bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Regulation of Single Microtubules and Bundles by a Three-Protein Module
Authors: Mani Nandini , Jiang Shuo , Neary Alex E. , Wijeratne Sithara S. , Subramanian Radhika 
Published: March 2020

ABSTRACTA remarkable feature of the microtubule cytoskeleton is co-existence of sub-populations having different dynamic properties. A prominent example is the anaphase spindle, where stable antiparallel bundles exist alongside dynamic microtubules and provide spatial cues for cytokinesis. How are dynamics of spatially proximal arrays differentially regulated? We reconstitute a minimal system of three midzone proteins: microtubule-crosslinker PRC1, and its interactors CLASP1 and Kif4A, proteins that promote and suppress microtubule elongation, respectively. We find their collective activity promotes elongation of single microtubules, while simultaneously stalling polymerization of crosslinked bundles. This differentiation arises from (i) Strong rescue activity of CLASP1, which overcomes weaker effects of Kif4A on single microtubules, (ii) Lower microtubule and PRC1-binding affinity of CLASP1, which permit dominance of Kif4A at overlaps. In addition to canonical mechanisms where antagonistic regulators set microtubule lengths, our findings illuminate design principles by which collective regulator activity creates microenvironments of arrays with distinct dynamic properties.
Mycobacterium tuberculosisRv0991c is a redox-regulated molecular chaperone
Authors: Becker Samuel H. , Ulrich Kathrin , Dhabaria Avantika , Ueberheide Beatrix , Beavers William , Skaar Eric P. , Iyer Lakshminarayan M. , Aravind L. , Jakob Ursula , Darwin K. Heran 
Published: March 2020

ABSTRACTThe bacterial pathogenMycobacterium (M.) tuberculosisis the leading cause of death by an infectious disease among humans. Here, we describe a previously uncharacterizedM. tuberculosisprotein, Rv0991c, as a molecular chaperone that is activated by oxidation. Rv0991c has homologues in most bacterial lineages and appears to function analogously to the well-characterizedEscherichia coliredox-regulated chaperone Hsp33, despite a dissimilar protein sequence. Rv0991c is transcriptionally co-regulated withhsp60andhsp70chaperone genes inM. tuberculosis, suggesting that Rv0991c functions with these chaperones in maintaining protein quality control. Supporting this hypothesis, we found that, like oxidized Hsp33, oxidized Rv0991c prevents the aggregation of a model unfolded proteinin vitro, and promotes its refolding by theM. tuberculosisHsp70 chaperone system. Furthermore, Rv0991c interacts with DnaK and associates with many otherM. tuberculosisproteins. Importantly, we found Rv0991c is required for the full virulence ofM. tuberculosisin mice. We therefore propose that Rv0991c, which we named “Ruc” (redox-regulated protein withunstructuredC-terminus), represents a founding member of a new chaperone family that protectsM. tuberculosisand other species from proteotoxicity during oxidative stress.IMPORTANCEM. tuberculosisinfections are responsible for more than one million human deaths per year. Developing effective strategies to combat this disease requires a greater understanding ofM. tuberculosisbiology. As in all cells, protein quality control is essential for the viability ofM. tuberculosis, which likely faces proteome stress within a host. Here, we identify anM. tuberculosisprotein, Ruc, that gains chaperone activity upon oxidation. Ruc represents a previously unrecognized family of redox-regulated chaperones found throughout the bacterial super-kingdom. In addition to elucidating the activity of this chaperone, we found that Ruc was required for fullM. tuberculosisvirulence in mice. This work contributes to a growing appreciation that oxidative stress may provide a particular strain on protein stability in cells, and may likewise play a role inM. tuberculosispathogenesis.
Building Blocks for Integrating Image Analysis Algorithms into a Clinical Workflow
Authors: Juluru Krishna , Shih Hao-Hsin , Elnajjar Pierre , El-Rowmeim Amin , Fox Josef , Siegel Eliot , Keshava Murthy Krishna Nand 
Published: March 2020

