bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are local dominance and inter-clade dynamics causally linked when one fossil clade displaces another?
Authors: Lidgard Scott , Di Martino Emanuela , Zágoršek Kamil , Liow Lee Hsiang 
Published: September 2020

AbstractDisputing the supposition that ecological competition drives macroevolutionary patterns is now a familiar goal in many fossil biodiversity studies. But it is an elusive goal, hampered by patchy sampling, few assemblage-level comparative analyses, unverified ecological equivalence of clades and a dearth of appropriate statistical tools. We address these concerns with a fortified and vetted compilation of 40190 fossil species occurrences of cyclostome and cheilostome bryozoans, a canonical example of one taxonomically dominant clade being displaced by another. Dramatic increases in Cretaceous cheilostome genus diversification rates begin millions of years before cheilostomes overtake cyclostomes in local species proportions. Moreover, analyses of origination and extinction rates over 150 Myr suggest that inter-clade dynamics are causally linked to each other, but not to changing assemblage-level proportions.One Sentence SummaryGlobal fossil diversification rates and local taxonomic dominance are not causally linked.
Large-scale identification of ubiquitination sites on membrane-associated proteins inArabidopsis thalianaseedlings
Authors: Grubb Lauren E. , Derbyshire Paul , Dunning Katherine , Zipfel Cyril , Menke Frank L.H. , Monaghan Jacqueline 
Published: September 2020

AbstractProtein phosphorylation and ubiquitination are two of the most abundant forms of post-translational modifications in eukaryotes, regulated by thousands of protein kinases, phosphatases, E3 ubiquitin ligases, and ubiquitin proteases. Although previous studies have catalogued several ubiquitinated proteins in plants (Walton et al., 2016), few membrane-localized proteins have been identified. Receptor kinases (RKs) initiate phosphorylation signal relays that regulate plant growth, development, and stress responses. While the regulatory role of phosphorylation on protein kinase function is well-documented (Couto and Zipfel, 2016), considerably less is known about the role of ubiquitination on protein kinase function, even though protein turnover is critical to their signaling competence and cellular homeostasis. Here we describe the large-scale identification of ubiquitination sites on Arabidopsis proteins associated with or integral to the plasma membrane, including over 100 protein kinases.
Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing
Authors: Wang Li , Sfakianos John P. , Beaumont Kristin G. , Akturk Guray , Horowitz Amir , Sebra Robert , Farkas Adam M. , Gnjatic Sacha , Hake Austin , Izadmehr Sudeh , Wiklund Peter , Oh William K , Szabo Peter , Wind-Rotolo Megan , Unsal-Kacmaz Kezi , Yao Xin , Schadt Eric , Sharma Padmanee , Bhardwaj Nina , Zhu Jun , Galsky Matthew D. 
Published: September 2020

AbstractAdaptive immunity and tumor-promoting inflammation exist in delicate balance in individual tumor microenvironments; however, the role of this balance in defining sensitivity and resistance to PD-1/PD-L1 blockade therapy in urothelial cancer and other malignancies is poorly understood. We pursued an unbiased systems biology approach using bulk RNA sequencing data to examine pre-treatment molecular features associated with sensitivity to PD-1/PD-L1 blockade in patients with metastatic urothelial cancer and identified an adaptive_immune_response module associated with response and an inflammatory_response module and stromal module associated with resistance. We mapped these gene modules onto single-cell RNA sequencing data demonstrating the adaptive_immune_response module emanated predominantly from T, NK, and B cells, the inflammatory_response module from monocytes/macrophages, and the stromal module from fibroblasts. The adaptive_immune_response:inflammatory_response module expression ratio in individual tumors, reflecting the balance between antitumor immunity and tumor-associated inflammation and coined the 2IR score, best correlated with clinical outcomes and was validated in an independent cohort. Individual monocytes/macrophages with low 2IR scores demonstrated upregulation of proinflammatory genes including IL1B and downregulation of antigen presentation genes, were unrelated to classical M1 versus M2 polarization, and were enriched in pre-treatment peripheral blood from patients with PD-L1 blockade-resistant metastatic urothelial cancer.Single sentence summaryProinflammatory monocytes/macrophages, present in tumor and blood, are associated with resistance to immune checkpoint blockade in urothelial cancer.
Function of the HYDROXYCINNAMOYL-CoA:SHIKIMATE HYDROXYCINNAMOYL TRANSFERASE is evolutionarily conserved in embryophytes
Authors: Kriegshauser Lucie , Knosp Samuel , Grienenberger Etienne , Tatsumi Kanade , Gütle Desirée D. , Sørensen Iben , Herrgott Laurence , Zumsteg Julie , Rose Jocelyn K.C. , Reski Ralf , Werck-Reichhart Danièle , Renault Hugues 
Published: September 2020

