Lipidomic studies revealing serological markers associated with the occurrence of retinopathy in type 2 diabetes.

PURPOSE: The duration of type 2 diabetes mellitus (T2DM) and blood glucose levels have a significant impact on the development of T2DM complications. However, currently known risk factors are not good predictors of the onset or progression of diabetic retinopathy (DR). Therefore, we aimed to investigate the differences in the serum lipid composition in patients with T2DM, without and with DR, and search for potential serological indicators associated with the development of DR. METHODS: A total of 622 patients with T2DM hospitalized in the Department of Endocrinology of the First Affiliated Hospital of Xi'an JiaoTong University were selected as the discovery set. One-to-one case-control matching was performed according to the traditional risk factors for DR (i.e., age, duration of diabetes, HbA1c level, and hypertension). All cases with comorbid chronic kidney disease were excluded to eliminate confounding factors. A total of 42 pairs were successfully matched. T2DM patients with DR (DR group) were the case group, and T2DM patients without DR (NDR group) served as control subjects. Ultra-performance liquid chromatography-mass spectrometry (LC-MS/MS) was used for untargeted lipidomics analysis on serum, and a partial least squares discriminant analysis (PLS-DA) model was established to screen differential lipid molecules based on variable importance in the projection (VIP) > 1. An additional 531 T2DM patients were selected as the validation set. Next, 1:1 propensity score matching (PSM) was performed for the traditional risk factors for DR, and a combined 95 pairings in the NDR and DR groups were successfully matched. The screened differential lipid molecules were validated by multiple reaction monitoring (MRM) quantification based on mass spectrometry. RESULTS: The discovery set showed no differences in traditional risk factors associated with the development of DR (i.e., age, disease duration, HbA1c, blood pressure, and glomerular filtration rate). In the DR group compared with the NDR group, the levels of three ceramides (Cer) and seven sphingomyelins (SM) were significantly lower, and one phosphatidylcholine (PC), two lysophosphatidylcholines (LPC), and two SMs were significantly higher. Furthermore, evaluation of these 15 differential lipid molecules in the validation sample set showed that three Cer and SM(d18:1/24:1) molecules were substantially lower in the DR group. After excluding other confounding factors (e.g., sex, BMI, lipid-lowering drug therapy, and lipid levels), multifactorial logistic regression analysis revealed that a lower abundance of two ceramides, i.e., Cer(d18:0/22:0) and Cer(d18:0/24:0), was an independent risk factor for the occurrence of DR in T2DM patients. CONCLUSION: Disturbances in lipid metabolism are closely associated with the occurrence of DR in patients with T2DM, especially in ceramides. Our study revealed for the first time that Cer(d18:0/22:0) and Cer(d18:0/24:0) might be potential serological markers for the diagnosis of DR occurrence in T2DM patients, providing new ideas for the early diagnosis of DR.

VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway.

BACKGROUND: CD4+ cytotoxic T cells (CD4 CTLs) are CD4+ T cells with major histocompatibility complex-II-restricted cytotoxic function. Under pathologic conditions, CD4 CTLs hasten the development of autoimmune disease or viral infection by enhancing cytotoxicity. However, the regulators of the cytotoxicity of CD4 CTLs are not fully understood. METHODS: To explore the potential regulators of the cytotoxicity of CD4 CTLs, bulk RNA and single-cell RNA sequencing (scRNA-seq), enzyme-linked immunosorbent assay, flow cytometry, quantitative PCR, and in-vitro stimulation and inhibition assays were performed. RESULTS: In this study, we found that VEGF-A promoted the cytotoxicity of CD4 CTLs through scRNA-seq and flow cytometry. Regarding the specific VEGF receptor (R) involved, VEGF-R1/R2 signaling was activated in CD4 CTLs with increased cytotoxicity, and the VEGF-A effects were inhibited when anti-VEGF-R1/R2 neutralizing antibodies were applied. Mechanistically, VEGF-A treatment activated the AKT/mTOR pathway in CD4 CTLs, and the increases of cytotoxic molecules induced by VEGF-A were significantly reduced when the AKT/mTOR pathway was inhibited. CONCLUSION: In conclusion, VEGF-A enhances the cytotoxicity of CD4 CTLs through the VEGF-R1/VEGF-R2/AKT/mTOR pathway, providing insights for the development of novel treatments for disorders associated with CD4 CTLs.

