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Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1-306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated.

Gastric cancer (GC) is a malignant tumor originated from gastric mucosa epithelium. It is the third leading cause of cancer mortality in China. The early symptoms are not obvious. When it is discovered, it has developed to the advanced stage, and the prognosis is poor. In order to screen for potential genes for GC development, this study obtained GSE118916 and GSE109476 from the gene expression omnibus (GEO) database for bioinformatics analysis.First, GEO2R was used to identify differentially expressed genes (DEG) and the functional annotation of DEGs was performed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The Search Tool for the Retrieval of Interacting Genes (STRING) tool was used to construct protein-protein interaction (PPI) network and the most important modules and hub genes were mined. Real time quantitative polymerase chain reaction assay was performed to verify the expression level of hub genes.A total of 139 DEGs were identified. The functional changes of DEGs are mainly concentrated in the cytoskeleton, extracellular matrix and collagen synthesis. Eleven genes were identified as core genes. Bioinformatics analysis shows that the core genes are mainly enriched in many processes related to cell adhesion and collagen.In summary, the DEGs and hub genes found in this study may be potential diagnostic and therapeutic targets.

The objective of this review is to systematically summarize the consensus on best practices for different NP conditions of the two most commonly utilized noninvasive brain stimulation (NIBS) technologies, repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). PubMed was searched according to the predetermined keywords and criteria. Only English language studies and studies published up to January 31, 2020 were taken into consideration. Meta-analyses, reviews, and systematic reviews were excluded first, and those related to animal studies or involving healthy volunteers were also excluded. Finally, 29 studies covering 826 NP patients were reviewed. The results from the 24 enrolled studies and 736 NP patients indicate that rTMS successfully relieved the pain symptoms of 715 (97.1%) NP patients. Also, five studies involving 95 NP patients (81.4%) also showed that tDCS successfully relieved NP. In the included studied, the M1 region plays a key role in the analgesic treatment of NIBS. The motor evoked potentials (MEPs), the 10–20 electroencephalography system (EEG 10/20 system), and neuro-navigation methods are used in clinical practice to locate therapeutic targets. Based on the results of the review, the stimulation parameters of rTMS that best induce an analgesic effect are a stimulation frequency of 10–20 Hz, a stimulation intensity of 80–120% of RMT, 1000–2000 pulses, and 5–10 sessions, and the most effective parameters of tDCS are a current intensity of 2 mA, a session duration of 20–30 min, and 5–10 sessions. Our systematically reviewed the evidence for positive and negative responses to rTMS and tDCS for NP patient care and underscores the analgesic efficacy of NIBS in patients with NP. The treatment of NP should allow the design of optimal treatments for individual patients.

Fraction of exhaled nitric oxide (FeNO) is a noninvasive indicator of eosinophilic airway inflammation and has been used for the diagnosis and treatment of asthma. The levels of FeNO are controversial in patients with stable chronic obstructive pulmonary disease (COPD). Accordingly, this study aimed to assess FeNO levels in patients with stable COPD.A search of the Medline, Embase, Web of Science, ClinicalTrials.gov and The Cochrane Library databases was performed in August 2019. The literature search was restricted to articles published in English. Studies were included if they reported data addressing FeNO levels in patients with stable COPD and healthy controls. Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for meta-analysis.A total of 19 studies were included. Analysis revealed that FeNO levels in patients with stable COPD were higher than those in the healthy control group (mean difference [MD] 2.49 [95% confidence interval {CI} 0.99-4.00]; P0.05), those in nonsmoking patients with stable COPD were higher than those in the healthy control group (MD 5.04 [95% CI 2.19-7.89]; P0.05) and those in smoking patients with stable COPD were not higher than those in the healthy control group (MD 0.30 [95% CI -2.81 to 3.41]; P = 0.85). FeNO measured using a chemiluminescence analyzer in nonsmoking patients with stable COPD was higher than those in the healthy control group (MD 4.84 [95% CI 1.83-7.86]; P0.05).Findings suggested that FeNO levels in patients with stable COPD were elevated, and that smokers exhibited decreased levels.

Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.