PurposeStarting from a broad-based needs assessment and utilizing an image analysis algorithm (IAA) developed at our institution, the purpose of this study was to define generalizable building blocks necessary for the integration of any IAA into a clinical practice.MethodsAn IAA was developed in our institution to process lymphoscintigraphy exams. A team of radiologists defined a set of building blocks for integration of this IAA into clinical workflow. The building blocks served the following roles: (1) Timely delivery of images to the IAA, (2) quality control, (3) IAA results processing, (4) results presentation & delivery, (5) IAA error correction, (6) system performance monitoring, and (7) active learning. Utilizing these modules, the lymphoscintigraphy IAA was integrated into the clinical workflow at our institution. System performance was tested over a 1 month period, including assessment of number of exams processed and delivered, and error rates and corrections.ResultsFrom June 26-July 27, 2019, the building blocks were used to integrate IAA results from 132 lymphoscintigraphy exams into the clinical workflow, representing 100% of the exams performed during the time period. The system enabled radiologists to correct 21 of the IAA results. All results and corrections were successfully stored in a database. A dashboard allowed the development team to monitor system performance in real-time.ConclusionsWe describe seven building blocks that optimize the integration of IAAs into clinical workflow. The implementation of these building blocks in this study can be used to inform development of more robust, standards-based solutions.
Computer-assisted beat-pattern analysis and the flagellar waveforms of bovine spermatozoa
Authors: Walker Benjamin J. , Phuyal Shiva , Ishimoto Kenta , Tung Chih-Kuan , Gaffney Eamonn A. 
Published: March 2020

AbstractPlagued by hurdles in information extraction, handling, and processing, computer-assisted sperm analysis (CASA) systems have typically neglected the complex flagellar waveforms of spermatozoa, despite their defining role in cell motility. Recent developments in imaging techniques and data processing have produced significantly-improved methods of waveform digitisation. Here, we utilise these improvements to demonstrate that near-complete flagellar capture is realisable on the scale of hundreds of cells, and, further, that meaningful statistical comparisons of flagellar waveforms may be readily performed with widely-available tools. Representing the advent of high-fidelity computer-assisted beat-pattern analysis (CABA), we show how such a statistical approach can distinguish between samples using complex flagellar beating patterns rather than crude summary statistics. Dimensionality-reduction techniques applied to entire samples also reveal qualitatively-distinct components of the beat, and a novel data-driven methodology for the generation of representative synthetic waveform data is proposed.
The extracellular matrix phenome across species
Authors: Statzer Cyril , Ewald Collin Y. 
Published: March 2020

AbstractExtracellular matrices are essential for cellular and organismal function. Recent genome-wide and phenome-wide association studies started to reveal a broad spectrum of phenotypes associated with genetic variants. However, the phenome or spectrum of all phenotypes associated with genetic variants in extracellular matrix genes is unknown. Here, we analyzed over two million recorded genotype-to-phenotype relationships across hundreds of species to define their extracellular matrix phenomes. By using previously defined matrisomes of humans, mice, zebrafish,Drosophila, andC. elegans, we found that the extracellular matrix phenome comprises of 3-10% of the entire phenome. Collagens (COL1A1, COL2A1) and fibrillin (FBN1) are each associated with more than 150 distinct phenotypes in humans, whereas collagenCOL4A1, Wnt- and sonic hedgehog (shh) signaling are predominantly associated in other species. We determined the phenotypic fingerprints of matrisome genes and found thatMSTN, CTSD, LAMB2, HSPG2, andCOL11A2 and their correspondingorthologues have the most phenotypes across species. Out of the 42’558 unique matrisome genotype-to-phenotype relationships across the five species with defined matrisomes, we have constructed interaction networks to identify the underlying molecular components connecting with orthologues phenotypes and with novel phenotypes. Thus, our networks provide a framework to predict unassessed phenotypes and their potential underlying molecular interactions. These frameworks inform on matrisome genotype-to-phenotype relationships and potentially provide a sophisticated choice of biological model system to study human phenotypes and diseases.Highlights7.6% of the human phenome originates from variations in matrisome genes11’671 phenotypes are linked to matrisome genes of humans, mice, zebrafish,Drosophila, andC. elegansExpected top ECM phenotypes are developmental, morphological and structural phenotypesNonobvious top ECM phenotypes include immune system, stress resilience, and age-related phenotypes
Typicality of Functional Connectivity robustly captures motion artifacts in rs-fMRI across datasets, atlases and preprocessing pipelines
Authors: Kopal Jakub , Pidnebesna Anna , Tomeček David , Tintěra Jaroslav , Hlinka Jaroslav 
Published: March 2020