Lower normal free thyroxine is associated with a higher risk of metabolic syndrome: a retrospective cohort on Chinese population.

BACKGROUND: Recently, the relationship between thyroid hormones (THs) across the euthyroid ranges and metabolic syndrome (MetS) has been widely discussed. This study aimed to present specific cutoff values of THs to assess the association between THs and MetS in a euthyroid cohort. METHODS: Data of 2694 subjects, aged 18-80 years, who attended health examination in Xi'an Electric Power Central Hospital from April 2011 to December 2015 were collected and analyzed. The first cohort enrolled 929 participants (followed up by 2221 person-years totally) to assess correlations between serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4) levels and MetS. The second cohort included 698 participants (followed up by 1709 person-years totally) to evaluate relationships between serum free triiodothyronine (FT3), free thyroxine (FT4) levels and MetS. MetS was defined according to the criteria of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) scientific statements of 2009. Euthyroidism was defined as serum TSH, FT3 and FT4 levels within the reference ranges without taking any thyroid medication. RESULTS: The cutoff values for TSH, T3, T4, FT3 and FT4 were 2.0mIU/L, 1.9 nmol/L, 117 nmol/L, 4.3 pmol/L and 16 pmol/L, respectively. Participants were categorized into two groups according to cutoff values: the lower-THs group and the higher-THs group. There was no significant difference in the risk of MetS between two groups in TSH, T3, T4 and FT3. The incidence of MetS was significantly higher in lower-FT4 group than higher-FT4 group (1.00 vs 0.622 (0.458, 0.846), P = 0.002). The lower-FT4/higher-TSH group had the highest hazard ratios of MetS. (2.131vs 1.0 (1.380,3.291), P = 0.006). CONCLUSIONS: Lower normal FT4 (FT4 ≤ 16.0 pmol/L) is an independent risk factor for MetS, and lower normal thyroid function (TSH > 2.0 mIU/L and FT4 ≤ 16.0 pmol/L) is associated with a higher risk of developing MetS.

The potential markers involved in newly diagnosed graves' disease and the development of active graves' orbitopathy.

BACKGROUND: Graves' disease (GD) patients experience two major issues: one is the severe hyperthyroidism associated with newly diagnosed GD, and the other involves the disfiguring and dysfunctional features of active Graves' orbitopathy (GO). Therefore, the aim of our study was to identify potential markers involved in the initial phase of GD dysfunction and the development of active GO. METHODS: Seventy-eight subjects were recruited: 40 with newly diagnosed GD, 20 with inactive GO and 18 with active GO. GO activity was evaluated by the clinical activity score (CAS, active GO = CAS ≥ 3), and severity was assessed according to the NOSPECS classification. Plasma selenium concentrations were determined by dual channel hydride generation atomic fluorescence photometry. A liquid chip assay was used to measure plasma Th1 cytokines IFN-γ and TNF-α; Th2 cytokines IL4, IL5 and IL6; Th17 cytokine IL23; Treg cytokines IL10 and TGF-ß; and two chemokines, CCL2 (Th2 chemokine) and CXCL10 (Th1 chemokine). RESULTS: Among the three groups, newly diagnosed GD patients showed significantly elevated plasma levels of CXCL10 and IL-23 (all p < 0.05). Both CXCL10 and IL23 were significantly correlated with hyperthyroidism severity, specifically, increasing FT3 and FT4 and decreasing TSH. Notably, a very strong positive relationship between IL23 and CXCL10 was revealed (adjusted R square = 0.795; p < 0.001). Moreover, the selenium level was lower, while that of CCL2 was higher, in active GO than in inactive GO (p = 0.007, p < 0.001, respectively). Likewise, we also discovered that increasing CCL2 levels and decreasing selenium levels were associated with high CAS. Remarkably, after adjusting for potential confounding factors, selenium (OR, 0.919) and CCL2 (OR, 1.042) were still independent predictors for the diagnosis of active GO, and similar conclusions were drawn by receiver operating characteristic (ROC) curve analysis. CONCLUSION: Pro-inflammatory cytokines, especially Th17-associated cytokines (e.g., IL23) and Th1 chemokines (e.g., CXCL10), appear to be involved in the initial phase of GD dysfunction. Moreover, we revealed for the first time that decreased plasma selenium levels and increased concentrations of Th2 chemokines (e.g., CCL2) may reflect GO disease activity, shedding light on the diagnosis and evaluation of active GO.

