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

Tapasin assembly surveillance by the RNF185/Membralin ubiquitin ligase complex regulates MHC-I surface expression

Immune surveillance by cytotoxic T cells eliminates tumor cells and cells infected by intracellular pathogens. This process relies on the presentation of antigenic peptides by Major Histocompatibility Complex class I (MHC-I) at the cell surface. The loading of these peptides onto MHC-I depends on the peptide loading complex (PLC) at the endoplasmic reticulum (ER). Here, we uncovered that MHC-I antigen presentation is regulated by ER-associated degradation (ERAD), a protein quality control process essential to clear misfolded and unassembled proteins. An unbiased proteomics screen identified the PLC component Tapasin, essential for peptide loading onto MHC-I, as a substrate of the RNF185/Membralin ERAD complex. Loss of RNF185/Membralin resulted in elevated Tapasin steady state levels and increased MHC-I at the surface of professional antigen presenting cells. We further show that RNF185/Membralin ERAD complex recognizes unassembled Tapasin and limits its incorporation into PLC. These findings establish a novel mechanism controlling antigen presentation and suggest RNF185/Membralin as a potential therapeutic target to modulate immune surveillance

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)

FAST INTEGER AMBIGUITY RESOLUTION IN GPS KINEMATIC POSITIONING USING LEFT NULL SPACE AND MULTI-TIME (INVERSE) PAIRED CHOLESKY DECORRELATION

Aiming at the problems that huge amount of computation in ambiguity resolution with multiple epochs and high-order matrix inversion occurred in the GPS kinematic relative positioning, a modified algorithm for fast integer ambiguity resolution is proposed. Firstly, Singular Value Decomposition (SVD) is applied to construct the left null space matrix in order to eliminate the baselines components, which is able to separate ambiguity parameters from the position parameters efficiently. Kalman filter is applied only to estimate the ambiguity parameters so that the real-time ambiguity float solution is obtained. Then, sorting and multi-time (inverse) paired Cholesky decomposition are adopted for decorrelation of ambiguity. After diagonal elements preprocessing and diagonal elements sorting according to the results of Cholesky decomposition, the efficiency of decomposition and decorrelation is improved. Lastly, the integer search algorithm implemented in LAMBDA method is used for searching the integer ambiguity. To verify the validity and efficacy of the proposed algorithm, static and kinematic tests are carried out. Experimental results show that this algorithm has good performance of decorrelation and precision of float solution, with computation speed also increased effectively. The final positioning accuracy result with static baseline error less than 1 cm and kinematic error less than 2 cm, which indicates that it can be used for fast kinematic positioning of high precision carrier