bluuebunny/crossref_metadata_2025_split huggingface dataset:
3D reconstruction identifies loci linked to variation in angle of individual sorghum leaves
Authors: Tross Michael C. , Gaillard Mathieu , Zweiner Mackenzie , Miao Chenyong , Grove Ryleigh J. , Li Bosheng , Benes Bedrich , Schnable James C. 
Published: June 2021

ABSTRACTSelection for yield at high planting density has reshaped the leaf canopy of maize, improving photosynthetic productivity in high density settings. Further optimization of canopy architecture may be possible. However, measuring leaf angles, the widely studied component trait of leaf canopy architecture, by hand is a labor and time intensive process. Here, we use multiple, calibrated, 2D images to reconstruct the 3D geometry of individual sorghum plants using a voxel carving based algorithm. Automatic skeletonization and segmentation of these 3D geometries enable quantification of the angle of each leaf for each plant. The resulting measurements are both heritable and correlated with manually collected leaf angles. This automated and scaleable reconstruction approach was employed to measure leaf-by-leaf angles for a population of 366 sorghum plants at multiple time points, resulting in 971 successful reconstructions and 3,376 leaf angle measurements from individual leaves. A genome wide association study conducted using aggregated leaf angle data identified a known large effect leaf angle gene, several previously identified leaf angle QTL from a sorghum NAM population, and novel signals. Genome wide association studies conducted separately for three individual sorghum leaves identified a number of the same signals, a previously unreported signal shared across multiple leaves, and signals near the sorghum orthologs of two maize genes known to influence leaf angle. Automated measurement of individual leaves and mapping variants associated with leaf angle reduce the barriers to engineering ideal canopy architectures in sorghum and other grain crops.
Deep Mutational Scanning of Dynamic Interaction Networks in the SARS-CoV-2 Spike Protein Complexes: Allosteric Hotspots Control Functional Mimicry and Resilience to Mutational Escape
Authors: Verkhivker Gennady M. 
Published: June 2021

ABSTRACTWe develop a computational approach for deep mutational scanning of residue interaction networks in the SARS-CoV-2 spike protein complexes to characterize mechanisms of functional mimicry and resilience to mutational escape by miniprotein inhibitors. Using a dynamic mutational profiling and sensitivity analysis of protein stability, binding interactions and global network parameters describing allosteric signaling, we identify regulatory hotspots in the SARS-CoV-2 S complexes with the ACE2 host receptor and ultra-potent miniproteins. The results revealed that global circulating variants are associated with allosteric control points that are dynamically coupled to structural stability hotspots. In this mechanism, variant-induced perturbations of flexible allosteric sites can result in global network changes and elicit specific protein responses. The binding affinity fingerprints and allosteric signatures of the SARS-CoV-2 complexes with miniproteins are determined by a dynamic cross-talk between regulatory control points and conformationally adaptable allosteric hotspots that collectively control structure-functional mimicry, signal transmission and resilience to mutational escape.
Comprehensive Phenotyping of Cutaneous Afferents Reveals Rapid-Onset Alterations in Nociceptor Response Properties Following Spinal Cord Injury
Authors: Eller Olivia C. , Stair Rena N. , Neal Christopher , Rowe Peter S. N. , Nelson-Brantley Jennifer , Young Erin E. , Baumbauer Kyle M. 
Published: June 2021

AbstractSpinal cord injury (SCI) is a complex syndrome that has profound effects on patient well-being, including the development of medically-resistant chronic pain. The mechanisms underlying SCI pain have been the subject of thorough investigation but remain poorly understood. While the majority of the research has focused on changes occurring within and surrounding the site of injury in the spinal cord, there is now a consensus that alterations within the peripheral nervous system, namely sensitization of nociceptors, contribute to the development and maintenance of chronic SCI pain. Here we demonstrate that thoracic spinal contusion injury results in the emergence of autotomy and spasticity, both indicators of spontaneous pain, in areas below the level of the injury within 24 hr of SCI. These behaviors were associated with hindpaw edema and elevated cutaneous calcitonin gene-related peptide (CGRP) concentration. Electrophysiological recordings using an ex vivo skin/nerve/DRG/spinal cord preparation demonstrated that SCI increased mechanical and thermal sensitivity, as well as the incidence of spontaneous activity (SA) and afterdischarge (AD), in below-level C-fiber nociceptors 24 hr following injury. Interestingly, the distribution of nociceptors that exhibit SA and AD are not identical, and the development of SA was observed more frequently in nociceptors with low thermal thresholds, while AD was found more frequently in nociceptors with high thermal thresholds. These results demonstrate that SCI causes the rapid-onset of peripheral inflammation-like processes that sensitize nociceptors, which may contribute to the early emergence and persistence of chronic SCI pain.
GIP: An open-source computational pipeline for mapping genomic instability from protists to cancer cells
Authors: Späth Gerald F. , Bussotti Giovanni 
Published: June 2021