ABSTRACTThe plant phenylpropanoid pathway generates a major class of specialized metabolites and precursors of essential extracellular polymers that initially appeared upon plant terrestrialization. Despite its evolutionary significance, little is known about the complexity and function of this major metabolic pathway in extant bryophytes, which represent the non-vascular stage of embryophyte evolution. Here, we report that theHYDROXYCINNAMOYL-CoA:SHIKIMATE HYDROXYCINNAMOYL TRANSFERASE(HCT) gene that plays a critical function in the phenylpropanoid pathway during seed plant development, is functionally conserved inPhyscomitrium patens(Physcomitrella), in the moss lineage of bryophytes. Phylogenetic analysis indicates thatbonafideHCT function emerged in the progenitor of embryophytes.In vitroenzyme assays, moss phenolic pathway reconstitution in yeast andin plantagene inactivation coupled to targeted metabolic profiling, collectively indicate thatP. patensHCT (PpHCT), similar to tracheophyte HCT orthologs, uses shikimate as a native acyl acceptor to produce ap-coumaroyl-5-O-shikimate intermediate. Phenotypic and metabolic analyses of loss-of-function mutants show that PpHCT is necessary for the production of caffeate derivatives, including previously reported caffeoyl-threonate esters, and for the formation of an intact cuticle. Deep conservation of HCT function in embryophytes is further suggested by the ability ofHCTgenes fromP. patensand the liverwortMarchantia polymorphato complement anArabidopsis thalianaCRISPR/Cas9hctmutant, and by the presence of phenolic esters of shikimate in representative species of the three bryophyte lineages.
IL-6 Trans-Signaling and Crosstalk Among Tumor, Muscle and Fat Mediate Pancreatic Cancer Cachexia
Authors: Rupert Joseph E. , Bonetto Andrea , Narasimhan Ashok , Liu Yunlong , O’Connell Thomas M. , Koniaris Leonidas G. , Zimmers Teresa A. 
Published: September 2020

ABSTRACTMost patients with pancreatic adenocarcinoma (PDAC) suffer unintentional weight loss, or cachexia. Interleukin-6 causes cachexia in mice and associates with mortality in PDAC. Here we show that tumor cell-derived IL-6 mediates crosstalk between tumor and peripheral tissues to promote cachexia. Tumor-cell IL-6 elicits expression of IL-6 in fat and IL-6 and IL-6 receptor (IL6R) in muscle, concomitantly raising both in blood. Inflammation-induced adipose lipolysis elevates circulating fatty acids, which cooperate with IL-6 to induce skeletal muscle dysmetabolism and wasting. Thus, PDAC induces crosstalk among tumor, fat and muscle via a feed-forward, IL-6 signaling loop. Tumor talks to muscle and fat through IL-6, and muscle to fat via IL6R trans-signaling, and fat to muscle through lipids and fatty acids. Disruption of this crosstalk by depletion of tumor-derived IL-6 halved fat wasting and abolished muscle loss, supporting IL-6, IL-6R and lipids as causal nodes for tissue crosstalk in PDAC cachexia.SignificancePDAC-associated cachexia significantly increases patient morbidity and mortality. This study identifies muscle and fat crosstalk via IL6R trans-signaling in concert with muscle steatosis as a main driver of PDAC-associated cachexia.
Novel genetic variants associated with brain functional networks in 18,445 adults from the UK Biobank
Authors: Foo Heidi , Thalamuthu Anbupalam , Jiang Jiyang , Koch Forrest C. , Mather Karen A. , Wen Wei , Sachdev Perminder S. 
Published: September 2020