AbstractFunctional connectivity analysis of resting state fMRI data has recently become one of the most common approaches to characterizing individual brain function. It has been widely suggested that the functional connectivity matrix, calculated by correlating signals from regions of interest, is a useful approximate representation of the brain’s connectivity, potentially providing behaviorally or clinically relevant markers. However, functional connectivity estimates are known to be detrimentally affected by various artifacts, including those due to in-scanner head motion. Treatment of such artifacts poses a standing challenge because of their high variability. Moreover, as individual functional connections generally covary only very weakly with head motion estimates, motion influence is difficult to quantify robustly, and prone to be neglected in practice. Although the use of individual estimates of head motion, or group-level correlation of motion and functional connectivity has been suggested, a sufficiently sensitive measure of individual functional connectivity quality has not yet been established. We propose a new intuitive summary index, the Typicality of Functional Connectivity, to capture deviations from normal brain functional connectivity pattern. Based on results of resting state fMRI for 245 healthy subjects we show that this measure is significantly correlated with individual head motion metrics. The results were further robustly reproduced across atlas granularity and preprocessing options, as well as other datasets including 1081 subjects from the Human Connectome Project. The Typicality of Functional Connectivity provides individual proxy measure of motion effect on functional connectivity and is more sensitive to inter-individual variation of motion than individual functional connections. In principle it should be sensitive also to other types of artifacts, processing errors and possibly also brain pathology, allowing wide use in data quality screening and quantification in functional connectivity studies as well as methodological investigations.
Establishment of a marine nematode model for animal functional genomics, environmental adaptation and developmental evolution
Authors: Xie Yusu , Zhang Pengchi , Xue Beining , Cao Xuwen , Ren Xiaoliang , Wang Lili , Sun Yuanyuan , Yang Hanwen , Zhang Liusuo 
Published: March 2020

ABSTRACTNematodes play key roles in marine ecosystem. Although oceans cover 71% of the Earth’s surface, none of marine model nematode has been reported. Here, we constructed the first inbred line of free-living marine nematodeLitoditis marina, sequenced and assembled its genome. Furthermore, we successfully applied CRISPR/Cas9 genome editing inL. marina. Comparative genomics revealed that immunity and oxygen regulation genes are expanded, which is probably central to its sediment adaptation. WhileL. marinaexhibits massive gene contractions in NHRs, chemoreceptors, xenobiotics detoxification and core histones, which could explain the more defined marine environment. Our experiments showed that dozens of H4 genes inCaenorhabditis elegansmight contribute to its adaptation to the complex terrestrial environments, while two H4 genes inL. marinaare involved in salinity stress adaptation. Additionally, ninety-two conserved genes appear to be positively selected inL. marina, which may underpin its osmotic, neuronal and epigenetic changes in the sea. With short generation time, highly inbred lines, and genomic resources, our report bringsL. marinaa promising marine animal model, and a unique satellite marine model to the well-known biomedical model nematodeC. elegans. This study will underpin ongoing work on animal functional genomics, environmental adaptation and developmental evolution.
Wide awake at bedtime? The effects of caffeine on sleep and circadian timing in teenagers - a randomized crossover trial
Authors: Reichert Carolin F. , Veitz Simon , Bühler Miriam , Gruber Georg , Rehm Sophia S. , Rentsch Katharina , Garbazza Corrado , Meyer Martin , Slawik Helen , Lin Yu-Shiuan , Weibel Janine 
Published: March 2020