The proportion of peripheral blood Tregs among the CD4+ T cells of autoimmune thyroid disease patients: a meta-analysis.

Autoimmune thyroid disease (AITD) is characterized by a loss of self-tolerance to thyroid antigen. Tregs, whose proportions are controversial among CD4+ T cell from AITD patients (AITDs), are crucial in immune tolerance. Considering that drugs might affect Treg levels, we assumed that the differences originated from different treatment statuses. Thus, we performed a meta-analysis to explore proportions of Tregs in untreated and treated AITDs. PubMed, Embase and ISI Web of Knowledge were searched for relevant studies. Review Manager 5.3 and Stata 14.0 were used to conduct the meta-analysis. Subgroup analysis based on different diseases and cell surface markers was performed. Egger linear regression analysis was used to assess publication bias. Approximately 1,100 AITDs and healthy controls (HCs) from fourteen studies were included. Proportions of Tregs among CD4+ T cells of untreated AITDs were significantly lower than those in HCs (p = 0.002), but were not in treated patients (p = 0.40). Subgroup analysis revealed lower proportions of Tregs in untreated Graves' disease patients (GDs) (p = 0.001) but did not show obvious differences in untreated Hashimoto's thyroiditis patients (HTs) (p = 0.62). Furthermore, proportions of circulating FoxP3+ Tregs were reduced in untreated GDs (p < 0.00001) and HTs (p = 0.04). No publication bias was found. In this first meta-analysis exploring proportions of circulating Tregs among CD4+ T cells of AITDs with different treatment statuses, we found that Tregs potentially contribute to the pathogenesis of AITD but function differently in GD and HT. Remarkably, FoxP3+ Tregs, which were decreased in both diseases, might be promising targets for novel therapies.

Factors associated with the efficacy of intravenous methylprednisolone in moderate-to-severe and active thyroid-associated ophthalmopathy: A single-centre retrospective study.

OBJECTIVE: Intravenous methylprednisolone (IVMP) is recommended as the first-line treatment for moderate-to-severe and active thyroid-associated ophthalmopathy (TAO). This study aimed to identify potential predictors and establish a multivariable prediction model for the efficacy of IVMP therapy. DESIGN: A single-centre retrospective study. PATIENTS: A total of 302 consecutive patients diagnosed with moderate-to-severe and active TAO who underwent the full course of IVMP therapy were included. METHODS: Participants were sequentially divided into the training set (n = 200) and the validation set (n = 102). Multivariate logistic regression analysis was used to identify the independent predictors and establish the predictive model. RESULTS: In addition to the pretreatment clinical activity score (OR = 3.506, P < 0.001), elevated thyroid-stimulating hormone (TSH) levels during treatment (OR = 0.145, P = 0.005), pretreatment anti-TSH receptor antibody levels (OR = 0.061, P < 0.001) and duration of eye symptoms (OR = 0.878, P = 0.017), a significant relationship was found between therapeutic efficacy and the pretreatment triglyceride levels (OR = 0.090, P = 0.001). The prediction model showed good calibration and excellent discrimination, with an area under curve of 0.915 (P < 0.001) and 0.885 (P < 0.001) in the training and validation sets, respectively. CONCLUSIONS: This study provides some novel insights into the factors associated with the efficacy of IVMP therapy. A multivariable prediction model has been established and validated to help determine the indication and prognosis of IVMP therapy. Moreover, several suggestions have been made in the management of TAO patients: early diagnosis and treatment (within 15 months); prompt restoration and maintenance of euthyroidism, especially meticulous control of TSH levels (≤5 µIU/mL); and regular monitoring of triglyceride levels.

