bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and utilization of a surrogate SARS-CoV-2 viral neutralization assay to assess mRNA vaccine responses
Authors: Wisnewski Adam V , Liu Jian , Lucas Carolina , Klein Jon , Iwasaki Akiko , Cantley Linda , Fazen Louis , Luna Julian Campillo , Slade Martin , Redlich Carrie A 
Published: August 2021

AbstractBackgroundTests for SARS-CoV-2 immunity are needed to help assess responses to vaccination, which can be heterogeneous and may wane over time. The plaque reduction neutralization test (PRNT) is considered the gold standard for measuring serum neutralizing antibodies but requires high level biosafety, live viral cultures and days to complete. We hypothesized that competitive enzyme linked immunoassays (ELISAs) based on SARS-CoV-2 spike protein’s receptor binding domain (RBD) attachment to its host receptor, the angiotensin converting enzyme 2 receptor (ACE2r), would correlate with PRNT, given the central role of RBD-ACE2r interactions in infection and published studies to date, and enable evaluation of vaccine responses.Methods and FindingsConfiguration and development of a competitive ELISA with plate-bound RBD and soluble biotinylated ACE2r was accomplished using pairs of pre/post vaccine serum. When the competitive ELISA was used to evaluate N=32 samples from COVID-19 patients previously tested by PRNT, excellent correlation in IC50 results were observed (rs= .83, p < 0.0001). When the competitive ELISA was used to evaluate N=41 vaccinated individuals and an additional N=14 unvaccinated recovered COVID-19 patients, significant differences in RBD-ACE2r inhibitory activity were associated with prior history of COVID-19 and type of vaccine received. In longitudinal analyses pre and up to 200 days post vaccine, surrogate neutralizing activity increased markedly after primary and booster vaccine doses, but fell substantially, up to <12% maximal levels within 6 months.ConclusionsA competitive ELISA based on inhibition of RBD-ACE2r attachment correlates well with PRNT, quantifies significantly higher activity among vaccine recipients with prior COVID (vs. those without), and highlights marked declines in surrogate neutralizing activity over a 6 month period post vaccination. The findings raise concern about the duration of vaccine responses and potential need for booster shots.
Associations of behavioral problems and white matter properties of the cerebellar peduncles in boys and girls born full term and preterm
Authors: Hosoki Machiko , Bruckert Lisa , Borchers Lauren R. , Marchman Virginia A. , Travis Katherine E. , Feldman Heidi M. 
Published: August 2021

ABSTRACTAccumulating evidence suggests that the role of cerebellum includes regulation of behaviors; Cerebellar impairment may lead to behavioral problems. Behavioral problems differ by sex: internalizing problems are more common in girls, externalizing problems in boys. Behavioral problems are also elevated in children born preterm (PT) compared to children born full-term (FT). The current study examined internalizing and externalizing problems in 8-year-old children in relation to sex, birth-group, FA of the cerebellar peduncles, and interactions among these predictor variables. Participants (N=78) were 44 boys (28 PT) and 34 girls (15 PT). We assessed behavioral problems via standardized parent-reports and FA of the cerebellar peduncles using deterministic tractography. Internalizing problems were higher in children born PT compared to children born FT (p=.032); the interaction of sex and birth-group was significant (p=.044). When considering the contribution of the mean-tract FA of cerebellar peduncles to behavioral problems, there was a significant interaction of sex and mean-tract FA of the ICP with internalizing problems; the slope was negative in girls (p=.020) but not boys. In boys, internalizing problems were only associated with mean-tract FA ICP in those born preterm (p=.010). We found no other significant associations contributing to internalizing or externalizing problems. Thus, we found sexual dimorphism and birth-group differences in the association of white matter metrics of the ICP and internalizing problems in school-aged children. The findings inform theories of the origins of internalizing behavioral problems in middle childhood and may suggest approaches to treatment at school age.
Distribution of rare LOXL1 missense alleles, haplotypes and diplotypes suggests association with reduced risk of glaucoma-related exfoliation syndrome
Authors: Igo Rob P. , Kinzy Tyler G. , Cooke Bailey Jessica N. , Khor Chiea Chuen , Aung Tin , Ritch Robert , Sit Arthur J. , Lee Richard K. , Pericak-Vance Margaret , Kang Jae H. , Haines Jonathan L. , Pasquale Louis R. , Wiggs Janey L. 
Published: August 2021

