85 research outputs found
Investigation of hybrid plasma-catalytic removal of acetone over CuO/gamma-Al2O3 catalysts using response surface method
Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing
BackgroundAtrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia. Growing evidence suggests that family aggregation and genetic factors are involved in AVNRT. However, in families with a history of AVNRT, disease-causing genes have not been reported.ObjectiveTo investigate the genetic contribution of familial AVNRT using a whole-exome sequencing (WES) approach.MethodsBlood samples were collected from 20 patients from nine families with a history of AVNRT and 100 control participants, and we systematically analyzed mutation profiles using WES. Gene-based burden analysis, integration of previous sporadic AVNRT data, pedigree-based co-segregation, protein-protein interaction network analysis, single-cell RNA sequencing, and confirmation of animal phenotype were performed.ResultsAmong 95 related reference genes, seven candidate pathogenic genes have been identified both in sporadic and familial AVNRT, including CASQ2, AGXT, ANK2, SYNE2, ZFHX3, GJD3, and SCN4A. Among the 37 reference genes from sporadic AVNRT, five candidate pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, ryanodine receptor 2 (RYR2), COL4A3, NOS1, and ATP2C2. To identify the common pathogenic mechanisms in all AVNRT cases, five pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, RYR2, COL4A3, NOS1, and ATP2C2. Considering the unique internal candidate pathogenic gene within pedigrees, three genes, TRDN, CASQ2, and WNK1, were likely to be the pathogenic genes in familial AVNRT. Notably, the core calcium-signaling pathway may be closely associated with the occurrence of AVNRT, including CASQ2, RYR2, TRDN, NOS1, ANK2, and ATP2C2.ConclusionOur pedigree-based studies demonstrate that RYR2 and related calcium signaling pathway play a critical role in the pathogenesis of familial AVNRT using the WES approach
Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice
De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs) compared with wild-type littermates. Asxl1(-/-) BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re-introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1(-/-) BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development
Towards Evaluating Pitch-Related Phonation Function in Speech Communication Using High-Density Surface Electromyography
Pitch, as a sensation of the sound frequency, is a crucial attribute toward constructing a natural voice for communication. Producing intelligible sounds with normal pitches depend on substantive interdependencies among facial and neck muscles. Clarifying the interrelations between the pitches and the corresponding muscular activities would be helpful for evaluating the pitch-related phonating functions, which would play a significant role both in training pronunciation and in assessing dysphonia. In this study, the speech signals and the high-density surface electromyography (HD sEMG) signals were synchronously acquired when phonating [a:], [i:], and [ә:] vowels with increasing pitches, respectively. The HD sEMG energy maps were constructed based on the root mean square values to visualize spatiotemporal characteristics of facial and neck muscle activities. Normalized median frequency (nMF) and root-mean square (nRMS) were correspondingly extracted from the speech and sEMG recordings to quantitatively investigate the correlations between sound frequencies and myoelectric characteristics. The results showed that the frame-wise energy maps built from sEMG recordings presented that the muscle contraction strength increased monotonously across pitch-rising, with left-right symmetrical distribution for the face/neck. Furthermore, the nRMS increased at a similar rate to the nMF when there were rising pitches, and the two parameters had a significant correlation across different vowel tasks [(a:) (0.88 ± 0.04), (i:) (0.89 ± 0.04), and (ә:) (0.87 ± 0.05)]. These findings suggested the possibility of utilizing muscle contraction patterns as a reference for evaluating pitch-related phonation functions. The proposed method could open a new window for developing a clinical approach for assessing the muscular functions of dysphonia
An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia
Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation
A Multidisciplinary Investigation of a Polycythemia Vera Cancer Cluster of Unknown Origin
