bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction
Authors: Liu Xiaoyan , Li Zhe , Liu Shuai , Chen Zhanghua , Sun Jing , Zhao Zhiyao , Huang Yi-you , Zhang Qingling , Wang Jun , Shi Yinyi , Xu Yanhui , Xian Huifang , Fang Rongli , Bai Fan , Ou Changxing , Xiong Bei , Lew Andrew M , Cui Jun , Huang Hui , Zhao Jincun , Hong Xuechuan , Zhang Yuxia , Zhou Fuling , Luo Hai-Bin 
Published: February 2020

AbstractThe human coronavirus HCoV-19 infection can cause acute respiratory distress syndrome (ARDS), hypercoagulability, hypertension, extrapulmonary multiorgan dysfunction. Effective antiviral and anti-coagulation agents with safe clinical profiles are urgently needed to improve the overall prognosis. We screened an FDA approved drug library and found that an anticoagulant agent dipyridamole (DIP) suppressed HCoV-19 replication at an EC50 of 100 nMin vitro. It also elicited potent type I interferon responses and ameliorated lung pathology in a viral pneumonia model. In analysis of twelve HCoV-19 infected patients with prophylactic anti-coagulation therapy, we found that DIP supplementation was associated with significantly increased platelet and lymphocyte counts and decreased D-dimer levels in comparison to control patients. Two weeks after initiation of DIP treatment, 3 of the 6 severe cases (60%) and all 4 of the mild cases (100%) were discharged from the hospital. One critically ill patient with extremely high levels of D-dimer and lymphopenia at the time of receiving DIP passed away. All other patients were in clinical remission. In summary, HCoV-19 infected patients could potentially benefit from DIP adjunctive therapy by reducing viral replication, suppressing hypercoagulability and enhancing immune recovery. Larger scale clinical trials of DIP are needed to validate these therapeutic effects.
Modeling the Epidemic Dynamics and Control of COVID-19 Outbreak in China
Authors: Zhao Shilei , Chen Hua 
Published: February 2020

BackgroundThe coronavirus disease 2019 (COVID-19) is rapidly spreading in China and more than 30 countries over last two months. COVID-19 has multiple characteristics distinct from other infectious diseases, including high infectivity during incubation, time delay between real dynamics and daily observed number of confirmed cases, and the intervention effects of implemented quarantine and control measures.MethodWe develop a Susceptible, Un-quanrantined infected, Quarantined infected, Confirmed infected (SUQC) model to characterize the dynamics of COVID-19 and explicitly parameterize the intervention effects of control measures, which is more suitable for analysis than other existing epidemic models.ResultsThe SUQC model is applied to the daily released data of the confirmed infections to analyze the outbreak of COVID-19 in Wuhan, Hubei (excluding Wuhan), China (excluding Hubei) and four first-tier cities of China. We found that, before January 30th, 2020, all these regions except Beijing had a reproductive number R > 1, and after January 30th, all regions had a reproductive number R < 1, indicating that the quarantine and control measures are effective in preventing the spread of COVID-19. The confirmation rate of Wuhan estimated by our model is 0.0643, substantially lower than that of Hubei excluding Wuhan (0.1914), and that of China excluding Hubei (0.2189), but jumps to 0.3229 after Feb 12th when clinical evidence was adopted in new diagnosis guidelines. The number of un-quarantined infected cases in Wuhan on February 12, 2020 is estimated to be 3,509 and declines to 334 on February 21th, 2020. After fitting the model with data as of February 21th, 2020, we predict that the end time of COVID-19 in Wuhan and Hubei is around late March, around mid March for China excluding Hubei, and before early March 2020 for the four tier-one cities. A total of 80,511 individuals are estimated to be infected in China, among which 49,510 are from Wuhan, 17,679 from Hubei (excluding Wuhan), and the rest 13,322 from other regions of China (excluding Hubei). Note that the estimates are from a deterministic ODE model and should be interpreted with some uncertainty.ConclusionWe suggest that rigorous quarantine and control measures should be kept before early March in Beijing, Shanghai, Guangzhou and Shenzhen, and before late March in Hubei. The model can also be useful to predict the trend of epidemic and provide quantitative guide for other countries in a high risk of outbreak, such as South Korea, Japan, Italy and Iran.
Accurate Classification of the Gut Microbiota of Patients in Intensive Care Units During the Development of Sepsis and Septic Shock
Authors: Liu Wanglin , Cheng Mingyue , Li Jinman , Zhang Peng , Fan Hang , Hu Qinghe , Han Maozhen , Su Longxiang , He Huaiwu , Tong Yigang , Ning Kang , Long Yun 
Published: February 2020