AbstractThis is the first study investigating the genetics of weighted functional brain network graph theory measures from 18,445 participants of the UK Biobank (44-80 years). The eighteen measures studied showed low heritability (mean h2SNP=0.12) and were highly genetically correlated. Genome-wide association studies for these measures observed 14 significant variants associated with strength of somatomotor and limbic networks. These intergenic variants were located near thePAX8gene on chromosome 2. Gene-based analyses identified five significantly associated genes for five of the network measures, which have been implicated in sleep duration, neuronal differentiation/development, cancer, and susceptibility to neurodegenerative diseases. Genetic correlations with other traits were examined and significant correlations were observed with sleep measures and psychiatric symptoms. Further analysis found that somatomotor network strength was phenotypically associated with sleep duration and insomnia. Single nucleotide polymorphism (SNP) and gene level associations with functional network measures were identified, which may help uncover novel biological pathways relevant to human brain functional network integrity and diseases that affect it.
The Impact of The Hydroxymethyl-Cytosine Epigenetic Signature on DNA Structure And Function
Authors: Battistini Federica , Dans Pablo D. , Terrazas Montserrat , Castellazzi Chiara L. , Portella Guillem , Labrador Mireia , Villegas Núria , Brun-Heath Isabelle , González Carlos , Orozco Modesto 
Published: September 2020

ABSTRACTWe present a comprehensive, experimental and theoretical study of the impact of 5-hydroxymethylation of DNA cytosine. Using molecular dynamics, biophysical experiments and NMR spectroscopy, we found that Ten-Eleven translocation (TET) dioxygenases generate an epigenetic variant with structural and physical properties not too different to those of 5-methylcytosine. Experiments and simulations demonstrate that 5-methyl-cytosine (mC) and 5-hydroxymethyl-cytosine (hmC) generally lead to more rigid duplexes with poorer circularization efficiencies and lower ability to form nucleosomes. In particular, we can rule out the hypothesis that hydroxymethylation reverts to unmodified cytosine physical properties, as hmC is even more rigid than mC. Thus, we do not expect dramatic changes in the chromatin structure induced by differences in physical properties between d(mCpG) and d(hmCpG). On the contrary, our simulations suggest that methylated-DNA binding domains (MBD), associated with repression activities, are very sensitive to the substitution d(mCpG)→ d(hmCpG), while MBD3 which has a dual activation/repression activity is not sensitive to the d(mCpG) → d(hmCpG) change. Overall, while changes in gene activity due to cytosine methylation are the result of the combination of stiffness-related chromatin reorganization and MBD binding, those associated to 5-hydroxylation of methylcytosine could be explained by a change in the balance of repression/activation pathways related to differential MBD binding.
Alterations to the cardiac metabolome induced by chronicT. cruziinfection relate to the degree of cardiac pathology
Authors: Hoffman Kristyn , Liu Zongyuan , Hossain Ekram , Bottazzi Maria Elena , Hotez Peter J. , Jones Kathryn M. , McCall Laura-Isobel 
Published: September 2020

AbstractChronic Chagasic cardiomyopathy (CCC) is a Neglected Tropical Disease caused by the parasiteTrypanosoma cruzi. The pathognomonic findings in symptomatic CCC patients and animal models includes diffuse cardiac fibrosis and inflammation with persistent parasite presence in the heart. This study investigated chemical alterations in different regions of the heart in relation to cardiac pathology indicators to better understand the long-term pathogenesis of this neglected disease. We used data from echocardiography, fibrosis biomarkers, and histopathological analysis to fully evaluate cardiac pathology. Metabolites isolated from the pericardial and endocardial sides of the right ventricular myocardium were analyzed by liquid chromatography tandem mass spectrometry. The endocardial sections contained significantly less cardiac inflammation and fibrosis than the pericardial sections. Cardiac levels of acylcarnitines, phosphocholines, and other metabolites were significantly disrupted in accordance with cardiac fibrosis, inflammation, and serum fibrosis biomarker levels. These findings have potential implications in treatment and monitoring for CCC patients.
Monocytes and macrophages, targets of SARS-CoV-2: the clue for Covid-19 immunoparalysis
Authors: Boumaza Asma , Gay Laetitia , Mezouar Soraya , Diallo Aïssatou Bailo , Michel Moise , Desnues Benoit , Raoult Didier , Scola Bernard La , Halfon Philippe , Vitte Joana , Olive Daniel , Mege Jean-Louis 
Published: September 2020

