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Summary: Clinical research indicates that SARS-CoV-2 infection is linked to several neurological consequences, and the virus is still spreading despite the availability of vaccinations and antiviral medications. To determine how hosts respond to SARS-CoV-2 infection, we employed LC-MS/MS to perform ubiquitinome and proteome analyses of the brain cortexes from K18-hACE2 mice in the presence and absence of SARS-CoV-2 infection. A total of 8,024 quantifiable proteins and 5,220 quantifiable lysine ubiquitination (Kub) sites in 2023 proteins were found. Glutamatergic synapse, calcium signaling pathway, and long-term potentiation may all play roles in the neurological consequences of SARS-CoV-2 infection. Then, we observed possible interactions between 26 SARS-CoV-2 proteins/E3 ubiquitin-protein ligases/deubiquitinases and several differentially expressed mouse proteins or Kub sites. We present the first description of the brain cortex ubiquitinome in K18-hACE2 mice, laying the groundwork for further investigation into the pathogenic processes and treatment options for neurological dysfunction following SARS-CoV-2 infection.

Although some cohort studies have indicated a close association between diabetes and HCC, the underlying mechanism about the contribution of diabetes to HCC progression remains largely unknown. In the study, we applied a novel HCC model in SD rat with diabetes and a series of high glucose-stimulated cell experiments to explore the effect of a high glucose environment on HCC metastasis and its relevant mechanism. Our results uncovered a novel regulatory mechanism by which nuclear translocation of metabolic enzyme PKM2 mediated high glucose-promoted HCC metastasis. Specifically, high glucose-increased PKM2 nuclear translocation downregulates chemerin expression through the redox protein TRX1, and then strengthens immunosuppressive environment to promote HCC metastasis. To the best of our knowledge, this is the first report to elucidate the great contribution of a high glucose environment to HCC metastasis from a new perspective of enhancing the immunosuppressive microenvironment. Simultaneously, this work also highlights a previously unidentified non-metabolic role of PKM2 and opens a novel avenue for cross research and intervention for individuals with HCC and comorbid diabetes.

Abstract Background Our previous work shows that increased matrix stiffness not only alters malignant characteristics of hepatocellular carcinoma (HCC) cells, but also attenuates metformin efficacy in treating HCC cells. Here, we identified differential membrane proteins related to matrix stiffness-mediated metformin resistance for better understand therapeutic resistance of metformin in HCC. Methods Differential membrane proteins in HCC cells grown on different stiffness substrates before and after metformin intervention were screened and identified using isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with the liquid chromatography-tandem mass spectrometry (LC–MS/MS), then bioinformatic analysis were applied to determine candidate membrane protein and their possible signaling pathway. Results A total of 5159 proteins were identified and 354 differential membrane proteins and membrane associated proteins, which might be associated with matrix stiffness-mediated metformin resistance were discovered. Then 94 candidate membrane proteins including 21 up-regulated protein molecules and 73 down-regulated protein molecules were further obtained. Some of them such as Annexin A2 (ANXA2), Filamin-A (FLNA), Moesin (MSN), Myosin-9 (MYH9), Elongation factor 2 (eEF2), and Tax1 binding Protein 3 (TAX1BP3) were selected for further validation. Their expressions were all downregulated in HCC cells grown on different stiffness substrates after metformin intervention. More importantly, the degree of decrease was obviously weakened on the higher stiffness substrate compared with that on the lower stiffness substrate, indicating that these candidate membrane proteins might contribute to matrix stiffness-mediated metformin resistance in HCC. Conclusions There was an obvious change in membrane proteins in matrix stiffness-mediated metformin resistance in HCC cells. Six candidate membrane proteins may reflect the response of HCC cells under high stiffness stimulation to metformin intervention, which deserve to be investigated in the future.

Conclusions: These results suggested that spexin might serve as a protective factor for diabetes against neuropathology and pain-related pathogenesis.

