bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility
Authors: Wang Jerry C. , Ramaswami Gokul , Geschwind Daniel H. 
Published: August 2020

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by motor neuron (MN) loss. Multiple genetic risk factors have been identified, implicating RNA and protein metabolism and intracellular transport, among other biological mechanisms. To achieve a systems-level understanding of the mechanisms governing ALS pathophysiology, we built gene co-expression networks using RNA-sequencing data from control human spinal cord samples, identifying 13 gene co-expression modules, each of which represents a distinct biological process or cell type. Analysis of four RNA-seq datasets from a range of ALS disease-associated contexts reveal dysregulation in numerous modules related to ribosomal function, wound response, and leukocyte activation, implicating astrocytes, oligodendrocytes, endothelia, and microglia in ALS pathophysiology. To identify potentially causal processes, we partitioned heritability across the genome, finding that ALS common genetic risk is enriched within two specific modules, SC.M4, representing genes related to RNA processing and gene regulation, and SC.M2, representing genes related to intracellular transport and autophagy and enriched in oligodendrocyte markers. Top hub genes of this module include ALS-implicated risk genes such as KPNA3, TMED2, and NCOA4, the latter of which regulates ferritin autophagy, implicating this process in ALS pathophysiology. These unbiased, genome-wide analyses confirm the utility of a systems approach to understanding the causes and drivers of ALS.
Transcriptome-wide Association Study of Circulating IgE Levels Identifies Novel Targets for Asthma and Allergic Diseases
Authors: Kathryn Recto , Tianxiao Huan , Heon Lee Dong , Young Lee Gha , Jessica Gereige , Chen Yao , Shih-Jen Hwang , Roby Joehanes , Kelly Rachel S , Jessica Lasky-Su , George O’Connor , Daniel Levy 
Published: August 2020

AbstractMeasurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study (TWAS) to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study (FHS) across 17,873 mRNA gene-level transcripts. We identified 216 significant transcripts at a false discovery rate (FDR)< 0.05. We conducted replication using the meta-analysis of two independent external studies: the Childhood Asthma Management Program (n = 610) and the Genetic Epidemiology of Asthma in Costa Rica Study (n = 326); we then reversed the discovery and replication cohorts, which revealed 59 significant genes that bidirectionally replicated. Gene ontology analysis revealed that many of these genes were implicated in immune function pathways, including defense response, inflammatory response, and cytokine production. Mendelian randomization (MR) analysis revealed four genes (CLC, CCDC21, S100A13, andGCNT1) as putatively causal (p< 0.05) regulators of IgE levels.GCNT1(beta = 1.5, p = 0.01)—which is a top result in the MR analysis of expression in relation to asthma and allergic diseases—plays a role in regulating T helper type 1 (Th1) cell homing, lymphocyte trafficking, and B cell differentiation. Our findings build upon prior knowledge of IgE regulation and provide a deeper understanding of underlying molecular mechanisms. The IgE-associated genes that we identified—particularly those implicated in MR analysis—can be explored as promising therapeutic targets for asthma and IgE-related diseases.
Risk factors associated with morbidity and mortality outcomes of COVID-19 patients on the 14th and 28th day of the disease course: a retrospective cohort study in Bangladesh
Authors: Islam M.Z. , Riaz B.K. , Islam ANMS , Khanam F. , Akhter J. , Choudhury R. , Farhana N. , Jahan N.A. , Uddin M.J. , Efa S.S. 
Published: August 2020

