bluuebunny/crossref_metadata_2025_split huggingface dataset:
JQ1, a bromodomain inhibitor, suppresses Th17 effectors by blocking p300‐mediated acetylation of RORγt
Authors: Wang Xiunan , Yang Yan , Ren Dandan , Xia Yuanyuan , He Wenguang , Wu Qingsi , Zhang Junling , Liu Miao , Du Yinan , Ren Cuiping , Li Bin , Shen Jijia , Zhang Yuxia 
Published: February 2020

Background and PurposeTh17 cells play critical roles in chronic inflammation, including fibrosis. Histone acetyltransferase p300, a bromodomain‐containing protein, acetylates RORγt and promotes Th17 cell development. The bromodomain inhibitor JQ1 was shown to alleviate Th17‐mediated pathologies, but the underlying mechanism remains unclear. We hypothesized that JQ1 suppresses the response of Th17 cells by impairing p300‐mediated acetylation of RORγt.Experimental ApproachThe effect of JQ1 on p300‐mediated acetylation of RORγt was investigated in HEK293T (overexpressing Flag‐p300 and Myc‐RORγt) and human Th17 cells through immunoprecipitation and western blotting. To determine the regions of p300 responsible for JQ1‐mediated suppression of HAT activity, we performed HAT assays on recombinant p300 fragments with/without the bromodomain, after exposure to JQ1. Additionally, the effect of JQ1 on p300‐mediated acetylation of RORγt and Th17 cell function was verified in vivo, using murine Schistosoma‐induced fibrosis models. Liver injury was assessed by histopathological examination and measurement of serum enzyme levels. Expression of Th17 effectors was detected by qRT‐PCR, whereas IL‐17‐ and RORγt‐positive granuloma cells were detected by FACS.Key ResultsJQ1 impaired p300‐mediated RORγt acetylation in human Th17 and HEK293T cells. JQ1 failed to suppress the acetyltransferase activity of p300 fragments lacking the bromodomain. JQ1 treatment attenuated Schistosoma‐induced fibrosis in mice, by inhibiting RORγt acetylation and IL‐17 expression.Conclusions and ImplicationsJQ1 impairs p300‐mediated RORγt acetylation, thus reducing the expression of RORγt target genes, including Th17‐specific cytokines. JQ1‐mediated inhibition of p300 acetylase activity requires the p300 bromodomain. Strategies targeting p300 may provide new therapeutic approaches for controlling Th17‐related diseases.
Implication of in vivo circulating fibrocytes ablation in experimental pulmonary hypertension murine model
Authors: Nikam Vandana S. , Nikam Sandeep , Sydykov Akyl , Ahlbrecht Katrin , Morty Rory E. , Seeger Werner , Voswinckel Robert 
Published: February 2020

Background and PurposeRecruitment and involvement of bone‐/blood‐derived circulating fibrocytes (CF) in the promotion of fibrotic tissue remodelling processes have been shown. However, their direct contribution to pathological changes is not clear. The present study investigates the causal role of CF in the pathogenesis of pulmonary hypertension (PH).Experimental ApproachFor selective ablation of CF, we applied the suicidal gene strategy with herpes simplex virus thymidine kinase (HSV‐TK) and ganciclovir. The transgenic mice were generated, having HSV‐TK‐GFP transgene under the collagen 1 promoter. To selectively target CF, HSV‐TK‐GFP+ bone marrow transplanted into irradiated wild type mice. These chimera mice were subjected to hypoxia for PH induction and ganciclovir for CF ablation.Key ResultsIn vivo CF ablation reduced right ventricular hypertrophy and vascular remodelling with reduced total collagen content. We quantified the CF recruited in the perivascular area and arterial wall of small pulmonary arteries. There was significant recruitment of CF in the lung in response to hypoxia. The characterization of CF showed the expression of CD45 and collagen1 (GFP) along with α‐smooth muscle actin (αSMA).Conclusion and ImplicationsOur data demonstrated that CF ablation has a potential impact on right ventricular hypertrophy and vascular remodelling in the setting of experimental pulmonary hypertension induced by hypoxia. The beneficial effects may be related to the direct contribution of fibrocytes or its paracrine effect on other resident cell types. Thus, clinical manipulation of CF may represent a novel therapeutic approach to ameliorate the disease state in pulmonary hypertension.
Myeloid‐specific dopamine D2 receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage
Authors: Han Xiao , Ni Jianbo , Wu Zengkai , Wu Jianghong , Li Bin , Ye Xin , Dai Juanjuan , Chen Congying , Xue Jing , Wan Rong , Wen Li , Wang Xingpeng , Hu Guoyong 
Published: February 2020

