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Peripheral Guanylate cyclase-c modulation of corticolimbic activation and corticotropin-releasing factor signaling in a rat model of stress-induced colonic hypersensitivity

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NEUROGASTROENTEROLOGY AND MOTILITY 2021年第3期33卷 e14076-e14076页

作者： Ligon, casey O. Hannig, Gerhard Greenwood-Van Meerveld, Beverley Univ Oklahoma Hlth Sci Ctr Oklahoma Ctr Neurosci Oklahoma City OK USA Ironwood Pharmaceut Boston MA USA Univ Oklahoma Dept Physiol Hlth Sci Ctr Oklahoma City OK USA

Background Psychological stress is a risk factor for irritable bowel syndrome, a functional gastrointestinal pain disorder featuring abnormal brain-gut connectivity. The guanylate cyclase-c (Gc-c) agonist linaclotide has been shown to relieve abdominal pain in IBS-c and exhibits antinociceptive effects in rodent models of post-inflammatory visceral hypersensitivity. However, the role Gc-c signaling plays in psychological stress-induced visceral hypersensitivity is unknown. Here, we test the hypothesis that Gc-c agonism reverses stress-induced colonic hypersensitivity via inhibition of nociceptive afferent signaling resulting in normalization of stress-altered corticotropin-releasing factor (cRF) expression in brain regions involved in pain perception and modulation. Methods Adult female rats were exposed to water avoidance stress or sham stress for 10 days, and the effects of linaclotide on stress-induced changes in colonic sensitivity, corticolimbic phospho-extracellular signal-regulated kinase (pERK), and cRF expression were measured using a combination of behavioral assessments, immunohistochemistry, and qRT-PcR. Key Results Stressed rats exhibited colonic hypersensitivity and elevated corticolimbic pERK on day 11, which was inhibited by linaclotide. qRT-PcR analysis revealed dysregulated cRF expression in the medial prefrontal cortex, paraventricular nucleus of the hypothalamus, and central nucleus of the amygdala on day 28. Dysregulated cRF expression was not affected by linaclotide treatment. conclusions and Inferences Our results demonstrate that exposure to repeated stress induces chronic colonic hypersensitivity in conjunction with altered corticolimbic activation and cRF expression. Gc-c agonism attenuated stress-induced colonic hypersensitivity and ERK phosphorylation, but had no effect on cRF expression, suggesting the analgesic effects of linaclotide occur independent of stress-driven cRF gene expression in corticolimbic circuitry.

关键词： guanylate cyclase‐ c Irritable bowel syndrome linaclotide nociception stress

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A novel frequent BRcA1 recurrent variant c.5117G >A (***1206Glu) identified after 20years of BRcA1/2 research in the Baltic region: cohort study and literature review

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HEREDITARY cANcER IN cLINIcAL PRAcTIcE 2021年第1期19卷 11-11页

作者： Loza, P. Irmejs, A. Daneberga, Z. Miklasevics, E. Berga-Svitina, E. Subatniece, S. Maksimenko, J. Trofimovics, G. Tauvena, E. Ukleikins, S. Gardovskis, J. Riga Stradins Univ Inst Oncol Riga Latvia Pauls Stradins Clin Univ Hosp Riga Latvia Riga Stradins Univ Dept Surg Riga Latvia

BackgroundSeveral recent studies in the Baltic region have found extended spectrum of pathogenic variants (PV) of the BRcA1/2 genes. The aim of current study is to analyze the spectrum of the BRcA1/2 PV in population of Latvia and to compare common PV between populations of the Baltic *** present a cohort of 9543 unrelated individuals including ones with cancer and unaffected individuals from population of Latvia, who were tested for three most common BRcA1 founder PV. In second line testing, 164 founder negative high-risk individuals were tested for PV of the BRcA1/2 using next generation sequencing (NGS). Local spectrum of the BRcA1/2 PV was compared with the Baltic region by performing a literature *** PV c.5266dupc, c.4035delA or c.181T>G was detected in 369/9543 (3.9%) cases. Other BRcA1/2 PV were found in 44/164 (26.8%) of NGS cases. Four recurrent BRcA1 variants c.5117G>A (***1706Glu), c.4675G>A (***1559Lys), c.5503c>T (***1835*) and c.1961delA (***654fs) were detected in 18/44 (41.0%), 5/44 (11.4%), 2/44 (4.5%) and 2/44 (4.5%) cases respectively. Additionally, 11 BRcA1 PV and six BRcA2 PV were each found in single *** combining three studies by our group of the same cohort in Latvia, frequency of the BRcA1/2 PV for unselected breast and ovarian cancer cases is 241/5060 (4.8%) and 162/1067 (15.2%) respectively. The frequency of three "historical" founder PV is up to 87.0% (369/424). Other non-founder PV contribute to at least 13.0% (55/424) and this proportion probably will rise by increasing numbers of the BRcA1/2 sequencing. In relative numbers, c.5117G>A is currently the third most frequent PV of the BRcA1 in population of Latvia, overcoming previously known third most common founder variant c.181T>G. In addition to three BRcA1 founder PV, a total of five recurrent BRcA1 and two recurrent BRcA2 PV have been reported in population of Latvia so far. Many of the BRcA1/2 PV reported in Latvia are shared a