SummaryDiverse risk factors intercede the outcomes of COVID-19. We conducted this retrospective cohort study to identify the risk factors associated with morbidity and mortality outcomes with a cohort of 1016 COVID-19 patients diagnosed in May 2020. Data were collected by telephone-interview and reviewing records using a questionnaire and checklist. Morbidity (64.4% Vs. 6.0%) and mortality (2.3% Vs. 2.5%) outcomes varied between the 14th and 28th day. Morbidity risk factors included chronic obstructive pulmonary disease (COPD) (RR=1.19, RR=2.68) both on the 14th and 18th day while elderly (AOR=2.56) and smokeless tobacco (SLT) (AOR=2.17) on the 28th day. Mortality risk factors included elderly (AOR=10.14), COPD (RR=5.93), and SLT (AOR=2.25) on the 14th day, and elderly (AOR=24.37) and COPD (RR=2.72) on the 28th day. The morbidity risk was higher with chronic kidney disease (CKD) (RR=3.33) and chronic liver disease (CLD) (RR=3.99) on the 28th day. The mortality risk was higher with coronary heart disease (RR=4.54) and CLD (RR=9.66) on the 14th while with diabetes mellitus (RR=3.08, RR=2.08), hypertension (RR=3.14, RR=2.30), CKD (RR=8.97, RR=2.71), and malignant diseases (RR=10.29) on both 14th and 28th day. We must espouse program interventions considering the morbidity and mortality risk factors to condense the aggressive outcomes of COVID-19.
Evidence and magnitude of seasonality in SARS-CoV-2 transmission: Penny wise, pandemic foolish?
Authors: Kaplin Adam , Junker Caesar , Kumar Anupama , de Amorim Ribeiro Mary Anne , Yu Eileen , Wang Michael , Smith Ted , Rai Shesh N , Bhatnagar Aruni 
Published: August 2020

AbstractImportanceIntensity and duration of the COVID-19 pandemic, and planning required to balance concerns of saving lives and avoiding economic collapse, could depend significantly on whether SARS-CoV-2 transmission is sensitive to seasonal changes.ObjectiveHypothesis is that increasing temperature results in reduced SARS CoV-2 transmission and may help slow the increase of cases over time.SettingFifty representative Northern Hemisphere countries meeting specific criteria had sufficient COVID-19 case and meteorological data for analysis.MethodsRegression was used to find relationship between the log of number of COVID-19 cases and temperature over time in 50 representative countries. To summarize the day-day variability, and reduce dimensionality, we selected a robust measure, Coefficient of Time (CT), for each location. The resulting regression coefficients were then used in a multivariable regression against meteorological, country-level and demographic covariates.ResultsMedian minimum daily temperature showed the strongest correlation with the reciprocal of CT (which can be considered as a rate associated with doubling time) for confirmed cases (adjusted R2 = 0.610, p = 1.45E-06). A similar correlation was found using median daily dewpoint, which was highly colinear with temperature, and therefore was not used in the analysis. The correlation between minimum median temperature and the rate of increase of the log of confirmed cases was 47% and 45% greater than for cases of death and recovered cases of COVID-19, respectively. This suggests the primary influence of temperature on SARS-CoV2 transmission more than COVID-19 morbidity. Based on the correlation between temperature and the rate of increase in COVID-19, it can be estimated that, between the range of 30 to 100 degrees Fahrenheit, a one degree increase leads to a 1% decrease--and a one degree decrease leads to a 3.7% increase--in the rate of increase of the log of daily confirmed cases.ConclusionThe results suggest that boreal summer months are associated with slower rates of COVID-19 transmission, with the reverse true in winter months. Knowledge of COVID-19 seasonality could prove useful in local planning for phased reductions social interventions and help to prepare for the timing of possible pandemic resurgence during cooler months.
PROFILING OF Y1 CELLS TREATED WITH FGF-2 REVEALS PARALLELS WITH ONCOGENE-INDUCED SENESCENCE
Authors: Lund Peder J. , Lopes Mariana , Sidoli Simone , Coradin Mariel , de Luna Vitorino Francisca Nathália , da Cunha Julia Pinheiro Chagas , Garcia Benjamin Aaron 
Published: August 2020

