bluuebunny/crossref_metadata_2025_split huggingface dataset:
PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response
Authors: Li Jie , Kaneda Megan M. , Ma Jun , Li Ming , Patel Kunal , Koga Tomoyuki , Sarver Aaron , Furnari Frank , Xu Beibei , Dhawan Sanjay , Ning Jianfang , Zhu Hua , Wu Anhua , You Gan , Jiang Tao , Venteicher Andrew S. , Rich Jeremy N. , Glass Christopher K. , Varner Judith A. , Chen Clark C. 
Published: May 2020

AbstractPrecision medicine in oncology leverages clinical observations of exceptional response. Towards an understanding of the molecular features that define this response, we applied an integrated, multi-platform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted isoform of PI3K, PI3Kγ, by pharmacologic inhibition or genetic inactivation, disrupted this signaling axis by suppressing microglia/macrophage accumulation and associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.Significance StatementUnderstanding the basis for exceptional responders represents a key pillar in the framework of precision medicine. In this study, we utilized distinct informatics platforms to analyze the expression profiles of clinically annotated tumor specimens derived from patients afflicted with glioblastoma, the most common form of primary brain cancer. These analyses converged on prognostic contributions from glioblastoma-associated microglia/macrophages. Glioblastoma-associated microglia secreted interleukin 11 (IL11) to activate a STAT3-MYC signaling axis in glioblastoma cells, facilitating resistance to the standard-of-care chemotherapy, temozolomide. Microglia recruitment and IL11 secretion were dependent on the myeloid specific phosphoinositide-3-kinase gamma isoform (PI3Kγ). Inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in specimens derived from exceptional responders, suggesting potential for clinical translation.
Management of large polyps in a colorectal cancer screening program with fecal immunochemical test: a population-based study
Authors: Denis Bernard , Gendre Isabelle , Perrin Philippe , Tuzin Nicolas , Pioche Mathieu 
Published: May 2020

ABSTRACTObjectiveTo analyze presentation, management and outcomes of large (≥ 20 mm) polyps (LPs) detected in a colorectal cancer (CRC) screening program using a fecal immunochemical test (FIT).DesignRetrospective population-based study of all LPs detected in patients aged 50-74 years between 2015 and 2019 during FIT-positive colonoscopies within the screening program organized in Alsace (France).ResultsAmong 13,633 FIT-positive colonoscopies, 1256 LPs (8.5% malignant and 51.8% non- pedunculated) were detected by 102 community gastroenterologists in 1164 patients (one in 12 colonoscopies). The sensitivity of optical diagnosis of malignancy was 54% for non-pedunculated and 27% for pedunculated T1 CRCs. Endoscopic resection rate was 82.7% [95% CI 80.3-84.9] for benign LPs (70.2% [95% CI 66.4-74.1] non-pedunculated, 95.2% [95% CI 93.4-97.1] pedunculated, p<0.001), varying from 0 to 100% depending on the endoscopist. It was correlated with cecal intubation (Pearson r = 0.49, p<0.01) and adenoma detection (r = 0.25, p=0.01) rates. Most endoscopists did not refer patients to more experienced endoscopists, so that 60 to 90% of 183 surgeries for benign LPs were unwarranted. Endoscopic resection was curative for 4.3% [95% CI 0.9-12.0] of non-pedunculated and 37.8% [95% CI 22.5-55.2] of pedunculated T1 CRCs. Overall, 22 endoscopic submucosal dissections had to be performed to avoid one surgery.ConclusionCompared with current recommendations, there is tremendous room for improvement of community endoscopy practices for the diagnosis and management of LPs. Detection and polypectomy competencies are correlated and highly variable among endoscopists. Endoscopic resection is curative in 83% of benign LPs and 16% of T1 CRCs.WHAT IS KNOWN➢Endoscopic resection of large polyps is effective (success in > 90% of cases) and safe in tertiary care centers.➢Surgery for benign colorectal polyps is far from negligible in current practice.WHAT IS NEW HERE➢One in 12 FIT-positive colonoscopies reveals a large polyp, that is 8 to 10 times more frequently than screening colonoscopies.➢In community practice, 4 of 5 benign large polyps only are removed endoscopically and 1 of 6 malignant large polyps cured endoscopically.➢Between 60% and 90% of surgeries for large benign polyps could be avoided if endoscopists having lesser polypectomy competency referred their patients to experienced endoscopists instead of surgeons.➢The benefit offered by endoscopic submucosal resection for the management of large polyps is marginal in community practice; here one surgery avoided for 22 endoscopic submucosal dissections performed.➢Detection and polypectomy competencies are correlated and highly variable among endoscopists.
Evaluate the risk of resumption of business for the states of New York, New Jersey and Connecticut via a pre-symptomatic and asymptomatic transmission model of COVID-19
Authors: Tian Ting , Tan Jianbin , Jiang Yukang , Wang Xueqin , Zhang Heping 
Published: May 2020