ABSTRACTPurposeCommon LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele has been associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study was to assess the contributions of rare LOXL1 variants to XFS/XFG risk in cases and controls from the United States.MethodsLOXL1 rare (minor allele frequency less than 1%) variants were identified from Humanexome BeadArray (Illumina) data for 1118 XFS/XFG cases and 3661 controls. Distribution of rare variants, haplotypes (defined using IMPUTE2) and diplotypes were examined using the Fisher’s exact test. Rare variant allele distribution was confirmed in an independent set of primary open angle glaucoma (POAG) controls and multi-ethnic datasets. Correlation of LOXL1 common allele homozygosity with disease risk used data from gnomAD (gnomad.broadinstitute.org/) and an existing multi-ethnic meta-analysis.ResultsFour rare LOXL1 missense alleles were identified, and all were more common in controls (combined P= 7.6E-4), with two of these located in a LOXL1 intrinsic disordered region (IDR) known to be involved in LOXL1 aggregation. Haplotypes that included the rare or minor variants were more common in controls compared to cases (OR= 0.33, P=1.7E-8). Heterozygous diplotypes were significantly associated with reduced risk overall (OR= 0.45 P= 1.7 E-89) with the largest effects observed for diplotypes with more than one heterozygous genotype (OR= 0.05, P= 1.0E-39). A homozygous diplotype was associated with increased disease risk (OR= 6.8, P= 4.7E-157) and homozygosity was correlated with disease risk for common LOXL1 variants across multi-ethnic populations (Pearson= 0.92, P<0.001).ConclusionsUsing exome array data from XFS/XFG cases and controls from the United States, we identify 4 rare protective LOXL1 missense variants and show that the distribution of the corresponding haplotypes and diplotypes are associated with reduced risk of XFS/XFG. The diplotype results also demonstrate that LOXL1 allelic heterozygosity is protective while homozygosity is associated with increased disease risk. These results suggest that LOXL1 minor allele frequency variation among populations, with corresponding variation in genotype heterozgyosity and homozygosity, determines the XFS/XFG association effects and that genotypic effects may also impact protein aggregation involving intrinsic disordered regions.
Evolutionary dynamics of DIRS-like and Ngaro-like retrotransposons in Xenopus laevis and Xenopus tropicalis genomes
Authors: Gazolla Camilla Borges , Ludwig Adriana , de Moura Gama Joana , Bruschi Daniel Pacheco 
Published: August 2021

ABSTRACTAnuran genomes have a large number and diversity of transposable elements, but are little explored, mainly in relation to their molecular structure and evolutionary dynamics. Here, we investigated the retrotransposons containing tyrosine recombinase (YR) (order DIRS) in the genome of Xenopus tropicalis and Xenopus laevis. These anurans show 2n = 20 and the 2n = 36 karyotypes, respectively. They diverged about 48 million years ago (mya) and X. laevis had an allotetraploid origin (around 17-18 mya). Our investigation is based on the analysis of the molecular structure and the phylogenetic relationships of 95 DIRS families of Xenopus belonging to DIRS-like and Ngaro-like superfamilies. We were able to identify molecular signatures in the 5’ and 3’ non-coding terminal regions, preserved open reading frames (ORFs) and conserved domains that are specific to distinguish each superfamily. We recognize two ancient amplification waves of DIRS-like elements that occurred in the ancestor of both species and a higher density of the old/degenerate copies detected in the X. laevis. X. tropicalis showed more recent amplification waves estimated around 16 mya and 3.2 mya and corroborate with high diversity-level of families in this species and with transcriptional activity evidence. Ngaro-like elements presented less diversity and quantity in the genomes, although potentially active copies were also found. Our findings highlight a differential diversity-level and evolutionary dynamics of the YR retrotransposons in the diploid X. tropicalis and X. laevis species expanding our comprehension of the behavior of these elements in both genomes during the diversification process.
Automated MRI Lung Segmentation and 3D Morphological Features for Quantification of Neonatal Lung Disease
Authors: Mairhörmann Benedikt , Castelblanco Alejandra , Häfner Friederike , Pfahler Vanessa , Haist Lena , Waibel Dominik , Flemmer Andreas , Ehrhardt Harald , Stoecklein Sophia , Dietrich Olaf , Foerster Kai , Hilgendorff Anne , Schubert Benjamin 
Published: August 2021

