bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Time Course of Clinical Oxygenator Failure Due to Clot Formation
Authors: Demarest Caitlin T. , Shoemaker Samantha J. , Salna Michael P. , Chicotka Scott R. , Fung Kenmond , Bacchetta Matthew D. , Antaki James F. , Cook Keith E. 
Published: November 2020

AbstractBackgroundLong-term use of extracorporeal membrane oxygenation (ECMO) remains limited because of poor biocompatibility, which often leads to clot formation and device failure. Despite this common pathway to failure, there are no published studies on the rate of clot formation and resulting performance deficits in current oxygenators.MethodsECMO cases with either Maquet’s CardioHelp (CH, n=28) or Quadrox (Qx, n=14) oxygenators were evaluated over a three-month period. Data was collected prospectively and included patient characteristics and hematological data. The inlet-outlet oxygen content difference (ΔCO2) and blood flow resistance were calculated as measures of device function, and device failure due to clot formation was defined as a resistance increase greater than 1 mmHg/(L/min)/day for more than one day.ResultsThere were no statistically significant differences in patient age, total days on ECMO, platelet count (PLT) prior to ECMO, activated partial thromboplastin time during ECMO, initial resistance, and device blood flow rate. During ECMO, the Qx group had a significantly greater change in PLT (Qx: - 34±10%; CH: 7±15%), rapidity to failure due to clot formation, and a greater decline in ΔCO2 (all p<0.05). Clot burden was focused at the center of the CH oxygenator, farthest from all inlets, whereas Qx devices developed a more diffuse clot pattern.ConclusionsQx oxygenators clot earlier than CH oxygenators with a correlated drop in ΔCO2 and greater PLT reduction. These differences are likely due to the distributed, four-inlet CH design vs. the single inlet Qx design and differences in pump-induced platelet activation.
Sensitivity Analysis on Predictive Capability of SIRD Model for Coronavirus Disease (COVID-19)
Authors: Sedaghat Ahmad , Alkhatib Fadi , Oloomi Seyed Amir Abbas , Malayer Mahdi Ashtian , Mosavi Amir 
Published: November 2020

AbstractSIR model is one of the simplest methods used in prediction of endemic/pandemic outbreaks. We examined SIRD model for development of COVID-19 in Kuwait which was started on 24 February 2020 by 5 patients in Kuwait. This paper investigates sensitivity of SIRD model for development of COVID-19 in Kuwait based on duration of progressed days of data. For Kuwait, we have fitted SIRD model to COVID-19 data for 20, 40, 60, 80, 100, and 116 days of data and assessed sensitivity of the model with number of days of data. The parameters of SIRD model are obtained using an optimization algorithm (lsqcurvefit) in MATLAB. The total population of 50,000 is equally applied for all Kuwait time intervals. Results of SIRD model indicates that after 40 days the peak infectious day can be adequately predicted; althogh, error percentage from sensetivity analysis indicates that different exposed population sizes are not correctly predicted. SIRD type models are too simple to robustly capture all features of COVID-19 and more precise methods are needed to tackle nonlinear dynamics of a pandemic.
Sensitive quantitative detection of SARS-CoV-2 in clinical samples using digital warm-start CRISPR assay
Authors: Ding Xiong , Yin Kun , Li Ziyue , Sfeir Maroun M. , Liu Changchun 
Published: November 2020

AbstractQuantifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinical samples is crucial for assessing the infectivity of coronavirus disease 2019 and the efficacy of antiviral drugs. Here, we describe a digital warm-start CRISPR (WS-CRISPR) assay for sensitive quantitative detection of SARS-CoV-2 in clinical samples. The WS-CRISPR assay combines low-temperature reverse transcription dual-priming mediated isothermal amplification (RT-DAMP) and CRISPR-Cas12a-based detection in one-pot, attributed to the mediation role by pyrophosphatase and phosphorothioated primers. The WS-CRISPR assay is initiated at above 50 °C and overcomes undesired premature target amplification at room temperature, enabling accurate digital nucleic acid quantification. By targeting SARS-CoV-2’s nucleoprotein gene, digital WS-CRISPR assay is able to detect down to 5 copies/μl SARS-CoV-2 RNA in the chip within 90 minutes. It is clinically validated by quantitatively determining 32 clinical swab samples and three clinical saliva samples, showing 100% agreement with RT-PCR results. Moreover, the digital WS-CRISPR assay has been demonstrated to directly detect SARS-CoV-2 in heat-treated saliva samples without RNA extraction, showing high tolerance to inhibitors. Thus, the digital WS-CRISPR method, as a sensitive and reliable CRISPR assay, facilitates accurate SARS-CoV-2 detection toward digitized quantification.
N439K variant in spike protein may alter the infection efficiency and antigenicity of SARS-CoV-2 based on molecular dynamics simulation
Authors: Zhou Wenyang , Xu Chang , Wang Pingping , Luo Meng , Xu Zhaochun , Cheng Rui , Jin Xiyun , Guo Yu , Xue Guangfu , Juan Liran , Nie Huan , Jiang Qinghua 
Published: November 2020