AbstractThe United States has the highest number of confirmed cases of COVID-19 in the world. The early hot spot states were New York, New Jersey, and Connecticut. The workforce in these states was required to work from home except for essential services. It was necessary to evaluate an appropriate date for resumption of business since the premature reopening of the economy would lead to a broader spread of COVID-19, while the opposite situation would cause greater loss of economy. To reflect the real-time risk of the spread of COVID-19, it was crucial to evaluate the population of infected individuals before or never being confirmed due to the pre-symptomatic and asymptomatic transmissions of COVID-19. To this end, we proposed an epidemic model and applied it to evaluate the real-time risk of epidemic for the states of New York, New Jersey, and Connecticut. We used California as the benchmark state because California began a phased reopening on May 8, 2020. The dates on which the estimated numbers of unidentified infectious individuals per 100,000 for states of New York, New Jersey, and Connecticut were close to those in California on May 8, 2020, were June 1, 22, and 22, 2020, respectively. By the practice in California, New York, New Jersey, and Connecticut might consider reopening their business. Meanwhile, according to our simulation models, to prevent the resurgence of infections after reopening the economy, it would be crucial to maintain sufficient measures to limit the social distance after the resumption of businesses. This precaution turned out to be critical as the situation in California quickly deteriorated after our analysis was completed and its interventions after the reopening of business were not as effective as those in New York, New Jersey, and Connecticut.
Leveraging pleiotropy in genome-wide association studies in multiple traits with per trait interpretations
Authors: Taraszka Kodi , Zaitlen Noah , Eskin Eleazar 
Published: May 2020

AbstractWe introduce pleiotropic association test (PAT) for joint analysis of multiple traits using GWAS summary statistics. The method utilizes the decomposition of phenotypic covariation into genetic and environmental components to create a likelihood ratio test statistic for each genetic variant. Though PAT does not directly interpret which trait(s) drive the association, a per trait interpretation of the omnibus p-value is provided through an extension to the meta-analysis framework, m-values. In simulations, we show PAT controls the false positive rate, increases statistical power, and is robust to model misspecifications of genetic effect.Additionally, simulations comparing PAT to two multi-trait methods, HIPO and MTAG show PAT having a 43.0% increase in the number of omnibus associations over the other methods. When these associations are interpreted on a per trait level using m-values, PAT has 52.2% more per trait interpretations with a 0.57% false positive assignment rate. When analyzing four traits from the UK Biobank, PAT identifies 22,095 novel associated variants. Through the m-values interpretation framework, the number of total per trait associations for two traits are almost tripled and are nearly doubled for another trait relative to the original single trait GWAS.
Developmental Normalization of Phenomics Data Generated by High Throughput Plant Phenotyping Systems
Authors: Lozano-Claros Diego , Meng Xiangxiang , Custovic Eddie , Deng Guang , Berkowitz Oliver , Whelan James , Lewsey Mathew G. 
Published: May 2020