ABSTRACTThe diagnosis of neonatal respiratory diseases is currently based on clinical criteria. However, lung structural information is generally lacking due to the unavailability of routinely applicable, radiation-free imaging tools as well as the time-consuming, often non-standardized manual analysis of imaging data. Increased efficiency, comparability and accuracy in image quantification is needed in this patient cohort as pulmonary complications determine immediate and long-term survival.We therefore developed an ensemble of deep convolutional neural networks to perform lung segmentation in magnetic resonance imaging (MRI) sequences obtained in premature infants near term (n=107), with subsequent reconstruction of the 3-dimensional neonatal lung and estimation of MRI lung descriptors for volume, shape, surface, and signal intensity distribution.Annotation of lung segments in quiet-breathing MRI for infants with and without Bronchopulmonary Dysplasia (BPD) was achieved by development of a deep learning model reaching a volumetric dice score (VDC) of 0.908 and validated in an independent cohort (VDC 0.880), thereby matching expert-level performance while demonstrating transferability, robustness towards technical (low spatial resolution, movement artifacts) and lung disease grades. MRI lung descriptors presented relevant correlations with lung lesion scores and enabled the separation of neonates with and without BPD (AUC 0.92±0.016), mild vs severe BPD (AUC 0.84±0.027), and single level prediction of BPD severity (AUC 0.75±0.013).Our work demonstrates the potential of AI-supported MRI markers as a diagnostic tool, characterizing changes in lung structure in neonatal respiratory disease while avoiding radiation exposure.
Ongoing mitigation strategies and further needs of the United States food industry to control COVID-19 in the work environment
Authors: Llanos-Soto Sebastian , Bulut Ece , Murphy Sarah I. , Henry Christopher J. , Zoellner Claire , Wiedmann Martin , Wetherington Diane , Adalja Aaron , Alcaine Samuel D. , Ivanek Renata 
Published: August 2021

AbstractThe COVID-19 pandemic has had dire effects on the United States (US) food industry through impacts on workers’ health and wellbeing and supply chain disruptions. The objectives of this study were to determine what the food industry needs to be able to control COVID-19 impacts in the work environment and what mitigation strategies are being implemented. A web-based needs assessment survey was distributed from January to April 2021, via 13 food professional/trade organizations and 2 social networks, targeting management professionals at food (produce, dairy, poultry, and beef/pork) processing facilities and produce farm operations in the US. Statistical analyses evaluated patterns in self-reported adoption of mitigation strategies against COVID-19 in the participants’ facilities/operations and perceived needs of the industry regarding COVID-Responses to open-ended questions were analyzed using thematic analysis. In total 145 responses were received, of which 79 were usable, including 38 (48%) from the dairy, 17 (22%) from the fresh produce, and 24 (30%) from a mixture of other food industry sectors. Only two usable responses were from the beef/pork sector and none from the poultry sector. Findings revealed that several social distancing, biosecurity, and surveillance mitigation strategies against COVID-19 are commonly implemented in the participants’ facilities/operations, but their implementation frequency differs by the facility/operation size and industry sector. Also, findings indicated that collaboration between the food industry and government agencies, contingency plans and appropriate training, and new technologies are needed to control COVID- 19 in the food industry. Subject to limitations associated with the relatively low response rate (possible selection bias), the findings suggest that the US food industry is prepared to safeguard workers’ health and businesses in the event of a new COVID-19 variant or similar future disaster, provided that appropriate structures are put in place to ensure coordination and compliance, both before and during such an outbreak.
Revealing how variations in antibody repertoires correlate with vaccine responses
Authors: Safonova Yana , Shin Sung Bong , Kramer Luke , Reecy James , Watson Corey T. , Smith Timothy P.L. , Pevzner Pavel A. 
Published: August 2021