BackgroundThe clinical spectrum of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is expanding over time. However, the long-term management and prognosis of this disorder are still controversial. Therefore, this study aimed to report the clinical profiles and treatment outcomes of MOGAD in our center.MethodsThis was a single-center case-series study. Clinical and para-clinical data, along with treatment outcomes of patients with MOGAD were analyzed.ResultsA total of 27 patients were identified, of which 19 (70%) patients were women, and the median age at disease onset was 40 years (range 20–67). A total of 47 episodes were observed, with optic neuritis (53%) being the most frequent presentation and 60% of them were unilateral. Other presentations included rhombencephalitis (RE) (17%), limbic encephalitis (9%), simultaneous optic neuritis and myelitis (9%), acute disseminated encephalomyelitis (ADEM)-like presentation (6%), myelitis (4%), and ADEM (2%). One patient presenting with RE also met the diagnostic criteria of area postrema syndrome (APS). Another patient with RE presented with imaging characteristics of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). A total of 29 lumbar punctures were recorded, among which an elevated protein level was found in 34% of the samples, pleocytosis was found in 14% of the samples, and positive intrathecal oligoclonal bands were found in 19% of the patients. One patient was found to have anti-N-methyl-D-aspartate receptor antibodies both in his serum and cerebrospinal fluid. Intravenous methylprednisolone (IVMP) was administrated for 85% of the attacks while both IVMP and intravenous immunoglobulin were for 6% of the attacks. Moreover, nine patients received maintenance therapy. Among them, six patients were treated with mycophenolate mofetil, three patients were treated with prednisone, rituximab, and teriflunomide, respectively. The median follow-up period was 20 months (range 6–127). At follow-up, twelve (44%) patients experienced a relapsing course, and the median time to the first relapse was 9.5 months (range 2–120). The median Expanded Disability Status Scale score at nadir was 3.5 (range 2–8) and was 0 (range 0–3) at the last follow-up.ConclusionThe clinical spectrum of MOGAD is heterogenous, wherein APS and CLIPPERS-form can occur. The long-term outcome of MOGAD seems benign. Further studies are warranted to determine the risk factors of relapse and identify the optimal steroid-sparing agents.

Mitochondria play an essential role in pathophysiology of both inflammatory and neuropathic pain (NP), but the mechanisms are not yet clear. Dynamin-related protein 1 (Drp1) is broadly expressed in the central nervous system and plays a role in the induction of mitochondrial fission process. Spared nerve injury (SNI), due to the dysfunction of the neurons within the spinal dorsal horn (SDH), is the most common NP model. We explored the neuroprotective role of Drp1 within SDH in SNI. SNI mice showed pain behavior and anxiety-like behavior, which was associated with elevation of Drp1, as well as increased density of mitochondria in SDH. Ultrastructural analysis showed SNI induced damaged mitochondria into smaller perimeter and area, tending to be circular. Characteristics of vacuole in the mitochondria further showed SNI induced the increased number of vacuole, widened vac-perimeter and vac-area. Stable overexpression of Drp1 via AAV under the control of the Drp1 promoter by intraspinal injection (Drp1 OE) attenuated abnormal gait and alleviated pain hypersensitivity of SNI mice. Mitochondrial ultrastructure analysis showed that the increased density of mitochondria induced by SNI was recovered by Drp1 OE which, however, did not change mitochondrial morphology and vacuole parameters within SDH. Contrary to Drp1 OE, down-regulation of Drp1 in the SDH by AAV-Drp1 shRNA (Drp1 RNAi) did not alter painful behavior induced by SNI. Ultrastructural analysis showed the treatment by combination of SNI and Drp1 RNAi (SNI + Drp1 RNAi) amplified the damages of mitochondria with the decreased distribution density, increased perimeter and area, as well as larger circularity tending to be more circular. Vacuole data showed SNI + Drp1 RNAi increased vacuole density, perimeter and area within the SDH mitochondria. Our results illustrate that mitochondria within the SDH are sensitive to NP, and targeted mitochondrial Drp1 overexpression attenuates pain hypersensitivity. Drp1 offers a novel therapeutic target for pain treatment., Graphical abstract Image 1, Highlights • SNI induces pain hypersensitivity and increases Drp1 within SDH in mice. • Targeted up-regulation of Drp1 in SDH attenuates SNI-pain hypersensitivity. • Targeted up-regulation of Drp1 restores mitochondrial fragmentation and swelling. • Targeted down-regulation of Drp1 does not alleviate pain with the deteriorated mitochondrial damages. • Drp1 offers a novel therapeutic target for pain treatment.

