The causal relationship between genetically determined telomere length and meningiomas risk

BackgroundStudies have shown that longer leukocyte telomere length (LTL) is significantly associated with increased risk of meningioma. However, there is limited evidence concerning the causal association of LTL with benign and malignant meningiomas or with the location of benign tumors.MethodsWe used three LTL datasets from different sources, designated by name and sample size as LTL-78592, LTL-9190, and LTL-472174. The linkage disequilibrium score (LDSC) was used to explore the association between LTL and meningioma. We utilized two-sample bidirectional Mendelian randomization (TSMR) to evaluate whether LTL is causally related to meningioma risk. We adjusted for confounders by conducting multivariable Mendelian randomization (MVMR).ResultsIn the LTL-78592, longer LTL was significantly associated with increased risk of malignant [odds ratio (OR) = 5.14, p = 1.04 × 10−5], benign (OR = 4.81, p < 0.05), benign cerebral (OR = 5.36, p < 0.05), and benign unspecified meningioma (OR = 8.26, p < 0.05). The same results were obtained for the LTL-9190. In the LTL-472174, longer LTL was significantly associated with increased risk of malignant (OR = 4.94, p < 0.05), benign (OR = 3.14, p < 0.05), and benign cerebral meningioma (OR = 3.59, p < 0.05). Similar results were obtained in the MVMR. In contrast, only benign cerebral meningioma displayed a possible association with longer LTL (OR = 1.01, p < 0.05). No heterogeneity or horizontal pleiotropy was detected.ConclusionIn brief, genetically predicted longer LTL may increase the risk of benign, malignant, and benign cerebral meningiomas, regardless of the LTL measure, in European populations

The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability

人类与其他动物相比的重要区别在于人类拥有高等认知能力，这种能力集中体现在学习记忆和语言表达方面。厦门大学医学院神经科学研究所王鑫教授团队发现人科动物特异性基因USP6作为一个新的NMDA受体调控因子，可通过去泛素化途径调节NMDA型谷氨酸受体的降解和稳定性，进而调控突触可塑性和学习记忆能力。 本研究工作由王鑫教授指导完成，博士生曾凡伟、马学海与硕士生朱琳为共同第一作者，王鑫教授为通讯作者。Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation and long-term depression in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.This work was partially supported by the National Natural Science Foundation of China (31871077, 81822014, 81571176 to XW; 81701349 to Hongfeng Z.; 81701130 to QZ; and 81471160 to HS), the National Key R&D Program of China (2016YFC1305900 to XW and HS), the Natural Science Foundation of Fujian Province of China (2017J06021 to XW), the Fundamental Research Funds for the Chinese Central Universities (20720150061 to XW and 20720180040 to ZS), Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2019KF012 to QZ), and China Postdoctoral Science Foundation (2017M612130 to QZ).该研究得到了国家自然科学基金面上项目和优秀青年基金项目的支持

A targeted metabolomic protocol for short-chain fatty acids and branched-chain amino acids

Research in obesity and metabolic disorders that involve intestinal microbiota demands reliable methods for the precise measurement of the short-chain fatty acids (SCFAs) and branched-chain amino acids (BCAAs) concentration. Here, we report a rapid method of simultaneously determining SCFAs and BCAAs in biological samples using propyl chloroformate (PCF) derivatization followed by gas chromatography mass spectrometry (GC-MS) analysis. A one-step derivatization using 100 µL of PCF in a reaction system of water, propanol, and pyridine (v/v/v = 8:3:2) at pH 8 provided the optimal derivatization efficiency. The best extraction efficiency of the derivatized products was achieved by a two-step extraction with hexane. The method exhibited good derivatization efficiency and recovery for a wide range of concentrations with a low limit of detection for each compound. The relative standard deviations (RSDs) of all targeted compounds showed good intra- and inter-day (within 7 days) precision (< 10%), and good stability (< 20%) within 4 days at room temperature (23–25 °C), or 7 days when stored at −20 °C. We applied our method to measure SCFA and BCAA levels in fecal samples from rats administrated with different diet. Both univariate and multivariate statistics analysis of the concentrations of these target metabolites could differentiate three groups with ethanol intervention and different oils in diet. This method was also successfully employed to determine SCFA and BCAA in the feces, plasma and urine from normal humans, providing important baseline information of the concentrations of these metabolites. This novel metabolic profile study has great potential for translational research