AbstractAn important challenge in vaccine development is to figure out why a vaccine succeeds in some individuals and fails in others. Although antibody repertoires hold a key to answering this question, there have been very few personalized immunogenomics studies so far aimed at revealing how variations in immunoglobulin genes affect a vaccine response. We conducted an immunosequencing study of 204 calves vaccinated against bovine respiratory disease (BRD) with the goal to reveal variations in immunoglobulin genes and somatic hypermutations that impact the efficacy of vaccine response. Our study represents the largest longitudinal personalized immunogenomics study reported to date across all species, including humans. To analyze the generated dataset, we developed an algorithm for identifying variations of the immunoglobulin genes (as well as frequent somatic hypermutations) that affect various features of the antibody repertoire and titers of neutralizing antibodies. In contrast to relatively short human antibodies, cattle have a large fraction of ultralong antibodies that have opened new therapeutic opportunities. Our study revealed that ultralong antibodies are a key component of the immune response against the costliest disease of beef cattle in North America. The detected variants of the cattle immunoglobulin genes, which are implicated in the success/failure of the BRD vaccine, have the potential to direct the selection of individual cattle for ongoing breeding programs.
Preferential interactions of a crowder protein with the specific binding site of a native protein complex
Authors: Dong Xu , Qin Ling-Yun , Gong Zhou , Qin Sanbo , Zhou Huan-Xiang , Tang Chun 
Published: August 2021

AbstractThe crowded cellular environments provide ample opportunities for proteins to interact with bystander macromolecules, yet direct evidence, let alone residue-specific information, for such nonspecific binding is rare. Here, by combining NMR spectroscopy and atomistic modeling, we investigated how crowders influence the association equilibrium and kinetics of two protein partners, EIN and HPr. Ficoll-70 increases the EIN-HPr binding affinity whereas bovine serum albumin (BSA) decreases the affinity. The opposite effects of the two crowders are quantitatively explained by atomistic modeling, which shows that the stabilizing effect of Ficoll-70 arises from volume exclusion favoring the bound state. In contrast, the destabilizing effect of BSA arises from preferential soft interactions with the free state; notably, BSA has favorable electrostatic interactions with positively charged HPr residues within the EIN-binding site. Some of the residues from this site indeed experience significant chemical shift perturbation when titrated with BSA, while the relaxation rates of HPr backbone amides exhibit overall elevation. Furthermore, relaxation dispersion data indicate that Ficoll-70 and BSA both slow down the EIN-HPr association rate, but change the dissociate rate in opposite directions. The observations on kinetics are accounted for by two effects of the crowders: increasing the solution microviscosity and reshaping the EIN-HPr interaction energy surface. The kind of preferential interactions between BSA and HPr that leads to competition with EIN should be prevalent in cellular environments. Our NMR results and atomistic modeling provide benchmarks, at both qualitative and quantitative levels, for the effects of crowded cellular environments on protein-protein specific interactions.Significance StatementAlthough nonspecific binding of crowder macromolecules with functional proteins is likely prevalentin vivo, direct evidence is rare. Here we present NMR characterizations showing that bovine serum albumin preferentially interacts with a specific binding site on HPr, leading to competition with the latter’s partner EIN. The preferential interactions result in destabilization of the EIN-HPr native complex and speedup of its dissociation, contrary to expectations from excluded-volume and viscosity effects. Atomistic modeling of macromolecular crowding rationalizes the experimental observations, and provides qualitative and quantitative insight into the influences of the crowded cellular environment on protein-protein specific interactions. Our work also has implications for evolution, regarding how nonspecific binding can be either minimized or exploited for gaining new functions.
Ciliary IFT88 safeguards coordinated epiphyseal vascularisation, resorption and ossification from disruptive physiological mechanical forces
Authors: Coveney C. R. , Samvelyan H. J. , Miotla-Zarebska J. , Carnegie J. , Chang E. , Corrin C. J. , Coveney T. , Stott B. , Parisi I. , Duarte C. , Vincent T. L. , Staines K. A. , Wann A.K.T. 
Published: August 2021