AbstractTo date, the Covid-19 pandemic affected more than 18 million individuals and caused more than 690, 000 deaths. Its clinical expression is pleiomorphic and severity is related to age and comorbidities such as diabetes and hypertension. The pathophysiology of the disease relies on aberrant activation of immune system and lymphopenia that has been recognized as a prognosis marker. We wondered if the myeloid compartment was affected in Covid-19 and if monocytes and macrophages could be infected by SARS-CoV-2. We show here that SARS-CoV-2 efficiently infects monocytes and macrophages without any cytopathic effect. Infection was associated with the secretion of immunoregulatory cytokines (IL-6, IL-10, TGF-β) and the induction of a macrophagic specific transcriptional program characterized by the upregulation of M2-type molecules. In addition, we found thatin vitromacrophage polarization did not account for the permissivity to SARS-CoV-2, since M1-and M2-type macrophages were similarly infected. Finally, in a cohort of 76 Covid-19 patients ranging from mild to severe clinical expression, all circulating monocyte subsets were decreased, likely related to massive emigration into tissues. Monocytes from Covid-19 patients exhibited decreased expression of HLA-DR and increased expression of CD163, irrespective of the clinical status. Hence, SARS-CoV-2 drives circulating monocytes and macrophages inducing immunoparalysis of the host for the benefit of Covid-19 disease progression.
Comparison of Rhesus and Cynomolgus macaques as an authentic model for COVID-19
Authors: Salguero Francisco J. , White Andrew D. , Slack Gillian S. , Fotheringham Susan A. , Bewley Kevin R. , Gooch Karen E. , Longet Stephanie , Humphries Holly E. , Watson Robert J. , Hunter Laura , Ryan Kathryn A. , Hall Yper , Sibley Laura , Sarfas Charlotte , Allen Lauren , Aram Marilyn , Brunt Emily , Brown Phillip , Buttigieg Karen R. , Cavell Breeze E. , Cobb Rebecca , Coombes Naomi S. , Daykin-Pont Owen , Elmore Michael J. , Gkolfinos Konstantinos , Godwin Kerry J. , Gouriet Jade , Halkerston Rachel , Harris Debbie J. , Hender Thomas , Ho Catherine M.K. , Kennard Chelsea L. , Knott Daniel , Leung Stephanie , Lucas Vanessa , Mabbutt Adam , Morrison Alexandra L. , Ngabo Didier , Paterson Jemma , Penn Elizabeth J. , Pullan Steve , Taylor Irene , Tipton Tom , Thomas Stephen , Tree Julia A. , Turner Carrie , Wand Nadina , Wiblin Nathan R. , Charlton Sue , Hallis Bassam , Pearson Geoffrey , Rayner Emma L. , Nicholson Andrew G. , Funnell Simon G. , Dennis Mike J. , Gleeson Fergus V. , Sharpe Sally , Carroll Miles W. 
Published: September 2020

ABSTRACTA novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques, resembling the mild clinical cases of COVID-19 in humans. Immune responses against SARS-CoV-2 were also similar in both species and equivalent to those reported in milder infections and convalescent human patients. Importantly, we have devised a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the optimal study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of novel and repurposed interventions against SARS-CoV-2. Accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.
Topoisomerase II deficiency leads to a postreplicative structural shift in all Saccharomyces cerevisiae chromosomes
Authors: Ayra-Plasencia Jessel , Ramos-Pérez Cristina , Santana-Sosa Silvia , Quevedo Oliver , Medina-Suarez Sara , Matos-Perdomo Emiliano , Zamora-Dorta Marcos , Brown Grant W , Lisby Michael , Machín Félix 
Published: September 2020