关键词： BRcA1 BRcA2 c 5266dupc c 4035delA c 181T > G c 5117G > A (p Gly1706Glu) c 4675G > A (p Glu1559Lys) c 1961delA (p Lys654fs) c 5503c > T (p Arg1835*)

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The c. elegans homolog of human panic-disorder risk gene TMEM132D orchestrates neuronal morphogenesis through the WAVE-regulatory complex

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MOLEcULAR BRAIN 2021年第1期14卷 54-54页

作者： Wang, Xin Jiang, Wei Luo, Shuo Yang, Xiaoyu Wang, changnan Wang, Bingying Dang, Yongjun Shen, Yin Ma, Dengke K. Univ Calif San Francisco Cardiovasc Res Inst San Francisco CA 94158 USA Univ Calif San Francisco Dept Physiol San Francisco CA 94158 USA Yunnan Univ State Key Lab Conservat & Utilizat Bioresources Y Kunming 650091 Yunnan Peoples R China Fudan Univ Key Lab Metab & Mol Med Sch Basic Med SciMinist Educ Dept Biochem & Mol BiolShanghai Med Coll Shanghai 200032 Peoples R China Univ Calif San Francisco Dept Neurol Inst Human Genet San Francisco CA 94158 USA

TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Defining a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in c. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in c. elegans tmem-132 that disrupt interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRc) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRc rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRc, leading to decreased abundance of select WRc components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRc activity, cytoskeletal and morphologic changes in the cell.

关键词： TMEM132D Panic disorder WAVE regulatory complex Actin c elegans

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Mechanism of the lifespan extension induced by submaximal SERcA inhibition in c. elegans

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MEcHANISMS OF AGEING AND DEVELOPMENT 2021年 196卷 111474-111474页

作者： Garcia-casas, Paloma Alvarez-Illera, Pilar Fonteriz, Rosalba, I Montero, Mayte Alvarez, Javier Univ Valladolid Fac Med Inst Biol & Mol Genet IBGM Dept Biochem & Mol Biol & Physiol Ramon Y Cajal 7 E-47005 Valladolid Spain CSIC Ramon Y Cajal 7 E-47005 Valladolid Spain

We have reported recently that submaximal inhibition of the Sarco Endoplasmic Reticulum ca2+ ATPase (SERcA) produces an increase in the lifespan of c. elegans worms. We have explored here the mechanism of this increased survival by studying the effect of SERcA inhibition in several mutants of signaling pathways related to longevity. Our data show that the mechanism of the effect is unrelated with the insulin signaling pathway or the sirtuin activity, because SERcA inhibitors increased lifespan similarly in mutants of these pathways. However, the effect required functional mitochondria and both the AMP kinase and TOR pathways, as the SERcA inhibitors were ineffective in the corresponding mutants. The same effects were obtained after reducing SERcA expression with submaximal RNAi treatment. The SERcA inhibitors did not induce ER-stress at the concentrations used, and their effect was not modified by inactivation of the OP50 bacterial food. Altogether, our data suggest that the effect may be due to a reduced ER-mitochondria ca2+ transfer acting via AMPK activation and mTOR inhibition to promote survival.