Three-Dimensional Nanoporous Tungsten Disulfide/Acetylene Black Nanoflower Composite as Efficient Electrocatalyst for Enhanced Hydrogen Evolution Reaction.

A novel three-dimensional nanoporous tungsten disulfide/acetylene black (nanoporous-WS2/AB) electrocatalyst was successfully prepared by template assisted hydrothermal method and further applied to hydrogen evolution reaction (HER) for the first time. Surface morphology and crystalline structure of as-prepared nanoporous-WS2/AB were characterized by scanning electron microscopy and X-ray diffractometer. The electrocatalytic properties of as-prepared materials modified electrodes for HER were investigated by polarization curves, electrochemical impedance spectroscopy and Tafel polarization curves in 0.50 M H2SO4 solution. Compared with WS2, AB and WS2/AB based electrodes, nanoporous-WS2/AB based electrode exhibited a much higher electrocatalytic activity which was attributed to the synergistic effect between nanoflower WS2 and amorphous AB, as well as the presences of dual templates of amorphous AB and porous 4A-zeolite. The exchange current density of nanoporous-WS2/AB electrode was 1.6 and 2.5 times larger than that of WS2/AB and pure WS2 based electrode at -400 mV, respectively. The results indicated that nanoporous-WS2/AB composite would be a promising candidate for the potential application in HER.

Stretchable Self-Healing Polymeric Dielectrics Cross-Linked Through Metal-Ligand Coordination.

A self-healing dielectric elastomer is achieved by the incorporation of metal-ligand coordination as cross-linking sites in nonpolar polydimethylsiloxane (PDMS) polymers. The ligand is 2,2'-bipyridine-5,5'-dicarboxylic amide, while the metal salts investigated here are Fe(2+) and Zn(2+) with various counteranions. The kinetically labile coordination between Zn(2+) and bipyridine endows the polymer fast self-healing ability at ambient condition. When integrated into organic field-effect transistors (OFETs) as gate dielectrics, transistors with FeCl2 and ZnCl2 salts cross-linked PDMS exhibited increased dielectric constants compared to PDMS and demonstrated hysteresis-free transfer characteristics, owing to the low ion conductivity in PDMS and the strong columbic interaction between metal cations and the small Cl(-) anions which can prevent mobile anions drifting under gate bias. Fully stretchable transistors with FeCl2-PDMS dielectrics were fabricated and exhibited ideal transfer characteristics. The gate leakage current remained low even after 1000 cycles at 100% strain. The mechanical robustness and stable electrical performance proved its suitability for applications in stretchable electronics. On the other hand, transistors with gate dielectrics containing large-sized anions (BF4(-), ClO4(-), CF3SO3(-)) displayed prominent hysteresis due to mobile anions drifting under gate bias voltage. This work provides insights on future design of self-healing stretchable dielectric materials based on metal-ligand cross-linked polymers.

Multistep π dimerization of tetrakis(n-decyl)heptathienoacene radical cations: a combined experimental and theoretical study.