AbstractBackgroundAdolescents frequently consume caffeine with unknown consequences on sleep and circadian rhythms. In adults, the evidence indicates that caffeine acutely reduces homeostatic sleep pressure and delays the circadian timing system.ObjectiveHere, we investigated the acute effects of caffeine intake on the developing sleep-wake regulatory system of teenagers.DesignIn a double-blind randomized crossover laboratory study, 18 teenagers (16.1 ± 1 years old, pubertal development scale [PDS]: 2.76 ± 0.35) ingested 80 mg caffeine (vs placebo) four hours prior to bedtime. Until bedtime, participants regularly filled in the Karolinska Sleepiness Scale and gave saliva samples to measure melatonin secretion. During nighttime, we quantified homeostatic sleep need by the electroencephalographically derived amount of slow wave sleep duration (SWS). After sleep, participants rated sleep quality by the Leeds Sleep Evaluation Questionnaire.ResultsWhile participants felt less sleepy after caffeine vs. placebo (P=0.038), their ratings of sleep quality were not strongly affected by the treatment. However, objectively, SWS was on average reduced by ∼20 min after caffeine vs. placebo (P=0.026). This caffeine-induced reduction was more pronounced in those individuals with more SWS under placebo (regression:P=0.042; standardized beta=0.622,P=0.011), even if controlling for habitual caffeine intake or pubertal stage (PDS). In melatonin onsets we observed both delays and advances in response to caffeine. This variance could partly be explained by differences in relative dose (i.e., mg caffeine/kg of bodyweight): the higher the relative dose, the more likely were delays (regression:P=0.01; standardized beta=0.592,P=0.01).ConclusionsIn teenagers, evening caffeine intake of already 80 mg (i.e. ∼8fl oz of common energy drinks) is sufficient to promote alertness at the costs of subsequent sleep. These costs might be more pronounced in adolescents with a higher need for SWS. Moreover, caffeine might disturb the circadian timing system, consequently hampering the balanced interplay of sleep-wake regulatory components.Sources of SupportMarie-Heim-Voegtlin Grant of the Swiss National Science Foundation (SNSF) PMPDP1_171364
Analyzing matched sets of microbiome data using the LDM and PERMANOVA
Authors: Zhu Zhengyi , Satten Glen A. , Mitchell Caroline , Hu Yi-Juan 
Published: March 2020

AbstractBackgroundMatched-set data arise frequently in microbiome studies. For example, we may collect pre- and post-treatment samples from a set of individuals, or use important confounding variables to match data from case participants to one or more control participants. Thus, there is a need for statistical methods for data comprised of matched sets, to test hypotheses against traits of interest (e.g., clinical outcomes or environmental factors) at the community level and/or the OTU (operational taxonomic unit) level. Optimally, these methods should accommodate complex data such as those with unequal sample sizes cross sets, confounders varying within sets, as well as continuous traits of interest.MethodsPERMANOVA is a commonly used distance-based method for testing hypotheses at the community level. We have also developed the linear decomposition model (LDM) that unifies the community-level and OTU-level tests into one framework. Here we present a strategy that can be used with both PERMANOVA and the LDM for analyzing matched-set data. We propose to include an indicator variable for each set as covariates, so as to constrain comparisons between samples within a set, and also permute traits within each set, which can account for exchangeable sample correlations. The flexible nature of PERMANOVA and the LDM allows discrete or continuous traits or interactions to be tested, within-set confounders to be adjusted, and unbalanced data to be fully exploited.ResultsOur simulations indicate that our proposed strategy outperformed alternative strategies in a wide range of scenarios. Using simulation, we also explored optimal designs for matched-set studies. The flexibility of PERMANOVA and the LDM for a variety of matched-set microbiome data is illustrated by the analysis of data from two real studies.ConclusionsIncluding set indicator variables and permuting within sets when analyzing matched-set data with PERMANOVA or the LDM is a strategy that performs well and is capable of handling the complex data structures that frequently occur in microbiome studies.
Short-range, orientation-reversing template-switching events occur at a high frequency in the human and yeast genomes
Authors: Tremblay-Belzile Samuel , Di Giorgio Juliana Pérez , Loubert-Hudon Audrey , Verreault Alain , Brisson Normand , Omichinski James G. 
Published: March 2020

