bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic divergence predicts morphological and ecological variation underlying an adaptive radiation
Authors: Bernal Moisés A. , Yule Daniel L. , Stott Wendylee , Evrard Lori , Dowling Thomas E. , Krabbenhoft Trevor J. 
Published: July 2021

AbstractGroups of sympatric taxa with low inter-specific genetic differentiation, but considerable ecological differences, offer great opportunities to study the dynamics of divergence and speciation. This is the case of ciscoes (Coregonusspp.) in the Laurentian Great Lakes, which are characterized by a complex evolutionary history and are commonly described as having undergone an adaptive radiation. In this study, morphometrics, stable isotopes and transcriptome sequencing were used to study the relationships within theCoregonus artedicomplex in western Lake Superior. We observed general concordance for morphological, ecological and genomic variation, but the latter was more taxonomically informative as it showed less overlap among species in multivariate space. Low levels of genetic differentiation were observed between individuals morphologically identified asC. hoyiandC. zenithicus, and we hypothesize this could be associated with recent hybridization between the two species. Transcriptome-based single nucleotide polymorphisms exhibited significant divergence for genes associated with vision, development, metabolism and immunity, among species that occupy different habitats. This study highlights the importance of using an integrative approach when studying groups of taxa with a complex evolutionary history, as individual-level analyses of multiple independent datasets can provide a clearer picture of the patterns and processes associated with the origins of biodiversity.
A novel benzoxaborole works by targeting FabI inEscherichia coli
Authors: Mandal Soma , Parish Tanya 
Published: July 2021

AbstractTo combat the looming crisis of antimicrobial-resistant infections, there is an urgent need for novel antimicrobial discovery and drug target identification. The benzoxaborole series were previously identified as inhibitors of mycobacterial growth. Here, we demonstrate that a benzoxaborole is also active against the Gram negative bacterium,Escherichia coliin vitro. We isolated resistant mutants ofE. coliand subjected them to whole genome sequencing. We found mutations in the enoyl acyl carrier protein FabI. Mutations mapped around the active center site located close to the co-factor binding site. This site partially overlaps with the binding pocket of triclosan, a known FabI inhibitor. Similar to triclosan, the interaction of the benzoxaborole with FabI was dependent on the co-factor NAD+. Identification of the target of this compound inE. coliprovides scope for further development and optimization of this series for Gram negative pathogens.
Pervasiveciseffects of variation in copy number of large tandem repeats on local epigenetics and gene expression
Authors: Garg Paras , Martin-Trujillo Alejandro , Rodriguez Oscar L. , Gies Scott J. , Jadhav Bharati , Sharp Andrew J. 
Published: July 2021

ABSTRACTVariable Number Tandem Repeats (VNTRs) are composed of large tandemly repeated motifs, many of which are highly polymorphic in copy number. However, due to their large size and repetitive nature, they remain poorly studied. To investigate the regulatory potential of VNTRs, we used read-depth data from Illumina whole genome sequencing to perform association analysis between copy number of ~70,000 VNTRs (motif size ≥10bp) with both gene expression (404 samples in 48 tissues) and DNA methylation (235 samples in peripheral blood), identifying thousands of VNTRs that are associated with local gene expression (eVNTRs) and DNA methylation levels (mVNTRs). Using large-scale replication analysis in an independent cohort we validated 73-80% of signals observed in the two discovery cohorts, providing robust evidence to support that these represent genuine associations. Further, conditional analysis indicated that many eVNTRs and mVNTRs act as QTLs independently of other local variation. We also observed strong enrichments of eVNTRs and mVNTRs for regulatory features such as enhancers and promoters. Using the Human Genome Diversity Panel, we defined sets of VNTRs that show highly divergent copy numbers among human populations, show that these are enriched for regulatory effects on gene expression and epigenetics, and preferentially associate with genes that have been linked with human phenotypes through GWAS. Our study provides strong evidence supporting functional variation at thousands of VNTRs, and defines candidate sets of VNTRs, copy number variation of which potentially plays a role in numerous human phenotypes.
MRBLE-pep measurements reveal accurate binding affinities for B56, a PP2A regulatory subunit
Authors: Hein Jamin B. , Cyert Martha S. , Fordyce Polly M. 
Published: July 2021