Background and PurposeMacrophage infiltration and activation is a critical step during acute pancreatitis (AP). We have shown that pancreas‐specific D2 receptor signalling protects against AP severity. As it is unclear to what extent myeloid‐specific D2 receptor mediates AP, we investigated the role of myeloid‐specific D2 receptor signalling in AP.Experimental ApproachUsing wild‐type and LysM+/creD2fl/fl mice, AP was induced by l‐arginine, caerulein and LPS. Murine bone marrow‐derived macrophages and human peripheral blood mononuclear cells (PBMCs) were isolated, cultured and then induced to M1 phenotype. AP severity was assessed by measurements of serum amylase and lipase and histological grading. Macrophage phenotype was assessed by flow cytometry and qRT‐PCR. NADPH oxidase‐induced oxidative stress and NF‐κB and NLRP3 inflammasome signalling pathways were also evaluated.Key ResultsWe found that dopaminergic system was activated and dopamine reduced inflammatory cytokine expression in M1‐polarized macrophages from human PBMCs. Dopaminergic synthesis was also activated, but D2 receptor expression was down‐regulated in M1‐polarized macrophages from murine bone marrows. During AP, myeloid‐specific D2 receptor deletion worsened pancreatic injury, systematic inflammation and promoted macrophages to M1 phenotype. Furthermore, M1 macrophages from LysM+/creD2fl/fl mice exhibited increased NADPH oxidase‐induced oxidative stress and enhanced NF‐κB and NLRP3 inflammasome activation. D2 receptor activation inhibited M1 macrophage polarization, oxidative stress‐induced NF‐κB and NLRP3 inflammasome activation.Conclusion and ImplicationsOur data for the first time showed that myeloid‐specific D2 receptor signalling controls pancreatic injury and systemic inflammation via inhibiting M1 macrophage, suggesting D2 receptor activation might serve as therapeutic target for AP.
Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives
Authors: Miyai Yuki , Esaki Nobutoshi , Takahashi Masahide , Enomoto Atsushi 
Published: February 2020

AbstractThe roles of cancer‐associated fibroblasts (CAF) in the progression of various types of cancers are well established. CAF promote cancer progression through pleiotropic mechanisms, including the secretion of soluble factors and extracellular matrix, physical interactions with cancer cells, and the regulation of angiogenesis, immunity and metabolism. Their contribution to therapeutic resistance is also well appreciated. Therefore, CAF have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAF exhibit cancer‐restraining roles, indicating that CAF are functionally and molecularly heterogeneous, which is supported by recent single‐cell transcriptome analyses. While cancer‐promoting CAF (pCAF) have been extensively studied, the nature and specific marker(s) of cancer‐restraining CAF (rCAF) have remained uncharacterized. Interestingly, a recent study provided insight into the nature of rCAF and suggested that they may share molecular properties with pancreatic stellate cells (PSC) and mesenchymal stem/stromal cells (MSC). Complicating this finding is that PSC and MSC have been shown to promote the formation of a tumor‐permissive and tumor‐promoting environment in xenograft tumor models. However, these cells undergo significant transcriptional and epigenetic changes during ex vivo culture, which confounds the interpretation of experimental results based on the use of cultured cells. In this short review, we describe recent studies and hypotheses on the identity of rCAF and discuss their analogy to fibroblasts that suppress fibrosis in fibrotic diseases. Finally, we discuss how these findings can be exploited to develop novel anticancer therapies in the future.
Design, microwave‐assisted synthesis, biological evaluation and molecular modeling studies of 4‐phenylthiazoles as potent fatty acid amide hydrolase inhibitors
Authors: Wilt Stephanie R. , Rodriguez Mark , Le Thanh N. H. , Baltodano Emily V. , Salas Adrian , Pecic Stevan 
Published: February 2020