Abstract The profile of antibodies against antigenic epitopes of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during neutralizing antibody (NAb) decay has not been clarified. Using a SARS‐CoV‐2 proteome microarray that contained viral antigenic peptides, we analyzed the characteristics of the humoral response in patients with coronavirus disease 19 (COVID‐19) in a longitudinal study. A total of 89 patients were recruited, and 226 plasma samples were serially collected in 2020. In the antigenic peptide microarray, the level of immunoglobulin G (IgG) antibodies against peptides within the S2 subunit (S‐82) and a conserved gene region in variants of interest, open reading frame protein 10 (ORF10‐3), were closely associated with the presence of SARS‐CoV‐2 NAbs. In an independent evaluation cohort of 232 plasma samples collected from 116 COVID‐19 cases in 2020, S82‐IgG titers were higher in NAbs‐positive samples (p = 0.002) than in NAbs‐negative samples using enzyme‐linked immunosorbent assay. We further collected 66 plasma samples from another cohort infected by Omicron BA.1 virus in 2022. Compared with the samples with lower S82‐IgG titers, NAb titers were significantly higher in the samples with higher S82‐IgG titers (p = 0.04). Our findings provide insights into the understanding of the decay‐associated signatures of SARS‐CoV‐2 NAbs.

Abstract Background The TM4 (UBAC2) protein, which contains 4 transmembrane domains and one ubiquitin binding domain, is mainly expressed in cell and nuclear membranes. The current research aimed to explore the role of TM4 in metabolic inflammation and to examine whether the ubiquitin–proteasome inhibitor PS-341 could regulate the function of TM4. Methods The metabolic phenotypes of TM4 knockout (KO) mice were studied. We next explored the association between the polymorphisms of TM4 and obesity in a Chinese Han population. TM4 expression in the visceral fat of obese patients who underwent laparoscopic cholecystectomy was also analysed. Finally, the effect of PS-341 on the degradation and function of the TM4 protein was investigated in vivo and in vitro. Results TM4 KO mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under a high-fat diet. TM4 counterregulated Nur77, IKKβ, and NF-kB both in vivo and in vitro. The TM4 SNP rs147851454 is significantly associated with obesity after adjusting for age and sex (OR 1.606, 95% CI 1.065–2.422 P = 0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults of Han Chinese. TM4 was significantly downregulated in the visceral fat of obese patients. PS-341 induced TM4 expression through inhibition of TM4 degradation in vitro. In db/db mice, PS-341 administration led to downregulation of Nur77/IKKβ/NF-κB expression in visceral fat and liver, and alleviation of hyperglycaemia, hypertension, and glucose intolerance. The hyperinsulinaemic-euglycaemic clamp demonstrated that PS-341 improved the glucose infusion rate and alleviated insulin resistance in db/db mice. Conclusions PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 degradation.

In massive open online courses (MOOCs), recommendation relationships present a collection of associations that imply a new form of integration, such as an interdisciplinary synergy among diverse disciplines. This study took a computer science approach, using the susceptible-infected (SI) model to simulate the process of learners accessing courses within networks of MOOC offerings, and emphasized the potential effects of a network structure. The current low rate of access suggests that a ceiling effect influences learners’ access to learning online, given that there are thousands of courses freely available. Interdisciplinary networks were created by adding recommended courses into four disciplinary networks. The diversity of interdisciplinarity was measured by three attributes, namely variety, balance, and disparity. The results attest to interesting changes in how the diversity of interdisciplinary knowledge grows. Particularly remarkable is the degree to which the diversity of interdisciplinarity increased when new recommended courses were first added. However, changing diversity implied that neighbouring disciplines were more likely to come to the forefront to attach to the interdisciplinarity of MOOC offerings, and that the pace of synergy among disparate disciplines slowed as time passed. In the absence of domain experts, expert knowledge is not sufficient to support interdisciplinary curriculum design. More evidence-based analytics studies showing how interdisciplinarity evolves in course offerings could help us to better design online courses that prepare learners with 21st-century skills.