AbstractSignal transduction pathways rely on dynamic interactions between protein globular domains and short linear motifs (SLiMs). The weak affinities of these interactions are essential to allow fast rewiring of signaling pathways and downstream responses, but pose technical challenges for interaction detection and measurement. We recently developed a technique (MRBLE-pep) that leverages spectrally encoded hydrogel beads to measure binding affinities between a single protein and 48 different peptide sequences in a single small volume. In prior work, we applied it to map the binding specificity landscape between calcineurin and the PxIxIT SLiM (Nguyen et al. 2019). Here, using peptide sequences known to bind the PP2A regulatory subunit B56, we systematically compare affinities measured by MRBLE-pep or isothermal calorimetry (ITC) and confirm that MRBLE-pep accurately quantifies relative affinity over a wide dynamic range while using a fraction of the material required for traditional methods such as ITC.
Phospho-RNA sequencing with CircAID-p-seq
Authors: Piano Alessia Del , Barbieri Ruggero , Schmid Michael , Brocchieri Luciano , Tornaletti Silvia , Firrito Claudia , Minati Luca , Bernabo Paola , Signoria Ilaria , Lauria Fabio , Gillingwater Thomas H. , Viero Gabriella , Clamer Massimiliano 
Published: July 2021

AbstractAccurate positional information concerning ribosomes and RNA binding proteins with respect to their transcripts is important to understand the global regulatory network underlying protein and RNA fate in living cells. Most footprinting approaches generate RNA fragments bearing a phosphate or cyclic phosphate groups at their 3′ end. Unfortunately, all current protocols for library preparation rely only on the presence of a 3′ hydroxyl group. Here, we developed circAID-p-seq, a PCR-free library preparation for 3′ phospho-RNA sequencing. We applied circAID-p-seq to ribosome profiling, which produces fragments protected by ribosomes after endonuclease digestion. CircAID-p-seq, combined with the dedicated computational pipeline circAidMe, facilitates accurate, fast, highly efficient and low-cost sequencing of phospho-RNA fragments from eukaryotic cells and tissues. While assessing circAID-p-seq to portray ribosomes engaged with transcripts, we provide a versatile tool to unravel any 3′-phospho RNA molecules.
DNR orders in SARS-CoV-2 patients: a retrospective validation study in a Swiss COVID-19 Center
Authors: Lo Presti Giorgia , Biggiogero Maira , Glotta Andrea , Biondi Carola , Horvath Zsofia , Leo Rosambra , Bona Giovanni , Franzetti-Pellanda Alessandra , Saporito Andrea , Ceruti Samuele , Capdevila Xavier 
Published: July 2021

ABSTRACTBackgroundThe worldwide pandemic situation forced many hospitals to adapt COVID-19 management strategies. In this scenario, theSwiss Academy of Medical Sciences(SAMW/ASSM) organized national guidelines based on expert opinion to identify Do-Not-Resuscitate (DNR) patients, to reduce futile ICU admission and resource misuse. However, the practical impact of this standardized national protocol has not been yet evaluated. In our specialized COVID-19 Center, we investigated characteristics and mortality of DNR patients identified according to national standardized protocol, comparing them to non-DNR patients.MethodsThis was a pilot retrospective validation study, evaluating consecutive hospital admitted COVID-19 patients. Primary outcome was 30-days survival ofDNR patientsin comparison to thecontrol group. Secondary outcomes reported quality of treatment of deceased patients, especially of agitation/sedation and dyspnea, using respectively the Richmond Agitation-Sedation Scale – Palliative care (RASS-PAL) for sedation and agitation (+4/-5) and the modified Borg Scale for dyspnea (1-10).ResultsFrom March 16 to April 1, 2020, 213 consecutive patients were triaged; at 30-days follow-up, 9 patients (22.5%) died in theDNR group, 4 (2.2%) in thecontrol group. The higher mortality rate in theDNR groupwas further confirmed by Log-Rank Mantel-Cox (23.104, p < 0.0001). In theDNR-groupdeceased patients, end-of-life support was performed with oxygen (100%), opioids (100%) and sedatives (89%); the mean RASS-PAL improved from 2.2 to -1.8 (p < 0.0001) and the Borg scale improved from 5.7 to 4.7 (p = 0.581).ConclusionA national standardized protocol identified patients at higher risk of short-term death. Although the legal status of DNRs varies from country to country, the implementation of national standardized protocol could be the way to guarantee a better treatment of COVID-19 patients in a pandemic situation with limited resources.
Modeling COVID-19 vaccine efficacy and coverage towards herd-immunity in the Basque Country, Spain
Authors: Stollenwerk Nico , Mar Javier , Van-Dierdonck Joseba Bidaurrazaga , Ibarrondo Oliver , Estadilla Carlo , Aguiar Maíra 
Published: July 2021