ABSTRACTParadoxically, oncogenes that drive cell cycle progression may also trigger pathways leading to senescence, thereby inhibiting the growth of tumorigenic cells. Along these lines, Y1 cells, which carry an amplification of Ras, become senescent after treatment with the mitogen FGF-2. To understand how FGF-2 promotes senescence, we profiled the epigenome, transcriptome, proteome, and phospho-proteome of Y1 cells stimulated with FGF-2. FGF-2 caused delayed acetylation of histone H4 and higher levels of H3K27me3. Sequencing analysis revealed decreased expression of cell cycle-related genes with concomitant loss of H3K27ac. In contrast, FGF-2 promoted the expression of p21, various cytokines, and MAPK-related genes. Nuclear envelope proteins, particularly lamin B1, displayed increased phosphorylation in response to FGF-2. Proteome analysis suggested alterations in cellular metabolism, as evident by modulated expression of enzymes involved in purine biosynthesis, tRNA aminoacylation, and the TCA cycle. Altogether, the response of Y1 cells to FGF-2 is consistent with oncogene-induced senescence. We propose that Y1 cells enter senescence due to deficient cyclin expression and high levels of p21, which may stem from DNA damage or TGFb signaling.
Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
Authors: Misheva Mariya , Kotzamanis Konstantinos , Davies Luke C , Tyrrell Victoria J , Rodrigues Patricia R S , Benavides Gloria A , Hinz Christine , Murphy Robert C , Kennedy Paul , Taylor Philip R , Rosas Marcela , Jones Simon A , McLaren James E , Deshpande Sumukh , Andrews Robert , Schebb Nils Helge , Czubala Magdalena A , Gurney Mark , Aldrovandi Maceler , Meckelmann Sven W , Ghazal Peter , Darley-Usmar Victor , White Daniel A , O’Donnell Valerie B 
Published: August 2020

AbstractOxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such asACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also,ACSL1/Acsl1upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.
A workflow for sizing oligomeric biomolecules based on cryo single molecule localization microscopy
Authors: Schneider Magdalena C. , Telschow Roger , Mercier Gwenael , López-Martinez Montserrat , Scherzer Otmar , Schütz Gerhard J. 
Published: August 2020

ABSTRACTSingle molecule localization microscopy (SMLM) has enormous potential for resolving subcellular structures below the diffraction limit of light microscopy: Localization precision in the low digit nanometer regime has been shown to be achievable. In order to record localization microscopy data, however, sample fixation is inevitable to prevent molecular motion during the rather long recording times of minutes up to hours. Eventually, it turns out that preservation of the sample’s ultrastructure during fixation becomes the limiting factor. We propose here a workflow for data analysis, which is based on SMLM performed at cryogenic temperatures. Since molecular dipoles of the fluorophores are fixed at low temperatures, such an approach offers the possibility to use the orientation of the dipole as an additional information for image analysis. In particular, assignment of localizations to individual dye molecules becomes possible with high reliability. We quantitatively characterized the new approach based on the analysis of simulated oligomeric structures. Side lengths can be determined with a relative error of less than 1% for tetramers with a nominal side length of 5 nm, even if the assumed localization precision for single molecules is more than 2 nm.
Synthesis and in vitro Activity of Eugenyl Benzoate Derivatives as BCL-2 Inhibitor in Colorectal Cancer with QSAR and Molecular Docking Approach
Authors: Fadilah Fadilah , Andrajati Retnosari , Arsianti Ade , Paramita Rafika Indah , Erlina Linda , Yanuar Arry 
Published: August 2020