Abstract Background Early alarm of hypoglycemia, detection of asymptomatic hypoglycemia, and effective control of blood glucose fluctuation make a great contribution to diabetic treatment. In this study, we designed a multi-level hypoglycemia early alarm system to mine potential information in Continuous Glucose Monitoring (CGM) time series and improve the overall alarm performance for different clinical situations. Methods Through symbolizing the historical CGM records, the Prefix Span was adopted to obtain the early alarm/non-alarm frequent sequence libraries of hypoglycemia events. The longest common subsequence was used to remove the common frequent sequence for achieving the hypoglycemia early alarm in different clinical situations. Then, the frequent sequence pattern libraries with different risk thresholds were designed as the core module of the proposed multi-level hypoglycemia early alarm system. Results The model was able to predict hypoglycemia events in the clinical dataset of level-I (sensitivity 85.90%, false-positive 23.86%, miss alarm rate 14.10%, average early alarm time 20.61 min), level-II (sensitivity 80.36%, false-positive 17.37%, miss alarm rate 19.63%, average early alarm time 27.66 min), and level-III (sensitivity 78.07%, false-positive 13.59%, miss alarm rate 21.93%, average early alarm time 33.80 min), respectively. Conclusions The proposed approach could effectively predict hypoglycemia events based on different risk thresholds to meet different prevention and treatment requirements. Moreover, the experimental results confirm the practicality and prospects of the proposed early alarm system, which reflects further significance in personalized medicine for hypoglycemia prevention.

Abstract Background Heat shock protein 27 (HSP27) has been proposed as a vital protective factor in atherosclerosis. The objective of the present study was to evaluate the association between circulating HSP27 and carotid intima–media thickness (IMT) in individuals with type 2 diabetes and to determine whether HSP27 represents an independent marker of subclinical atherosclerosis in this patient population. Methods We performed a cross-sectional community-based study in 186 Chinese subjects with a median duration of type 2 diabetes of 8.2 years who underwent ultrasound carotid IMT measurement. Serum HSP27 levels were assessed by ELISA. Results Serum HSP27 levels were significantly higher in the IMT (+, > 1.0 mm) group than in the IMT (−, ≤1.0 mm) group, with the median values of 8.80 ng/mL (5.62–12.25) and 6.93 ng/mL (4.23–9.60), respectively (P = 0.006). The discriminative value of HSP27 to evaluate IMT was 7.16 ng/mL and the area under the curve was 0.72 (95%CI = 0.64–0.80, P = 0.0065). Spearman’s rank correlation analysis demonstrated that the concentrations of circulating HSP27 were positively associated with carotid IMT (r = 0.198, P = 0.007) and blood urea nitrogen (r = 0.170, P

Introduction: In the past two decades, urbanization in many Asian countries has led to sedentary lifestyle and overnutrition, which has set the stage for the epidemic of obesity. Those who have obesity during adolescence usually have obesity into adulthood, which causes many medical and psychological issues that can result in premature death. Recent data suggest that short sleep duration may contribute to the risk of obesity, opening a new avenue for potential intervention. The aim of this study was to describe the prevalence of sleeping time, body mass index (BMI), and fat mass in Chinese freshmen and to indicate the relationship among them. Methods: We conducted a cross-sectional study consisting of 1,938 freshmen aged from 18 to 24 years, including 684 (35.3%) men and 1,254 (64.7%) women. BMI, sleeping time, and other potential related variables were collected by questionnaire. Obesity and overweight were defined as BMI ≥28.0 and ≥24.0, respectively. All students were divided into three groups according to the tertiles of body fat percentage (Fat%), which were measured by bioelectrical impedance analysis. Sleeping time was divided into 3 categories based on the duration, 8 h per day. Results: Participants who slept longer had lower BMI and Fat%. Sex, diet control, and maternal obesity were all significantly associated with BMI or Fat% after adjustment. There were significant differences between sleeping time 8 h in both overweight group and Fat% tertiles independent of adjustment used. The significant difference between sleeping time 6–8 and >8 h only existed in overweight group, while irrelevant relation was observed in both models of obesity group. Conclusion: Longer sleeping time was associated with a lower BMI in Chinese freshmen, even after adjustment for multiple confounders. The overweight stage is a critical period of weight management intervention by changing sleeping time. If adolescents have entered the obesity stage, the effect size of lifestyle intervention might be significantly limited.

