Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain

In mammals, specific lipids and amino acids serve as crucial signaling molecules. In bacteria, conjugates of lipids and amino acids (referred to as lipoamino acids) have been identified and found to possess biological activity. Here, we report that mammals also produce lipoamino acids, specifically the arachidonyl amino acids. We show that the conjugate of arachidonic acid and glycine (N-arachidonylglycine (NAGly)) is present in bovine and rat brain as well as other tissues and that it suppresses tonic inflammatory pain. The biosynthesis of NAGly and its degradation by the enzyme fatty acid amide hydrolase can be observed in rat brain tissue. In addition to NAGly, bovine brain produces at least two other arachidonyl amino acids: N-arachidonyl gamma-aminobutyric acid (NAGABA) and N-arachidonylalanine. Like NAGly, NAGABA inhibits pain. These findings open the door to the identification of other members of this new class of biomolecules, which may be integral to pain regulation and a variety of functions in mammals

Acute Homeostatic Responses to Increased Fat Consumption in MCH1R Knockout Mice

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide which has been shown to regulate energy homeostasis. Using genetic knockout mice lacking the MCH1 receptor (MCH1R), we investigated how these mice adapt to metabolic changes caused by excessive caloric consumption. We show that the MCH system is one of the players mediating behavioral and metabolic responses upon increased caloric consumption. MCH1R knockout mice showed decreased tendency of food intake upon exposure to a high-fat diet. They also are resistant to gain weight upon high-fat diet by increasing fat metabolism. Therefore, the MCH system is important in regulating metabolic responses upon various environmental stimuli such as high-fat diet

Natural and Induced Environment around the International Space Station (ISS) as Observed during On-Orbit Operations of the Robotic External Leak Locator (RELL)

Final Document is attached. The Robotic External Leak Locator (RELL) was deployed to the International Space Station (ISS) with the goal of detecting and locating on-orbit leaks around the ISS. Three activities to investigate and corroborate the background natural and induced environment of ISS were performed with RELL as part of the on-orbit validation and demonstration conducted in November December 2016. The first demonstration activity pointed RELL directly in the ram and wake directions for one orbit each. The ram facing measurements showed high partial pressure for mass-to-charge ratio 16, corresponding to atomic oxygen (AO), as well as the presence of mass-to-charge ratio 17. RELLs view in the wake-facing direction included more ISS structure and several Environmental Control and Life Support System (ECLSS) on-orbit vents were detected, including the Carbon Dioxide Removal Assembly (CDRA), Russian segment ECLSS, and Sabatier vents. The second demonstration activity pointed RELL at three faces of the P1 Truss segment. Effluents from ECLSS and European Space Agency (ESA) Columbus module on-orbit vents were detected by RELL. The partial pressures of mass-to-charge ratios 17 and 18 remained consistent with the first on-orbit activity of characterizing the natural environment. The third demonstration activity involved RELL scanning an Active Thermal Control System (ATCS) radiator. Three locations along the radiator were scanned and the angular position of RELL with respect to the radiator was varied. Mass-to-charge ratios 16 and 17 both had upward shifts in partial pressure when pointing toward the Radiator Beam Valve Modules (RBVMs), likely corresponding to a known, small ammonia leak

International Space Station (ISS) Environmental Control and Life Support System (ECLSS) Vent Flow Reflection and Detection by Robotic External Leak Locator (RELL)

On-orbit Robotic External Leak Locator (RELL) (i.e., mass spectrometer and ion gauge) measurements on the International Space Station (ISS) are presented to show the detection of recurring Environmental Control and Life Support System (ECLSS) vents at multiple ISS locations and RELL pointing directions. The path of ECLSS effluents to the RELL detectors is not entirely obvious at some locations, but the data indicates that diffuse gas-surface reflection or scattering resulting from plume interaction with vehicle surfaces is responsible. RELL was also able to confirm the ISS ECLSS constituents and distinguish them from the ammonia leak based on the ion mass spectra and known venting times during its operation to locate a leak in the ISS port-side External Active Thermal Control System (EATCS) coolant loop