关键词： c elegans SERcA Thapsigargin Lifespan Endoplasmic reticulum Mitochondria AMP kinase TOR

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APc/c cDH1 ubiquitinates IDH2 contributing to ROS increase in mitosis

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cELLULAR SIGNALLING 2021年 86卷 110087-110087页

作者： Lambhate, Surbhi Bhattacharjee, Debanjan Jain, Nishant CSIR Indian Inst Chem Technol Dept Appl Biol Uppal Rd Hyderabad 500007 India Acad Sci & Innovat Res AcSIR Ghaziabad 201002 India

NADPH is a cofactor used by reactive oxygen species (ROS) scavenging enzymes to block ROS produced in cells. Recently, it was shown that in cancer cells, ROS progressively increases in tune to cell cycle leading to a peak in mitosis. Loss of IDH2 is known to cause severe oxidative stress in cell and mouse models as ROS increases in mitochondria. Therefore, we hypothesized that IDH2, a major NADPH-producing enzyme in mitochondria is ubiquitinated for ROS to increase in mitosis. To test this hypothesis, in cancer cells we examined IDH2 ubiquitination in mitosis and measured the ROS produced. We found that IDH2 is ubiquitinated in mitosis and on inhibiting anaphase-promoting complex/cyclosome (APc/c) IDH2 was stabilized. Further, we observed that overexpressing APc/c coactivator cDH1 decreased IDH2, whereas depleting cDH1 decreased IDH2 ubiquitination. To understand the link between IDH2 ubiquitination and ROS produced in mitosis, we show that overexpressing mitochondria-targeted-IDH1 decreased ROS by increasing NADPH in IDH2 ubiquitinated cells. We conclude that APc/c cDH1 ubiquitinates IDH2, a major NADPH-producing enzyme in mitochondria contributing to ROS increase in mitosis. Based on our results, we suggest that mitosis can be a therapeutic window in mutant IDH2-linked pathologies.

关键词： IDH2 APc c cDH1 NADPH ROS Mitosis

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Expanding the phenotype of E318K (c.952G > A) MITF germline mutation carriers: case series and review of the literature

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HEREDITARY cANcER IN cLINIcAL PRAcTIcE 2021年第1期19卷 32-32页

作者： Oliveira, Leandro Jonata carvalho Gongora, Aline Bobato Lara Lima, Fabiola Ambrosio Silveira canedo, Felipe Sales Nogueira Amorim Quirino, carla Vanessa Pisani, Janina Pontes Achatz, Maria Isabel Rossi, Benedito Mauro Ctr Oncol Hosp Sirio Libanes Serv Oncogenet Rua Dona Adma Jafet 91 BR-01308050 Sao Paulo Brazil

Background The microphthalmia-associated transcription factor gene (MITF) belongs to the MYc supergene family and plays an important role in melanocytes' homeostasis. Individuals harboring MITF germline pathogenic variants are at increased risk of developing cancer, most notably melanoma and renal cell carcinoma. case presentation We describe a cohort of ten individuals who harbor the same MITF c.952G > A (*** 318Lys), or p.E318K, germline pathogenic variant. Six carriers developed at least one malignancy (4 cases of breast cancer;1 cervical cancer;1 colon cancer;1 melanoma;1 ovarian/fallopian tube cancer). A significant phenotypic heterogeneity was found among these individuals and their relatives. Breast cancer was, overall, the most frequent malignancy observed in this case series, with 13 occurrences of 60 (21.67 %) total cancer cases described among the probands and their relatives. conclusions Our retrospective analysis data raise the hypothesis of a possible association of the MITF p.E318K pathogenic variant with an increased risk of breast cancer.

关键词： MITF c 952G > A p E318K Hereditary cancer Multigene sequencing panel Breast cancer

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cRAcK GROWTH IN cARBON AND c-0.5MO STEELS IN HIGH TEMPERATURE HYDROGEN: LABORATORY DATA AND FITNESS FOR SERVIcE MODELLING

CRACK GROWTH IN CARBON AND C-0.5MO STEELS IN HIGH TEMPERATUR...

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ASME Pressure Vessels and Piping conference (PVP)

作者： Rollins, Brandon c. Sutton, Nathaniel DNV Dublin OH 43017 USA Equ Engn Grp Shaker Hts OH USA

ISBN: (纸本)9780791886175

High temperature hydrogen attack (HTHA) is a known degradation mechanism in the refining industry for carbon and low alloy steels operating at temperatures above 400 degrees F in hydrogen service. Historically the integrity of operating equipment subject to these conditions has been ensured by using the empirically derived Nelson curves to identify safe operating regions. This approach was largely successful, but failures still occurred and, in some cases, required overly conservative operational limits. Additionally, this approach did not allow for a defect tolerance approach to fitness for service (FFS) assessments. An on-going joint-industry project (JIP) has been addressing these issues by generating laboratory crack growth data and developing models to apply the acquired knowledge in FFS assessments. A testing program was conducted on three (3) c-0.5 Mo steels to generate crack growth data in hydrogen at a range of temperatures (316 to 399 degrees c [600 to 750 degrees F]), 5.52 MPa (800 psig H-2) hydrogen pressure, and stress intensity values between (10.5 to 35.4 MPavm [9 to 32 ksi root in]). These results were used to validate and refine a crack growth model based on the creep crack growth fracture mechanics approach, c*. The results of the test program and modeling efforts are described in detail.