AbstractBackgroundSowing time is commonly used as the temporal reference forArabidopsis thaliana(Arabidopsis) experiments in high throughput plant phenotyping (HTPP) systems. This relies on the assumption that germination and seedling establishment are uniform across the population. However, individual seeds have different development trajectories even under uniform environmental conditions. This leads to increased variance in quantitative phenotyping approaches. We developed the Digital Adjustment of Plant Development (DAPD) normalization method. It normalizes time-series HTPP measurements by reference to an early developmental stage and in an automated manner. The timeline of each measurement series is shifted to a reference time. The normalization is determined by cross-correlation at multiple time points of the time-series measurements, which may include rosette area, leaf size, and number.ResultsThe DAPD method improved the accuracy of phenotyping measurements by decreasing the statistical dispersion of quantitative traits across a time-series. We applied DAPD to evaluate the relative growth rate inA. thalianaplants and demonstrated that it improves uniformity in measurements, permitting a more informative comparison between individuals. Application of DAPD decreased variance of phenotyping measurements by up to 2.5 times compared to sowing-time normalization. The DAPD method also identified more outliers than any other central tendency technique applied to the non-normalized dataset.
Sexually dimorphic roles for the type 2 diabetes-associatedC2cd4bgene in murine glucose homeostasis
Authors: Gharavy S. Neda Mousavy , Owen Bryn , Millership Steven J. , Chabosseau Pauline , Pizza Grazia , Martinez-Sanchez Aida , Tasoez Emirhan , Georgiadou Eleni , Hu Ming , Fine Nicholas H.F. , Jacobson David A. , Dickerson Matthew , Idevall-Hagren Olof , Montoya Alex , Kramer Holger , Mehta Zenobia , Withers Dominic J. , Ninov Nikolay , Gadue Paul J. , Cardenas-Diaz Fabian L. , Cruciani-Guglielmacci Céline , Magnan Christophe , Ibberson Mark , Leclerc Isabelle , Voz Marianne , Rutter Guy A. 
Published: May 2020

AbstractVariants close to theVPS13C/C2CD4A/C2CD4Blocus are associated with altered risk of type 2 diabetes in genome-wide association studies. Whilst previous functional work has suggested roles forVPS13CandC2CD4Ain disease development, none has explored the role ofC2CD4B. Here, we show that systemic inactivation ofC2cd4bin mice leads to marked, but highly sexually dimorphic, changes in body weight and glucose homeostasis. FemaleC2cd4bmice display unchanged body weight but abnormal glucose tolerance and defectivein vivo,but notin vitro,insulin secretion, associated with a marked decrease in follicle stimulating hormone levels. In sharp contrast, maleC2cd4bnull mice displayed normal glucose tolerance but an increase in body weight and fasting glycemia after maintenance on high fat diet. No metabolic disturbances were observed after global inactivation ofC2cd4ain mice, or in pancreatic β cell function at larval stages inC2cd4abnull zebrafish. These studies suggest thatC2cd4bmay act centrally to influence sex-dependent circuits which control pancreatic β cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles forC2CD4AorVPS13Cin the control of glucose homeostasis in man.
Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development
Authors: Geusz Ryan J. , Wang Allen , Chiou Joshua , Lancman Joseph J. , Wetton Nichole , Kefalopoulou Samy , Wang Jinzhao , Qiu Yunjiang , Yan Jian , Aylward Anthony , Ren Bing , Dong P Duc Si , Gaulton Kyle J. , Sander Maike 
Published: May 2020

ABSTRACTGenetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genesLAMA1andCRB2. Knockdown oflama1orcrb2in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D.
The role of intolerance of uncertainty in the acquisition and extinction of reward
Authors: Morriss Jayne , Biagi Nicolo , Lonsdorf Tina B. , Andreatta Marta 
Published: May 2020

AbstractIndividuals, who score high in self-reported intolerance of uncertainty (IU), tend to find uncertainty anxiety-provoking. IU has been reliably associated with disrupted threat extinction. However, it remains unclear whether IU would be related to disrupted extinction to other arousing stimuli that are not threatening (i.e., rewarding). We addressed this question by conducting a reward associative learning task with acquisition and extinction training phases (n= 58). Throughout the associative learning task, we recorded valence ratings (i.e. liking), skin conductance response (SCR) (i.e. sweating), and corrugator supercilii activity (i.e. brow muscle indicative or negative and positive affect) to learned reward and neutral cues. During acquisition training with partial reward reinforcement, higher IU was associated with greater corrugator supercilii activity to neutral compared to reward cues. IU was not related to valence ratings or SCR’s during the acquisition or extinction training phases. These preliminary results suggest that IU-related deficits during extinction may be limited to situations with threat. The findings further our conceptual understanding of IU’s role in the associative learning and extinction of reward, and in relation to the processing of threat and reward more generally.
In silicomolecular target prediction unveils mebendazole as a potent MAPK14 inhibitor
Authors: Ariey-Bonnet Jeremy , Carrasco Kendall , Le Grand Marion , Hoffer Laurent , Betzi Stéphane , Feracci Mickael , Tsvetkov Philipp , Devred Francois , Collette Yves , Morelli Xavier , Ballester Pedro , Pasquier Eddy 
Published: May 2020

