bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chloroplast-derived photo-oxidative stress causes changes in H2O2andEGSHin other subcellular compartments
Authors: Ugalde José Manuel , Fuchs Philippe , Nietzel Thomas , Cutolo Edoardo A. , Vothknecht Ute C. , Holuigue Loreto , Schwarzländer Markus , Müller-Schüssele Stefanie J. , Meyer Andreas J. 
Published: July 2020

ABSTRACTMetabolic fluctuations in chloroplasts and mitochondria can trigger retrograde signals to modify nuclear gene expression. Mobile signals likely to be involved are reactive oxygen species (ROS), which can operate protein redox switches by oxidation of specific cysteine residues. Redox buffers such as the highly reduced glutathione pool serve as reservoirs of reducing power for several ROS scavenging and ROS-induced damage repair pathways. Formation of glutathione disulfide (GSSG) and a shift of the glutathione redox potential (EGSH) towards less negative values is considered a hallmark of several stress conditions. Here we used the herbicide methyl viologen (MV) to generate ROS locally in chloroplasts of intact Arabidopsis seedlings and recorded dynamic changes inEGSHand H2O2levels with the genetically-encoded biosensors Grx1-roGFP2 (forEGSH) and roGFP2-Orp1 (for H2O2) targeted to chloroplasts, the cytosol or mitochondria. Treatment of seedlings with MV caused a rapid oxidation in chloroplasts and subsequently also in the cytosol and mitochondria. The MV-induced oxidation was significantly boosted by illumination with actinic light and largely abolished by inhibitors of photosynthetic electron transport. In addition, MV also induced an autonomous oxidation in the mitochondrial matrix in an electron transport chain activity-dependent manner that was milder than the oxidation triggered in chloroplasts by the combination of MV and light.In vivoredox biosensing resolves the spatiotemporal dynamics of compartmental responses to local ROS generation and provide a basis for understanding how compartment-specific redox dynamics may operate in retrograde signaling and stress acclimation in plants.One sentence summaryMethyl viologen-induced photooxidative stress causes an increase of H2O2and oxidation of glutathione in chloroplasts, cytosol and mitochondria as well as autonomous oxidation in mitochondria.
Severe COVID-19 is associated with elevated serum IgA and antiphospholipid IgA-antibodies
Authors: Ali Omar Hasan , Bomze David , Risch Lorenz , Brugger Silvio D. , Paprotny Matthias , Weber Myriam , Thiel Sarah , Kern Lukas , Albrich Werner C. , Kohler Philipp , Kahlert Christian R. , Vernazza Pietro , Bühler Philipp K. , Schüpbach Reto A. , Gómez-Mejia Alejandro , Popa Alexandra M. , Bergthaler Andreas , Penninger Josef M. , Flatz Lukas 
Published: July 2020

ABSTRACTBackgroundWhile the pathogenesis of coronavirus disease 2019 (COVID-19) is becoming increasingly clear, there is little data on IgA response, the first line of bronchial immune defense.ObjectiveTo determine, whether COVID-19 is associated with a vigorous total IgA response and whether IgA autoantibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome (APS), our approach focused on antiphospholipid antibodies (aPL).Materials and methodsIn this retrospective cohort study we compared clinical data and aPL from 64 patients with COVID-19 from three independent centers (two in Switzerland, one in Liechtenstein). Samples were collected from April 9, 2020 to May 1, 2020. Total IgA and aPL were measured with FDA-approved commercially available clinical diagnostic kits.ResultsClinical records of the 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID,n=26 [41%]), a discovery cohort with severe illness (sdCOVD,n=14 [22%]) and a confirmation cohort with severe illness (scCOVID,n=24 [38%]). Severe illness was significantly associated with increased total IgA (sdCOVID,P=0.01; scCOVID,P<0.001). Total IgG levels were similar in both cohorts. Among aPL, both cohorts with severe illness significantly correlated with elevated anti-Cardiolipin IgA (sdCOVID and scCOVID,P<0.001), anti-Cardiolipin IgM (sdCOVID,P=0.003; scCOVID,P<0.001), and anti-Beta2 Glycoprotein-1 IgA (sdCOVID and scCOVID,P<0.001). Systemic lupus erythematosus was excluded from all patients as a potential confounder of APS.ConclusionsHigher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response triggered in the bronchial mucosa induces systemic autoimmunity.
COVID-19 Vulnerability of Transgender Women With and Without HIV Infection in the Eastern and Southern U.S.
Authors: Poteat Tonia C. , Reisner Sari L. , Miller Marissa , Wirtz Andrea L. 
Published: July 2020

