bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards biomarkers for outcomes after pancreatic ductal adenocarcinoma and ischemic stroke, with focus on (co-)morbidity and aging / cellular senescence (SASKit): protocol for a prospective cohort study
Authors: Henze Larissa , Walter Uwe , Escobar Hugo Murua , Junghanß Christian , Jaster Robert , Köhling Rüdiger , Lange Falko , Salehzadeh-Yazdi Ali , Wolkenhauer Olaf , Hamed Mohamed , Barrantes Israel , Palmer Daniel , Möller Steffen , Kowald Axel , Heussen Nicole , Fuellen Georg 
Published: April 2020

AbstractAging-related processes such as cellular senescence are believed to underlie the accumulation of diseases in time, causing (co-)morbidity, including cancer, thromboembolism and stroke. Intervening into these processes may delay, stop or reverse morbidity. To study the link between (co-)morbidity and aging, by exploring biomarkers and molecular mechanisms of disease-triggered deterioration, we will recruit 50 patients with pancreatic ductal adenocarcinoma, 50 patients with (thromboembolic) ischemic stroke and 50 controls, at Rostock University Medical Center. We will gather routine blood data, clinical performance measurements and patient-reported outcomes at up to 9 points in time, and in-depth transcriptomics & proteomics at two early time points. Aiming for clinically relevant biomarkers, the primary outcome is a composite of probable sarcopenia, clinical performance (described by ECOG Performance Status for patients with pancreatic ductal adenocarcinoma and the Modified Rankin Scale for patients with stroke) and quality of life. Further outcomes cover other aspects of morbidity such as cognitive decline, and of comorbidity such as vascular or cancerous events. The data analysis is comprehensive in that it includes biostatistics & machine learning, both following standard role models & additional explorative approaches. Predictive biomarkers for interventions addressing senescence may become available if the biomarkers that we find are predominantly related to aging / cellular senescence. Similarly, diagnostic biomarkers will be explored for their relationship to aging / cellular senescence. Our findings will require validation in independent studies, and our dataset shall be useful to validate the findings of other studies. In some of the explorative analyses, we shall include insights from systems biology modeling as well as insights from preclinical animal models. We humbly suggest that our detailed study protocol and data analysis plan may also guide other biomarker exploration trials.In BriefThe SASKit (“Senescence-Associated Systems diagnostics Kit for cancer and stroke”) study primarily aims to discover novel biomarkers for deterioration of health and (co-)morbidities triggered by pancreatic ductal adenocarcinoma or ischemic stroke.
Neutrophil extracellular traps (NETs) as markers of disease severity in COVID-19
Authors: Zuo Yu , Yalavarthi Srilakshmi , Shi Hui , Gockman Kelsey , Zuo Melanie , Madison Jacqueline A. , Blair Christopher , Weber Andrew , Barnes Betsy J. , Egeblad Mikala , Woods Robert J. , Kanthi Yogendra , Knight Jason S. 
Published: April 2020

ABSTRACTIn severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have potential to propagate inflammation and microvascular thrombosis—including in the lungs of patients with acute respiratory distress syndrome. While elevated levels of blood neutrophils predict worse outcomes in COVID-19, the role of NETs has not been investigated. We now report that sera from patients with COVID-19 (n=50 patients, n=84 samples) have elevated levels of cell-free DNA, myeloperoxidase(MPO)-DNA, and citrullinated histone H3 (Cit-H3); the latter two are highly specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute phase reactants including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. In summary, these data reveal high levels of NETs in many patients with COVID-19, where they may contribute to cytokine release and respiratory failure. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts, and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.
An Objective Structural and Functional Reference Standard for Diagnostic Studies in Glaucoma
Authors: Mariottoni Eduardo B. , Jammal Alessandro A. , Berchuck Samuel I. , Tavares Ivan M. , Medeiros Felipe A. 
Published: April 2020