Radical cations of a heptathienoacene α,ß-substituted with four n-decyl side groups (D4T7(.) (+) ) form exceptionally stable π-dimer dications already at ambient temperature (Chem. Comm. 2011, 47, 12622). This extraordinary π-dimerization process is investigated here with a focus on the ultimate [D4T7(.) (+) ]2 π-dimer dication and yet-unreported transitory species formed during and after the oxidation. To this end, we use a joint experimental and theoretical approach that combines cyclic voltammetry, in situ spectrochemistry and spectroelectrochemistry, EPR spectroscopy, and DFT calculations. The impact of temperature, thienoacene concentration, and the nature and concentration of counteranions on the π-dimerization process is also investigated in detail. Two different transitory species were detected in the course of the one-electron oxidation: 1) a different transient conformation of the ultimate [D4T7(.) (+) ]2 π-dimer dications, the stability of which is strongly affected by the applied experimental conditions, and 2) intermediate [D4T7]2 (.) (+) π-dimer radical cations formed prior to the fully oxidized [D4T7]2 (.) (+) π-dimer dications. Thus, this comprehensive work demonstrates the formation of peculiar supramolecular species of heptathienoacene radical cations, the stability, nature, and structure of which have been successfully analyzed. We therefore believe that this study leads to a deeper fundamental understanding of the mechanism of dimer formation between conjugated aromatic systems.

Association between Lipoprotein(a) and diabetic nephropathy in patients with type 2 diabetes.

Background: Diabetic nephropathy (DN) is one of the most prevalent and severe microvascular complications of type 2 diabetes (T2DM). However, little is currently known about the pathogenesis and its associated risk factors in DN. The present study aims to investigate the potential risk factors of DN in patients with T2DM. Methods: A total of 6,993 T2DM patients, including 5,089 participants with DN and 1,904 without DN, were included in this cross-sectional study. Comparisons between the two groups (DN vs. non-DN) were carried out using Student's t-test, Mann-Whitney U-test, or Pearson's Chi-squared test. Spearman's correlation analyses were performed to assess the correlations of serum lipids and indicators of renal impairment. Logistic regression models were applied to assess the relationship between blood lipid indices and the presence of DN. Results: T2DM patients with DN were older, and had a longer duration of diagnosed diabetes compared to those without DN. Of note, the DN patients also more likely develop metabolic disorders. Among all serum lipids, Lipoprotein(a) [Lp(a)] was the most significantly correlated indicators of renal impairment. Moreover, univariate logistic regression showed that elevated Lp(a) level was associated with an increased risk of DN. After adjusted for confounding factors, including age, gender, duration of T2DM, BMI, SBP, DBP and lipid-lowering drugs usage, Lp(a) level was independently positively associated with the risk of DN [odds ratio (OR):1.115, 95% confidence interval (CI): 1.079-1.151, P=6.06×10-11]. Conclusions: Overall, we demonstrated that serum Lp(a) level was significantly positively associated with an increased risk of DN, indicating that Lp(a) may have the potential as a promising target for the diagnosis and treatment of diabetic nephropathy.

Highly stretchable polymer semiconductor thin films with multi-modal energy dissipation and high relative stretchability.

Stretchable polymer semiconductors (PSCs) have seen great advancements alongside the development of soft electronics. But it remains a challenge to simultaneously achieve high charge carrier mobility and stretchability. Herein, we report the finding that stretchable PSC thin films (<100-nm-thick) with high stretchability tend to exhibit multi-modal energy dissipation mechanisms and have a large relative stretchability (rS) defined by the ratio of the entropic energy dissipation to the enthalpic energy dissipation under strain. They effectively recovered the original molecular ordering, as well as electrical performance, after strain was released. The highest rS value with a model polymer (P4) exhibited an average charge carrier mobility of 0.2 cm2V-1s-1 under 100% biaxial strain, while PSCs with low rS values showed irreversible morphology changes and rapid degradation of electrical performance under strain. These results suggest rS can be used as a parameter to compare the reliability and reversibility of stretchable PSC thin films.

Rapamycin improves Graves' orbitopathy by suppressing CD4+ cytotoxic T lymphocytes.

CD4+ cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves' orbitopathy (GO). However, little is known about therapeutic targeting of CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mTOR complex 1 (mTORC1) inhibitor, in a GO mouse model, in vitro, and in patients with refractory GO. In the adenovirus-induced model, rapamycin significantly decreased the incidence of GO. This was accompanied by the reduction of both CD4+ CTLs and the reduction of orbital inflammation, adipogenesis, and fibrosis. CD4+ CTLs from patients with active GO showed upregulation of the mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and the clinical activity score in steroid-refractory patients with GO. Single-cell RNA-Seq revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.