AbstractBackgroundCOVID-19 is a new global pandemic and people with HIV may be particularly vulnerable. Gender identity is not reported, therefore data are absent on the impact of COVID-19 on transgender people, including transgender people with HIV. Baseline data from the American Cohort to Study HIV Acquisition Among Transgender Women in High Risk Areas (LITE) Study provide an opportunity to examine pre-COVID vulnerability among transgender women.SettingAtlanta, Baltimore, Boston, Miami, New York City, Washington, DCMethodsBaseline data from LITE were analysed for demographic, psychosocial, and material factors that may affect risk for COVID-related harms.ResultsThe 1020 participants had high rates of poverty, unemployment, food insecurity, homelessness, and sex work. Transgender women with HIV (n=273) were older, more likely to be Black, had lower educational attainment, and were more likely to experience material hardship. Mental and behavioural health symptoms were common and did not differ by HIV status. Barriers to healthcare included being mistreated mistreatment, uncomfortable providers, and past negative experiences; as well as material hardships, such as cost and transportation. However, most reported access to material and social support – demonstrating resilience.ConclusionsTransgender women with HIV may be particularly vulnerable to pandemic harms. Mitigating this harm would have positive effects for everyone, given the highly infectious nature of this coronavirus. Collecting gender identity in COVID-19 data is crucial to inform an effective public health response. Transgender-led organizations’ response to this crisis serve as an important model for effective community-led interventions.
Initial Experience in Predicting the Risk of Hospitalization of 496 Outpatients with COVID-19 Using a Telemedicine Risk Assessment Tool
Authors: O’Keefe James B. , Tong Elizabeth J. , Taylor Thomas H. , O’Keefe Ghazala A. Datoo , Tong David C. 
Published: July 2020

AbstractTitleInitial Experience in Validation of a Telemedicine Risk Assessment Tool for Hospitalization of Patients with COVID-19ImportanceRisk assessment of patients with acute coronavirus disease 2019 (COVID-19) in a telemedicine context is not well described. In the setting of large numbers of patients, a risk assessment tool may guide resource allocation not only for patient care but also for maximum healthcare and public health benefit.ObjectiveTo determine whether a risk prediction tool developed and implemented in March 2020 (“COVID-19 Telemedicine Risk Tier Assessment”) accurately predicts subsequent hospitalizations.DesignRetrospective cohort study, enrollment from March 24 to May 26, 2020 with follow-up calls until hospitalization or clinical improvement (final call date range March 27 to June 19, 2020)SettingSingle center “Virtual Outpatient Management Clinic” (VOMC) assessing and managing outpatients from a large quaternary medical system in Atlanta, GeorgiaParticipants496 patients with COVID-19 confirmed by nasopharyngeal sampling in isolation at home at the time of diagnosis. Exclusion criteria included: (1) hospitalization prior to VOMC enrollment, (2) immediate discharge from VOMC with no follow-up calls due to resolution.ExposureAcute COVID-19 illnessMain Outcome and MeasuresHospitalization was the outcome. Days to hospitalization was the metric. Survival analysis using Cox regression was used to determine factors associated with hospitalization.ResultsThe risk-assessment rubric assigned 496 outpatients to tiers as follows: Tier 1, 237 (47.8%); Tier 2, 185 (37.3%); Tier 3, 74 (14.9%). Subsequent hospitalizations numbered 3 (1%), 15 (7%), and 17 (23%) and for Tiers 1-3, respectively. From a Cox regression model with age ≥ 60, gender, and self-reported obesity as covariates, the adjusted hazard ratios using Tier 1 as reference were: Tier 2 HR=3.74 (95% CI, 1.06-13.27; P=0.041); Tier 3 HR=10.87 (95% CI, 3.09-38.27; P<0.001). Tier was the strongest predictor of time to hospitalization.Conclusions and RelevanceA telemedicine risk assessment tool prospectively applied to an outpatient population with COVID-19 identified both low-risk (Tier 1) and high-risk (Tier 3) patients with better performance than individual risk factors alone. This approach may be appropriate for optimum allocation of resources.
Multi-layered network-based pathway activity inference using directed random walks: application to predicting clinical outcomes in urologic cancer
Authors: Kim So Yeon , Choe Eun Kyung , Shivakumar Manu , Kim Dokyoon , Sohn Kyung-Ah 
Published: July 2020

