Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure, it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease (CVD). Here, our findings revealed that sleep fragmentation (SF) displayed notable hepatic detrimental phenotypes, including steatosis and oxidative damage, along with significant abnormalities in cardiac structure and function. All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more, displaying memory properties. Mechanistically, persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in the liver was the key initiator of SF-accelerated damage phenotypes. SF epigenetically controlled the acetylation of histone H3 lysine 27 (H3K27ac) enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery. Moreover, fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1 (Sirt1) transcription after circadian misalignment. Accordingly, genetic manipulation of liver-specific Nox4 or Sirt1, along with pharmacological intervention targeting NOX4 (GLX351322) or SIRT1 (Resveratrol), could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology, thereby counteracting SF-evoked sustained CVD. Collectively, our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.

A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF's detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Fgfr1 knockout (Fgfr1-KO ^+/- ) diabetic mice. Meanwhile, testicular-specific overexpression of Tak1 abolished the protective effect of FGF1^mut on diabetic mouse testis. Our findings offer valuable insights into the molecular mechanisms underlying the testicular pathogenesis associated with SF and propose a novel therapeutic approach for addressing male infertility in T2DM.

Objective To develop a Traditional Chinese Medicine(TCM)syndrome diagnosis scale suitable for evaluating the overall health status of participants in long-term simulated weightlessness experiments,and preliminarily evaluate its reliability and validity.Methods Based on the understanding of the pathogenesis of TCM in different stages of long-term manned spaceflight,a scale was developed through literature research and expert consultation.Test-retest reliability and internal consistency coefficient were used to test the reliability of the scale.Item analysis and factor principal component analysis were used to evaluate the validity of the scale,and a rotating component matrix was used to analyze the correlation between each item and dimension using 36 volunteers in a 90 days head down bed rest experiment as the research subjects.Results The scale contains eight dimensions and 57 items.The reliability analysis showed that the correlation coefficient of the total score of the scale for the first and second tests of 30 participants was 0.889,indicating high stability of the scale.The Cronbach coefficient of the scale was 0.934,indicating very good internal consistency.The split half reliability after correction was 0.858,indicating a high reliability of the scale.The validity analysis showed that the difference between the high score group and the low score one for each of the 57 items was statistically significant(P<0.01),and the Pearson correlation coefficient between each item and the total score of the scale was greater than 0.4(P<0.001).The cumulative contribution rate of 8 common factors extracted using principal component factor analysis was 55.293%,and the results of rotating component matrix analysis,after applying TCM theory and expert feedback,had a coincidence of up to 87.5%with the initial 8 dimensions,indicating good structural validity of the scale.Conclusion The scale has good reliability and validity,and can diagnose TCM syndromes.It is suitable for long-term simulated weightlessness experiment and provides an objective and quantitative new method for evaluating the subjective feelings of participants.

Objective This study investigated whether gut microbiota and its metabolites are altered in myasthenia gravis(MG)patients.Methods We collected fresh stool specimens from MG patients and healthy controls.16S rRNA gene sequencing and gas chromatography-mass spectrometry were used to measure abundance of gut microbiota and metabolite levels in two groups,respectively.Clinical data of the subjects were also collected including quantitative MG score(QMGS),MG-activities of daily living(MG-ADL),MG-specific quality-of-life 15(MG-QOL15),manual muscle testing(MMT),and the acetylcholine receptor antibody(AchR-Ab)titers.The correlation between the differential microbiota and the clinical characteristics was investigated.Results A total of 50 MG patients and 15 healthy controls were recruited.Simpson's index was significantly higher in the MG group(0.936±0.041)than in the control group(0.888±0.123).Alpha diversity was significantly decreased in the MG group(t=2.349,P=0.022).There was a significant difference in microbial phenotype between the two groups(R=0.966,P=0.001,Adonis).The results of LEfSe showed that the abundance of Esherichia-Shigella,Succinivibrio,Fusobacterium,and Ruminococcus-gnavus-group were up-regulated while the abundance of Lachnospira,Roseburia,Desulfovibrio,and Coprococcus were down-regulated.The results showed that the metabolites of the MG group were significantly different from those of the control group.There were 28 metabolites up-regulated and 71 metabolites down-regulated in the MG patient group.Kyoto Encyclopedia of Genes and Genomes analyses demonstrated that the majority of metabolic pathways in which differential metabolites were involved were related to amino acid metabolism and nucleotide metabolism.61.2% (30/49)of bacterial amplicon sequence variant(ASV)were significantly associated with multiple metabolites(P<0.001).The relative abundance of Lachnospiraceae in the group with MG was negatively correlated with the QMGS(r=-0.496,P<0.001),MG-ADL(r=-0.542,P<0.001),MG-QOL15(r=-0.464,P=0.007),and the AchR-Ab(r=-0.315,P=0.026).The relative abundance of Lachnospiraceae in the group with MG was positively correlated with the MMT(r=0.374,P=0.008).Conclusion The intestinal flora of MG patients is down-regulated in the abundance of beneficial bacteria and up-regulated in the abundances of harmful bacteria.Disturbance of metabolites are also present in MG patients.Regulating gut microbiota in MG patients may be a new target for treating the disease.