ABSTRACTThe identification of structural variations in genomes using next-generation sequencing approaches greatly facilitates the study of genetic and genomic diseases. The data generated using these approaches also provide interesting new means to examine DNA repair, recombination, and replication to better understand sources of genomic instability. To better utilize this data, we developed SCARR (Systematic Combination of Alignments to Recreate Rearrangements) to identify DNA rearrangements, and used it to examine the occurrence of orientation-reversing events in human and budding yeast genomes. SCARR exceeds the sensitivity of previous genome sequencing approaches, and identifies rearrangements genome-wide with base-pair resolution, which helps provide insights into the mechanisms involved in their formation. We find that short-range orientation-reversing events occur at high rates in both human and yeast genomes. We quantified these rearrangements in yeast strains lacking various DNA repair factors, and propose that these short-range events often occur through template-switching events within a replication fork. We hypothesize that this mechanism may act as an error-prone alternative to fork reversal to restart stalled replication forks.
Combined abdominal heterotopic heart and aorta transplant model in mice
Authors: Dun Hao , Ye Li , Zhu Yuehui , Wong Brian W. 
Published: March 2020

AbstractBackgroundAllograft vasculopathy (AV) remains a major obstacle to long-term allograft survival. While the mouse aortic transplantation model has been proven as a useful tool for study of the pathogenesis of AV, simultaneous transplantation of the aorta alongside the transplantation of another organ may reveal more clinically relevant mechanisms that contribute to the pathogenesis of chronic allograft rejection. Therefore, we developed a combined abdominal heart and aorta transplantation model in mice which benefits from reducing animal and drug utilization, while providing an improved model to study the progressive nature of AV.MethodsThe middle of the infrarenal aorta of the recipient mouse was ligatured between the renal artery and its bifurcation. Proximal and distal aortotomies were performed at this site above and below the ligature, respectively, for the subsequent anastomoses of the donor aorta and heart grafts to the recipient infrarenal aorta in an end-to-side fashion. The distal anastomotic site of the recipient infrarenal aorta was connected with the outlet of the donor aorta. Uniquely, the proximal anastomotic site on the recipient infrarenal aorta was shared to connect with both the inlet of the donor aorta and the inflow tract to the donor heart. The outflow tract from the donor heart was connected to the recipient inferior vena cava (IVC).ResultsThe median times for harvesting the heart graft, aorta graft, recipient preparation and anastomosis were 11.5, 8.0, 9.0 and 40.5 min, respectively, resulting in a total median ischemic time of 70 min. The surgery survival rate was more than 96% (29/30). Both the syngeneicC57Bl/6aorta and heart grafts survived more than 90 days in 29C57Bl/6recipients. Further,Balb/ctoC57Bl/6allografts treated with anti-CD40L and CTLA4.Ig survived more than 90 days with a 100% (3/3) survival rate. (3/3).ConclusionsThis model is presented as a new tool for researchers to investigate transplant immunology and assess immunosuppressive strategies. It is possible to share a common anastomotic stoma on the recipient abdominal aorta to reconstruct both the aorta graft entrance and heart graft inflow tract. This allows for the study of allogeneic effects on both the aorta and heart from the same animal in a single survival surgery.
Genome Report:De novogenome assembly and annotation for the Taita white-eye (Zosterops silvanus)
Authors: Engler Jan O. , Lawrie Yvonne , Gansemans Yannick , Van Nieuwerburgh Filip , Suh Alexander , Lens Luc 
Published: March 2020

AbstractThe Taita White-eye (Zosterops silvanus) is an endangered songbird endemic to the Taita Hills of Southern Kenya, where it is confined to small areas of fragmented forest. With diversification rates exceeding those reported in most other vertebrates, White-eyes are a prime example of a ‘great speciator’. Nevertheless, we still know surprisingly little about the genomic underpinnings leading to this extraordinary fast radiation. Here, we present a draft genome assembly (ZSil_MB_1.0) for the Taita White-eye generated from a blood sample of a wild, female bird captured in the Taita Hills, Kenya. By performing ade novoassembly with linked-reads and annotation of the assembly with the MAKER pipeline, we generated a 1.069 Gb assembly with a scaffold N50 of 1.105 Mb and an L50 of 244. After quality evaluation of the assembly, we identified 92.1% of BUSCOs complete or fragmented, indicating that ourde novoassembly is of high quality. This new assembly provides a genomic resource for future studies into the evolutionary and comparative genomics of this rapidly diversifying group of birds.