AbstractThe key role of Topoisomerase II (Top2) is the removal of topological intertwines between sister chromatids. In yeast, inactivation of Top2 brings about distinct cell cycle responses. In the case of the conditional top2-5 allele, interphase and mitosis progress on schedule but cells suffer from a segregation catastrophe. We here show that top2-5 chromosomes fail to enter a Pulsed-Field Gel Electrophoresis (PFGE) in the first cell cycle, a behavior traditionally linked to the presence of replication and recombination intermediates. We distinguished two classes of affected chromosomes: the rDNA-bearing chromosome XII, which fails to enter a PFGE at the beginning of S-phase, and all the other chromosomes, which fail at a postreplicative stage. In synchronously cycling cells, this late PFGE retention is observed in anaphase; however, we demonstrate that this behavior is independent of cytokinesis, stabilization of anaphase bridges, spindle pulling forces and even anaphase onset. Strikingly, once the PFGE retention has occurred it becomes refractory to Top2 re-activation. DNA combing, two-dimensional electrophoresis, genetic analyses and GFP-tagged DNA damage markers suggest that non-recombinational modifications of late replication intermediates may account for the shift in the PFGE behavior. The fact that this shift does not trigger G2/M checkpoints further supports this statement since checkpoints are active for other replicative stresses in the absence of Top2. We propose that the prolonged absence of Top2 activity leads to a general chromosome structural change. This change might interlock chromatids together with catenations and thus contribute to the formation of anaphase bridges in top2 mutants.
Existence of log-phase Escherichia coli persisters and lasting memory of a starvation pulse
Authors: Svenningsen Mikkel Skjoldan , Svenningsen Sine Lo , Sørensen Michael Askvad , Mitarai Namiko 
Published: September 2020

AbstractThe vast majority of a bacterial population is quickly killed when treated with a lethal concentration of antibiotics. The time scale of this killing is often comparable with the bacterial generation time before addition of antibiotics. Yet, a small subpopulation typically survives for an extended period. However, the long-term killing dynamics of bacterial cells has not been fully quantified even in well-controlled laboratory conditions. We constructed a week-long killing assay and followed the survival fraction ofEscherichia coliK12 exposed to a high concentration of ciprofloxacin. We found that long-term survivors were formed during exponential growth, with some cells surviving at least 7 days. The long-term dynamics contained at least three timescales, which greatly enhances predictions of the population survival time compared to the biphasic extrapolation from the short term behavior. Furthermore, we observed a surprisingly long memory effect of a brief carbon starvation pulse, which was dependent on the (p)ppGpp synthaserelA. Specifically, one hour of carbon starvation prior to antibiotics exposure increased the surviving fraction by nearly 100-fold even after 4 days of ciprofloxacin treatment.
Mutational signatures in countries affected by SARS-CoV-2: Implications in host-pathogen interactome
Authors: Singh J. , Singh H. , Hasnain S E. , Rahman S.A. 
Published: September 2020

AbstractWe are in the midst of the third severe coronavirus outbreak caused by SARS-CoV-2 with unprecedented health and socio-economic consequences due to the COVID-19. Globally, the major thrust of scientific efforts has shifted to the design of potent vaccine and anti-viral candidates. Earlier genome analyses have shown global dominance of some mutations purportedly indicative of similar infectivity and transmissibility of SARS-CoV-2 worldwide. Using high-quality large dataset of 25k whole-genome sequences, we show emergence of new cluster of mutations as result of geographic evolution of SARS-CoV-2 in local population (≥10%) of different nations. Using statistical analysis, we observe that these mutations have either significantly co-occurred in globally dominant strains or have shown mutual exclusivity in other cases. These mutations potentially modulate structural stability of proteins, some of which forms part of SARS-CoV-2-human interactome. The high confidence druggable host proteins are also up-regulated during SARS-CoV-2 infection. Mutations occurring in potential hot-spot regions within likely T-cell and B-cell epitopes or in proteins as part of host-viral interactome, could hamper vaccine or drug efficacy in local population. Overall, our study provides comprehensive view of emerging geo-clonal mutations which would aid researchers to understand and develop effective countermeasures in the current crisis.SignificanceOur comparative analysis of globally dominant mutations and region-specific mutations in 25k SARS-CoV-2 genomes elucidates its geo-clonal evolution. We observe locally dominant mutations (co-occurring or mutually exclusive) in nations with contrasting COVID-19 mortalities per million of population) besides globally dominant ones namely, P314L (ORF1b) and D164G (S) type. We also see exclusive dominant mutations such as in Brazil (I33T in ORF6 and I292T in N protein), England (G251V in ORF3a), India (T2016K and L3606F in ORF1a) and in Spain (L84S in ORF8). The emergence of these local mutations in ORFs within SARS-CoV-2 genome could have interventional implications and also points towards their potential in modulating infectivity of SARS-CoV-2 in regional population.