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing an outbreak of coronavirus disease 2019 (COVID-19), has been undergoing various mutations. The analysis of the structural and energetic effects of mutations on protein-protein interactions between the receptor binding domain (RBD) of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) or neutralizing monoclonal antibodies will be beneficial for epidemic surveillance, diagnosis, and optimization of neutralizing agents. According to the molecular dynamics simulation, a key mutation N439K in the SARS-CoV-2 RBD region created a new salt bridge which resulted in greater electrostatic complementarity. Furthermore, the N439K-mutated RBD bound hACE2 with a higher affinity than wild-type, which may lead to more infectious. In addition, the N439K-mutated RBD was markedly resistant to the SARS-CoV-2 neutralizing antibody REGN10987, which may lead to the failure of neutralization. These findings would offer guidance on the development of neutralizing antibodies and the prevention of COVID-19.
Interactions of anti-COVID-19 drug candidates with multispecific ABC and OATP drug transporters
Authors: Telbisz Ágnes , Ambrus Csilla , Mózner Orsolya , Szabó Edit , Várady György , Bakos Éva , Sarkadi Balázs , Özvegy-Laczka Csilla 
Published: November 2020

AbstractIn the COVID-19 epidemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied together with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, here we examined the interactions of the repurposed drugs with the key human multidrug transporters, present in the major tissue barriers and strongly affecting pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine, the antihelmintic ivermectin, and the proposed antiviral compounds, ritonavir, lopinavir, favipiravir and remdesivir with the ABCB1/Pgp, ABCG2/BCRP and ABCC1/MRP1 exporters, as well as the OATP2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning for the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic.
Metabolic profile discriminates and predictsArabidopsissusceptibility to virus under field conditions
Authors: Rubio Bernadette , Fernandez Olivier , Cosson Patrick , Berton Thierry , Caballero Mélodie , Roux Fabrice , Bergelson Joy , Gibon Yves , Schurdi-Levraud Valérie 
Published: November 2020

SummaryAs obligatory parasites, plant viruses alter host cellular metabolism. There is a lack of information on the variability of virus-induced metabolic responses among genetically diverse plants in a natural context with daily changing conditions. To decipher the metabolic landscape of plant-virus interactions in a natural setting, one hundred and thirty-two and twenty-six accessions ofArabidopsis thalianawere inoculated withTurnip mosaic virus(TuMV), in two field experiments over 2 years. The accessions were phenotyped for viral accumulation, above-ground biomass, targeted and untargeted metabolic profiles. The accessions revealed quantitative response to the virus, from susceptibility to resistance. Susceptible accessions accumulate primary and secondary metabolites upon infection, at the cost of hindered growth. Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) revealed that the primary metabolites sucrose, glucose and glutamate discriminate susceptible and resistant accessions. Twenty-one metabolic signatures were found to significantly accumulate in resistant accessions whereas they maintained their growth at the same level as mock-inoculated plants without biomass penalty.Metabolic content was demonstrated to discriminate and to be highly predictive of the susceptibility of inoculatedArabidopsis. The PLS coefficient estimated in the training data set reveals, after cross-validation, a correlation of 0.61 between predicted and true viral accumulation. This study is the first to describe the metabolic landscape of plant-virus interactions in a natural setting and its predictive link to susceptibility. It reveals that, in this undomesticated species and in ecologically realistic conditions, growth and resistance are in a permanent conversation and provides new insights on plant-virus interactions.
Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19
Authors: Steuten Kas , Kim Heeyoung , Widen John C. , Babin Brett M. , Onguka Ouma , Lovell Scott , Bolgi Oguz , Cerikan Berati , Cortese Mirko , Muir Ryan K. , Bennett John M. , Geiss-Friedlander Ruth , Peters Christoph , Bartenschlager Ralf , Bogyo Matthew 
Published: November 2020