AbstractPurposeTo propose a reference standard for the definition of glaucomatous optic neuropathy (GON) consisting of objective parameters from spectral-domain optical coherence tomography (SDOCT) and standard automated perimetry (SAP), and to apply it to the development and evaluation of a deep learning (DL) algorithm to detect glaucomatous damage on fundus photographs.DesignRetrospective, cross-sectional study.MethodsData were extracted from the Duke Glaucoma Registry and included 2,927 eyes of 2,025 participants with fundus photos, SDOCT and SAP acquired within six months. Eyes were classified as GON versus normal based on a combination of objective SDOCT and SAP criteria. A DL convolutional neural network was trained to predict the probability of GON from fundus photos. The algorithm was tested on an independent sample with performance assessed by sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and likelihood ratios (LR).ResultsThe test sample included 585 eyes of 405 participants. The median DL probability of glaucoma in eyes with GON was 99.8% versus 0.03% for normal eyes (P < 0.001), with an AUC of 0.92 and sensitivity of 77% at 95% specificity. LRs indicated that the DL algorithm provided large changes in the post-test probability of disease for the majority of eyes.ConclusionsThe DL algorithm had high performance to discriminate eyes with GON from normal. The newly proposed objective definition of GON used as reference standard may increase the comparability of diagnostic studies of glaucoma across devices and populations, helping to improve the development and assessment of tests in clinical practice.
Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection
Authors: Wang Allen , Chiou Joshua , Poirion Olivier B , Buchanan Justin , Valdez Michael J , Verheyden Jamie M , Hou Xiaomeng , Guo Minzhe , Newsome Jacklyn M , Kudtarkar Parul , Faddah Dina A , Zhang Kai , Young Randee E , Barr Justinn , Misra Ravi , Huyck Heidie , Rogers Lisa , Poole Cory , Whitsett Jeffery A. , Pryhuber Gloria , Xu Yan , Gaulton Kyle J , Preissl Sebastian , Sun Xin ,   NHLBI LungMap Consortium
Published: April 2020

SUMMARYRespiratory failure is the leading cause of COVID-19 death and disproportionately impacts adults more than children. Here, we present a large-scale snATAC-seq dataset (90,980 nuclei) of the human lung, generated in parallel with snRNA-seq (46,500 nuclei), from healthy donors of ~30 weeks, ~3 years and ~30 years of age. Focusing on genes implicated in SARS-CoV-2 cell entry, we observed an increase in the proportion of alveolar epithelial cells expressingACE2andTMPRSS2in adult compared to young lungs. Consistent with expression dynamics, 10 chromatin peaks linked toTMPRSS2exhibited significantly increased activity with age and harbored IRF and STAT binding sites. Furthermore, we identified 14 common sequence variants in age-increasing peaks with predicted regulatory function, including several associated with respiratory traits andTMPRSS2expression. Our findings reveal a plausible contributor to why children are more resistant to COVID-19 and provide an epigenomic basis for transferring this resistance to older populations.
Laparoscopic vs open gastrectomy- An updated metanalysis of randomized control trials for short term outcomes
Authors: Vasavada Bhavin , Patel Hardik 
Published: April 2020

AbstractIntroductionAim of this metanalysis was to compare short term outcomes of laparoscopic and open gastrectomy for gastric cancer.Material and methodsEMBASE, MEDLINE, PubMed and the Cochrane Database were searched for randomized control trials comparing outcomes in patients undergoing laparoscopic gastrectomies with those patients undergoing open gastrectomies. The primary outcome was 30 days morbidity and mortality. Secondary outcomes studied included length of stay, blood loss, d2gastrectomies, lymph node retrieval, operative time, distal gastrectomy, wound complications and intraabdominal complications Systemic review and Metanalysis were done according to MOOSE and PRISMA guidelines.ResultsMorbidity was significantly low in laparoscopic group (P=0.003).There was no significant difference between mortality between the two groups. (P=0.75). There fewer wound complications in laparoscopic group, no difference intra-abdominal complications in both the groups. Blood loss was significantly lesser in laparoscopic group.(p <0.001). Hospital stay was similar in laparoscopic group. (P=0.30). Operative time was significantly higher in laparoscopic group. (P< 0.001). Laparoscopic group patients had less number of lymph node retrieval compared to laparoscopic group.(p = 0.002). Laparoscopic group also contained similar advanced staged gastric cancer than open gastrectomies. (p= 0.64)ConclusionsLaparoscopic gastrectomies were associated with better short term outcomes.
Marburg and Ebola virus infections elicit a complex, muted inflammatory state in bats
Authors: Jayaprakash Anitha D. , Ronk Adam J. , Prasad Abhishek N. , Covington Michael F. , Stein Kathryn R. , Schwarz Toni M. , Hekmaty Saboor , Fenton Karla A. , Geisbert Thomas W. , Basler Christopher F. , Bukreyev Alexander , Sachidanandam Ravi 
Published: April 2020