AbstractGenome instability has been recognized as a key driver for microbial and cancer adaptation and thus plays a central role in many human pathologies. Even though genome instability encompasses different types of genomic alterations, most available genome analysis software are limited to just one kind mutation or analytical step. To overcome this limitation and better understand the role of genetic changes in enhancing pathogenicity we established GIP, a novel, powerful bioinformatic pipeline for comparative genome analysis. Here we show its application to whole genome sequencing datasets ofLeishmania,Plasmodium, Candida, and cancer. Applying GIP on available data sets validated our pipeline and demonstrated the power of our analysis tool to drive biological discovery. Applied toPlasmodium vivaxgenomes, our pipeline allowed us to uncover the convergent amplification of erythrocyte binding proteins and to identify a nullisomic strain. Re-analyzing genomes of drug adaptedCandida albicansstrains revealed correlated copy number variations of functionally related genes, strongly supporting a mechanism of epistatic adaptation through interacting gene-dosage changes. Our results illustrate how GIP can be used for the identification of aneuploidy, gene copy number variations, changes in nucleic acid sequences, and chromosomal rearrangements. Altogether, GIP can shed light on the genetic bases of cell adaptation and drive disease biomarker discovery.One Sentence SummaryGIP - a novel pipeline for detecting, comparing and visualizing genome instability.
Atlantic salmon farms are a likely source of Tenacibaculum maritimum infection in migratory Fraser River sockeye salmon
Authors: Bateman Andrew W. , Teffer Amy K. , Bass Arthur , Ming Tobi , Hunt Brian P. V. , Krkošek Martin , Miller Kristina M. 
Published: June 2021

AbstractInfectious disease from domestic hosts, held for agriculture, can impact wild species that migrate in close proximity, potentially reversing selective advantages afforded by migration. For sockeye salmon in British Columbia, Canada, juveniles migrate past numerous Atlantic salmon farms from which they may acquire a number of infectious agents. We analyse patterns of molecular detection in juvenile sockeye salmon for one bacterial pathogen, Tenacibaculum maritimum, known to cause disease in fish species around the globe and to cause mouthrot disease in farmed Atlantic salmon in BC. Our data show a clear peak in T. maritimum detections in the Discovery Islands region of BC, where sockeye migrate close to salmon farms. Using well established differential-equation models to describe sockeye migration and T. maritimum infection spread, we fit models to our detection data to assess support for multiple hypotheses describing farm- and background-origin infection. Despite a data-constrained inability to resolve certain epidemiological features of the system, such as the relative roles of post infection mortality and recovery, our models clearly support the role of Discovery-Islands salmon farms in producing the observed patterns. Our best models (with 99.8% empirical model support) describe relatively constant (background) infection pressure, except around Discovery-Islands salmon farms, where farm-origin infection pressure peaked at 12.7 (approximate 95% CI: 4.5 to 31) times background levels. Given the evidence for farm-origin transfer of T. maritimum to Fraser-River sockeye salmon, the severity of associated disease in related species, and the imperilled nature of Fraser River sockeye generally, our results suggest the need for a more precautionary approach to managing farm/wild interactions in sockeye salmon.
Structural Modeling of the TMPRSS Subfamily of Host Cell Proteases Reveals Potential Binding Sites
Authors: Escalante Diego E. , Wang Austin , Ferguson David M. 
Published: June 2021