Background: Islet autoantibodies occur in type 2 diabetes. Our study aimed to investigate the prevalence of positive islet autoimmunity in community patients with type 2 diabetes. Methods: A total of 495 community patients with type 2 diabetes were recruited using the method of cluster sampling in this cross-sectional study. Three islet autoantibodies including glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA) and islet cell antibody (ICA) were measured, and clinical characteristics involved in those individuals were evaluated. Results: The positive rate of islet autoantibodies was 28.5% in total, while combinations of different autoantibodies were rarely seen. Compared with GADA -negative group, positive counterparts significantly tended to have lower levels of body mass index (BMI), waist-hip ratio (WHR), and urinary microalbumin (mALB) (P < 0.05). Adjusted for confounding factors, WHR, triglycerides (TG), and mALB seemed to be negative independent predictors of GADA (OR < 1, P < 0.05). Patients with positive IAA tended to receive insulin treatment (P < 0.0001). Besides, fasting blood glucose (FBG), serum levels of high-density lipoprotein cholesterol (HDL-CH), aspartate transaminase (AST), and γ-glutamyltransferase (GGT) were more likely to be higher in IAA positive subgroup in comparison with the negative counterparts. While after AST w as adjusted by unconditional logistic regression analysis, history of insulin treatment, FBG, HDL-CH, and GGT were confirmed as positive predictors of IAA. Furthermor e, in patients who were IAA positive, those treated with exogenous insulin tended to have longer duration of diabetes than non-insulin treatment counterparts (P < 0.0001). With regard to ICA, however, there were no significant differences between the two su bgroups, except that serum level of AST/ALT seemed to be slightly different ( P = 0.064). Conclusion: These data suggested that type 2 diabetic community patients with positive GADA tended to be lean and were able to maintain normal lipid metabolism, while patients with positivity of IAA were frequently accompanied with insulin treatment and more closely associated with diabetic liver damage.

BackgroundSolitary intracranial hypothalamic mass occurs rarely. The etiological diagnosis of solitary hypothalamus lesion is challenging and often unachievable. Although previous studies indicated that lesions affecting the hypothalamus often cause significant metabolic disorders, few reports about the metabolic disturbances of patients with solitary hypothalamic mass have been reported.MethodTwenty-five patients with solitary hypothalamus lesions who had been evaluated and treated in Huashan Hospital from January 2010 to December 2020 were retrospectively enrolled. The clinical manifestations, radiological features, endocrine and metabolic disorders, and pathology were analyzed.ResultsThe male to female ratio was 5/20. The median age of onset was 22 (19, 35) years old. The most common initial symptom was polydipsia/polyuria (19/25, 76.0%) and amenorrhea (9/20, 45.0%). A high prevalence of hypopituitarism of different axes was found, with almost all no less than 80%. Central hypogonadism (21/22, 95.5%) and central diabetes insipidus (19/21, 90.5%) were the top two pituitary dysfunctions. Conclusive diagnoses were achieved by intracranial surgical biopsy/resection or stereotactic biopsy in 16 cases and by examining extracranial lesions in 3 cases. The pathological results were various, and the most common diagnoses were Langerhans cell histiocytosis (7/19) and hypothalamitis (5/19). The mean timespan from onset to diagnosis in the 19 cases was 34 ± 26 months. Metabolic evaluations revealed remarkable metabolic disorders, including hyperlipidemia (13/16, 81.3%), hyperglycemia (10/16, 62.5%), hyperuricemia (12/20, 60%), overweight/obesity (13/20, 65.0%), and hepatic adipose infiltration (10/13, 76.6%).ConclusionEither surgical or stereotactic biopsy will be a reliable and relatively safe procedure to help to confirm the pathological diagnosis of solitary hypothalamic mass. Metabolic disorders were severe in patients with solitary hypothalamic mass. The management of such cases should cover both the treatment of the primary disease, as well as the endocrine and metabolic disorders