AbstractEndocannabinoids, anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG), are endogenous lipids that activate cannabinoid receptors. Activation of these receptors produces anti‐inflammatory and analgesic effects. Fatty acid amide hydrolase (FAAH) is a membrane enzyme that hydrolases endocannabinoids; thus, inhibition of FAAH represents an attractive approach to develop new therapeutics for treating inflammation and pain. Previously, potent rat FAAH inhibitors containing 2‐naphthyl‐ and 4‐phenylthiazole scaffolds were identified, but up to the present time, very little structure–activity relationship studies have been performed on these moieties. We designed and synthesized several analogs containing these structural motifs and evaluated their inhibition potencies against human FAAH enzyme. In addition, we built and validated a homology model of human FAAH enzyme and performed docking experiments. We identified several inhibitors in the low nanomolar range and calculated their ADME predicted values. These FAAH inhibitors represent promising drug candidates for future preclinical in vivo studies.
Primary anastomosis and nonrestorative resection for perforated diverticulitis with peritonitis: meta‐analysis of randomized trials
Authors: Gachabayov M. , Tuech J. J. , Tulina I. , Coget J. , Bridoux V. , Bergamaschi R. 
Published: February 2020

AbstractAimThe aim of this meta‐analysis was to comparatively evaluate the outcomes of primary anastomosis (PRA) and nonrestorative resection (NRR) as emergency surgery and ostomy reversal in patients with perforated diverticulitis and peritonitis.MethodsPubMed, MEDLINE via Ovid, Embase, CINAHL, Cochrane Library and Web of Science databases were systematically searched. Postoperative morbidity following emergency resection was the primary end‐point. Quality assessment of the included studies was performed using the Cochrane Quality Assessment Tool including recruitment bias and crossover with intention‐to‐treat analysis. The Haenszel–Mantel method with odds ratios (OR, 95% CI) and the inverse variance method with mean difference (MD, 95% CI) as effect measures were utilized for dichotomous and continuous outcomes, respectively.ResultsFour randomized controlled trials totaling 382 patients (180 PRA vs 204 NRR) were included. Morbidity rates following emergency resection did not differ (OR = 0.99, 95% CI 0.65, 1.51; P = 0.95; number needed to treat/harm (NNT) 96). Organ/space surgical site infection rates were 3.3% in PRA vs 11.3% in NRR (OR = 0.29, 95% CI 0.12, 0.74; P = 0.009; NNT = 13). Postoperative morbidity rates following ostomy reversal were significantly lower in PRA (OR = 0.31, 95% CI 0.15, 0.64; P = 0.001; NNT = 7). Pooled ostomy non‐reversal rates were 16% in PRA vs 35.5% in NRR (OR = 0.37, 95% CI 0.22, 0.62; P = 0.0001; NNT = 6) with high heterogeneity (I2 = 63%; τ2 = 8.17). Meta‐regression analysis revealed significant negative correlation between the PRA‐to‐NRR crossover rate and the ostomy non‐reversal rate (P = 0.029).ConclusionThis meta‐analysis found that PRA was associated with better short‐ and long‐term outcomes at the cost of significantly longer operating time at emergency surgery.
Conservation decision‐making under uncertainty: Identifying when to reintroduce tiger Panthera tigris to Cambodia
Authors: Gray Thomas N. E. , Grainger Matthew J. , Grosu Romica 
Published: February 2020

AbstractConservationists need to present biological monitoring data to decision makers in a way which clearly represents uncertainty. Providing results in terms of the probability of a hypothesis being true may have greater utility for decision‐making than traditionally used frequentist statistical approaches. Here, we demonstrate such an approach with regard to assessing the suitability of the Cardamom Rainforest Landscape, Cambodia for Panthera tigris (tiger) reintroduction. We estimated the density of tiger prey in the core of the landscape using the Random Encounter Model from camera‐trap data and used Monte Carlo simulation to prorogate uncertainty around our model parameter estimates. This suggests there is currently a low probability that the core area of the landscape supports sufficient prey for a population of 25 adult tigers and that significant prey recovery is thus required prior to any reintroduction into the landscape. The Random Encounter Model contains a number of assumptions and we stress our main purpose is to illustrate an approach to incorporating uncertainty into conservation decision‐making rather than providing robust estimation of current tiger prey densities in the Cardamom Rainforest Landscape. Our approach has wide utility for conveying species monitoring information to conservation planners in a simple to understand fashion.
A retrospective comparison of salivary gland fine needle aspiration reporting with the Milan system for reporting salivary gland cytology
Authors: Mullen Dorinda , Gibbons David 
Published: February 2020