AbstractMotivationTo better understand the molecular features of cancers, a comprehensive analysis using multi-omics data has been conducted. Additionally, a pathway activity inference method has been developed to facilitate the integrative effects of multiple genes. In this respect, we have recently proposed a novel integrative pathway activity inference approach, iDRW, and demonstrated the effectiveness of the method with respect to dichotomizing two survival groups. However, there were several limitations, such as a lack of generality. In this study, we designed a directed gene-gene graph using pathway information by assigning interactions between genes in multiple layers of networks.ResultsAs a proof-of-concept study, it was evaluated using three genomic profiles of urologic cancer patients. The proposed integrative approach achieved improved outcome prediction performances compared with a single genomic profile alone and other existing pathway activity inference methods. The integrative approach also identified common/cancer-specific candidate driver pathways as predictive prognostic features in urologic cancers. Furthermore, it provides better biological insights into the prioritized pathways and genes in an integrated view using a multi-layered gene-gene network. Our framework is not specifically designed for urologic cancers and can be generally applicable for various datasets.AvailabilityiDRW is implemented as the R software package. The source codes are available athttps://github.com/sykim122/iDRW.
Comparative Evaluation of 19 Reverse Transcription Loop-Mediated Isothermal Amplification Assays for Detection of SARS-CoV-2
Authors: Dong Yajuan , Wu Xiuming , Li Shenwei , Lu Renfei , Wan Zhenzhou , Qin Jianru , Yu Guoying , Jin Xia , Zhang Chiyu 
Published: July 2020

AbstractCoronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has caused a global pandemics. To facilitate the detection of SARS-CoV-2 infection, various RT-LAMP assays using 19 sets of primers had been developed, but never been compared. We performed comparative evaluation of the 19 sets of primers using 4 RNA standards and 29 clinical samples from COVID-19 patients. Six of 15 sets of primers were firstly identified to have faster amplification when tested with four RNA standards, and were further subjected to parallel comparison with the remaining four primer sets using 29 clinical samples. Among these 10 primer sets, Set-4 had the highest positive detection rate of SARS-CoV-2 (82.8%), followed by Set-10, Set-11, Set-13 and Set-14 (75.9%), and Set-14 showed the fastest amplification speed (< 8.5 minutes), followed by Set-17 (< 12.5 minutes). Based on the overall detection performance, Set-4, Set-10, Set-11, Set-13, Set-14 and Set-17 that target Nsp3, S, S, E, N and N gene regions of SARS-CoV-2, respectively, are determined to be better than the other primer sets. Two RT-LAMP assays with the Set-14 primers in combination with any one of four other primer sets (Set-4, Set-10, Set-11, and Set-13) are recommended to be used in the COVID-19 surveillance.
Microtubules tune mechanosensitive cell responses
Authors: Seetharaman Shailaja , Vianay Benoit , Roca Vanessa , De Pascalis Chiara , Boëda Batiste , Dingli Florent , Loew Damarys , Vassilopoulos Stéphane , Théry Manuel , Etienne-Manneville Sandrine 
Published: July 2020

AbstractMechanotransduction is a process by which cells sense the mechanical properties of their surrounding environment and adapt accordingly to perform cellular functions such as adhesion, migration and differentiation. Integrin-mediated focal adhesions are major sites of mechanotransduction and their connection with the actomyosin network is crucial for mechanosensing as well as the generation and transmission of forces onto the substrate. Despite having emerged as major regulators of cell adhesion and migration, the contribution of microtubules to mechanotransduction still remains elusive. Here, we show that actomyosin-dependent mechanosensing of substrate rigidity controls microtubule acetylation, a tubulin post-translational modification, by promoting the recruitment of the alpha-tubulin acetyl transferase (αTAT1) to focal adhesions. Microtubule acetylation, in turn, promotes GEF-H1 mediated RhoA activation, actomyosin contractility and traction forces. Our results reveal a fundamental crosstalk between microtubules and actin in mechanotransduction, which contributes to mechanosensitive cell adhesion and migration.
Modeling Alpha-Synuclein Pathology in a Human Brain-Chip to Assess Blood-Brain Barrier Disruption in Parkinson’s Disease
Authors: Pediaditakis Iosif , Kodella Konstantia R. , Manatakis Dimitris V. , Hinojosa Chris D. , Manolakos Elias S. , Rubin Lee L. , Hamilton Geraldine A. , Karalis Katia 
Published: July 2020

AbstractParkinson’s disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis in the substantia nigra. Although clinical evidence andin vitrostudies indicate disruption of the Blood-Brain Barrier in Parkinson’s disease, the mechanisms mediating the endothelial dysfunction remain elusive. Lack of relevant models able to recapitulate the order of events driving the development of the disease in humans has been a significant bottleneck in the identification of specific successful druggable targets. Here we leveraged the Organs-on-Chips technology to engineer a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow. Our αSyn fibril-induced model was capable of reproducing several key aspects of Parkinson’s disease, including accumulation of phosphorylated αSyn (pSer129-αSyn), mitochondrial impairment, neuroinflammation, and compromised barrier function. This model is poised to enable research into the dynamics of cell-cell interactions in human synucleinopathies and to serve as testing platform for novel therapeutic interventions, including target identification and target validation.
Centennial clonal stability of asexualDaphniain Greenland lakes despite climate variability
Authors: Dane Maison , Anderson N. John , Osburn Christopher L. , Colbourne John K. , Frisch Dagmar 
Published: July 2020