Thieno[3,2-b]thiophene-2-carboxylic acid derivatives as GPR35 agonists.

The optimization of a series of thieno[3,2-b]thiophene-2-carboxylic acid derivatives for agonist activity against the GPR35 is reported. Compounds were optimized to achieve ß-arrestin-biased agonism for developing probe molecules that may be useful for elucidating the biology and physiology of GPR35. Compound 13 was identified to the most potent GPR35 agonist, and compounds 30 and 36 exhibited the highest efficacy to cause ß-arrestin translocation.

Time-restricted eating with or without low-carbohydrate diet reduces visceral fat and improves metabolic syndrome: A randomized trial.

Overconsumption of carbohydrate-rich food combined with adverse eating patterns contributes to the increasing incidence of metabolic syndrome (MetS) in China. Therefore, we conducted a randomized trial to determine the effects of a low-carbohydrate diet (LCD), an 8-h time-restricted eating (TRE) schedule, and their combination on body weight and abdominal fat area (i.e., primary outcomes) and cardiometabolic outcomes in participants with MetS. Compared with baseline, all 3-month treatments significantly reduce body weight and subcutaneous fat area, but only TRE and combination treatment reduce visceral fat area (VFA), fasting blood glucose, uric acid (UA), and dyslipidemia. Furthermore, compared with changes of LCD, TRE and combination treatment further decrease body weight and VFA, while only combination treatment yields more benefits on glycemic control, UA, and dyslipidemia. In conclusion, without change of physical activity, an 8-h TRE with or without LCD can serve as an effective treatment for MetS (ClinicalTrials.gov: NCT04475822).

Efficacy and tolerability of sitagliptin and metformin compared with insulin as an initial therapy for newly diagnosed diabetic patients with severe hyperglycaemia.

The safety and efficacy of dipeptidyl peptidase-4 inhibitors in patients newly diagnosed type 2 diabetes mellitus (T2DM) with severe hyperglycaemia have remained to be sufficiently demonstrated. The aim of the present study was to determine whether sitagliptin combined with metformin as an initial treatment had non-inferior outcomes with regards to glycaemic remission and ß-cell function recovery to those of standard insulin therapy in this patient group. A prospective observational study was performed comparing the effects of sitagliptin combined with metformin and insulin therapy in a real-world clinical setting. A total of 168 participants were enrolled and received sitagliptin combined with metformin (Sig) or insulin (Ins) for almost 4 weeks. In addition, each group was further stratified into three subgroups, according to glycosylated haemoglobin (HbA1c) levels (<10, 10-12 and >12%). The primary outcomes were ß-cell function and changes in fasting plasma glucose (FPG) and HbA1c at the 3-month follow-up. Both insulin and sitagliptin combined with metformin reduced hyperglycaemia and achieved similar glycaemic outcomes, and no significant differences in FPG and HbA1c levels were obtained. No significant changes were observed in ß-cell function concomitant with the glucose-lowering effects of the treatments. Of note, participants in the Ins group exhibited weight gain, whereas those in the Sig group had weight loss, with significant differences becoming evident after 1 month, particularly in the HbA1c <10% subgroup. As compared with insulin injection, early treatment with sitagliptin combined with metformin in newly diagnosed patients with T2DM and severe hyperglycaemia produced non-inferior outcomes with regards to glycaemic remission. Therefore, combination of sitagliptin and metformin may be a viable initial treatment option for patients who prefer an alternative to insulin injection. This study was registered with ClinicalTrials.gov under no. NCT03180281.

A Promising Mouse Model of Graves' Orbitopathy Induced by Adenovirus Expressing Thyrotropin Receptor A Subunit.