IntroductionBrown adipose tissue (BAT) becomes the favorite target for preventing and treating metabolic diseases because the activated BAT can produce heat and consume energy. The brain, especially the hypothalamus, which secretes Neuropeptide Y (NPY), is speculated to regulate BAT activity. However, whether NPY is involved in BAT activity’s central regulation in humans remains unclear. Thus, it’s essential to explore the relationship between brain glucose metabolism and human BAT activity.MethodsA controlled study with a large sample of healthy adults used Positron emission tomography/computed tomography (PET/CT) to noninvasively investigate BAT’s activity and brain glucose metabolism in vivo. Eighty healthy adults with activated BAT according to the PET/CT scan volunteered to be the BAT positive group, while 80 healthy adults without activated BAT but with the same gender, similar age, and BMI, scanning on the same day, were recruited as the control (BAT negative). We use Statistical parametric mapping (SPM) to analyze the brain image data, Picture Archiving & Communication System (PACS), and PET/CT Viewer software to calculate the semi-quantitative values of brain glucose metabolism and BAT activity. ELISA tested the levels of fasting plasma NPY. The multiple linear regression models were used to analyze the correlation between brain glucose metabolism, the level of NPY, and the BAT activity in the BAT positive group.Results(1) Compared with controls, BAT positive group showed significant metabolic decreases mainly in the right Insula (BA13a, BA13b) and the right claustrum (uncorrected P 0.05), while the correlation between the BA13a metabolic values and BAT activity still was significant (P< 0.05).ConclusionsRegional brain glucose metabolism is closely related to healthy adults’ BAT activity, which may be mediated by NPY.

Objective: The aim of this study was to evaluate thyroid functions in Cushing’s syndrome (CS), the dynamic changes of thyroid hormones and antithyroid antibodies in Cushing’s disease (CD) pre- and postoperatively. Design and methods: This is a retrospective study enrolling 118 patients with CS (102 CD, 10 adrenal CS and 6 ectopic adrenocorticotropic syndrome (EAS)). Thyroid functions (thyroid-stimulation hormone (TSH), T3, free T3 (FT3), T4 and free T4 (FT4)) were measured in all CS at the time of diagnosis and in all CD 3 mon ths after transsphenoidal pituitary tumor resection. Postoperative hormone monitoring within 3 months was conducted in 9 CD patients completing remission. Twenty-eight remitted CD patients experienced hormone and antithyroid antibody evaluation preoperatively and on the 3rd, 6th and 12th month after surgery. Results: TSH, T3 and FT3 were below the reference range in 31%, 69% and 44% of the 118 CS patients. Remitted CD patients (81/102) had significantly higher TSH (P = 0.000), T3 (P = 0.000) and FT3 (P = 0.000) than those in the non-remission group (21/102). After remission of CD, TSH, T3 and FT3 showed a significant increase, with a few cases above the reference range. By 12 months, most CD patients’ thyroid fu nctions returned to normal. Thyroid hormones (including TSH, T3 and FT3) were negatively associated with serum cortisol levels both before and after surgery. No signific ant changes of antithyroid autoantibodies were observed. Conclusions: TSH, T3 and FT3 are suppressed in endogenous hypercortisolemia. After remission of CD, TSH, T3 and FT3 increased significantly, even a bove the reference range, but returned to normal 1 year after surgery in most cases. Anti thyroid antibodies did not change significantly after remission of CD.