RPS23RG1 modulates tau phosphorylation and axon outgrowth through regulating p35 proteasomal degradation

Tau蛋白病（Tauopathies）是由过度磷酸化的tau蛋白聚集形成神经纤维缠结为特征的一类神经退行性疾病，包括阿尔茨海默病（Alzheimer’s disease, AD）、进行性核上性麻痹（Progressive superanuclear palsy, PSP）、额颞叶痴呆（Frontotemporal dementia, FTD）等。随着全球社会结构的老龄化，tau蛋白病患者比率迅速增加，给个人和社会带来巨大的经济及精神负担。厦门大学神经科学研究所张云武教授团队最新发现RPS23RG1（RR1）的胞内羧基端区域能够与Cdk5激酶的激活蛋白p35的氨基端相互作用，介导p35的膜定位并影响其泛素化降解，从而调控在tau蛋白异常磷酸化过程中发挥重要作用的Cdk5激酶的活性。团队研究表明RPS23RG1通过其胞内羧基端与p35相互作用，介导p35膜结合和降解，从而抑制Cdk5活性，平衡tau磷酸化水平，促进轴突生长。此外，RPS23RG1的跨膜区与腺苷酸环化酶AC相互作用，抑制GSK3-β活性，同样控制tau过度磷酸化。提示RPS23RG1是改善tau过度磷酸化水平及治疗tau蛋白病的潜在靶点。 厦门大学医学院神经科学研究所博士后赵东栋为该研究第一作者，张云武教授为通讯作者。【Abstract】Tauopathies are a group of neurodegenerative diseases characterized by hyperphosphorylation of the microtubule-binding protein, tau, and typically feature axon impairment and synaptic dysfunction. Cyclin-dependent kinase5 (Cdk5) is a major tau kinase and its activity requires p35 or p25 regulatory subunits. P35 is subjected to rapid proteasomal degradation in its membrane-bound form and is cleaved by calpain under stress to a stable p25 form, leading to aberrant Cdk5 activation and tau hyperphosphorylation. The type Ib transmembrane protein RPS23RG1 has been implicated in Alzheimer’s disease (AD). However, physiological and pathological roles for RPS23RG1 in AD and other tauopathies are largely unclear. Herein, we observed retarded axon outgrowth, elevated p35 and p25 protein levels, and increased tau phosphorylation at major Cdk5 phosphorylation sites in Rps23rg1 knockout (KO) mice. Both downregulation of p35 and the Cdk5 inhibitor roscovitine attenuated tau hyperphosphorylation and axon outgrowth impairment in Rps23rg1 KO neurons. Interestingly, interactions between the RPS23RG1 carboxyl-terminus and p35 amino-terminus promoted p35 membrane distribution and proteasomal degradation. Moreover, P301L tau transgenic (Tg) mice showed increased tau hyperphosphorylation with reduced RPS23RG1 levels and impaired axon outgrowth. Overexpression of RPS23RG1 markedly attenuated tau hyperphosphorylation and axon outgrowth defects in P301L tau Tg neurons. Our results demonstrate the involvement of RPS23RG1 in tauopathy disorders, and implicate a role for RPS23RG1 in inhibiting tau hyperphosphorylation through homeostatic p35 degradation and suppression of Cdk5 activation. Reduced RPS23RG1 levels in tauopathy trigger aberrant Cdk5-p35 activation, consequent tau hyperphosphorylation, and axon outgrowth impairment, suggesting that RPS23RG1 may be a potential therapeutic target in tauopathy disorders.This work was supported by grants from National Key Research and Development Program of China (2016YFC1305903 and 2018YFC2000400 to Y-wZ), National Natural Science Foundation of China (81771377, U1705285, 91332112, and 81225008 to Y-wZ), Fundamental Research Funds for the Central Universities (20720180049 to Y-wZ), the Fujian Provincial Health Commission-Education Department Joint Tackling Plan (WKJ2016-2-18 to F-rL), and Postdoctoral Science Foundation of China (2020M671948 to DZ)

Consensus recommendations for a standardized brain tumor imaging protocol for clinical trials in brain metastases.