The objective of this research was to evaluate the effect of wheat gluten on gut microbiota from hamsters and also analyse whether alterations in microbiota could result in wheat gluten's lipid-lowering properties. Four weeks male hamsters were divided into 3 groups (n=10). Two hypercholesterolemic groups were fed for 35 days with hypercholesterolemic diet, containing 20% (w/w) wheat gluten or casein. Wheat gluten significantly reduced serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) concentrations, and also decreased the liver total cholesterol (TC), free cholesterol (FC), cholesterol ester (CE), triglycerides (TG) concentrations. Wheat gluten group had a higher fecal lipids, total cholesterol (TC) and bile acids (BA) than that of casein group (p < 0.05). Moreover, wheat gluten significantly increased total short-chain fatty acids (SCFA) concentrations in feces. Sequencing of 16S rRNA gene revealed that intake of wheat gluten decreased the relative abundances of Firmicutes and Erysipelotrichaceae, but to increased the relative abundances of Bateroidetes, Bacteroidales_S24-7_group and Ruminococcaceae. The lipid lowering properties of wheat gluten was associated with the lower ratio of Firmicutes/Bateroidetes, the lower of the bacterial taxa Erysipelotrichaceae and the higher of the bacterial taxa Bacteroidales_S24-7_group and Ruminococcaceae. These results suggest that wheat gluten modulate cholesterol metabolism by altering intestinal microflora.

OBJECTIVE: To investigate the clinical and immunological characteristics, treatment and prognosis of common variable immune deficiency (CVID) in adult patients. METHODS: We retrospectively analyzed the clinical data of 13 adult patients hospitalized in our hospital for CVID diagnosed according to the criteria in International Consensus Document (2016), and analyzed their clinical manifestations, laboratory test results, imaging findings, pathological examinations and treatments. RESULTS: The mean age of onset was 24.46±16.82 years in these patients, who had a mean age of 32.54±14.86 years at diagnosis with a median diagnostic delay of 5 years (IQR: 2-15 years). The main manifestation of the patients was repeated infections, including repeated respiratory tract infection (10 cases; 76.9%) and repeated diarrhea (3 cases; 23.1%). Three (23.1%) of the patients had autoimmune disease and 10 (76.9%) had chronic pulmonary disease. IgG, IgA and IgM were decreased in all the patients. The proportion of CD4+T cells decreased in 10 patients (76.9%), CD8+T cells increased in 11 patients (84.6%), and CD4/ CD8 decreased in 10 patients (76.9%). Complement C3 decreased in 58.3% (7/12) and C4 decreased in 33.3% (4/12) of the patients. Twelve patients (92.3%) were treated with intravenous infusion of gamma globulin with symptomatic treatments. One patient died due to massive gastrointestinal hemorrhage, and the other patients showed improve ments after the treatments and were discharged. CONCLUSION: The clinical manifestations of CVID are diverse, and recurrent respiratory tract infection is the most common manifestation. Decreased IgG often accompanied by lowered IgA and IgM levels is a common finding in laboratory tests. The treatment of CVID currently relies on gamma globulin with symptomatic treatments for the complications.

Protrusions on the satellite surface, especially the antennas might occlude the solar array when the satellite deploying in-orbit. This paper presents a line segment intersection method based on collision detection to simulate and calculate the solar array occlusion. First, the rectangular battery cells of solar array are divided to triangle meshes, and the subdivision degree of the meshes can be improved by linear interpolation. Then, a 3D graph scene is built to simulate the satellite deploying in-orbit. The line segments from the sun point to the entire triangle meshes’ center are created, and the intersection between the line segment and satellites’ other parts are tested during the real-time rendering process of the scene by the line segment intersection method. Then the occlusion rate can be calculated by the quantity of intersections, and the calculation precision can be improved by increasing the interpolations times. Meanwhile, the occluded triangles of the solar array are rendered to generate the shadow effect to improve the sense of reality. Finally, the method is verified by an example, and the result shows that it has a good precision and a good sense of reality.