AbstractThe gut microbiota of intensive care unit (ICU) patients display extreme dysbiosis, which is associated with increased susceptibility to organ failure, sepsis and septic shock. However, this dysbiosis is hard to be characterized for each patient, owing to the highly dimensional complexity of gut microbiota. We thus tested whether the concept of enterotype can be applied to the gut microbiota of ICU patients, to describe the dysbiosis. We collected 131 fecal samples from a cohort of 64 ICU patients diagnosed with sepsis or septic shock, using 16S rRNA gene sequencing to dissect their gut microbiota compositions. We find that during the development of sepsis or septic shock, as well as various medical treatments, ICU patients always contain two patterns of dysbiotic microbiota named as ICU-enterotypes, which cannot be explained by the individual host properties such as age, gender and body mass index, as well as external stressors such as infection sites and antibiotic use. ICU-enterotype I comprised predominantly Bacteroides and an unclassified genus of family Enterobacteriaceae, while ICU-enterotype II comprised predominantly Enterococcus. Among more critically ill patients with acute physiology and chronic health evaluation (APACHE) II score > 18, samples of septic shock were more likely to present with ICU-enterotype I (p = 0.041). Additionally, ICU-enterotype I was correlated with high serum lactate level (p = 0.007). Therefore, different patterns of dysbiosis are correlated with different clinical outcomes, suggesting that the diagnosis of ICU-enterotypes as an independent clinical index is crucial. For this purpose, the microbial-based human index (MHI) classifier we proposed shows high precision and effectiveness in timely monitoring of ICU-enterotypes of an individual patient. Together, our work serves as the first step toward precision medicine for septic patients based on the gut microbiota profile.
Tumor-infiltrating immune cells signature predicts recurrence free survival after complete resection of localized primary gastrointestinal stromal tumors
Authors: Yi Mengshi , Zhao Rui , Wan Qianyi , Wu Xiaoting , Zhuang Wen , Yang Hanshuo , Wu Chuncheng , Xia Lin , Chen Yi , Zhou Yong 
Published: February 2020

AbstractBackgroundGrowing evidence has proposed prognostic value of immune infiltration in gastrointestinal stromal tumors (GISTs). Therefore, we aimed to develop a novel immune-based prognostic classifier (IPC) to help better stratify and predict prognosis of GISTs.MethodsThe gene expression profiles of 22 immune features of GISTs were detected from GEO dataset. The IPC was constructed using the LASSO Cox regression model and validated in a cohort including 54 patients with complete resection of localized primary GISTs via immunohistochemistry process. The performance assessment of the IPC was estimated, then compared with conventional risk prognostic criteria.ResultsThe IPC was established based on 4 features: CD8, CD8/CD3, CD68, CD163/CD68 and validated to be an independent predictor of RFS for GISTs (HR 5.2, 95%CI 1.99-13.65). Significant differences were found between low- and high-IPC group in 5-year RFS (92.6% vs 48.1%, p < 0.001). Using the IPC, the high-risk group of the Modified NIH classification was split into two groups in 5-year RFS (low-IPC vs high-IPC, 85.7% vs 30.0%, p < 0.001). The IPC showed a higher net benefit than both “treat all” or “treat none” methods for the threshold probability within a range of 0-0.62 and exhibited a performance (AUC 0.842) superior to modified NIH classification (AUC 0.763).ConclusionThe IPC was effective to predict RFS after complete resection of localized primary GISTs, adding prognostic value to the routine clinical prognostic criteria. Prospective studies are needed to further validate the analytical accuracy and practicability of the IPC in estimating prognosis of GISTs.
A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex
Authors: Smith Rebecca G. , Pishva Ehsan , Shireby Gemma , Smith Adam R. , Roubroeks Janou A.Y. , Hannon Eilis , Wheildon Gregory , Mastroeni Diego , Gasparoni Gilles , Riemenschneider Matthias , Giese Armin , Sharp Andrew J. , Schalkwyk Leonard , Haroutunian Vahram , Viechtbauer Wolfgang , van den Hove Daniel L.A. , Weedon Michael , Brokaw Danielle , Francis Paul T. , Thomas Alan J , Love Seth , Morgan Kevin , Walter Jörn , Coleman Paul D. , Bennett David A. , De Jager Philip L. , Mill Jonathan , Lunnon Katie 
Published: February 2020

ABSTRACTEpigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further > 600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).
Future climate change promotes novel gene-climate associations in balsam poplar (Populus balsamiferaL.), a forest tree species
Authors: Gougherty Andrew V. , Keller Stephen R. , Chhatre Vikram E. , Fitzpatrick Matthew C. 
Published: February 2020

ABSTRACTA central challenge to predicting climate change effects on biodiversity is integrating information on intraspecific variation, specifically population-level local adaptation to climate. Assessing how climate change could disrupt local adaptation to climate can provide a new way of understanding population risk and vulnerability to climate change. For the wide-ranging boreal tree species, balsam poplar (Populus balsamiferaL.), we used models of existing population-level genetic differentiation to estimate three key components of population’s vulnerability to climate change: (1) predicted shifts in genetic composition with and without migration, (2) the potential for future novel gene-climate associations, and (3) the distance populations would need to migrate to minimize future maladaptation. When assessed across the range of balsam poplar, these three metrics suggest that vulnerability to climate change is greatest in the eastern portion of balsam poplar’s range, where future maladaptation peaked, migration distances to sites that minimized maladaptation were greatest, and the emergence of novel gene-climate associations were highest. Our results further suggest greater maladaptation to climate when migration distances were limited – consistent with the possibility of migration to lessen maladaptation to future climate. Our work provides a comprehensive evaluation of population’s vulnerability to climate change by simultaneously assessing population maladaptation to future climate and the distances populations would need to migrate to minimize maladaptation, in a way that goes beyond species-level bioclimatic modelling. In doing so, our work helps advance towards the long-held goal of incorporating genomic information in models of species responses to climate change.
TP53abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia
Authors: Lai Catherine , Vadakekolathu Jayakumar , Reeder Stephen , Church Sarah E. , Hood Tressa , Aldoss Ibrahim , Godwin John , Wieduwilt Matthew J. , Arellano Martha , Muth John , Ravandi Farhad , Sweet Kendra , Altmann Heidi , Foulds Gemma A. , Stölzel Friedrich , Middeke Jan Moritz , Ciciarello Marilena , Curti Antonio , Valk Peter J.M. , Löwenberg Bob , Bornhäuser Martin , DiPersio John F. , Davidson-Moncada Jan K. , Rutella Sergio 
Published: February 2020

AbstractPurposeSomaticTP53mutations and 17p deletions with genomic loss ofTP53occur in 37-46% of acute myeloid leukemia (AML) cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to characterize the immune landscape ofTP53mutated AML and to determine whetherTP53abnormalities identify a patient subgroup that may benefit from T-cell targeting immunotherapy approaches.Experimental DesignThe NanoString Pan-Cancer IO 360™ assay was used for the immune transcriptomic analysis of 64 diagnostic bone marrow (BM) samples from adults withTP53mutated AML (n=42) orTP53wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (11 cases withTP53mutations and/or 17p deletion with genomic loss ofTP53) who received immunotherapy with flotetuzumab, an investigational CD123×CD3 bispecific DART®molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort and a Dutch–Belgian Cooperative Trial Group for Hematology–Oncology (HOVON) cohort.ResultsAll TCGA cases withTP53mutations (n=13) expressed higher levels of negative immune checkpoints, inflammatory chemokines, interferon (IFN)-γ-inducible molecules, and had a higher tumor inflammation signature (TIS) score, compared with TCGA cases with other risk-defining molecular lesions. The comparison betweenTP53mutated andTP53wild type primary BM samples showed higher expression ofIFNG, FoxP3, immune checkpoints and markers of exhaustion and senescence in the former cohort and allowed the computation of a 34-gene immune classifier prognostic for overall survival.In vitromodeling experiments with AML cell lines showed heightened expression of IFN-γ and inflammation pathway genes in KG-1 cells (loss-of-function mutation ofTP53) compared with Kasumi-1 cells (gain-of-function mutation ofTP53). Finally, 5 out of 11 (45.5%) patients with R/R AML andTP53abnormalities showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS,FoxP3, CD8 T-cell abundance, inflammatory chemokine andPD1gene expression scores at baseline compared with non-responders.ConclusionsThis study provides evidence for a correlation between IFN-γ-dominant immune subtypes andTP53abnormalities. The anti-leukemic activity with flotetuzumab encourages further study of this immunotherapeutic approach in this patient subgroup.
Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage
Authors: Prevot Thomas D. , Sumitomo Akiko , Tomoda Toshifumi , Knutson Daniel E. , Li Guanguan , Cook James M. , Sibille Etienne 
Published: February 2020