Objective:To explore the risk factors for poor prognosis in patients with tuberculous meningitis (TBM), and establish their nomogram predictive models.Methods:Three hundred and fifty-eight patients with TBM, admitted to Department of Neurology, 940 th Hospital of Chinese People's Liberation Army Joint Logistic Support Force from January 2010 to February 2022, were chosen and divided into model group ( n=287) and validation group ( n=71) according to the simple random sampling at a ratio of 8:2. Their clinical data were retrospectively analyzed. Independent risk factors for poor prognosis of TBM were analyzed by least absolute shrinkage and selection operator (LASSO) and Logistic regression, and the risk factors were visualized by nomogram. Bootstrap method was used for 1 000 repeated samples for internal verification, and data from validation group were used for external verification. The discrimination and calibration of the models were evaluated by area under receiver operating characteristic (ROC) curve, calibration curve and Hosmer-Lemeshow goodness of fit test. Results:Multivariate Logistic regression analysis showed that mental symptoms ( OR=3.593, 95% CI: 1.790-7.211, P<0.001), limb weakness ( OR=3.087, 95% CI: 1.551-6.144, P=0.001), pulmonary infection ( OR=5.162, 95% CI: 2.373-11.227, P<0.001), improved British Medical Research Council (mBMRC) staging II ( OR=4.291, 95% CI: 2.037-9.039, P<0.001), mBMRC staging III ( OR=13.073, 95% CI: 3.352-50.975, P<0.001) were independent risk factors for poor prognosis in TBM patients. Consistency indexes indicated by area under ROC curves by internal verification and external verification were 0.880 and 0.823, respectively; the calibration curve coincided with the ideal curve, enjoying good Hosmer-Lemeshow fit ( P=0.546, P=0.401). Conclusion:Based on these 4 prognostic factors (mental symptoms, limb weakness, lung infection and mBMRC stages), the nomogram is helpful in predicting the risk of poor prognosis in TBM patients.

Objective　To investigate the prognostic value of NLR,PLR,PNR and PWR in acute cerebral infarction.Methods　We enrolled 139 patients who were diagnosed with acute cerebral infarction from Chengde Central Hospital from September 2018 to September 2019.Routine blood test results were collected.Patients were divided into mild stroke and moderate-severe stroke groups according to the NIHSS at admission.After three months,subjects were divided into two groups according to the modified Rankin score (mRS),one group with good prognosis (mRS 0~2) and the other with poor prognosis (mRS 3~6).Logistic regression analysis was performed,the ROC curve was used to evaluate inflammatory markers in predicting prognosis.Results　After adjusting for confounders,PLR and NLR in the group with good prognosis were significantly lower than that of the other group (P<0.005),PWR was higher in good prognosis group (P<0.05).In addition,PLR and NLR in the mild stroke group were significantly lower than the moderate-severe stoke group (P<0.05).The ROC curve showed that the area under the curve of PLR and NLR for predicting the prognosis of acute cerebral infarction at 3 months was 0.721 (95%CI 0.630~0.813;P<0.001),0.765 (95%CI 0.678~0.851;P<0.001) and the area under the curve of the PWR is 0.642.Conclusion　NLR and PLR,as new inflammatory indicators,may be independent factors for predicting the prognosis of AIS,and can also be used to judge the severity of stroke.