An intresting signature observed shortly after the onset of magnetotail reconnection is the gradual appearance of a local peak of ion phase space density (PSD) in the duskward and downstream direction separated from the colder, nearly-isotropic ion population. Such a characteristic ion distribution, served as a diagnostic signature of magnetotail reconnection and well reproduced by a particle-tracing Liouville simulation, are found to appear only near the off-equatorial boundaries of the reconnection outflow region. Further analysis on ion trajectories suggests that the ions within the local peak and within the neighboring PSD cleft both belong to the outflowing population; on top of their outflowing motion, they both meander across the neutral sheet to exhibit duskward velocities near the off-equatorial edges of their trajectories. The difference between them is that the local peak originates from ions previously constituting the pre-onset plasma sheet, whereas the cleft corresponds to the inflowing lobe ions before they are repelled in the downstream direction. As reconnection proceeds, the local PSD peak gradually attenuates and then disappears, which is a signature of reconnection flushing effect that depletes the ions in the pre-onset plasma sheet and eventually replaces them by lobe ions.

The new generation apogee engine is the key equipment in the satellite propulsion system, and accompanied by the whole life cycle of AIT development and production. Therefore, there are many assembly processes around the new generation apogee engine itself and its surroundings, and the engine belongs to the star catalogue prominent product, which has the risk of bumping and scratching. In this paper, a new generation of apogee engine protection tooling is designed, and the general design and detailed design are carried out. The implementation effect is good. It can be extended to all models equipped with a new generation of apogee engine to meet the needs of scientific research and production.

The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.

The computer network attack graph generation method obtained mostly through network scanning, this network reachability information, this approach takes a long presence information and incomplete defects by analyzing network reachability main task of research and developing trends is proposed based on binary decision diagrams algorithm approach to achieve network reachability studies. The algorithm uses the decision diagram modeling firewall rules, through the collection operations to achieve network reachability studies.

PAK1 is an important oncogene involved in the progression of a variety of cancer types including lung cancer. Although PAK1 inhibition is shown to suppress tumor progression, specific PAK1 inhibitors are not available due to the complex structure and insufficient understanding of this protein. In an attempt to find TAZ (WW domain-containing transcription regulator 1) regulated tumor suppressor, a member of ankyrin repeat proteins, ankyrin repeat domain 52 (ANKRD52), is observed to suppress PAK1 phosphorylation. Ankyrin repeat proteins are known to function as a platform for protein-protein interactions, and ANKRD52 was shown to interact with protein phosphatase 6 (PP6). Immunohistochemistry staining in lung cancer tissue revealed prolonged disease-free survival in high ANKRD52 expressing cases. Using lung cancer cell lines, ANKRD52 knockdowns showed significantly increased cell mobility while forced expressed ANKRD52 decreased cell mobility. Using mass spectrometry analysis, p21-activated kinases (PAK1) was identified to interact with ANKRD52. Upregulated PAK1 phosphorylation was detected in the knockdowns of ANKRD52 or PP6. Our model demonstrated a novel anti-metastatic protein, ANKRD52, that regulates cell mobility through interactions with PP6 and dephosphorylation of PAK1. Citation Format: Ting-Fang Lee, Yin-Pu Liu, Yen-Fan Lin, Chong-Fang Hsu, Cheng-Wen Wu. ANKRD52 inhibited tumor metastasis through dephosphorylation of PAK1 in lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1782.

By analyzing the principles of blue tooth transmission, it turns out that the Four-Hierarchy Bluetooth Transmission System can be made by applying the embedded Linux technology. Comparison analysis showed that the data transmission between multiple Bluetooth devices is available through a system created upon the Bluez protocol and openobex protocol. Besides, this also proofed that a combination of Linux and Bluetooth can make it possible to create a fair stable data transmission system, which could be used as a reference for the application in other areas.

For the problem of spectrum correction in phase difference method, a weighed correction method starting from phase difference of secondary largest value is presented in this paper. By the analysis on correction error of maximum and the second largest value in phase difference method, It determines the maximum correction error and the second largest value and conducts error correction method of weighted joint calibration. In addition, it makes analysis on variance for correction result. Finally, the experimental result shows that the method can greatly improve spectral resolution than conventional phase difference method.