ABSTRACTTwo proteases produced by the SARS-CoV-2 virus, Mproand PLpro, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mproand PLproproteases. These efforts identified a small number of hits for the Mproprotease and no viable hits for the PLproprotease. Of the Mprohits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead Mproinhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mproinhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L and B and showed similar loss in activity in cells expressing TMPRSS2. Our results highlight the challenges of targeting Mproand PLproproteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.
Association of renal function with diabetic retinopathy and macular edema among patients with type 2 diabetes mellitus
Authors: Wang Lanhua , Jin Ling , Wang Wei , Gong Xia , Li Yuting , Li Wangting , Meng Jie , Liang Xiaoling , Huang Wenyong , Liu Yizhi 
Published: November 2020

AbstractPurposeTo investigate the associations between renal function and the presence of diabetic retinopathy (DR) in diabetic patients.MethodsA total of 1877 diabetic participants aged 30 to 80 years were consecutively recruited from October 2017 to April 2019. All participants underwent blood and urine analyses and standardized 7-field fundus imaging. The presence of DR, vision-threatening DR (VTDR) and DME was graded based on the fundus photographs. Renal function was defined as normal, mildly impaired or chronic kidney disease (CKD) based on different estimated glomerular filtration rates (GFRs).ResultsUnlike a normal GFR, CKD was significantly associated with any DR (OR=1.89, P=0.017) and VTDR (OR=2.76, P=0.009), and mildly impaired renal function was associated with only any DR (OR=1.39, P=0.031). The analysis of the effect of microalbuminuria on relationship between GFR and DR showed that the GFR was associated with any DR only in the presence of microalbuminuria, while the GFR was an independent risk factor for VTDR regardless of microalbuminuria status (all P<0.05). The risks of any DR (OR=1.74 for quartile 2 and 3.09 for quartile 4) and VTDR (OR=3.27 for quartile 2 and 6.41 for quartile 4) increased gradually as the microalbuminuria quartile increased (all P<0.05). The third (OR=2.99, P=0.029) and fourth microalbuminuria quartiles (OR=4.74, P=0.002) were independent DME risk factors.ConclusionsThere was a strong association between GFR and VTDR, whereas the association of GFR and any DR was significant only under the premise of microalbuminuria. High microalbuminuria was significantly associated with DR and DME.
Peptide Ancestry Informative Markers in Uterine Neoplasms from Women of European, African and Asian Ancestry
Authors: Bateman Nicholas W. , Tarney Christopher M. , Abulez Tamara S. , Hood Brian L. , Conrads Kelly A. , Zhou Ming , Soltis Anthony R. , Teng Pang-ing , Jackson Amanda , Tian Chunqiao , Dalgard Clifton L. , Wilkerson Matthew D. , Kessler Michael D. , Goecker Zachary , Loffredo Jeremy , Shriver Craig D , Hu Hai , Cote Michele , Parker Glendon J. , Segars James , Al-Hendy Ayman , Risinger John R. , Darcy Kathleen M. , Casablanca Yovanni , Maxwell G. Larry , Conrads Thomas P. , O’Connor Timothy D. 
Published: November 2020

AbstractCharacterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes.In silicoanalysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.
Different RNA profiles in plasma derived small and large extracellular vesicles of Neurodegenerative diseases patients
Authors: Sproviero Daisy , Gagliardi Stella , Zucca Susanna , Arigoni Maddalena , Giannini Marta , Garofalo Maria , Olivero Martina , Dell’Orco Michela , Pansarasa Orietta , Bernuzzi Stefano , Avenali Micol , Ramusino Matteo Cotta , Diamanti Luca , Minafra Brigida , Perini Giulia , Zangaglia Roberta , Costa Alfredo , Ceroni Mauro , Perrone-Bizzozero Nora I. , Calogero Raffaele A. , Cereda Cristina 
Published: November 2020

AbstractBackgroundIdentifying robust biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different mRNA/miRNA signatures in plasma derived LEVs and SEVs of Alzheimer’s Disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients.MethodsLEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and ultracentrifugation and RNA was extracted. Whole transcriptome and miRNA libraries were carried out by Next Generation Sequencing (NGS).ResultsWe detected different deregulated RNAs in LEVs and SEVs from patients with the same disease. MiRNAs resulted to be the most interesting subpopulation of transcripts transported by plasma derived SEVs since they appeared to discriminate all NDs disease from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were mainly linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway.ConclusionLEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading/protection of the disease. The study of common and different RNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.
Antagonistic fungal enterotoxins intersect at multiple levels with host innate immune defences
Authors: Zhang Xing , Harding Benjamin , Aggad Dina , Courtine Damien , Chen Jia-Xuan , Pujol Nathalie , Ewbank Jonathan J. 
Published: November 2020