AbstractEugenol derivatives can inhibit BCL-2 in HT29 colorectal cancer cells. This study is aimed to acquiring new compounds of Eugenyl benzoate (2-methoxy-4-(prop-2-en-1-yl)phenyl benzoate) derivatives that can inhibit HT29 colorectal cancer cells. In this research, we used several chemical reactions to synthesize novel compounds, such as Esterification, Demethylation, Halohydrin, and Sharpless reaction. Cytotoxicity assays were performed to test the inhibitory activity of compounds against HT29 colon cancer cells. QSAR analysis were carried out to analyse the relationship of chemical structure of the novel compounds with their cytotoxic activity. Ten novel compounds were successfully synthesized and testedin vitroagainst the HT29 cell. The IC50of the novel compounds were between 26.56 μmol/ml - 286.81 μmol/ml which compound 4-[(2S)-2,3-dihydroxypropyl]-2-methoxyphenyl 2-hydroxybenzoate(9)showed as best active compound as BCL-2 inhibitors better than other synthesized compounds and Eugenol as well. QSAR analysis of thein vitroresults gave a Log equation: 1/IC50= −0.865-0.210 (LogP)2+ 1,264 (logP)-0.994 CMR (n = 10; r = 0.706; SE: 0.21; F = 0.497, sig = 7.86). The equation shows the log variable P and CMR affect IC50. The properties of hydrophobicity (log P) are more instrumental than the ones of steric (CMR).
The impact of intravenous dodecafluoropentane on a murine model of acute lung injury
Authors: Mosier Jarrod M , Sammani Saad , Kempf Carrie , Unger Evan , Garcia Joe GN 
Published: August 2020

AbstractAcute hypoxemic respiratory failure presents therapeutic challenges due to ventilation/perfusion mismatch and shunt. The goal of management strategies is to improve arterial oxygenation, however each management strategy presents risk to patients from iatrogenic injury. Intravenous oxygen therapeutics present an appealing option to improve arterial oxygenation without these risks. We used a two-hit murine model of acute lung injury to evaluate the effect of intravenous dodecafluoropentane (NanO2) on oxygen saturation and bronchoalveolar lavage cell count and protein. Mice were given intratracheal lipopolysaccharide and 20 hours later were intubated and ventilated with high tidal volumes. NanO2was given by bolus injection at the initiation of mechanical ventilation and again at 2 hours, while oxygen saturation was measured every 15 minutes. At the conclusion of the experiment (4 hours), a bronchoalveolar lavage was performed. There was no difference in mean O2saturation at time zero, however the difference between the mean O2saturation immediately prior to injection and the mean first O2saturation after injection in the control saline group were 91% and 83%, mean difference −7.5%; whereas mean O2saturation in the NanO2treated group rose from 89% to 91%, mean difference +2.5%, net difference 10% [95% CI: 2.7,17.3], p=0.01). There was a statistically significant difference in cell count, but not protein, on the bronchoalveolar lavage analysis. These data show that NanO2rapidly improves oxygen saturation in a two-hit model of acute lung injury, and shows potential as an intravenous oxygen therapeutic in the management in acute hypoxemic respiratory failure.
Transcriptomic profiling of human corona virus (HCoV)-229E -infected human cells and genomic mutational analysis of HCoV-229E and SARS-CoV-2
Authors: Friedman Nehemya , Jacob-Hirsch Jasmine , Drori Yaron , Eran Eyal , Kol Nitzan , Nayshool Omri , Mendelson Ella , Rechavi Gideon , Mandelboim Michal 
Published: August 2020