ABSTRACTOver the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years. With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death. Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer’s disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM.
Intraspecific variation in land use-related functional traits inPlantago lanceolata
Authors: Gáspár Bence , Bossdorf Oliver , Parepa Madalin 
Published: February 2020

AbstractBackground and aimsIntraspecific variation in functional traits is essential for the evolutionary success of organisms. The co-variation between trait variation and environment, as well as between different traits, can help us to understand which ecological factors drive habitat adaptation, and to what extent adaptation may be constrained by trait correlations and trade-offs. In managed grasslands, plants experience a combination of competition, recurrent biomass removal and nutrient pulses. Each of these ecological challenges requires specific plant tolerances, and populations should locally adapt if intraspecific variation exists in these traits.MethodsWe studied variation in land use-related traits in the common grassland plantPlantago lanceolata. In a common environment, we quantified the competitive ability (R*), clipping tolerance and responses to a nitrogen pulse of plants from 54 populations with different land use intensities across Germany.Key resultsWe found significant population differentiation in competitive ability but there was little evidence that trait variation was related to land use intensity. There was a positive relationship between competitive ability and clipping tolerance at the population level, indicating a genetic, and possibly functional, link between these two traits. In contrast, clipping tolerance and nitrogen responses were negatively correlated at the levels of plant individuals, indicating a physiological trade-off between plant responses to these two land-use processes.ConclusionsOur results show that there is substantial intraspecific variation in some of the key functional traits for plant success in managed grasslands, and that rapid evolution and adaptation is therefore possible in these traits.
Live-cell imaging of circadian clock protein dynamics in CRISPR-generated knock-in cells
Authors: Gabriel Christian H. , del Olmo Marta , Zehtabian Amin , Reischl Silke , van Dijk Hannah , Koller Barbara , Grudziecki Astrid , Maier Bert , Ewers Helge , Herzel Hanspeter , Granada Adrian E. , Kramer Achim 
Published: February 2020

ABSTRACTThe current model of the mammalian circadian oscillator is predominantly based on data from genetics and biochemistry experiments, while the cell biology of circadian clocks is still in its infancy. Here, we describe a new strategy for the efficient generation of knock-in reporter cell lines using CRISPR technology that is particularly useful for lowly or transiently expressed genes, such as those coding for circadian clock proteins. We generated single and double knock-in cells with endogenously expressed PER2 and CRY1 fused to fluorescent proteins, which allowed to simultaneously monitor the dynamics of CRY1 and PER2 proteins in live single cells. Both proteins are highly rhythmic in the nucleus of human cells with PER2 showing a much higher amplitude than CRY1. Surprisingly, CRY1 protein is nuclear at all circadian times indicating the absence of circadian gating of nuclear import. Furthermore, in the nucleus of individual cells CRY1 abundance rhythms are phase-delayed (∼5 hours), and CRY1 levels are much higher (>6 times) compared to PER2 questioning the current model of the circadian oscillator. Our knock-in strategy will allow the generation of additional single, double or triple knock-in cells for circadian clock proteins, which should greatly advance our understanding about the cell biology of circadian clocks.
A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities
Authors: Haas Eva , Incebacak Rana D. , Hentrich Thomas , Maringer Yacine , Schmidt Thorsten , Zimmermann Frank , Casadei Nicolas , Mills James D. , Aronica Eleonora , Riess Olaf , Schulze-Hentrich Julia M. , Hübener-Schmid Jeannette 
Published: February 2020

AbstractBackgroundSpinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and is caused by a CAG repeat expansion in theAtaxin-3gene resulting in a polyQ expansion in the corresponding protein. The disease is characterized by neuropathological (aggregate formation, cell loss), phenotypical (gait instability, body weight reduction), and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed to gain a better understanding of the disease pathomechanism.MethodsHere, we characterized a novel Ataxin-3 knock-in mouse model, expressing either a heterozygous or homozygous expansion of 304 CAG/CAAs in the murineAtaxin-3locus using biochemical, behavioral, and transcriptomic approaches. Further, we compared the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to evaluate the comparability of our model.ResultsThe novel Ataxin-3 knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these transcriptional changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.ConclusionThe novel Ataxin-3 knock-in model shares neuropathological, behavioral, and transcriptomic features with human SCA3 patients and, therefore, represents an ideal model to investigate early-onset developments, therapy studies, or longitudinal biomarker alterations.