AbstractThe transmembrane protease serine subfamily (TMPRSS) has at least eight members with known protein sequence: TMPRSS2, TMPRRS3, TMPRSS4, TMPRSS5, TMPRSS6, TMPRSS7, TMPRSS9, TMPRSS11, TMPRSS12 and TMPRSS13. A majority of these TMPRSS proteins have key roles in human hemostasis as well as promoting certain pathologies, including several types of cancer. In addition, TMPRSS proteins have been shown to facilitate the entrance of respiratory viruses into human cells, most notably TMPRSS2 and TMPRSS4 activate the spike protein of the SARS-CoV-2 virus. Despite the wide range of functions that these proteins have in the human body, none of them have been successfully crystallized. The lack of structural data has significantly hindered any efforts to identify potential drug candidates with high selectivity to these proteins. In this study, we present homology models for all members of the TMPRSS family including any known isoform (the homology model of TMPRSS2 is not included in this study as it has been previously published). The atomic coordinates for all homology models have been refined and equilibrated through molecular dynamic simulations. The structural data revealed potential binding sites for all TMPRSS as well as key amino acids that can be targeted for drug selectivity.
Extracellular RNA moves from the glomerulus to the renal tubule
Authors: Hunter Robert W , Kumar Sujai , Coward Richard JM , Buck Amy H , Dear James W 
Published: June 2021

AbstractThere is a wealth of indirect evidence that extracellular RNA (exRNA) signalling can regulate renal tubular epithelial cell function. However, the physiological importance of this signalling is uncertain. We sought to determine the extent of extracellular RNA transfer between cells in a healthy kidney. We tested the hypothesis that RNA travels from glomerular podocytes to renal tubular epithelial cells.We developed a method to track exRNA in the kidney using SLAMseq (SH-linked alkylation for the metabolic sequencing of RNA in tissue). We crossed podocin-Cre mice with floxed-stop-UPRT mice to express recombinant uracil phosphoribosyl transferase (UPRT) in podocytes. Mice were injected with the modified nucleobase 4-thiouracil, which is incorporated into nascent RNA with high efficiency only in UPRT-expressing cells. We harvested glomeruli or tubular cells, extracted RNA and prepared libraries for SLAMseq, in which sites of mRNA labelling with 4-thiouracil are detected as T>C conversions in 3’UTRs.In glomeruli, we detected labelling of known podocyte genes but not of genes known to be restricted to endothelial, renal tubular or white blood cells. Setting a false-discovery rate of 1%, the proportion of genes deemed to be labelled with high confidence was 7.1% (95% confidence interval 6.8 – 7.4%) in 4TU-treated podocyte-UPRT mice, 2.5% (2.3 – 2.7%) in Cre-negative controls and 1.0% (0.9 – 1.1%) in 4TU-naïve controls.In tubular cells, we detected a small but statistically significant increase in RNA labelling in podocyte-UPRT mice compared to Cre-negative controls (p = 7.4 × 10−16 in a zero-inflated Poisson regression model). We conclude that RNA is transferred from podocytes to renal tubular epithelial cells in vivo under physiological conditions. Our model provides the opportunity to explore the consequences of this novel signalling pathway in health and kidney disease.
Fungi anaesthesia
Authors: Adamatzky Andrew , Gandia Antoni 
Published: June 2021

AbstractElectrical activity of fungus Pleurotus ostreatus is characterised by slow (hours) irregular waves of baseline potential drift and fast (minutes) action potential likes spikes of the electrical potential. An exposure of the mycelium colonised substrate to a chloroform vapour lead to several fold decrease of the baseline potential waves and increase of their duration. The chloroform vapour also causes either complete cessation of spiking activity or substantial reduction of the spiking frequency. Removal of the chloroform vapour from the growth containers leads to a gradual restoration of the mycelium electrical activity.
SARS-CoV-2 Viral Replication in a High Throughput Human Primary Epithelial Airway Organ Model
Authors: Fisher Christine R. , Medie Felix Mba , Luu Rebeccah J. , Gaibler Robert , Miller Caitlin R. , Mulhern Thomas J. , Vijayakumar Vidhya , Marr Elizabeth , Alladina Jehan , Medoff Benjamin , Borenstein Jeffrey T. , Gard Ashley L. 
Published: June 2021