AbstractBackgroundFine needle aspiration (FNA) is a routine sampling method in the diagnostic work up of salivary gland lesions. Despite universal use, no standardised classification existed for the cytopathological reporting of such entities until recently. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) aims to standardise the reporting of these lesions, offering risk of malignancy rates and clinical management recommendations.MethodsWe retrospectively applied MSRSGC to cases reported over a 5‐year period. Salivary FNA specimens were reclassified according to the MSRSGC as (I) non‐diagnostic, (II) non‐neoplastic, (III) atypia of undetermined significance (AUS), (IV) benign neoplasm and salivary gland neoplasm of uncertain malignant potential, (V) suspicious for malignancy, and (VI) malignant. Cases with surgical resections were documented and risk of malignancy calculated for each group, where possible. We compared our outcomes with similar studies performed since publication of the Milan criteria.ResultsIn total, 192 specimens were reassigned as non‐diagnostic (n = 30), non‐neoplastic (n = 31), AUS (n = 1), benign neoplasm (n = 97) and salivary gland neoplasm of uncertain malignant potential (n = 4), suspicious for malignancy (n = 3), and malignant (n = 26). There were 73 surgical resections. Our calculated risk of malignancy was within the proposed MSRSGC rates for the non‐diagnostic, benign neoplasm and malignant groups. One AUS case did not undergo surgery. Benign and malignant sensitivities and specificities for the original reporting categories were 88.24% and 95.72%, and 100% and 95.45% for the MSRSGC, respectively.ConclusionSalivary gland FNA has high diagnostic accuracy and the MSRSGC offers standardised reporting and assistance in the stratification of cases. This may improve communication between pathologists and clinicians with improved outcomes for patients.
Callosal agenesis and congenital mirror movements: outcomes associated with DCC mutations
Authors: Spencer‐Smith Megan , Knight Jacquelyn L , Lacaze Emmanuelle ,   Irc5 Consortium, Depienne Christel , Lockhart Paul J , Richards Linda J , Heron Delphine , Leventer Richard J , Robinson Gail A 
Published: February 2020

Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8–50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability.What this paper adds

Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum.

A DCC pathogenic variant in isolation is associated with the best prognosis.
Intracranial hypertension and cortical thickness in syndromic craniosynostosis
Authors: Wilson Alexander T , Den Ottelander Bianca K , De Goederen Robbin , Van Veelen Marie‐Lise C , Dremmen Marjolein H G , Persing John A , Vrooman Henri A , Mathijssen Irene M J 
Published: February 2020

AimTo evaluate the impact of risk factors for intracranial hypertension (ICH) on cerebral cortex thickness in syndromic craniosynostosis.MethodICH risk factors including papilloedema, hydrocephalus, obstructive sleep apnea (OSA), cerebellar tonsillar position, occipitofrontal circumference (OFC) curve deflection, age, and sex were collected from the records of patients with syndromic craniosynostosis (Apert, Crouzon, Pfeiffer, Muenke, Saethre‐Chotzen syndromes) and imaging. Magnetic resonance images were analysed and exported for statistical analysis. A linear mixed model was developed to determine correlations with cerebral cortex thickness changes.ResultsIn total, 171 scans from 107 patients (83 males, 88 females [including repeated scans], mean age 8y 10mo, range 1y 1mo–34y, SD 5y 9mo) were evaluated. Mean cortical thickness in this cohort was 2.78mm (SD 0.17). Previous findings of papilloedema (p=0.036) and of hydrocephalus (p=0.007) were independently associated with cortical thinning. Cortical thickness did not vary significantly by sex (p=0.534), syndrome (p=0.896), OSA (p=0.464), OFC (p=0.375), or tonsillar position (p=0.682).InterpretationDetection of papilloedema or hydrocephalus in syndromic craniosynostosis is associated with significant changes in cortical thickness, supporting the need for preventative rather than reactive treatment strategies.What this paper adds

Papilloedema is associated with thinning of the cerebral cortex in syndromic craniosynostosis, independently of hydrocephalus.
Clinical observation of noncoronary cardiac abnormalities in Chinese children with Kawasaki disease
Authors: Liu Fei Fei , Liu Hui Hui , Qiu Zhen , Wang Jing Jing , Samadli Sama , Wu Yue , Wu Yang Fang , Xu Yao , Luo Huang Huang , Chen Wei Xia , Zhang Dong Dong , Hu Peng 
Published: February 2020