AbstractThe Marburg and Ebola filoviruses cause a severe, often fatal, disease in humans and nonhuman primates but have only subclinical effects in bats, including Egyptian rousettes, which are a natural reservoir of Marburg virus. A fundamental question is why these viruses are highly pathogenic in humans but fail to cause disease in bats. To understand how bats resist the disease caused by filoviruses, we infected one cohort of Egyptian rousette bats with Marburg virus and another cohort with Ebola virus and harvested multiple tissues for mRNA expression analysis. While virus transcripts were found primarily in the liver, Principal component analysis (PCA) revealed coordinated changes across multiple tissues. Gene signatures in kidney and liver pointed at induction of vasodilation, reduction of coagulation and changes in the regulation of iron metabolism. Signatures of immune response detected in spleen and liver indicated a robust anti-inflammatory state signified by macrophages in the M2 state and an active T cell response. Many of the responsive genes were found to be evolutionarily divergent, providing a framework for understanding the differences in outcomes of filovirus infections between bats and humans. In this study, we outline multiple interconnected pathways that respond to infection by MARV and EBOV, providing insights into the complexity of the mechanisms that enable bats to resist the disease caused by filoviral infections. The results have the potential to aid in the development of new strategies to effectively mitigate and treat the disease caused by these viruses in humans.
High-surety isothermal amplification and detection of SARS-CoV-2, including with crude enzymes
Authors: Bhadra Sanchita , Riedel Timothy E. , Lakhotia Simren , Tran Nicholas D. , Ellington Andrew D. 
Published: April 2020

ABSTRACTIsothermal nucleic acid amplification tests (iNAT), such as loop-mediated isothermal amplification (LAMP), are good alternatives to polymerase chain reaction (PCR)-based amplification assays, especially for point-of-care and low resource use, in part because they can be carried out with relatively simple instrumentation. However, iNATs can generate spurious amplicons, especially in the absence of target sequences, resulting in false positive results. This is especially true if signals are based on non-sequence-specific probes, such as intercalating dyes or pH changes. In addition, pathogens often prove to be moving, evolving targets, and can accumulate mutations that will lead to inefficient primer binding and thus false negative results. Internally redundant assays targeting different regions of the target sequence can help to reduce such false negatives. Here we describe rapid conversion of three previously described SARS-CoV-2 LAMP assays that relied on non-sequence-specific readout into assays that can be visually read using sequence-specific fluorogenic oligonucleotide strand exchange (OSD) probes. We evaluate one-pot operation of both individual and multiplex LAMP-OSD assays and demonstrate detection of SARS-CoV-2 virions in crude human saliva.
Nairobi Sheep Disease Virus: a historical and epidemiological perspective
Authors: Krasteva Stephanie , Jara Manuel , Frias-De-Diego Alba , Machado Gustavo 
Published: April 2020