关键词： Fitness-for-service mechanical properties low alloy carbon steel Hydrogen high temperature hydrogen attack creep c

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An Open Source c code Generator and a Tiny Machine Learning Toolchain for the SENSIPLUS Platform 8

An Open Source C Code Generator and a Tiny Machine Learning ...

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8th IEEE International conference on Smart computing (SMARTcOMP)

作者： Bria, A. Ferrigno, L. Marrocco, c. Molinara, M. Vitelli, M. Ria, A. cicalini, M. Manfredini, G. Bruschi, P. Univ Cassino & Southern Lazio Dept Elect & Informat Engn Cassino Italy Italian Natl Council Reasearch CNR Pisa Italy Sensichips Srl Aprilia Italy Univ Pisa Pisa Italy

ISBN: (纸本)9781665481526

The use of Machine Learning in IoT devices has become the only viable path in today's landscape, where millions of connected devices surround us and increasingly affect our lives. These resource-limited devices interact with the surrounding world via actuators and sensors. Many of these devices use Machine Learning techniques to be able to interpret the world and choose the appropriate action to take. Therefore the purpose of this work is to create a system that allows the application of Machine Learning algorithms directly to the ends of the network, where sensors and actuators reside. The system is designed to rely on the SENSIPLUS smart-sensor as a data acquisition device, and consists of an automatic code generation and compilation system, which through the use of a Toolchain, allows to run artificial intelligence algorithms directly on microcontroller devices.

关键词： Machine Learning IoT Pollution Monitoring Smart city Toolchain c code Generator

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Integrated filler metal/base metal manufacturing via cold spray additive manufacturing for brazing c f /Sic and superalloy

Transactions of Materials Research

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Transactions of Materials Research 2025年第1期1卷

作者： Pengcheng Wang Weihan Liu Lei Gu Hao Ran Xiaoguo Song Zhaoyi Pan Haiyan chen Wenya Li State Key Laboratory of Solidification Processing Shaanxi Key Laboratory of Friction Welding Technologies Northwestern Polytechnical University Xi'an 710072 China State Key Laboratory of Advanced Welding and Joining Harbin Institute of Technology Harbin 150001 China Xi'an Space Engine Company Limited Xi'an 710072 China

A new integrated filler metal/base metal manufacturing method by cold spray additive manufacturing is proposed. The integrated cuTi filler metal/GH3536 and cuTi + W composite filler metal/GH3536 are prepared by cold spray additive manufacturing techniques. The large plastic deformation of cu and Ti particles and the tamping effect of W particles promote the interfacial bonding of particles, which improves the weldability of cold sprayed cuTi + W composite filler metals. Based on the cold sprayed cuTi + W composite filler metal, the c f /Sic composites and GH3536 are successfully brazed, and the typical microstructure and brazing mechanism are investigated. As a result, the shear strength of c f /Sic-GH3536 joint brazed by cold sprayed cuTi + W composite filler metal reaches 77 MPa. This study highlightes the great potential of cold spray additive manufacturing for integrated filler metal/base metal manufacturing in brazing.

关键词： Brazing cold spray additive manufacturing composite filler Interface reaction c f /Sic composite

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基于Simulink与c混合编程的插补算法的可视化仿真技术

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机械设计与研究 2021年第2期37卷 16-19,23页

作者：严相王堂辉伍相宇王晨光刘秀峰华中科技大学机械科学与工程学院武汉430074

插补算法在整个数控系统中起着至关重要的作用,在使用面向过程的c语言编写插补算法的过程中缺乏直观性,不能很好观察算法的效果。针对该问题,设计开发了一套基于Simulink与c很合编程的插补算法仿真平台,对插补算法的S型加减速进行了实... 详细信息

插补算法在整个数控系统中起着至关重要的作用,在使用面向过程的c语言编写插补算法的过程中缺乏直观性,不能很好观察算法的效果。针对该问题,设计开发了一套基于Simulink与c很合编程的插补算法仿真平台,对插补算法的S型加减速进行了实验仿真,实验结果表明插补算法速度规划和单周期位置插补均符合S型加减速规律,该平台利用Simulink适应面广、结构和流程清晰、贴近实际、灵活等优点,既能使用户减少进行算法仿真的代码书写量,又能在Simulink当中很直观地观察算法的效果。

关键词：插补算法 Simulink c 混合编程可视化

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