BackgroundCathepsin S, as an adipokine, was reported to play a critical role in various disease, including atherosclerosis and diabetes. The present study aims to elucidate the relationship between circulating cathepsin S and cardiovascular disease (CVD) in patients with type 2 diabetes.MethodsA total of 339 type 2 diabetes individuals were enrolled in this cross-sectional community-based study. Basic information, medical and laboratory data were collected. Serum cathepsin S levels were assessed by ELISA.ResultsCompared to the CVD (−) group, levels of serum cathepsin S were significantly higher in the CVD (+) group, with the median 23.68 ng/ml (18.54–28.02) and 26.81 ng/ml (21.19–37.69) respectively (P < 0.001). Moreover, patients with acute coronary syndrome (ACS) had substantially higher levels of serum cathepsin S than those with stable angina pectoris (SAP), with the median 34.65 ng/ml (24.33–42.83) and 25.52 ng/ml (20.53–31.47) respectively (P < 0.01). The spearman correlation analysis showed that circulating cathepsin S was correlated with several cardiovascular risk factors. The univariate and multivariate logistic regression analysis revealed that circulating cathepsin S was an independent risk factor for CVD (all P < 0.001) after adjustment for potential confounders. Restricted cubic spline analysis showed circulating cathepsin S had a linearity association with CVD. In addition, receiver operating characteristic (ROC) curve analysis demonstrated that the area under curve (AUC) values of cathepsin S was 0.80 (95% CI: 0.75–0.84, P < 0.001), with the optimal cutoff value of cathepsin 26.28 ng/ml.ConclusionCirculating cathepsin S was significantly higher in the CVD (+) group than that in the CVD (−) one among type 2 diabetes. The increased serum cathepsin S levels were associated with increased risks of CVD, even after adjusting for potential confounders. Thus, cathepsin S might be a potential diagnostic biomarker for CVD.

BackgroundMetformin, a traditional first-line anti-hyperglycemic agent for diabetes, recently exhibits better antitumor effect in hepatocellular carcinoma (HCC). However, its resistance and tolerance mechanism in HCC remains largely unknown. Here, we investigated whether increased matrix stiffness attenuated the intervention effects of metformin on HCC invasion and metastasis, and explored its underlying molecular mechanism.MethodsFN-coated gel substrates with 6, 10, and 16 kPa, which simulated the stiffness of normal, fibrotic, and cirrhotic liver tissues respectively, were established to evaluate matrix stiffness-mediated effects on HCC cells. Alterations in morphology, proliferation, motility, and invasive/metastatic-associated genes (PTEN, MMP2, MMP9) of HCC cells grown on different-stiffness substrates were comparatively analyzed before and after metformin intervention. Subsequently, the underlying molecular mechanism by which higher matrix stiffness attenuates antitumor effects of metformin in HCC was further elucidated.ResultsMetformin significantly inhibited proliferation, migration, and invasion of HCC cells. Compared with the controls on lower-stiffness substrate, HCC cells grown on higher-stiffness substrate exhibited an obvious resistance to intervention effects of metformin on proliferation, migration, invasion and metastasis. High stiffness stimulation significantly activated the miR-17-5p/PTEN/PI3K/Akt signaling pathway in HCC cells via integrin β1 and in turn resulted in MMP2 and MMP9 upregulation. Meanwhile, integrin β1 knockdown or PI3K inhibitor partially reversed the activation of the above signaling molecules. For HCC cells grown on the same-stiffness substrate, metformin remarkably upregulated PTEN expression and suppressed the activation of the PI3K/Akt/MMP pathway, but no effect on integrin β1 expression. Importantly, the increase in fold of PTEN expression and decrease in folds of Akt phosphorylation level and MMP2 and MMP9 expressions in the treated HCC cells with metformin on 16-kPa stiffness substrate were evidently weakened compared with those in the controls on the 6-kPa stiffness substrate.Conclusions:Increased matrix stiffness significantly attenuates the inhibitory effect of metformin on HCC invasion and metastasis, and a common pathway of PTEN/PI3K/Akt/MMPs activated by mechanical stiffness signal and inactivated by metformin contributes to matrix stiffness-caused metformin resistance. To the best of our knowledge, this is the first report to clarify the mechanism of metformin intervention resistance from the perspective of tumor biophysical microenvironment.

Introduction: The purpose of the study was to describe lipid profile and explore pathogenetic role of LDL-c on hypertension in patients with Cushing’s disease (CD). Hypertension is a common feature in patients with CD. Previous study found low-density lipoprotein cholesterol (LDL-c) uptake in vascular cells might be involved in vascular remodeling in patients with CD. Therefore, we evaluated the relationship between lipid profile and the blood pressure in patients with CD. Methods: This retrospective study included 84 patients referred to Huashan Hospital for the evaluation and diagnosis of CD from January 2012 to December 2013. All subjects had detailed clinical evaluation by the same group of endocrinology specialists to avoid subjective influences. Results: We found that high LDL-c patients had significant higher body mass index (BMI), systolic blood pressure (SBP), cholesterol (CHO), triglyceride (TG), and apolipoproteinB (apoB) (P < 0.05). An association was detected between SBP values and lipids profile including CHO, TG, LDL-c, apolipoproteinA (apoA), apoB and lipoprotein(a) (LP(a)). After adjustment for all covariates, the LDL-c remained positively associated with SBP. In patients with or without taking statins, patients with LDL-c ≥3.37 mmol/L had higher SBP than patients with LDL-c

