Th17 cells, a lymphocyte subpopulation that is characterized by the expression of the transcription factor "retinoic acid receptor-related orphan receptor gamma-t" (RORγt), plays an important role in the pathogenesis of autoimmune disease. The current study was set up to discover novel and non-steroidal small-molecule inverse agonists of RORγt and to determine their effects on autoimmune disease. Structure-based virtual screening (SBVS) was used to find compounds targeting RORγt. Flow cytometry was used to detect the Th17 cell differentiation. Inverse agonists were intraperitoneally administered to mice undergoing experimental autoimmune uveitis (EAU), experimental autoimmune encephalomyelitis (EAE) or type 1 diabetes. The effects of the inverse agonists were evaluated by clinical or histopathological scoring. Among 1.3 million compounds screened, CQMU151 and CQMU152 were found to inhibit Th17 cell differentiation without affecting the differentiation of Th1 and Treg lineages (both P = 0.001). These compounds also reduced the severity of EAU (P = 0.01 and 0.013) and functional studies showed that they reduced the number of Th17 cell and the expression of IL-17(Th17), but not IFN-γ(Th1) and TGF-β(Treg) in mouse retinas. Further studies showed that these compounds may reduce the expression of p-STAT3 by reducing the positive feedback loop of IL-17/IL-6/STAT3. These compounds also reduced the impaired blood-retinal barrier function by upregulating the expression of tight junction proteins. These compounds were also found to reduce the severity of EAE and type 1 diabetes. Our results showed that RORγt inverse agonists may inhibit the development of autoimmune diseases and may provide new clues for the treatment of Th17-mediated immune diseases.
  Maternal adherence to healthy lifestyle behaviors during pregnancy has been associated with reduced risk of obesity in the offspring. Our objective is to examine associations between a composite healthy lifestyle score (HLS) in expectant mothers and adverse offspring birth outcomes and childhood obesity.
 
  The Lifeways Study comprises 665 mother-child pairs. A composite HLS (scored 0-5) based on high dietary quality (top 40% of the Healthy Eating Index (HEI)-2015), moderate to vigorous physical activity (MVPA), healthy pre-pregnancy BMI (18.5-24.9 kg/m
  ), never smoker, and no/moderate alcohol intake was calculated. Birth outcomes were abstracted from hospital records. Offspring waist circumference (WC) and BMI was determined at age 5 and 9.  https://www.selleckchem.com/products/bay-1816032.html  Logistic regression tested HLS associations with offspring outcomes.
 
  Offspring birth weight, length, and head circumference were positively associated with the maternal HLS (p < 0.001), whereas child BMI and incidence of overweight/obesity at age 5 and 9 were negatggest that maternal adherence to a healthy lifestyle during pregnancy, in particular having a good quality diet, not smoking, and no/low alcohol intake in combination with a healthy pre-pregnancy BMI, is associated with reduced risk of adverse offspring birth outcomes and childhood obesity.Synaptic interactions between parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and pyramidal neurons evoke cortical gamma oscillations, which are known to be abnormal in schizophrenia. These cortical gamma oscillations can be indexed by the gamma-band auditory steady-state response (ASSR), a robust electroencephalographic (EEG) biomarker that is increasingly used to advance the development of novel therapeutics for schizophrenia, and other related brain disorders. Despite promise of ASSR, the neural substrates of ASSR have not yet been characterized. This study investigated the sources underlying ASSR in healthy subjects and schizophrenia patients. In this study, a novel method for noninvasively characterizing source locations was developed and applied to EEG recordings obtained from 293 healthy subjects and 427 schizophrenia patients who underwent ASSR testing. Results revealed a distributed network of temporal and frontal sources in both healthy subjects and schizophrenia patients. In both groups, primary contributing ASSR sources were identified in the right superior temporal cortex and the orbitofrontal cortex. In conjunction with normal activity in these areas, schizophrenia patients showed significantly reduced source dipole density of gamma-band ASSR (ITC > 0.25) in the left superior temporal cortex, orbitofrontal cortex, and left superior frontal cortex. In conclusion, a distributed network of temporal and frontal brain regions supports gamma phase synchronization. We demonstrated that failure to mount a coherent physiologic response to simple 40-Hz stimulation reflects disorganized network function in schizophrenia patients. Future translational studies are needed to more fully understand the neural mechanisms underlying gamma-band ASSR network abnormalities in schizophrenia.Radiomics has potential advantages in the noninvasive histopathological and molecular diagnosis of gliomas. We aimed to develop a novel image signature (IS)-based radiomics model to achieve multilayered preoperative diagnosis and prognostic stratification of gliomas. Herein, we established three separate case cohorts, consisting of 655 glioma patients, and carried out a retrospective study. Image and clinical data of three cohorts were used for training (N = 188), cross-validation (N = 411), and independent testing (N = 56) of the IS model. All tumors were segmented from magnetic resonance (MR) images by the 3D U-net, followed by extraction of high-throughput network features, which were referred to as IS. IS was then used to perform noninvasive histopathological diagnosis and molecular subtyping. Moreover, a new IS-based clustering method was applied for prognostic stratification in IDH-wild-type lower-grade glioma (IDHwt LGG) and triple-negative glioblastoma (1p19q retain/IDH wild-type/TERTp-wild-type GBM). The average accuracies of histological diagnosis and molecular subtyping were 89.8 and 86.1% in the cross-validation cohort, while these numbers reached 83.9 and 80.4% in the independent testing cohort. IS-based clustering method was demonstrated to successfully divide IDHwt LGG into two subgroups with distinct median overall survival time (48.63 vs 38.27 months respectively, P = 0.023), and two subgroups in triple-negative GBM with different median OS time (36.8 vs 18.2 months respectively, P = 0.013). Our findings demonstrate that our novel IS-based radiomics model is an effective tool to achieve noninvasive histo-molecular pathological diagnosis and prognostic stratification of gliomas. This IS model shows potential for future routine use in clinical practice.