AbstractCOVID-19 emerged as a worldwide pandemic early in 2020, and at this writing has caused over 170 million cases and 3.7 million deaths worldwide, and almost 600,000 deaths in the United States. The rapid development of several safe and highly efficacious vaccines stands as one of the most extraordinary achievements in modern medicine, but the identification and administration of efficacious therapeutics to treat patients suffering from COVID-19 has been far less successful. A major factor limiting progress in the development of effective treatments has been a lack of suitable preclinical models for the disease, currently reliant upon various animal models and in vitro culture of immortalized cell lines. Here we report the first successful demonstration of SARS-CoV-2 infection and viral replication in a human primary cell-based organ-on-chip, leveraging a recently developed tissue culture platform known as PREDICT96. This successful demonstration of SARS-CoV-2 infection in human primary airway epithelial cells derived from a living donor represents a powerful new pathway for disease modeling and an avenue for screening therapeutic candidates in a high throughput platform.
Systematic dissection of a complex gut bacterial community
Authors: Cheng Alice G. , Aranda-Díaz Andrés , Jain Sunit , Yu Feiqiao , Iakiviak Mikhail , Meng Xiandong , Weakley Allison , Patil Advait , Shiver Anthony L. , Deutschbauer Adam , Neff Norma , Huang Kerwyn Casey , Fischbach Michael A. 
Published: June 2021

ABSTRACTEfforts to model the gut microbiome have yielded important insights into the mechanisms of interspecies interactions, the impact of priority effects on ecosystem dynamics, and the role of diet and nutrient availability in determining community composition. However, the model communities studied to date have been defined or complex but not both, limiting their utility. Here, we construct a defined community of 104 bacterial strains composed of the most common taxa from the human gut microbiota. By propagating this community in growth media missing one amino acid at a time, we show that branched-chain amino acids have an outsize impact on community structure and identify a pathway in Clostridium sporogenes for generating ATP from arginine. We constructed and propagated the complete set of single-strain dropout communities, revealing a sparse network of strain-strain interactions including a novel interaction between C. sporogenes and Lactococcus lactis driven by metabolism. This work forms a foundation for studying strain-strain and strain-nutrient interactions in highly complex defined communities, and it provides a starting point for interrogating the rules of synthetic ecology at the 100+ strain scale.
Sirtuin 5 levels are limiting in preserving cardiac function and suppressing fibrosis in response to pressure overload
Authors: Guo Angela H. , Baliira Rachael K. , Skinner Mary E. , Kumar Surinder , Andren Anthony , Zhang Li , Michan Shaday , Davis Norma J. , Maccani Merissa W. , Day Sharlene M. , Sinclair David A. , Lyssiotis Costas A. , Stein Adam B. , Lombard David B. 
Published: June 2021

AbstractHeart failure (HF) is defined as an inability of the heart to pump blood adequately to meet the body’s metabolic demands. HF with reduced systolic function is characterized by cardiac hypertrophy, ventricular fibrosis and remodeling, and decreased cardiac contractility, leading to cardiac functional impairment and death. Transverse aortic constriction (TAC) is a well-established model for inducing hypertrophy and HF in rodents. Mice globally deficient in sirtuin 5 (SIRT5), a NAD+-dependent deacylase, are hypersensitive to cardiac stress and display increased mortality after TAC. Prior studies assessing SIRT5 functions in the heart have all employed loss-of-function approaches. In this study, we generated SIRT5 overexpressing (SIRT5OE) mice, and evaluated their response to chronic pressure overload induced by TAC. Compared to littermate controls, SIRT5OE mice were protected from left ventricular dilation and impaired ejection fraction, adverse functional consequences of TAC. Transcriptomic analyses revealed that SIRT5 suppresses key HF sequelae, including the metabolic switch from fatty acid oxidation to glycolysis, immune activation, and increased fibrotic signaling. We conclude that SIRT5 is a limiting factor in the preservation of cardiac function in response to experimental pressure overload.
Multiple RSV strains infecting HEp-2 and A549 cells reveal cell line-dependent differences in resistance to RSV infection
Authors: Rajan Anubama , Piedra Felipe-Andrés , Aideyan Letisha , McBride Trevor , Robertson Matthew , Johnson Hannah L. , Aloisio Gina Marie , Henke David , Coarfa Cristian , Stossi Fabio , Menon Vipin Kumar , Doddapaneni Harshavardhan , Muzny Donna Marie , Cregeen Sara Joan Javornik , Hoffman Kristi Louise , Petrosino Joseph , Gibbs Richard A , Avadhanula Vasanthi , Piedra Pedro A. 
Published: June 2021