Abstract Biomarkers are measurable changes associated with the disease. Urine can reflect the changes of the body while blood is under control of the homeostatic mechanisms; thus, urine is considered an important source for early and sensitive disease biomarker discovery. A comprehensive profile of the urinary proteome will provide a basic understanding of urinary proteins. In this paper, we present an in-depth analysis of the urinary proteome based on different separation strategies, including direct one dimensional liquid chromatography–tandem mass spectrometry (LC/MS/MS), two dimensional LC/MS/MS, and gel-eluted liquid fraction entrapment electrophoresis/liquid-phase isoelectric focusing followed by two dimensional LC/MS/MS. A total of 6085 proteins were identified in healthy urine, of which 2001 were not reported in previous studies and the concentrations of 2571 proteins were estimated (spanning a magnitude of 106) with an intensity-based absolute quantification algorithm. The urinary proteins were annotated by their tissue distribution. Detailed information can be accessed at the “Human Urine Proteome Database” (www.urimarker.com/urine).

Glucagon-like peptide-1 (GLP-1), an incretin hormone plays an important role in regulating glucose homeostasis. The therapeutic use of native GLP-1 is inadequate due to its short in vivo half-life. We recently developed a novel GLP-1 mimetics supaglutide, and demonstrated that this formulation retained native GLP-1 biological activities and possessed long-lasting GLP-1 actions. In this study, we further examined its abilities in regulating blood glucose in diabetic mice. We found that supaglutide stimulated insulin secretion in both mouse and human islets in a dose-dependent fashion. Oral glucose tolerance test conducted in normal ICR mice showed that supaglutide significantly decreased postprandial glucose excursions in a dose-dependent fashion. In type 2 diabetic db/db mice, a single-dose injection of supaglutide significantly decreased blood glucose levels, and this efficacy was lasted for at least 72 h in a dose-dependent fashion. During a 4-weeks intervention course supaglutide (twice injections per week) dose-dependently and significantly decreased fasting and random blood glucose levels in hyperglycemic db/db mice. Supaglutide, at a dose of 1.2 mg/kg, significantly reduced serum fructosamine levels. This was associated with significant enlargement of beta-cell mass, increased pancreatic insulin content, and increased plasma insulin level. Notably, during the intervention course supaglutide significantly reduced body-weight gain in these obese diabetic mice, associated with reduced fat mass (but not the lean mass), improved lipid profile, i.e., declined serum triglyceride, and free fatty acid levels compared to the placebo control. These finding reveals that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic db/db mice.

This paper incorporates a manager’s time-inconsistent preferences into the unified dynamic q-theoretic framework to investigate their impact on the optimal external financing and dividend payout strategies in a regime switching economy. We find that with a higher degree of time inconsistency, either in a favorable market condition or in a financial crisis, dividends are paid out earlier and the equity issues are smaller in size in each occurrence; in a favorable market condition equity financing occurs particularly early. Hence, time inconsistency would result in a decreasing of a firm’s precautionary savings, which may directly cause capital chain rupture and make liquidation more likely. It also implies that corporate external financing and dividend payout are highly dependent on the degree of the manager’s time-inconsistent preferences in a regime switching economy.