Cancer cluster investigations rarely receive significant public health resource allocations due to numerous inherent challenges and the limited success of past efforts. In 2008, a cluster of polycythemia vera, a rare blood cancer with unknown etiology, was identified in northeast Pennsylvania. A multidisciplinary group of federal and state agencies, academic institutions, and local healthcare providers subsequently developed a multifaceted research portfolio designed to better understand the cause of the cluster. This research agenda represents a unique and important opportunity to demonstrate that cancer cluster investigations can produce desirable public health and scientific outcomes when necessary resources are available
Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK
葡萄糖是生物中最基本、最主要的营养物质,它不仅是机体能量的主要来源,也是生物质合成的主要原料。因此,葡萄糖的水平对于生物体是极其重要的。然而,在生活中,体内葡萄糖水平的波动是十分常见的,这是因为我们不可能每时每刻都在摄入葡萄糖:睡一大觉、剧烈运动几个小时或者太忙了没时间吃饭,都会引起葡萄糖水平的显著下降。这时,机体能够触发一套有效的过程应对这类“不利情况”,其中最为关键的就是激活“代谢的核心调节”——AMPK。在葡萄糖水平下降时,被激活的AMPK能够迅速启动脂肪、蛋白质的分解代谢,关闭它们的合成代谢,从而起到维持机体的能量和物质代谢的平衡,弥补机体因葡萄糖不足引起的胁迫压力。那么,机体如何感受葡萄糖水平下降,并“传递”给AMPK使其激活呢?林圣彩教授课题组的这项研究正是发现了生理状态下机体感受葡萄糖水平的机制。通过研究他们发现,无论在不含葡萄糖的细胞培养条件下,还是在饥饿的低血糖的动物体内,都不能观测到AMP水平的上升,这充分说明了机体有一套尚不为人知的、独立于AMP的感应葡萄糖水平的机制。在进一步的研究中他们揭示了这一完整过程:葡萄糖水平下降将引起的葡萄糖代谢中间物——果糖1,6-二磷酸(fructose-1,6-bisphosphate)水平的下降,该过程进一步地被糖酵解通路上的代谢酶——醛缩酶(aldolase)感应,因为醛缩酶正是将含有6个碳原子的果糖1,6-二磷酸裂解成三碳糖的酶,一旦醛缩酶“吃不到”由葡萄糖衍生的果糖1,6-二磷酸,它便“翻脸”,传递给也正是林圣彩教授课题组先前发现的溶酶体途径进而激活AMPK。该过程完全不涉及AMP水平,即能量水平的变化,是一条全新的、完全建立在实际的生理情况上的通路。林圣彩教授进一步地把葡萄糖水平总结为一种“状态信号”,以区别于传统的“能量信号”。据悉,该葡萄糖感知通路的发现对开发用于治疗肥胖症,乃至延长寿命的药物具有深远的意义。【Abstract】The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK)1, but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK2, 3, 4, 5. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation6, 7. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.D.G.H. was supported by an Investigator Award from the Wellcome Trust (097726) and a Programme Grant from Cancer Research UK (C37030/A15101). S.-C.L. was supported by grants from the National Key Research and Development Project of China (2016YFA0502001) and the National Natural Science Foundation of China (#31430094, #31690101, #31571214, #31601152 and #J1310027)
The Lysosomal v-ATPase-Ragulator Complex Is a Common Activator for AMPK and mTORC1, Acting as a Switch between Catabolism and Anabolism
林圣彩教授课题组长期致力于细胞信号转导的研究。近年来,该课题组潜心研究,不断攻关,取得了一系列重大成果,如揭示细胞如何应对生长因子缺乏的内在机理,发现了细胞自噬“路线图”、还发现了细胞如何感应“饥饿”信号AMP的信号传导通路等。其中,“发现细胞自噬‘路线图’”成果曾登上《科学》杂志,并入选2012年度“中国科学十大进展”。AMPK and mTOR play principal roles in governing metabolic programs; however, mechanisms underlying the coordination of the two inversely regulated kinases remain unclear. In this study we found, most surprisingly, that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, the guanine nucleotide exchange factor (GEF) activity of Ragulator toward RAG is inhibited by AXIN, causing dissociation from endosome and inactivation of mTORC1. We have thus revealed that the v-ATPase-Ragulator complex is also an initiating sensor for energy stress and meanwhile serves as an endosomal docking site for LKB1-mediated AMPK activation by forming the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex, thereby providing a switch between catabolism and anabolism. Our current study also emphasizes a general role of late endosome/lysosome in controlling metabolic programs
Web site & customer value : from a marketing perspective
The purpose of this dissertation is to find the key factors of web site which influence customer value. Through literature review, we find the role of web site from a marketing perspective is a medium of marketing, enhancing the marketing mix and endowing the marketing mix with new features; we also find that customer value is a comparison of benefit and cost, having both psychic value and utility value and covering the whole customer activity. On base of these, we identify eight factors of web site which, we hypothesize, influence customer value: Attractiveness, Ease of use, Accuracy, Customization, Responsiveness, Community, Comparison and Assurance. Then a survey with questionnaire method was employed. As to the design and analysis of the questionnaire, the Kano model was used. The result of our survey showed that seven factors of web site - Assurance, Ease of use, Accuracy, Responsiveness, Customization, Attractiveness and Comparison, have positive influence to customer value while Factor of Community, has little influence to customer value. In addition, we introduced Importance index and Indifference index to evaluate influence during analyzing; under this way, we proved the validity and reliability of our investigation
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