AbstractVaccines have measurable efficacies, obtained first from vaccine trials. However, vaccine efficacy is not a static measure upon licensing, and the long term population studies are very important to evaluate vaccine performance and impact. COVID-19 vaccines were developed in record time and although the extent of sterilizing immunity is still under evaluation, the currently licensed vaccines are extremely effective against severe disease, with vaccine efficacy significantly higher after the full immunization schedule. We investigate the impact of vaccines which have different efficacies after first dose and after the second dose administration schedule, eventually considering different efficacies against severe disease as opposed to overall infection. As a proof of concept, we model the vaccine performance of hospitalization reduction at the momentary scenario of the Basque Country, Spain, with population in a mixed vaccination setting, giving insights into the population coverage needed to achieve herd immunity in the current vaccination context.
Longitudinal monitoring of DNA viral loads in transplant patients using quantitative metagenomic next-generation sequencing
Authors: Carbo Ellen C. , Russcher Anne , Kraakman Margriet E.M. , de Brouwer Caroline S. , Sidorov Igor A. , Feltkamp Mariet C.W. , Kroes Aloys C.M. , Claas Eric C.J. , de Vries Jutte J.C. 
Published: July 2021

AbstractIntroductionImmunocompromised patients are prone to reactivations of multiple latent DNA viruses. Viral load monitoring by single-target quantitative PCRs (qPCR) is the current cornerstone for virus quantification. In this study, a metagenomic next-generation sequencing (mNGS) approach was used for identification and load monitoring of transplantation-related DNA viruses.MethodsLongitudinal plasma samples from six patients that were qPCR-positive for cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK polyoma virus (BKV, adenovirus (ADV), parvovirus B19 (B19V), and torque teno-virus (TTV) were sequenced using the quantitative metagenomic Galileo Viral Panel Solution (Arc Bio, LLC) reagents and bioinformatics pipeline combination. Qualitative and quantitative performance was analysed with focus on viral load ranges relevant for clinical decision-making.ResultsAll pathogens identified by qPCR were also identified by mNGS. In addition, BKV, CMV, and HHV6B were detected by mNGS which were not ordered initially but could be confirmed by qPCR. Viral loads determined by mNGS correlated with the qPCR results, with inter-method differences in viral load per virus ranging from 0.19 log10 IU/ml for EBV to 0.90 log10 copies/ml for ADV. TTV, analysed by mNGS in a semi-quantitative way, showed a mean difference of 3.0 log10 copies/ml. Trends over time in viral load determined by mNGS and qPCR were comparable, and clinical thresholds for initiation of treatment were equally indicated by mNGS.ConclusionThe Galileo Viral Panel for quantitative mNGS performed comparable to qPCR with regard to detection and viral load determination, within clinically relevant ranges of patient management algorithms.
Changes in seam number and location induce holes within microtubules assembled from porcine brain tubulin and in Xenopus egg cytoplasmic extracts
Authors: Guyomar Charlotte , Bousquet Clément , Ku Siou , Heumann John , Guilloux Gabriel , Gaillard Natacha , Heichette Claire , Duchesne Laurence , Steinmetz Michel O. , Gibeaux Romain , Chrétien Denis 
Published: July 2021