ABSTRACTRespiratory syncytial virus (RSV) is a leading cause of pediatric acute respiratory infection worldwide. There are currently no approved vaccines or antivirals to combat RSV disease. A few transformed cell lines and two historic strains have been extensively used to study RSV. Here we report a thorough molecular and cell biological characterization of HEp-2 and A549 cells infected with four strains of RSV representing both major subgroups as well as historic and more contemporaneous genotypes -- [RSV/A/Tracy (GA1), RSV/A/Ontario (ON), RSV/B/18537 (GB1), RSV/B/Buenos Aires (BA)] -- via measurements of viral replication kinetics and viral gene expression, immunofluorescence-based imaging of gross cellular morphology and cell-associated RSV, and measurements of host response including transcriptional changes and levels of secreted cytokines and growth factors. Our findings strongly suggest 1) the existence of a conserved difference in gene expression between RSV subgroups A and B; 2) the A549 cell line is a more stringent and natural host of replicating RSV than the HEp-2 cell line; and 3) consistent with previous studies, determining the full effects of viral genetic variation in RSV pathogenesis requires model systems as tractable as transformed cell lines but better representative of the human host.IMPORTANCEInfection with respiratory syncytial virus (RSV) early in life is essentially guaranteed and can lead to severe disease. In vitro data from two historic RSV/A strains and two cell lines, HEp-2 and A549, constitute most of our knowledge; but RSV contains ample variation from two evolving subgroups (A and B) showing recent convergent evolution. Here we measure viral action and host response in HEp-2 and A549 cells infected with four RSV strains from both subgroups and representing both historic and more contemporaneous strains. We discover a subgroup-dependent difference in viral gene expression and find A549 cells are more potently antiviral and more sensitive, albeit subtly, to viral variation. Our findings reveal important differences between RSV subgroups and two widely used cell lines and provide baseline data for experiments with model systems better representative of natural RSV infection.
The microtubule plus-end tracking protein Bik1 is required for chromosome congression
Authors: Julner Alexander , Abbasi Marjan , Menéndez-Benito Victoria 
Published: June 2021

AbstractDuring mitosis, sister chromatids congress on both sides of the spindle equator to facilitate the correct partitioning of the genomic material. Chromosome congression requires a finely tuned control of microtubule dynamics by the kinesin motor proteins. In Saccharomyces cerevisiae, the kinesin proteins Cin8, Kip1, and Kip3 have a pivotal role in chromosome congression. It has been hypothesized that additional proteins that modulate microtubule dynamics are also involved. Here, we show that the microtubule plus-end tracking protein Bik1 – the budding yeast ortholog of CLIP-170 – is essential for chromosome congression. We find that nuclear Bik1 localizes to the kinetochores in a cell-cycle-dependent manner. Disrupting the nuclear pool of Bik1 with a nuclear export signal (Bik1-NES) leads to a slower cell cycle progression characterized by a delayed metaphase-anaphase transition. Bik1-NES cells have mispositioned kinetochores along the spindle in metaphase. Furthermore, using proximity-dependent methods, we identify Cin8 as an interaction partner of Bik1. Deleting CIN8 reduces the amount of Bik1 at the spindle. In contrast, Cin8 retains its typical bilobed distribution in the Bik1-NES mutant and does not localize to the unclustered kinetochores. Thus, we propose that Bik1 functions with Cin8 to regulate kinetochore-microtubule dynamics for correct kinetochore positioning and chromosome congression.
The Association Between Poor Sleep and Accelerated Brain Ageing
Authors: Ramduny Jivesh , Bastiani Matteo , Huedepohl Robin , Sotiropoulos Stamatios N. , Chechlacz Magdalena 
Published: June 2021

ABSTRACTThe ageing brain undergoes widespread gray (GM) and white matter (WM) degeneration. But numerous studies indicate large heterogeneity in the age-related brain changes, which can be attributed to modifiable lifestyle factors, including sleep. Inadequate sleep has been previously linked to GM atrophy and WM changes. However, the reported findings are highly inconsistent. By contrast to previous research independently characterizing patterns of either the GM or the WM changes, we used here linked independent component analysis (FLICA) to examine covariation in GM and WM in a group of older adults. Next, we employed a novel technique to estimate the brain age delta (i.e. difference between chronological and apparent brain age assessed using neuroimaging data) and study its associations with sleep quality and sleep fragmentation, hypothesizing that poor sleep accelerates brain ageing. FLICA revealed a number of multimodal (including both GM and WM) neuroimaging components, associated with age, but also with sleep quality and sleep fragmentation. Brain age delta estimates were highly sensitive in detecting the effects of sleep problems on the ageing brain. Specifically, we show significant associations between brain age delta and poor sleep quality, suggesting two years deviation above the chronological age. Our findings indicate that sleep problems in healthy older adults should be considered a risk factor for accelerated brain ageing.