AbstractNairobi Sheep Disease virus (NSDv) is a zoonotic and tick-borne disease that can cause over 90% mortality in small ruminants. NSDv has historically circulated in East Africa and has recently emerged in the Asian continent. Despite efforts to control the disease, some regions, mostly in warmer climates, persistently report disease outbreaks. Consequently, it is necessary to understand how environmental tolerances and factors that influence transmission may shed light on its possible emergence in other regions. In this study, we quantified the available literature of NSDv from which occurrence data was extracted. In total, 308 locations from Uganda, Kenya, Tanzania, Somalia, India, Sri Lanka and China were coupled with landscape conditions to reconstruct the ecological conditions for NSDv circulation and identify areas of potential disease transmission risk. Our results identified areas suitable for NSDv in Ethiopia, Malawi, Zimbabwe, Southeastern China, Taiwan, and Vietnam. Unsuitable areas included Democratic Republic of Congo, Zambia, and Southern Somalia. In summary, soil moisture, livestock density, and precipitation predispose certain areas to NSDv circulation. It is critical to investigate the epidemiology of NSDv in order to promote better allocation of resources to control its spread in regions that are more at risk. This will help reduce disease impact worldwide as climate change will favor emergence of such vector-borne diseases in areas with dense small ruminant populations.
Association of common genetic variants in theCPSF7andSDHAF2genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier
Authors: Piras Ignazio S. , Bleul Christiane , Siniard Ashley , Wolfe Amanda J. , De Both Matthew D. , Hernandez Alvaro G. , Huentelman Matthew J. 
Published: April 2020

AbstractCanine Idiopathic Pulmonary Fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a Genome-Wide Association Study (GWAS) in the WHWT using Whole Genome Sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide™ DNA library prep kit. After quality controls, 28 affected, 44 unaffected and 1,843,695 informative Single Nucleotide Polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both theCPSF7andSDHAF2genes (adjusted p = 0.016 and p = 0.025, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389, however it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT.CPSF7was recently associated with lung adenocarcinoma further highlighting the potential relevance of our results since IPF and lung cancer share several pathological mechanisms.
Global trends in biodiversity and ecosystem services from 1900 to 2050
Authors: Pereira Henrique M. , Rosa Isabel M.D. , Martins Inês S. , Kim HyeJin , Leadley Paul , Popp Alexander , van Vuuren Detlef P. , Hurtt George , Anthoni Peter , Arneth Almut , Baisero Daniele , Chaplin-Kramer Rebecca , Chini Louise , Di Fulvio Fulvio , Di Marco Moreno , Ferrier Simon , Fujimori Shinichiro , Guerra Carlos A. , Harfoot Michael , Harwood Thomas D. , Hasegawa Tomoko , Haverd Vanessa , Havlík Petr , Hellweg Stefanie , Hilbers Jelle P. , Hill Samantha L. L. , Hirata Akiko , Hoskins Andrew J. , Humpenöder Florian , Janse Jan H. , Jetz Walter , Johnson Justin A. , Krause Andreas , Leclère David , Matsui Tetsuya , Meijer Johan R. , Merow Cory , Obsersteiner Michael , Ohashi Haruka , Poulter Benjamin , Purvis Andy , Quesada Benjamin , Rondinini Carlo , Schipper Aafke M. , Settele Josef , Sharp Richard , Stehfest Elke , Strassburg Bernardo B. N. , Takahashi Kiyoshi , Talluto Matthew V. , Thuiller Wilfried , Titeux Nicolas , Visconti Piero , Ware Christopher , Wolf Florian , Alkemade Rob 
Published: April 2020

AbstractDespite the scientific consensus on the extinction crisis and its anthropogenic origin, the quantification of historical trends and of future scenarios of biodiversity and ecosystem services has been limited, due to the lack of inter-model comparisons and harmonized scenarios. Here, we present a multi-model analysis to assess the impacts of land-use and climate change from 1900 to 2050. During the 20th century provisioning services increased, but biodiversity and regulating services decreased. Similar trade-offs are projected for the coming decades, but they may be attenuated in a sustainability scenario. Future biodiversity loss from land-use change is projected to keep up with historical rates or reduce slightly, whereas losses due to climate change are projected to increase greatly. Renewed efforts are needed by governments to meet the 2050 vision of the Convention on Biological Diversity.One Sentence SummaryDevelopment pathways exist that allow for a reduction of the rates of biodiversity loss from land-use change and improvement in regulating services but climate change poses an increasing challenge.
Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex
Authors: Halff Els F. , Cotel Marie-Caroline , Natesan Sridhar , McQuade Richard , Ottley Chris J. , Srivastiva Deepak P. , Howes Oliver D. , Vernon Anthony C. 
Published: April 2020