AbstractHuman coronaviruses (HCoVs) cause mild to severe respiratory infection. Most of the common cold illnesses are caused by one of four HCoVs, namely HCoV-229E, HCoV-NL63, HCoV-HKU1 and HCoV-OC43. Several studies have applied global transcriptomic methods to understand host responses to HCoV infection, with most studies focusing on the pandemic severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV) and the newly emerging SARS-CoV-2. In this study, Next Generation Sequencing was used to gain new insights into cellular transcriptomic changes elicited by alphacoronavirus HCoV-229E. HCoV-229E-infected MRC5 cells showed marked downregulation of superpathway of cholesterol biosynthesis and eIF2 signaling pathways. Moreover, upregulation of cyclins, cell cycle control of chromosomal replication, and the role of BRCA1 in DNA damage response, alongside downregulation of the cell cycle G1/S checkpoint, suggest that HCoV-229E favors S phase for viral infection. Intriguingly, a significant portion of key factors of cell innate immunity, interferon-stimulated genes (ISGs) and other transcripts of early antiviral response genes were downregulated early in HCoV-229E infection. On the other hand, early upregulation of the antiviral response factor Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B)was observed. APOBEC3B cytidine deaminase signature (C-to-T) was previously observed in genomic analysis of SARS-CoV-2 but not HCoV-229E. Higher levels of C-to-T mutations were found in countries with high mortality rates caused by SARS-CoV-2. APOBEC activity could be a marker for new emerging CoVs. This study will enhance our understanding of commonly circulating HCoVs and hopefully provide critical information about still-emerging coronaviruses.Author summaryHuman coronaviruses (HCoVs) generate respiratory tract infections. HCoV-229E is one of four known HCoV strains that circulate annually in the population for several decades. Beside these, three pandemic CoV emerged since year 2002, the Severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2. These three strains attracted most attention for extensive research and less consideration has been given to the commonly infecting HCoVs. In this study we use Next generation sequencing analysis to understand global transcriptomic changes in human host cells following HCoV-229E infection. We found several cellular pathways that change during infection that involve cholesterol biosynthesis, cell cycle control, DNA replication, DNA repair, innate immune response and an interesting RNA editing enzyme which could be involve in CoVs pathogenesis.
PIE-1 promotes SUMOylation and activation of HDAC1 during theC. elegansoogenesis
Authors: Kim Heesun , Ding Yue-He , Lu Shan , Zuo Mei-Qing , Conte Darryl , Dong Meng-Qiu , Mello Craig C. 
Published: August 2020

SummaryGermlines shape and balance heredity, integrating and regulating information from both parental and foreign sources. Insights into how the germline handles information have come from the identification of factors that specify or maintain the germline fate. In earlyC. elegansembryos, the CCCH zinc-finger protein PIE-1 localizes to the germline where it prevents somatic differentiation programs. Here we show that PIE-1 also functions in the meiotic ovary where it becomes SUMOylated and engages the SUMO-conjugating machinery. Using whole-proteome mass spectrometry to detect SUMO-conjugated proteins, we identify HDAC SUMOylation as a target of PIE-1. Our findings suggest that SUMOylation activates HDAC, lowering histone acetylation and enhancing Argonaute-mediated surveillance in the germline.
Nitrogen availability and plant functional composition modify biodiversity-multifunctionality relationships
Authors: Pichon Noémie A. , Cappelli Seraina L. , Soliveres Santiago , Mannall Tosca , Nwe Thu Zar , Hölzel Norbert , Klaus Valentin H. , Kleinebecker Till , Vincent Hugo , Allan Eric 
Published: August 2020

AbstractThe ability of an ecosystem to deliver multiple functions at high levels (multifunctionality) typically increases with biodiversity but there is substantial variation in the strength and direction of biodiversity effects, suggesting context-dependency. A better understanding of the drivers of this context dependency is essential to predict effects of global change on ecosystems. To determine how different factors modulate the effect of diversity on multifunctionality, we established a large grassland experiment with 216 communities, crossing a manipulation of plant species richness (1, 4, 8, 20 species) with manipulations of resources (nitrogen enrichment), plant functional composition (gradient in mean specific leaf area [SLA] to manipulate abundances of exploitative, fast-growing vs. conservative, slow-growing species), plant functional diversity (variance in SLA) and enemy abundance (foliar fungal pathogen removal). We measured ten above- and belowground functions, related to productivity, nutrient cycling and energy transfer between trophic levels, and calculated ecosystem multifunctionality. Plant species richness and functional diversity both increased multifunctionality, but their effects were context dependent. Species richness increased multifunctionality only when communities were assembled with fast growing (high SLA) species. This was because slow species were more redundant in their functional effects, whereas different fast species tended to promote different functions. Functional diversity also increased multifunctionality but this effect was dampened by nitrogen enrichment. However, unfertilised, functionally diverse communities still delivered more functions than low diversity, fertilised communities. Our study suggests that a shift towards fast-growing exploitative communities will not only alter ecosystem functioning but also the strength of biodiversity-functioning relationships, which highlights the potentially complex effects of global change on multifunctionality.