Objective:To analyse and discuss the variance and mass spectrometry of proteomics of rats 'lung tissues between groups of normal and simulated cold environments.Methods:A total of 20 SD rats were randomly divided into two groups of normal and simulated cold environments with 10 rats in each group.The temperature of normal environment group was controlled in 21℃ with a fluctuation of 2℃lasting 24 h per day.In contrast, the temperature of simulated cold environment group was controlled in 6℃ with a fluctuation of 2℃lasting 4 h per day while the temperature and humidity for the rest of time were exactly the same as the situation in normal environment group.The preoperative fasting , water-deprivation and weighting were adopted 12 h before anaesthesia to both groups after the continuing 7-day experimentation.Left lung tissues of each rat in both groups were removed by the amount of 10 mg, whereas three random samples from each group were tested by experiments of protein extraction , bidirectional electrophoresis , image analysis and mass spectrometry identification.Results: Given the proteomics analysis of two differential sets , it is indicated that in simulated cold environment group , among nine sorts of protein , four sorts perform rising while five falling compared to that of normal group.Conclusion:There exists a correlation between protein and cold environment based on the results of proteomic analysis .

Objective:Normal and lung qi deficiency rats of proteomics of lung tissue of rats differentially expressed and mass spectrometry.Methods:A total of 20 SD rats were randomly divided into control group,lung qi deficiency group,with 10 rats in each roup.Lung qi deficiency group model replication using composite method by intratracheal injection of lipopolysaccaride and smoked.All rats in each group before anesthesia 12 hours of fasting,water deprivation,weight after 28 days modeling,Thoracotomy to remove left lung tissue after anesthesia was 10 mg from each rat, 3 rats from each group, using two-dimensional electrophorsis analysis, two-dimensional gel electrophoresis image, peptide mass fingerprinting and electrospray tandem by mass spectrometry to protein identification.Results:2 differntial protin profiles for proteomics analysis,identified 14 protein in rat lung tissue,protein 5 expression, regulation 9 expression.Conclusion:By proteomic analysis,identify the protein have correlation with lung deficiency syndrome.

Hot-melt extrusion technology was used to prepare solid dispersion of posaconazole for improving its dissolution. Solubility parameter, glass transition temperature and melting method were utilized to screen polymers. Using KollidonVA64, Soluplus, Eudragit L100 and combined carrier KollidonVA64-Eudragit L100 as polymer carrier, solid dispersion was prepared by hot-melt extrusion technology and characterized by drug dissolution. The formulation and process factor affecting dissolution were studied. The state of posaconazole in solid dispersion was characterized by differential scanning calorimetry and preliminary analysis of the stability was studied by influencing factors experiments. When using KollidonVA64-Eudragit L100(2 ∶8)as the carrier, 10 % triethyl citrate as the plasticizer and extrusion temperature of 150 °C, the dissolution of posaconazole was improved significantly. Drug was molecular or amorphous form in the carrier. Proportion of Eudragit L100 and KollidonVA64, temperature, drug loading and plasticizer influenced dissolution of posaconazole. Solid dispersion was stable for high temperature and strong light but sensitive to high humidity. Solid dispersion using hot-melt extrusion technology can significantly improve the dissolution of posaconazole.

AIM:To explore the therapeutic effect of a novel Rho kinase inhibitor WAR 5 on the experimental autoimmune encephalomyelitis (EAE) and its possible mechanism.METHODS: Female C57BL/6 mice were randomly divided into EAE group and WAR5 group.EAE model was induced by the application of MOG 35-55 peptide.WAR5 was in-jected intraperitoneally every other day from post-immunization (PI) day 3 to PI day 27.The clinical score and body weight were recorded every other day .On PI day 28, the animals were sacrificed and spinal cords were obtained for HE and mye-lin staining .The splenocytes were isolated and the expression of CD 16/32 and CD206 were analyzed by flow cytometry . The protein extracts from the brains and spinal cords were collected for the measurement of inducible nitric oxide synthase ( iNOS) by Western blotting .RESULTS:The administration of WAR 5 delayed the onset of EAE and attenuated the clini-cal symptoms .The results of the pathological examination revealed that WAR 5 inhibited the infiltration of inflammatory cells and improved myelination in spinal cords , accompanied with the poralization of M 1 macrophages to M2 phenotype in the spleen.WAR5 inhibited the expression of iNOS in the central nervous system , especially in the spinal cords .CON-CLUSION:The therapeutic effect of WAR5 on EAE may be related to the shift of M1 macrophages to M2 phenotype and inhibition of inflammation in the central nerve system .