AbstractThe pathophysiology of the majority of neuropsychiatric disorders, including schizophrenia and mood disorders, involves synaptic dysfunction and/or loss, manifesting as lower levels of several presynaptic and postsynaptic marker proteins. Whether chronic exposure to antipsychotic drugs may contribute to this pattern of synaptic loss remains controversial. In contrast, the mood stabiliser lithium has shown to exhibit neurotrophic actions and is thought to enhance synapse formation. Whilst these data are not unequivocal, they suggest that antipsychotic drugs and lithium have contrasting effects on synapse density. We therefore investigated the effect of chronic exposure to lithium and to two different antipsychotics, haloperidol and olanzapine, on presynaptic Synaptic Vesicle glycoprotein 2A (SV2A) and postsynaptic Neuroligin (NLGN) clusters in the rat frontal cortex. Chronic exposure (28 days) to haloperidol (0.5 mg/kg/d) or olanzapine (7.5 mg/kg/d) had no effect on either SV2A or NLGN clusters and no overall effect on synaptic clusters. In contrast, chronic lithium exposure (2 mmol/L eq./d) significantly increased NLGN cluster density as compared to vehicle, but did not affect either SV2A or total synaptic clusters. These data are consistent with and extend our prior work, confirming no effect of either antipsychotics or lithium on SV2A clustering, but suggest contrasting effects of these drugs on the post-synapse. Although caution needs to be exerted when extrapolating results from animals to patients, these data provide clarity with regard to the effect of antipsychotics and lithium on synaptic markers, thus facilitating discrimination of drug from illness effects in human studies of synaptic pathology in psychiatric disorders.
Synchronized cardiac impulses emerge from multi-scale, heterogeneous local calcium signals within and among cells of heart pacemaker tissue
Authors: Bychkov Rostislav , Juhaszova Magdalena , Tsutsui Kenta , Coletta Christopher , Stern Michael D. , Maltsev Victor A. , Lakatta Edward G. 
Published: April 2020

ABSTRACTBackgroundThe current paradigm of Sinoatrial Node (SAN) impulse generation: (i) is that full-scale action potentials (APs) of a common frequency are initiated at one site and are conducted within the SAN along smooth isochrones; and (ii) does not feature fine details of Ca2+signalling present in isolated SAN cells, in which small subcellular, subthreshold local Ca2+releases (LCRs) self-organize to generate cell-wide APs.ObjectivesTo study subcellular Ca2+signals within and among cells comprising the SAN tissue.MethodsWe combined immunolabeling with a novel technique to detect the occurrence of LCRs and AP-induced Ca2+transients (APCTs) in individual pixels (chonopix) across the entire mouse SAN images.ResultsAt high magnification, Ca2+signals appeared markedly heterogeneous in space, amplitude, frequency, and phase among cells comprising an HCN4+/CX43-cell meshwork. The signalling exhibited several distinguishable patterns of LCR/APCT interactions within and among cells. Apparently conducting rhythmic APCTs of the meshwork were transferred to a truly conducting HCN4-/CX43+network of straited cells via narrow functional interfaces where different cell types intertwine, i.e. the SAN anatomical/functional unit. At low magnification, the earliest APCT of each cycle occurred within a small area of the HCN4 meshwork and subsequent APCT appearance throughout SAN pixels was discontinuous.ConclusionsWe have discovered a novel, microscopic Ca2+signalling paradigm of SAN operation that has escaped detection using low-resolution, macroscopic tissue isochrones employed in prior studies: APs emerge from heterogeneous subcellular subthreshold Ca2+signals, resembling multiscale complex processes of impulse generation within clusters of neurons in neuronal networks.Condensed abstractBy combining immunolabeling with a novel optical technique we detected markedly heterogenous Ca2+signals within and among cell clusters of an HCN4+/CX43-meshwork in mouse sinoatrial node. These Ca2+signals self-organized and transferred, throughout the node, to projections from an HCN4-/CX43+network connected to a highly organized, rapidly conducting part of the CX43+network. Thus, APs emerge from heterogeneous, subthreshold Ca2+signaling not detected in low-resolution macroscopic isochrones. Our discovery requires a fundamental paradigm shift from concentric impulse propagation initiated within a leading site, to a multiscale/complex process, resembling the emergence of organized signals from heterogeneous local signals within neuronal networks.