AbstractMicrotubules are tubes of about 25 nm in diameter that are critically involved in a variety of cellular functions including motility, compartmentalization, and division. They are considered as pseudo-helical polymers whose constituent αβ-tubulin heterodimers share lateral homotypic interactions, except at one unique region called the seam. Here, we used a segmented sub-tomogram averaging strategy to reassess this paradigm and analyze the organization of the αβ-tubulin heterodimers in microtubules assembled from purified porcine brain tubulin in the presence of GTP and GMPCPP, and in Xenopus egg cytoplasmic extracts. We find that in all conditions, microtubules incorporate variable protofilament and/or tubulin subunit helical-start numbers, as well as variable numbers of seams. Strikingly, the seam number and location vary along individual microtubules, generating holes of one to a few subunits in size within their lattices. Together, our results reveal that the formation of mixed and discontinuous microtubule lattices is an intrinsic property of tubulin that requires the formation of unique lateral interactions without longitudinal ones. They further suggest that microtubule assembly is tightly regulated in a cytoplasmic environment.
Structure of bacterial communities in Japanese-style bathrooms: Comparative sequencing of bacteria in shower water and showerhead biofilms using a portable nanopore sequencer
Authors: Fujiyoshi So , Nishiuchi Yukiko , Maruyama Fumito 
Published: July 2021

AbstractShowers are one of the main exposure routes to diverse microbes for end users in built environments. Bacteria in water are responsible for biofilm formation on surfaces, and the inside of a showerhead is a specific niche. Here, for the purpose of microbial characterization, source estimation and possibility of infection, the bacterial compositions of both shower water and showerhead biofilms in the same bathroom were determined and compared using a portable nanopore sequencer. The results suggest that specific bacteria in source water would primarily adhere to the surface of the showerhead where they subsequently form biofilms, and the community compositions within biofilms largely vary depending on environmental factors. The relative abundance of several pathogenic bacterial genera in both water and biofilm samples was low. We suggest that it is important to manage risk of infection in each household, and rapid on-site analysis of microbial communities will allow the realization.
The myotendinous junction marker collagen XXII enables zebrafish postural control learning and optimal swimming performance through its force transmission activity
Authors: Malbouyres Marilyne , Guiraud Alexandre , Lefrançois Christel , Salamito Mélanie , Nauroy Pauline , Bernard Laure , Sohm Frédéric , Allard Bruno , Ruggiero Florence 
Published: July 2021

AbstractAlthough the myotendinous junction (MTJ) is essential for skeletal muscle integrity, its contribution to skeletal muscle function remains largely unknown. Here, we show that CRISPR-Cas9-mediated gene ablation of the MTJ marker col22a1 in zebrafish identifies two distinctive phenotypic classes: class 1 individuals reach adulthood with no overt muscle phenotype while class 2 display severe movement impairment and eventually dye before metamorphosis. Yet mutants that are unequally affected are all found to display defective force transmission attributed to a loss of ultrastructural integrity of the MTJ and myosepta, though with distinct degrees of severity. The behavior-related consequences of the resulting muscle weakness similarly reveal variable phenotypic expressivity. Movement impairment at the critical stage of swimming postural learning eventually causes class 2 larval death by compromising food intake while intensive exercise is required to uncover a decline in muscle performance in class 1 adults. By confronting MTJ gene expression compensation and structural, functional and behavioral insights of MTJ dysfunction, our work unravels variable expressivity of col22a1 mutant phenotype. This study also underscores COL22A1 as a candidate gene for myopathies associated with dysfunctional force transmission and anticipates a phenotypically heterogeneous disease.
Joint Gene Network Construction by Single-Cell RNA Sequencing Data
Authors: Dong Meichen , He Yiping , Jiang Yuchao , Zou Fei 
Published: July 2021