AbstractThe concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already-approved drugs to target key factors involved in human diseases. Herein, we used anin silicotarget prediction algorithm to investigate the mechanism of action of mebendazole, an anti-helminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cellsin vitro. Ourin silicoapproach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly up-regulated at the gene level in glioblastoma as compared to normal brain tissue. Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2 and MAPK14/p38α. Mebendazole could inhibit the activity of these kinasesin vitroin a dose-dependent manner, with a high potency against MAPK14. Its direct binding to MAPK14 was further validatedin vitroand inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases.Significance StatementThis study provides a framework to investigate drug polypharmacology by rapidly identifying novel molecular targets of already-approved drugs. It unveils a new mechanism involved in the anticancer activity of anti-helminthic drug, mebendazole, which is currently being repurposed for the treatment of brain tumors. By helping to decipher the mechanism(s) of action of repurposed drugs in their new indications, this approach could contribute to the development of safer and more effective therapeutic strategies in oncology and beyond.
Choice activity stabilizes sensory representations and mediates sensorimotor associations in parietal cortex
Authors: Chang Ting-Yu , Doudlah Raymond , Kim Byounghoon , Sunkara Adhira , Lowe Meghan , Rosenberg Ari 
Published: May 2020

AbstractSelecting actions which achieve desired goals often requires three-dimensional (3D) representations of the environment. Because the sensory epithelia cannot directly encode the world’s 3D spatial features, sensory signals must be converted into 3D representations. Here we investigated the relationships between the quality of 3D visual representations, choice-related activity, and motor-related activity in the parietal cortex of macaque monkeys using an eight-alternative 3D orientation discrimination task, visually guided saccade task, and laminar probe recordings. We found that choice activity was preferentially carried by caudal intraparietal area neurons with more robust 3D representations. Choice activity further stabilized the 3D representations, rather than attenuating information not directly relevant to the behavioral task (nuisance variables). An experience-dependent, sensorimotor association additionally aligned sensory and saccade direction preferences, particularly for neurons with choice activity. These findings reveal novel roles for choice activity in improving the fidelity of ecologically relevant object representations and mediating sensorimotor associations.
A singleton NLR of recent origin causes hybrid necrosis inArabidopsis thaliana
Authors: Barragan A. Cristina , Collenberg Maximilian , Wang Jinge , Lee Rachelle R.Q. , Cher Wei Yuan , Rabanal Fernando A. , Ashkenazy Haim , Weigel Detlef , Chae Eunyoung 
Published: May 2020

AbstractHybrid necrosis in plants arises from conflict between divergent alleles of immunity genes contributed by different parents, resulting in autoimmunity. We investigate a severe hybrid necrosis case inArabidopsis thaliana, where the hybrid does not develop past the cotyledon stage and dies three weeks after sowing. Massive transcriptional changes take place in the hybrid, including the upregulation of most NLR disease resistance genes. This is due to an incompatible interaction between the singleton TIR-NLR geneDANGEROUS MIX 10(DM10), which was recently relocated from a larger NLR cluster, and an unlinked locus,DANGEROUS MIX 11 (DM11). There are multipleDM10allelic variants in the globalA. thalianapopulation, several of which have premature stop codons. One of these, which has a truncated LRR domain, corresponds to theDM10risk allele. TheDM10locus and the adjacent genomic region in the risk allele carriers are highly differentiated from those in the non-risk carriers in the globalA. thalianapopulation, suggesting that this allele became geographically widespread only relatively recently. TheDM11risk allele is much rarer and found only in two accessions from southwestern Spain – a region from which theDM10risk haplotype is absent – indicating that the ranges ofDM10andDM11risk alleles may be non-overlapping.