Targeting the gut barrier for the treatment of alcoholic liver disease

Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide. Intriguingly, dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver disease (ALD). A functional gut barrier, which consists of a mucus layer, an intact epithelial monolayer and mucosal immune cells, supports nutrient absorption and prevents bacterial penetration. Compromised gut barrier function is associated with the progression of ALD. Indeed, alcohol consumption disrupts the gut barrier, increases gut permeability, and induces bacterial translocation both in ALD patients and in experimental models with ALD. Moreover, alcohol consumption also causes enteric dysbiosis with both numerical and proportional perturbations. Here, we review and discuss mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD. Unfortunately, there is no effectual Food and Drug Administration-approved treatment for any stage of ALD. Therefore, we conclude with a discussion of potential strategies aimed at restoring the gut barrier in ALD. The principle behind antibiotics, prebiotics, probiotics and fecal microbiota transplants is to restore microbial symbiosis and subsequently gut barrier function. Nutrient-based treatments, such as dietary supplementation with zinc, niacin or fatty acids, have been shown to regulate tight junction expression, reduce intestinal inflammation, and prevent endotoxemia as well as liver injury caused by alcohol in experimental settings. Interestingly, saturated fatty acids may also directly control the gut microbiome. In summary, clinical and experimental studies highlight the significance and efficacy of the gut barrier in treating ALD. Keywords: Alcoholic liver disease (ALD), Gut barrier, Gut hyperpermeability, Dietary intervention, Microbiota treatmen

Zinc and Hepatocyte Nuclear Factor-4α in Alcohol-Induced Intestinal Barrier Dysfunction under a Creative Commons Attribution-Non Commercial License (CC BY-NC); http://creativecommons.org/licenses/by-nc/3.0/ Zinc and Hepatocyte Nuclear Factor-4 in Alcohol-

Increasing evidence support that zinc homeostasis has significant impact on the intestinal barrier via regulation of epithelial tight junction proteins. Intestinal barrier plays a critical role in the prevention of endotoxin penetration from the intestinal lumen to the blood. Disruption of the intestinal barrier leads to elevation of blood endotoxin level, namely endotoxemia. Endotoxemia may lead to proinflammatory cytokine production and inflammation, thereby being an etiological factor in the pathogenesis of alcoholic liver disease (ALD). Recent studies demonstrated that oxidative stress and zinc deficiency correlate well with alcohol-induced gut leakiness. Alcohol exposure induces oxidative stress which, in turn, releases zinc from proteins. Hepatocyte nuclear factor-4 (HNF-4 ) is a zinc finger transcription factor which abundantly distributes in the intestine, particularly the distal intestine. Inactivation of HNF-4 correlates well with alcohol-induced downregulation of tight junction proteins. This review discusses mechanisms involved in alcohol-induced intestinal epithelial barrier disruption with emphasis on the relationship among oxidative stress, zinc deficiency, and HNF-4 inactivation

Adipose Triglyceride Lipase in Hepatic Physiology and Pathophysiology

The liver is extremely active in oxidizing triglycerides (TG) for energy production. An imbalance between TG synthesis and hydrolysis leads to metabolic disorders in the liver, including excessive lipid accumulation, oxidative stress, and ultimately liver damage. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme that catalyzes the first step of TG breakdown to glycerol and fatty acids. Although its role in controlling lipid homeostasis has been relatively well-studied in the adipose tissue, heart, and skeletal muscle, it remains largely unknown how and to what extent ATGL is regulated in the liver, responds to stimuli and regulators, and mediates disease progression. Therefore, in this review, we describe the current understanding of the structure&ndash;function relationship of ATGL, the molecular mechanisms of ATGL regulation at translational and post-translational levels, and&mdash;most importantly&mdash;its role in lipid and glucose homeostasis in health and disease with a focus on the liver. Advances in understanding the molecular mechanisms underlying hepatic lipid accumulation are crucial to the development of targeted therapies for treating hepatic metabolic disorders

A BERT-Span model for Chinese named entity recognition in rehabilitation medicine

Background Due to various factors such as the increasing aging of the population and the upgrading of people’s health consumption needs, the demand group for rehabilitation medical care is expanding. Currently, China’s rehabilitation medical care encounters several challenges, such as inadequate awareness and a scarcity of skilled professionals. Enhancing public awareness about rehabilitation and improving the quality of rehabilitation services are particularly crucial. Named entity recognition is an essential first step in information processing as it enables the automated extraction of rehabilitation medical entities. These entities play a crucial role in subsequent tasks, including information decision systems and the construction of medical knowledge graphs. Methods In order to accomplish this objective, we construct the BERT-Span model to complete the Chinese rehabilitation medicine named entity recognition task. First, we collect rehabilitation information from multiple sources to build a corpus in the field of rehabilitation medicine, and fine-tune Bidirectional Encoder Representation from Transformers (BERT) with the rehabilitation medicine corpus. For the rehabilitation medicine corpus, we use BERT to extract the feature vectors of rehabilitation medicine entities in the text, and use the span model to complete the annotation of rehabilitation medicine entities. Result Compared to existing baseline models, our model achieved the highest F1 value for the named entity recognition task in the rehabilitation medicine corpus. The experimental results demonstrate that our method outperforms in recognizing both long medical entities and nested medical entities in rehabilitation medical texts. Conclusion The BERT-Span model can effectively identify and extract entity knowledge in the field of rehabilitation medicine in China, which supports the construction of the knowledge graph of rehabilitation medicine and the development of the decision-making system of rehabilitation medicine