SummaryIn contrast to differential gene expression analysis at single gene level, gene regulatory networks (GRN) analysis depicts complex transcriptomic interactions among genes for better understandings of underlying genetic architectures of human diseases and traits. Recently, single-cell RNA sequencing (scRNA-seq) data has started to be used for constructing GRNs at a much finer resolution than bulk RNA-seq data and microarray data. However, scRNA-seq data are inherently sparse which hinders direct application of the popular Gaussian graphical models (GGMs). Furthermore, most existing approaches for constructing GRNs with scRNA-seq data only consider gene networks under one condition. To better understand GRNs under different but related conditions with single-cell resolution, we propose to construct Joint Gene Networks with scRNA-seq data (JGNsc) using the GGMs framework. To facilitate the use of GGMs, JGNsc first proposes a hybrid imputation procedure that combines a Bayesian zero-inflated Poisson (ZIP) model with an iterative low-rank matrix completion step to efficiently impute zero-inflated counts resulted from technical artifacts. JGNsc then transforms the imputed data via a nonparanormal transformation, based on which joint GGMs are constructed. We demonstrate JGNsc and assess its performance using synthetic data. The application of JGNsc on two cancer clinical studies of medulloblastoma and glioblastoma identifies novel findings in addition to confirming well-known biological results.
Nucleotide Biosynthesis Links Glutathione Metabolism to Ferroptosis Sensitivity
Authors: Tarangelo Amy , Kim Joon Tae , Long Jonathan Z. , Dixon Scott J. 
Published: July 2021

AbstractNucleotide synthesis is a metabolically demanding process essential for cell division. Several anti-cancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2. RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR conserves glutathione which can then be used to limit the accumulation of toxic lipid peroxides, preventing the onset of ferroptosis. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death.
Circular-Linear Copulae for Animal Movement Data
Authors: Hodel Florian H. , Fieberg John R. 
Published: July 2021

ABSTRACTAnimal movement is often modeled in discrete time, formulated in terms of steps taken between successive locations at regular time intervals. Steps are characterized by the distance between successive locations (step-lengths) and changes in direction (turn angles). Animals commonly exhibit a mix of directed movements with large step lengths and turn angles near 0 when traveling between habitat patches and more wandering movements with small step lengths and uniform turn angles when foraging. Thus, step-lengths and turn angles will typically be cross-correlated.Most models of animal movement assume that step-lengths and turn angles are independent, likely due to a lack of available alternatives. Here, we show how the method of copulae can be used to fit multivariate distributions that allow for correlated step lengths and turn angles.We describe several newly developed copulae appropriate for modeling animal movement data and fit these distributions to data collected on fishers (Pekania pennanti). The copulae are able to capture the inherent correlation in the data and provide a better fit than a model that assumes independence. Further, we demonstrate via simulation that this correlation can impact movement patterns (e.g. rates of dispersion overtime).We see many opportunities to extend this framework (e.g. to consider autocorrelation in step attributes) and to integrate it into existing frameworks for modeling animal movement and habitat selection. For example, copula could be used to more accurately sample available locations when conducting habitat-selection analyses.
Chromatin alterations in the aging lung change progenitor cell activity
Authors: Rowbotham Samuel P. , Pessina Patrizia , de Alba Rivas Carolina Garcia , Li Jingyun , Wong Irene G. , Yoon Joon , Fahey Caroline , Moye Aaron , Chongsaritsinsuk Joann , Bronson Roderick , Sui Shannan J. Ho , Kim Carla F. 
Published: July 2021

AbstractThe lung contains multiple progenitor cell types that respond to damage, but how their responses are choreographed and why they decline with age is poorly understood. We report that histone H3 lysine 9 di-methylation (K9me2), mediated by histone methyltransferase G9a, regulates the dynamics of lung epithelial progenitor cells, and this regulation deteriorates with age. In aged mouse lungs, K9me2 loss coincided with lower frequency and activity of alveolar type 2 (AT2) cell progenitors. In contrast, K9me2 loss resulted in increased frequency and activity of multipotent progenitor cells with bronchiolar and alveolar potential (BASCs) and bronchiolar progenitors. K9me2 depletion in young mice through deletion or inhibition of G9a decreased AT2 progenitor activity and impaired alveolar injury regeneration. Conversely, K9me2 depletion increased chromatin accessibility of bronchiolar cell genes, increased BASC frequency and accelerated bronchiolar repair. K9me2 depletion also resulted in increased bronchiolar cell expression of the SARS-CoV2 receptor Ace2 in aged lungs. These data point to K9me2 and G9a as a critical regulator of the balance of lung progenitor cell regenerative responses and prevention of susceptibility to age-related lung diseases. These findings indicate that epigenetic regulation coordinates progenitor cell populations to expedite regeneration in the most efficient manner and disruption of this regulation presents significant challenges to lung health.