ABSTRACTAnimals and plants need to defend themselves from pathogen attack. Their defences drive innovation in virulence mechanisms, leading to never-ending cycles of co-evolution in both hosts and pathogens. A full understanding of host immunity therefore requires examination of pathogen virulence strategies. Here, we take advantage of the well-studied innate immune system ofCaenorhabditis elegansto dissect the action of two virulence factors from its natural fungal pathogenDrechmeria coniospora. We show that these two enterotoxins have strikingly different effects when expressed individually in the nematode epidermis. One is able to interfere with diverse aspects of host cell biology, altering vesicle trafficking and preventing the key STAT-like transcription factor STA-2 from activating defensive antimicrobial peptide gene expression. The second, potentially as a consequence of a host surveillance mechanism, increases STA-2 levels in the nucleus, modifies the nucleolus, and causes increased defence gene expression. Our results highlight the remarkably complex and potentially antagonistic mechanisms that come into play in the interaction between co-evolved hosts and pathogens.
The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by pausing POL II at pro-differentiation genes
Authors: Garipler Görkem , Lu Congyi , Morrissey Alexis , Lopez-Zepeda Lorena S. , Vidal Simon E. , Aydin Begüm , Stadtfeld Matthias , Ohler Uwe , Mahony Shaun , Sanjana Neville E. , Mazzoni Esteban O. 
Published: November 2020

AbstractIn pluripotent cells, a delicate activation-repression balance maintains pro-differentiation genes ready for rapid activation. The identity of transcription factors (TFs) that specifically repress pro-differentiation genes remains obscure. By targeting ~1,700 TFs with CRISPR loss-of-function screen, we found that ZBTB11 and ZFP131 are required for embryonic stem cell (ESC) pluripotency. ZBTB11 and ZFP131 maintain promoter-proximally paused Polymerase II at pro-differentiation genes in ESCs. ZBTB11 or ZFP131 loss leads to NELF pausing factor release, an increase in H3K4me3, and transcriptional upregulation of genes associated with all three germ layers. Together, our results suggest that ZBTB11 and ZFP131 maintain pluripotency by preventing premature expression of pro-differentiation genes and present a generalizable framework to maintain cellular potency.One-sentence summaryA Transcription Factor-wide CRISPR screen identifies ZBTB11 and ZFP131 maintaining pluripotency by pausing POL II at pro-differentiation genes
Neural signatures of predictive language processing in parkinson’s disease with and without mild cognitive impairment
Authors: León-Cabrera Patricia , Pagonabarraga Javier , Morís Joaquín , Martínez-Horta Saúl , Marín-Lahoz Juan , Horta-Barba Andrea , Bejr-Kasem Helena , Kulisevsky Jaime , Rodríguez-Fornells Antoni 
Published: November 2020

ABSTRACTCognitive deficits are common in Parkinson’s disease (PD), with some PD patients meeting criteria for mild cognitive impairment (MCI). An unaddressed question is whether linguistic prediction is preserved in PD. This ability is nowadays deemed crucial in achieving fast and efficient comprehension, and it may be negatively impacted by cognitive deterioration. To fill this gap of knowledge, we used event-related potentials (ERPs) to evaluate mechanisms of linguistic prediction in a sample of PD patients (on dopamine compensation) with and without MCI. To this end, participants read sentence contexts that were predictive or not about a sentence-final word. The final word appeared after 1 second, matching or mismatching the prediction. The introduction of the interval allowed to capture neural responses both before and after sentence-final words, reflecting semantic anticipation and processing. PD patients with normal cognition (N = 58) showed ERP responses comparable to those of matched controls. Specifically, in predictive contexts, a slow negative potential developed prior to sentence-final words, reflecting semantic anticipation. Later, expected words elicited reduced N400 responses (compared to unexpected words), indicating facilitated semantic processing. Besides, PD patients with MCI (N = 20) showed a prolongation of the N400 congruency effect (compared to matched PD patients without MCI), indicating that further cognitive decline impacts semantic processing. Finally, lower verbal fluency scores correlated with prolonged N400 congruency effects and with reduced pre-word differences in all PD patients (N = 78). This relevantly points to a role of deficits in temporal-dependent mechanisms in PD, besides prototypical frontal dysfunction, in altered semantic anticipation and semantic processing during sentence comprehension.