Background: Graves' orbitopathy (GO) is the most common and serious manifestation of Graves' disease (GD). It is characterized by orbital inflammation and tissue remodeling. Although several GO models have been reported, most lack a full assessment or mechanistic evaluation. Here, we established a promising mouse model mimicking many aspects of human GO with a frequency of 70% and characterized the key role of T cells in the progression of GO. Methods: An adenovirus expressing the human thyrotropin (TSH) receptor A subunit (Ad-TSHRA) was injected in the muscles of female BALB/C mice nine times to induce GO. At predetermined time points, histological examinations of retrobulbar tissues and thyroid glands were performed to dynamically monitor changes; serum autoantibodies and total thyroxine levels were examined to evaluate thyroid function. Flow cytometry of CD4+ T cell subgroups and RNA sequencing (RNA-Seq) of splenocytes were also performed to explore the underlying mechanism. Results: After nine injections, 7 of 10 mice challenged with Ad-TSHRA developed the orbital changes associated with GO. Seven mice manifested retrobulbar fibrosis, and four mice showed adipogenesis. Exophthalmia, conjunctival redness, and orbital lymphocyte infiltration were also observed in a subset of mice. The orbitopathy was first detected after seven injections and followed the hyperplastic change observed in thyroids after four injections. Flow cytometry revealed increased proportions of Th1 cells and decreased proportions of Th2 cells and regulatory T (Treg) cells in the splenocytes of GO mice. This change in CD4+ T cell subgroups was confirmed by orbital immunohistochemical staining. Genes involved in T cell receptor signaling, proliferation, adhesion, inflammation, and cytotoxicity were upregulated in GO mice according to the RNA-Seq; a trend of upregulation of these GO-specific genes was observed in mice with hyperthyroidism without orbitopathy after four injections. Conclusions: A GO mouse model was successfully established by administering nine injections of Ad-TSHRA. The model was achieved with a frequency of 70% and revealed the importance of T cell immunity. A potential time window from Graves' hyperthyroidism to GO was presented for the first time. Therefore, this model could be used to study the pathogenesis and novel treatments for GO.

A comprehensive nano-interpenetrating semiconducting photoresist toward all-photolithography organic electronics.

Owing to high resolution, reliability, and industrial compatibility, all-photolithography is a promising strategy for industrial manufacture of organic electronics. However, it receives limited success due to the absence of a semiconducting photoresist with high patterning resolution, mobility, and performance stability against photolithography solution processes. Here, we develop a comprehensive semiconducting photoresist with nano-interpenetrating structure. After photolithography, nanostructured cross-linking networks interpenetrate with continuous phases of semiconducting polymers, enabling submicrometer patterning accuracy and compact molecular stacking with high thermodynamic stability. The mobility reaches the highest values of photocrosslinkable organic semiconductors and maintains almost 100% after soaking in developer and stripper for 1000 min. Owing to the comprehensive performance, all-photolithography is achieved, which fabricates organic inverters and high-density transistor arrays with densities up to 1.1 × 105 units cm-2 and 1 to 4 orders larger than conventional printing processes, opening up a new approach toward manufacturing highly integrated organic circuits and systems.

High-fat diet-induced adipose tissue expansion occurs prior to insulin resistance in C57BL/6J mice.