A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The "minimum standard" recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)-prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An "ideal" protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given

Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation

厦门大学医学院、神经科学研究所张杰教授团队发现了抑郁症新的致病基因MEN1，并阐明了MEN1调控星形胶质细胞炎症导致抑郁发生发展的新机制，为抑郁症的诊治提供了新靶点和方向。抑郁症是严重威胁人类健康的重大神经系统疾病，危及全球30%的人口。但对其发病机制并不清楚。张杰教授团队发现，在慢性不可预测以及LPS处理的模拟抑郁小鼠模型中，多发性内分泌肿瘤蛋白(menin)在大脑中的表达显著降低，并且在星形胶质细胞中降低最明显。为了研究menin是否参与了小鼠抑郁表型的产生，研究团队制作了多种神经系统menin条件性敲除小鼠。通过对这些小鼠行为学的检测，锁定了只有在星形胶质细胞中敲除menin后，小鼠才会表现出抑郁样表型。证实了menin可能是通过调控星形胶质细胞的功能促进了抑郁的发生。 MEN1基因的突变会导致多发性内分泌肿瘤，而内分泌的紊乱和抑郁等精神疾病有着密切的联系。下丘脑-垂体-肾上腺轴（HPA轴）的功能紊乱直接参与了抑郁的产生。基于此研究团队推测MEN1的基因突变是否也会导致抑郁的发生。通过和中国医学科学院基础所的许琪教授合作，研究团队对1000多例重度抑郁患者和800多例对照人群进行了MEN1基因的外显子测序。通过测序发现MEN1的一个SNP s375804228和抑郁的发生有着显著关联。该SNP导致menin第503位的氨基酸由G突变成D。通过功能研究进一步证实该突变可以阻断menin和p65的结合，从而过度激活NF-κB-IL-1β通路，导致神经炎症的发生。 张杰，厦门大学特聘教授、博士生导师。国家优秀青年科学基金；教育部新世纪优秀人才；福建省杰出青年科学基金；厦门市五四青年奖章等获得者。2011年8月加入厦门大学医学院神经科学研究所担任教授至今。张杰博士主要从事重大神经系统疾病（老年痴呆、帕金森、抑郁症、自闭症、术后认知障碍、胶质瘤）等的发病机制和药物开发研究。至今以第一作者或者通讯作者在国际知名期刊发表研究论文21篇。其中回国独立开展研究工作以后，作为通讯作者在 Neuron，Cell Reports, PNAS, The Journal of Neuroscience, Clinical Cancer Research，Cell Death and Disease, JBC, Chemistry，Chem. Biol. Drug Des.等杂志上发表多篇研究论文。【Abstract】Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.We thank Prof. Guanghui Jin (Xiamen University) and Prof. Xianxin Hua (University of Pennsylvania) for providing the Men1-floxp mice. This work was supported by the National Natural Science Foundation of China (grants 81522016, 81271421, and 31571055 to J.Z.; 81625008 and 31430048 to Q.X.; 81630026 to Z.Y.; 81771163 and U1405222 to H.X.; U1505227 to G.B.; 81472725 to W.M.), the Natural Science Foundation of Fujian Province of China (grant 2013J01147 and 2014J06019 to J.Z.), the Fundamental Research Funds for the Central Universities (grants 20720150062 and 20720180049 to J.Z.), the National Key Research and Development Program of China (2016YFC1305903), and CAMS Innovation Fund for Medical Sciences (grant 2016I2M1004 to Q.X.).研究工作得到国家自然科学基金项目（81522016、81271421、31571055）以及厦门大学校长基金等资助