AbstractClimate and environmental condition drive biodiversity at many levels of biological organisation, from populations to ecosystems. Combined with palaeoecological reconstructions, palaeogenetic information on resident populations provides novel insights into evolutionary trajectories and genetic diversity driven by environmental variability. While temporal observations of changing genetic structure are often made of sexual populations, little is known about how environmental change affects the long-term fate of asexual lineages. Here, we provide information on obligately asexual, triploidDaphniapopulations from three Arctic lakes in West Greenland through the past 200-300 years to test the impact of a changing environment on the temporal and spatial population genetic structure. The contrasting ecological state of the lakes, specifically regarding salinity and habitat structure may explain the observed lake-specific clonal composition over time. Palaeolimnological reconstructions show considerable environmental fluctuations since 1700 (the end of the Little Ice Age), but the population genetic structure in two lakes was almost unchanged with at most two clones per time period. Their local populations were strongly dominated by a single clone that has persisted for 250-300 years. We discuss three possible explanations for the apparent population genetic stability: (1) the persistent clones are general purpose genotypes that thrive under broad environmental conditions, (2) clonal lineages evolved subtle genotypic differences that are unresolved by microsatellite markers, or (3) epigenetic modifications allow for clonal adaptation to changing environmental conditions. Our results will motivate research into the mechanisms of adaptation in these populations, as well as their evolutionary fate in the light of accelerating climate change in the polar regions.
SARS-CoV-2-induced humoral immunity through B cell epitope analysis and neutralizing activity in COVID-19 infected individuals in Japan
Authors: Yoshida Shota , Ono Chikako , Hayashi Hiroki , Shiraishi Satoshi , Tomono Kazunori , Arase Hisashi , Matsuura Yoshiharu , Nakagami Hironori 
Published: July 2020

AbstractThe aim of this study is to understand adaptive immunity to SARS-CoV-2 through the analysis of B cell epitope and neutralizing activity in coronavirus disease 2019 (COVID-19) patients. We obtained serum from thirteen COVID-19 patients. Most individuals revealed neutralizing activity against SARS-CoV-2 assessed by a pseudotype virus-neutralizing assay. The antibody production against the spike glycoprotein (S protein) or receptor-binding domain (RBD) of SARS-CoV-2 was elevated, with large individual differences, as assessed by ELISA. In the analysis of the predicted the linear B cell epitopes, two regions (671-690 aa. and 1146-1164 aa.), which were located in S1 and S2 but not in the RBD, were highly reactive with the sera from patients. In the further analysis of the B cell epitope within the S protein by utilizing a B cell epitope array, a hot spot in the N-terminal domain of the S protein but not the RBD was observed in individuals with neutralizing activity. Overall, the analysis of antibody production and B cell epitopes of the S protein from patient serum may provide a novel target for the vaccine development against SARS-CoV-2.
Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response
Authors: Johnson Kevin C. , Anderson Kevin J. , Courtois Elise T. , Barthel Floris P. , Varn Frederick S. , Luo Diane , Seignon Martine , Yi Eunhee , Kim Hoon , Estecio Marcos RH , Tang Ming , Navin Nicholas E. , Maurya Rahul , Ngan Chew Yee , Verburg Niels , De Witt Hamer Philip C , Bulsara Ketan , Samuels Michael L. , Das Sunit , Robson Paul , Verhaak Roel GW 
Published: July 2020

ABSTRACTGlioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.
Pharmacological insights into safety and efficacy determinants for the development of adenosine receptor biased agonists in the treatment of heart failure
Authors: Rueda Patricia , Merlin Jon , Chimenti Stefano , Feletou Michel , Paysant Jerome , White Paul J. , Christopoulos Arthur , Sexton Patrick M. , Summers Roger J. , Charman William N. , May Lauren T. , Langmead Christopher J. 
Published: July 2020

ABSTRACTAdenosine A1receptors (A1R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been hampered by on-target side effects such as bradycardia and altered renal haemodynamics. Biased agonism has emerged as an attractive mechanism for A1R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A1R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterised, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A1R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca2+influx relative to NECA and the cAMP pathway at the A1R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A1R. In contrast to VCP746, which displays more ‘adenosine-like’ signalling at the A2BR, neladenoson was a highly selective A1R agonist, with biased, weak agonism at the A2BR. Together these results show that unwanted haemodynamic effects of A1R agonists can be avoided by compounds biased away from Ca2+influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A1R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients.ONE-SENTENCE SUMMARYBiased agonists that preference against calcium influx relative to the cyclic AMP pathway, when compared to a conventional agonist, confer clinical safety to A1adenosine receptor ligands.