AbstractIn the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. Despite this, how mechanical cues are integrated into biological programmes remains unclear. Primary cilia are microtubule-based organelles that tune a range of cell activities, including signalling cascades activated or modulated, by extracellular biophysical cues. Here, we demonstrate that the inducible, cartilage-specific deletion of Intraflagellar transport protein 88 (IFT88), which reduces ciliation in the adolescent mouse growth plate (GP), uncouples chondrocyte differentiation from cartilage resorption and mineralisation in a mechano-dependent manner. Targeting IFT88, inhibits hypertrophic chondrocyte VEGF expression, vascular recruitment, osteoclastic activity and the replacement of cartilage with bone. These effects are largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. Increases in physiological loading, in control mice, also impairs ossification in the peripheral GP, mimicking the effects of IFT88 deletion. Strikingly, limb immobilisation rescues disrupted VEGF and restores epiphyseal dynamics inIft88cKO mice. These data indicate, that during this pivotal phase in adolescent skeletal maturation that defines the cessation of growth, ciliary IFT88 protects the coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces.
Comparative cytogenomics reveals genome reshuffling and centromere repositioning in the legume tribe Phaseoleae
Authors: Montenegro Claudio , do Vale Martins Lívia , de Oliveira Bustamante Fernanda , Brasileiro-Vidal Ana Christina , Pedrosa-Harand Andrea 
Published: August 2021

ABSTRACTThe tribe Phaseoleae (Leguminosae; Papilionoideae) includes several legume crops with assembled genomes. Comparative genomic studies indicate the preservation of large genomic blocks among legumes, however, the chromosome dynamics during Phaseoleae evolution has not been investigated yet. We conducted a comparative genomic analysis to define an informative genomic block (GB) system and to reconstruct the ancestral Phaseoleae karyotype (APK). We defined the GBs based on the orthologous genes betweenPhaseolus vulgarisandVigna unguiculatagenomes. We searched for these GBs in different genome species belonging to the Phaseolinae (P. lunatus) and Glycininae subtribes (Amphicarpaea edgeworthiiandSpatholobus suberectus), and in theMedicago truncalutaoutgroup. To support ourin silicoanalysis, we used oligo-FISH probes ofP. vulgarischromosomes 2 and 3 to paint the orthologous chromosomes of two non-sequenced Phaseolinae species (Macroptilium atropurpureumandLablab purpureus). We inferred the APK withn= 11 and 19 GBs (A to S). We hypothesized five chromosome fusions that reduced the ancestral legume karyotype withn= 16 ton= 11 in APK. Furthermore, we identified the main rearrangements within Phaseolinae and observed an extensive centromere repositioning resulting from evolutionary new centromeres (ENC) in thePhaseoluslineage. Additionally, we demonstrated that theA. edgeworthiigenome is more reshuffled than the dysploidS. suberectusgenome, in which we could reconstruct the main events that lead the chromosome number reduction. The development of the GB system and the proposed APK provide useful approaches for future comparative genomic analyses of legume species.
Visualising the cytoskeletal machinery in neuronal growth cones using cryo-electron tomography
Authors: Atherton Joseph , Stouffer Melissa , Francis Fiona , Moores Carolyn A. 
Published: August 2021

ABSTRACTNeurons navigate long distances and extend axons to form the complex circuitry of the mature brain. This depends on the coordinated response and continuous remodelling of the microtubule and F-actin networks in the axonal growth cone. Growth cone architecture remains poorly understood at nanoscales. We therefore investigated mouse hippocampal neuron growth cones using cryo-electron tomography to directly visualise their three-dimensional subcellular architecture with molecular detail. Our data show the hexagonal arrays of actin bundles that form filopodia penetrate the growth cone interior and terminate in the transition zone. We directly observe the modulation of these and other growth cone actin bundles by alteration of individual F-actin helical structures. Blunt-ended microtubules predominate in the growth cone, frequently contain lumenal particles and carry lattice defects. Investigation of the effect of absence of doublecortin, a neurodevelopmental cytoskeleton regulator, on growth cone cytoskeleton shows no major anomalies in overall growth cone organisation or in F-actin subpopulations. However, our data suggest that microtubules sustain more structural defects, highlighting the importance of microtubule integrity during growth cone migration.Summary statementCryo-electron tomographic reconstruction of neuronal growth cone subdomains reveals distinctive F-actin and microtubule cytoskeleton architectures and modulation at molecular detail.