Gaseous Signaling Compounds (Hydrogen Sulfide and Nitric Oxide) and Their Relative Roles in Affecting Anaerobic HeLa 229 Cell Viability
Authors: Plotkin Balbina J. , Sigar Ira M. , Kaminski Amber 
Published: May 2021

AbstractMetabolic pathways supporting long-term anaerobic cell viability have not been identified. The effect NO and H2S pathway effectors have on HeLa 229 cell viability was measured after 10 days anaerobic incubation. The addition of arginine or xanthine (NO pathway precursors) consistently increased HeLa cell viability by 13.1- and 4.4-fold, respectively. Allopurinol, a xanthine oxidase inhibitor, also increased viability, as compared to control levels. In contrast, inhibition of iNOS by 1400W increased cell viability by 79-fold. Regarding the H2S pathway, precursor cysteine enhanced viability by 9.8-fold with the greatest number of viable cells measured in response to the presence of a H2S donor (GYY4137), or an inhibitor of glutathione synthesis, propargylglycine (40- and 85-fold, respectively). These results demonstrate that the constitutive level of cell viability after extended (10 days) growth without oxygen can be modulated by affecting NO or H2S generating pathways.
Natural variation in a short region of the Acidovorax citrulli type III-secreted effector AopW1 is associated with differences in cytotoxicity
Authors: Jiménez-Guerrero Irene , Sonawane Monica , Eckshtain-Levi Noam , Da Silva Gustavo Mateus , Pérez-Montaño Francisco , Leibman-Markus Meirav , Noda-Garcia Lianet , Bar Maya , Burdman Saul 
Published: May 2021

ABSTRACTBacterial fruit blotch (BFB) is a serious disease of melon and watermelon caused by the Gram-negative bacterium Acidovorax citrulli. The strains of the pathogen can be divided into two major genetic groups, I and II. While group I strains are strongly associated with melon, group II strains are more aggressive on watermelon. Like many pathogenic bacteria, A. citrulli secretes a variety of protein effectors to the host cell via the type III secretion system. In the present study, we characterized AopW1, an A. citrulli type III-secreted effector that shares similarity with the actin cytoskeletondisrupting effector HopW1 of Pseudomonas syringae and with effectors from other plant-pathogenic bacterial species. aopW1 is present in group I and II strains, encoding products of 485 amino acids. Although highly conserved in most of the sequence, AopW1 has a highly variable region (HVR) within amino acid positions 147 to 192, including 14 amino acid differences between groups. Here we show that group I AopW1 is more toxic to yeast and plant cells than group II AopW1, having a stronger actin filament disruption activity, and increased ability to reduce plant callose deposition. We demonstrate the role of some of these 14 amino acid positions in determining the phenotypic differences between the two versions of the effector. Moreover, cellular analyses revealed that in addition to the interaction with actin filaments, AopW1 is localized to the endoplasmic reticulum, chloroplasts, and early and recycling plant endosomes, with differences observed between the two AopW1 versions. Finally, we show that overexpression of the endosome-associated protein EHD1 that increases cellular recycling, attenuates the toxic effects exerted by AopW1 and increases defence responses. This study provides insights into the HopW1 family of bacterial effectors and their interactions with the plant cell and provides first evidence on the involvement of EHD1 in response to biotic stress.
Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice
Authors: Hioe Catarina E. , Li Guangming , Liu Xiaomei , Tsahouridis Ourania , He Xiuting , Funaki Masaya , Klingler Jéromine , Tang Alex F. , Feyznezhad Roya , Heindel Daniel W. , Wang Xiao-Hong , Spencer David A. , Hu Guangna , Satija Namita , Prévost Jérémie , Finzi Andrés , Hessell Ann , Wang Shixia , Lu Shan , Chen Benjamin K. , Zolla-Pazner Susan , Upadhyay Chitra , Alvarez Raymond , Su Lishan 
Published: May 2021