BackgroundSome elderly citizens with a clinical diagnosis of type 2 diabetes had evidence of positive islet autoantibodies. We aimed to discover their islet autoantibody patterns and independent correlative factors that might lead to a better understanding of significance of islet autoimmunity in the progression of elderly diabetes.MethodsA total of 541 inpatients of clinically diagnosed type 2 diabetes aged 60 and over were recruited. Three islet autoantibodies including insulin autoantibody (IAA), islet cell antibody (ICA), and glutamic acid decarboxylase antibody (GADA) as well as clinical and biochemical characteristics were tested and collected in Huashan Hospital. Associations between these antibodies and clinical features were analyzed by Spearman correlation and binary logistic analyses.ResultsIn our current study, total positive rate of islet autoantibodies (IAA, ICA, and GADA) was 35.67% with 26.62% for individual IAA, 5.55% for ICA, and 5.91% for GADA, in elderly with type 2 diabetes. None of combinations of such autoantibodies were observed, with the exception of IAA + ICA (0.74%, n = 4), IAA + GADA (1.48%, n = 8), and ICA + GADA (0.18%, n = 1). Compared with GADA negative group, patients in positive group tended to have lower level of fasting and postprandial C peptide, fasting blood glucose (FBG), and body mass index (BMI). After adjusted for the BMI, FBG, and postprandial C peptide, fasting C peptide seemed to be an independent factor related to GADA positivity (OR = 0.52, p = 0.02). As for patients with positive IAA, they were more likely to have insulin treatment with longer duration of diabetes, higher level of BMI, and lower level of postprandial C peptide. After adjusted for the duration of diabetes, BMI, and postprandial C peptide, insulin treatment was a significant predictor for IAA positivity (OR = 5.20, p

Knowledge about the normal human cerebrospinal fluid (CSF) proteome serves as a baseline reference for CSF biomarker discovery and provides insight into CSF physiology. In this study, high-pH reverse-phase liquid chromatography (hp-RPLC) was first integrated with a TripleTOF 5600 mass spectrometer to comprehensively profile the normal CSF proteome. A total of 49,836 unique peptides and 3256 non-redundant proteins were identified. To obtain high-confidence results, 2513 proteins with at least 2 unique peptides were further selected as bona fide CSF proteins. Nearly 30% of the identified CSF proteins have not been previously reported in the normal CSF proteome. More than 25% of the CSF proteins were components of CNS cell microenvironments, and network analyses indicated their roles in the pathogenesis of neurological diseases. The top canonical pathway in which the CSF proteins participated was axon guidance signaling. More than one-third of the CSF proteins (788 proteins) were related to neurological diseases, and these proteins constitute potential CSF biomarker candidates. The mapping results can be freely downloaded at http://122.70.220.102:8088/csf/, which can be used to navigate the CSF proteome. For more information about the data, please refer to the related original article [1], which has been recently accepted by Journal of Proteomics.

This paper investigates the modified function projective synchronization between fractional-order chaotic systems, which are partially linear financial systems with uncertain parameters. Based on the stability theory of fractional-order systems and the Lyapunov matrix equation, a controller is obtained for the synchronization between fractional-order financial chaotic systems. Using the controller, the error systems converged to zero as time tends to infinity, and the uncertain parameters were also estimated so that the phenomenon of parameter distortion was effectively avoided. Numerical simulations demonstrate the validity and feasibility of the proposed method.

Cushing’s disease (CD) is remarkably prevalent among females; however, more severe clinical presentation and adverse outcomes have been found in males. The purpose of this study was to investigate the overall clinical profile and biochemical parameters in patients with CD to identify the gender differences. Here we describe our series of CD patients referred to our medical center during 2012-2013. Among 73 cases, females presented a marked preponderance compared to males. Males had significantly higher ACTH, BMI, HbA1c, systolic blood pressure, and hemoglobin than females. For the first time, the incidence of fatty liver and hepatic function was also shown to be elevated in males. Multiple linear regression analysis was performed to further investigate the correlation of risk factors with hypokalemia, HbA1c, and systolic blood pressure. Gender and serum cortisol were associated with hypokalemia. Age, gender, and serum cortisol were significantly associated with HbA1c. Additionally, only gender was significantly associated with systolic blood pressure. Regarding clinical presentation, purple striae seemed to occur more frequently in males than in females. Thus, more severe clinical presentation, biochemical parameters, and complications were found in males than in females. Clinical professionals should pay more attention to the diagnosis and management of males with CD.