AbstractBackgroundKawasaki disease (KD) is an acute, self‐limited vasculitis. Coronary artery aneurysm (CAA) serves as a major contributor to the long‐term prognosis of KD. In addition, acute KD usually also leads to several kinds of noncoronary cardiac abnormalities (NCA) involving the pericardium, myocardium and endocardium.Materials and methodsA total of 142 Chinese children with KD were recruited from July 2015 to April 2018. Blood samples were collected at 24 hours pre‐intravenous immunoglobulin (IVIG) therapy. Several inflammatory mediators and biomarkers for acute myocardial infarction were detected. Echocardiography and electrocardiography (ECG) were performed.ResultsPlasma white blood cell counts (WBC) were significantly increased in patients with IVIG‐nonresponsive KD when compared with their IVIG‐responsive counterparts. A total of 106 children (74.65%) suffered from NCA, including 8 patients (5.63%) with pericardial effusion, 23 patients (16.20%) with acute myocarditis, 101 patients (71.13%) with valvular regurgitation and 8 patients (5.63%) with abnormal ECG. No significant differences were observed in the distribution of clinical classification and the response to IVIG therapy regardless of NCA exhibited or not.ConclusionsNoncoronary cardiac abnormalities is almost universal in acute KD and mainly manifests as valvular regurgitation. However, it has no influence on clinical classification and the response to IVIG therapy.
The power and limitations of gene expression pathway analyses toward predicting population response to environmental stressors
Authors: Stanford Brenna C.M. , Clake Danielle J. , Morris Matthew R.J. , Rogers Sean M. 
Published: February 2020

AbstractRapid environmental changes impact the global distribution and abundance of species, highlighting the urgency to understand and predict how populations will respond. The analysis of differentially expressed genes has elucidated areas of the genome involved in adaptive divergence to past and present environmental change. Such studies however have been hampered by large numbers of differentially expressed genes and limited knowledge of how these genes work in conjunction with each other. Recent methods (broadly termed “pathway analyses”) have emerged that aim to group genes that behave in a coordinated fashion to a factor of interest. These methods aid in functional annotation and uncovering biological pathways, thereby collapsing complex datasets into more manageable units, providing more nuanced understandings of both the organism‐level effects of modified gene expression, and the targets of adaptive divergence. Here, we reanalyze a dataset that investigated temperature‐induced changes in gene expression in marine‐adapted and freshwater‐adapted threespine stickleback (Gasterosteus aculeatus), using Weighted Gene Co‐expression Network Analysis (WGCNA) with PANTHER Gene Ontology (GO)‐Slim overrepresentation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Six modules exhibited a conserved response and six a divergent response between marine and freshwater stickleback when acclimated to 7°C or 22°C. One divergent module showed freshwater‐specific response to temperature, and the remaining divergent modules showed differences in height of reaction norms. PPARAa, a transcription factor that regulates fatty acid metabolism and has been implicated in adaptive divergence, was located in a module that had higher expression at 7°C and in freshwater stickleback. This updated methodology revealed patterns that were not found in the original publication. Although such methods hold promise toward predicting population response to environmental stressors, many limitations remain, particularly with regard to module expression representation, database resources, and cross‐database integration.
Metabolic remodeling in Escherichia coli MG1655. A prophage e14‐encoded small RNA, co293, post‐transcriptionally regulates transcription factors HcaR and FadR
Authors: Madikonda Ashok Kumar , Shaikh Akbarpasha , Khanra Sonali , Yakkala Harshita , Yellaboina Sailu , Lin‐Chao Sue , Siddavattam Dayananda 
Published: February 2020

In previous studies, we have shown the existence of metabolic remodeling in glucose‐grown Escherichia coli MG1655 cells expressing the esterase Orf306 from the opd island of Sphingobium fuliginis. We now show that Orf306‐dependent metabolic remodeling is due to regulation of a novel small RNA (sRNA). Endogenous propionate, produced due to the esterase/lipase activity of Orf306, repressed expression of a novel E. coli sRNA, co293. This sRNA post‐transcriptionally regulates expression of the transcription factors HcaR and FadR either by inhibiting translation or by destabilizing their transcripts. Hence, repression of co293 expression elevates the levels of HcaR and FadR with consequent activation of alternative carbon catabolic pathways. HcaR activates the hca and MHP operons leading to upregulation of the phenyl propionate and hydroxy phenyl propionate (HPP) degradation pathways. Similarly, FadR stimulates the expression of the transcription factor IclR which negatively regulates the glyoxylate bypass pathway genes, aceBAK.