AbstractAntibodies are principal immune components elicited by vaccines to induce protection from microbial pathogens. In the Thai RV144 HIV-1 vaccine trial, vaccine efficacy was 31% and the sole primary correlate of reduced risk was shown to be vigorous antibody response targeting the V1V2 region of HIV-1 envelope. Antibodies against V3 also were inversely correlated with infection risk in subsets of vaccinees. Antibodies recognizing these regions, however, do not exhibit potent neutralizing activity. Therefore, we examined the antiviral potential of poorly neutralizing monoclonal antibodies (mAbs) against immunodominant V1V2 and V3 sites by passive administration of human mAbs to humanized mice engrafted with CD34+ hematopoietic stem cells, followed by mucosal challenge with an HIV-1 infectious molecular clone (IMC) expressing the envelope of a tier 2 resistant HIV-1 strain. Treatment with anti-V1V2 mAb 2158 or anti-V3 mAb 2219 did not prevent infection, but both reduced the virus burden, and V3 mAb 2219 displayed a superior potency compared to V1V2 mAb 2158. While these mAbs had no or weak neutralizing activity and elicited undetectable levels of antibody-dependent cellular cytotoxicity (ADCC), V3 mAb 2219 displayed a greater capacity to bind virus- and cell-associated HIV-1 envelope and to mediate antibody-dependent cellular phagocytosis (ADCP) and C1q complement binding as compared to V1V2 mAb 2158. Mutations in the Fc region of 2219 abolished these effector activities and abrogated virus control in humanized mice. These results demonstrate the importance of Fc functions other than ADCC for antibodies without potent neutralizing activity.
Structure-function relationship for a divergent Atg8 protein required for a non-autophagic function in malaria parasites
Authors: Walczak Marta , Meister Thomas R. , Zhu Yili , Yeh Ellen 
Published: May 2021

AbstractAtg8 family proteins are highly-conserved eukaryotic proteins with diverse autophagy and non-autophagic functions in eukaryotes. While the structural features required for conserved autophagy functions of Atg8 are well-established, little is known about the molecular changes that facilitated acquisition of divergent, non-autophagic functions of Atg8. The malaria parasite Plasmodium falciparum offers a unique opportunity to study non-autophagic functions of Atg8 family proteins because it encodes a single Atg8 homolog whose only essential function is in the inheritance of an unusual secondary plastid called the apicoplast. Here we used functional complementation to investigate the structure-function relationship for this divergent Atg8 protein. We showed that the LC3-interacting region (LIR) docking site (LDS), the major interaction interface of Atg8 protein family, is not sufficient for PfAtg8 apicoplast function. Other regions previously implicated in canonical Atg8 interactions, the ubiquitin-interacting motif (UIM) docking site (UDS) and the N-terminal helix are not required for PfAtg8 function. Finally, the unique Apicomplexan-specific loop previously implicated in interaction with membrane conjugation machinery in vitro, is not required in vivo neither for membrane conjugation nor for the effector function of PfAtg8. These results suggest that the effector function of PfAtg8 is mediated by structural features distinct from those previously identified for macroautophagy and selective autophagy functions.ImportanceThe most extensively studied role of Atg8 proteins is in autophagy. However, it is clear that they have other non-autophagic functions critical to cell function and disease pathogenesis yet understudied compared to their canonical role in autophagy. Mammalian cells contain multiple Atg8 paralogs that have diverse, specialized functions. Gaining molecular insight into their non-autophagic functions is difficult because of redundancy between the homologs and their role in both autophagy and non-autophagic pathways. Malaria parasites such as Plasmodium falciparum are a unique system to study a novel, non-autophagic function of Atg8 separate from its role in autophagy: They have only one Atg8 protein whose only essential function is in the inheritance of the apicoplast, a unique secondary plastid organelle. Insights into the molecular basis of PfAtg8’s function in apicoplast biogenesis will have important implications for the evolution of diverse non-autophagic functions of the Atg8 protein family.
Cholesterol Oxidation Modulates the Formation of Liquid-Ordered Domains in Model Membranes
Authors: Smith Paul , Petrov Peter G. , Lorenz Christian D. 
Published: May 2021

Abstract7-ketocholesterol (KChol) is one of the most cytotoxic oxysterols found in the plasma membrane, and increased levels of KChol are associated with numerous pathologies. It is thought to induce apoptosis via inactivation of the phosphatidylinositol 3-kinase/Akt signaling pathway — a pathway that depends on lipid-rafts as signaling platforms. By means of coarse-grained molecular dynamics simulations, we demonstrate that KChol disrupts the liquid-liquid phase separation seen in an equimolar mixture of (dipalmitoylphosphatidylcholine) DPPC, (dioleoylphosphatidylcholine) DOPC, and Cholesterol (Chol). This disruption occurs via two mechanisms: i) KChol adopts a wider range of orientations with the membrane, which disrupts the packing of neigh-boring lipids and ii) KChol has no preference for DPPC over DOPC, which is the main driving force for lateral demixing in DPPC/DOPC/Chol membranes. This provides a molecular description of the means by which KChol induces apoptosis, and illustrates that a single chemical substitution to cholesterol can have a profound impact on the lateral organization of lipid membranes.Graphical TOC Entry