BACKGROUND: To date, there is only scare evidence characterizing the temporal features and progression of metabolic dysfunction in high-fat diet (HFD)-fed obese mice. Hence, its specific pathogenesis remains unclear. METHODS: Sixty 6-week-old male C57BL/6J mice were randomly divided into HFD and control diet (CD) groups and sacrificed at 1, 5, 9, 13, 17, and 21 weeks, respectively. At weekly intervals, intraperitoneal glucose tolerance testing (IPGTT) and intraperitoneal insulin tolerance testing (IPITT) were performed in both groups. A detailed time course in HFD-fed mice was investigated by evaluating the initiation of glucose homeostasis impairment, dyslipidemia, systemic insulin sensitivity, monocyte chemoattractant protein-1 (MCP-1) levels, epididymal white adipose tissue (eWAT) expansion, macrophage content changes, pro-inflammatory (M1)/anti-inflammatory (M2) macrophage imbalance, lipid accumulation in the liver, and ß-cell morphometry in the pancreas. RESULTS: In the HFD group, progressive weight gain and impairments in glucose metabolism (elevated fasting blood glucose and area under the curve (AUC) of IPGTT) were observed from the 3rd week, and a significantly elevated AUC of IPITT was first detected after week 7 of HFD feeding. As for dyslipidemia, after 9 weeks of feeding, the low-density lipoprotein cholesterol level and total cholesterol level in HFD group were significantly higher than those in the CD group (all P < 0.05), whereas no significant differences were shown in triglyceride level. Adipocyte size increased significantly in the HFD group in the 1st week, a phenotypic switch in eWAT from anti-inflammatory (M2) to pro-inflammatory (M1) macrophages was observed in the 5th week, and the metabolic inflammation was distinct in eWAT in the 9th week. Additionally, liver steatosis was considerably obvious at the 17th week and pancreatic ß-cell morphometry did not change during 21 weeks of HFD feeding. CONCLUSION: The eWAT expansion was detected early in HFD-induced obese mice, which occurred prior to obvious insulin resistance.

Alkylsubstituted thienothiophene semiconducting materials: structure-property relationships.

A family of conjugated polymers with fused structures consisting of three to five thiophene rings and with the same alkyl side chains has been synthesized as a means to understand structure-property relationships. All three polymers showed well-extended conjugation through the polymer backbone. Ionization potentials (IP) ranged from 5.15 to 5.21 eV; these large values are indicative of their excellent oxidative stability. X-ray diffraction and AFM studies suggest that the polymer with the even number of fused thiophene rings forms a tight crystalline structure due to its tilted side chain arrangement. On the other hand, the polymers with the odd number of fused thiophene rings packed more loosely. Characterization in a field-effect transistor configuration showed that the mobility of the polymer with the even number of rings is 1 order of magnitude higher than its odd-numbered counterparts. Through this structure-property study, we demonstrate that proper design of the molecules and properly arranged side chain positions on the polymer backbone can greatly enhance polymer electronic properties.

Sphingolipid metabolism in type 2 diabetes and associated cardiovascular complications.

Sphingolipid metabolism is dysregulated in type 2 diabetes mellitus (T2DM); however, the focus of previous studies was mostly limited to ceramide (Cer), and only few studies have investigated other metabolites, including sphingosine-1 phosphate (So1P). The present study aimed to examine the involvement of 8 major sphingolipid metabolites, including Cer, glucosyl ceramide (GluCer), lactosyl ceramide (LacCer), sphingomyelin (SM), sphinganine (Sa), So1P, sphingosine (So) and sphinganine-1-phosphate (Sa1P), during the progression of T2DM, and to evaluate the ability of serum sphingolipids to predict cases of diabetes with an elevated risk of cardiovascular complications. Blood samples were obtained from 245 participants who were divided into 3 groups: Healthy controls, pre-diabetes (pre-DM) and diagnosed diabetes. The 8 major sphingolipid metabolites were measured by high-performance liquid chromatography-tandem mass spectrometry and blood parameters were determined by routine laboratory assays for all subjects. Among the sphingolipid metabolites, So1P was associated with sex and lean mass index, but not with the body mass index. So1P was highest in healthy controls and gradually decreased when the disease proceeded to pre-DM and T2DM. GluCer, SM, Sa and So decreased in pre-DM and rose again in T2DM, graphically exhibiting a 'U' shape change during the progression of diabetes. So1P and Sa were identified to be significantly associated with cardiovascular complications by multivariate logistic regression analysis. Receiver operating characteristic curve analysis also suggested that So1P and Sa were able to indicate cardiovascular complications in diabetic patients. Pre-DM and diabetes were significantly associated with decreased So1P, SM, Sa and So, compared with the healthy controls. So1P was correlated with the progression of T2DM, and was a predictor of an elevated risk of cardiovascular complications among T2DM patients, along with Sa. The present study was registered with ClinicalTrials.gov (no. NCT02826759; April 2016).