ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia.

ARMC5 is implicated in several pathological conditions, but its function remains unknown. We have previously identified CUL3 and RPB1 (the largest subunit of RNA polymerase II (Pol II) as potential ARMC5-interacting proteins. Here, we show that ARMC5, CUL3 and RBX1 form an active E3 ligase complex specific for RPB1. ARMC5, CUL3, and RBX1 formed an active E3 specific for RPB1. Armc5 deletion caused a significant reduction in RPB1 ubiquitination and an increase in an accumulation of RPB1, and hence an enlarged Pol II pool in normal tissues and organs. The compromised RPB1 degradation did not cause generalized Pol II stalling nor depressed transcription in the adrenal glands but did result in dysregulation of a subset of genes, with most upregulated. We found RPB1 to be highly expressed in the adrenal nodules from patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) harboring germline ARMC5 mutations. Mutant ARMC5 had altered binding with RPB1. In summary, we discovered that wildtype ARMC5 was part of a novel RPB1-specific E3. ARMC5 mutations resulted in an enlarged Pol II pool, which dysregulated a subset of effector genes. Such an enlarged Pol II pool and gene dysregulation was correlated to adrenal hyperplasia in humans and KO mice.

Hyperoside ameliorates cerebral ischaemic-reperfusion injury by opening the TRPV4 channel in vivo through the IP3-PKC signalling pathway.

CONTEXT: Hyperoside (Hyp), one of the active flavones from Rhododendron (Ericaceae), has beneficial effects against cerebrovascular disease. However, the effect of Hyp on vasodilatation has not been elucidated. OBJECTIVE: To explore the effect of Hyp on vasodilatation in the cerebral basilar artery (CBA) of Sprague-Dawley (SD) rats suffering with ischaemic-reperfusion (IR) injury. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into sham, model, Hyp, Hyp + channel blocker and channel blocker groups. Hyp (50 mg/kg, IC50 = 18.3 µg/mL) and channel blocker were administered via tail vein injection 30 min before ischaemic, followed by 20 min of ischaemic and 2 h of reperfusion. The vasodilation, hyperpolarization, ELISA assay, haematoxylin-eosin (HE), Nissl staining and channel-associated proteins and qPCR were analysed. Rat CBA smooth muscle cells were isolated to detect the Ca2+ concentration and endothelial cells were isolated to detect apoptosis rate. RESULTS: Hyp treatment significantly ameliorated the brain damage induced by IR and evoked endothelium-dependent vasodilation rate (47.93 ± 3.09% vs. 2.99 ± 1.53%) and hyperpolarization (-8.15 ± 1.87 mV vs. -0.55 ± 0.42 mV) by increasing the expression of IP3R, PKC, transient receptor potential vanilloid channel 4 (TRPV4), IKCa and SKCa in the CBA. Moreover, Hyp administration significantly reduced the concentration of Ca2+ (49.08 ± 7.74% vs. 83.52 ± 6.93%) and apoptosis rate (11.27 ± 1.89% vs. 23.44 ± 2.19%) in CBA. Furthermore, these beneficial effects of Hyp were blocked by channel blocker. DISCUSSION AND CONCLUSIONS: Although Hyp showed protective effect in ischaemic stroke, more clinical trial certification is needed due to the difference between animals and humans.

Silencing Tautomerization to Isolate Unstable Physalins from Physalis minima.

The inherent structural instability of some physalins has hampered the isolation and identification of these compounds for approximately 50 years, and an effective method to overcome these challenges remains unavailable. In the present study, the unprecedented tautomerization mechanism of unstable physalins was elucidated by performing isotopic labeling experiments and DFT calculations, which led to the successful separation of tautomers and isolation of highly pure products for the first time. As a result, 15 new physalins, physaminins A-O (1-15), as well as 17 known analogues (16-32), were isolated from the whole plants of Physalis minima L. The chemical structures of the new compounds were established by performing a comprehensive analysis of spectroscopic data, and their absolute configurations were confirmed by using computational ECD calculations and/or single-crystal X-ray diffraction analyses. All obtained isolates were evaluated for their antiproliferative effects against four human cancer cell lines (A549, HepG2, MCF-7, and SCG-7901) and two noncancerous cell lines (RAW 264.7 and human normal hepatocytes L02), as well as their anti-inflammatory activities by measuring their abilities to inhibit NO production in LPS-stimulated murine RAW 264.7 cells in vitro. Compounds 1-5, 13, 16, 18, 19, 23, and 30 exerted significant antiproliferative effects on the four human cancer lines, with IC50 values ranging from 0.2(0) to 24.7(2) µM, and these compounds were not toxic to the two noncancerous cell lines at a concentration of 10 µM. Moreover, compounds 7, 10, 11, 12, 14, 17, 22, and 27 significantly inhibited NO production, with IC50 values ranging from 2.9(1) to 9.5(2) µM.

Organophosphorus insecticides exposure and sex hormones in general U.S. population: A cross-sectional study.

BACKGROUND: Evidence showed organophosphorus (OPs) insecticide exposure is common in general population with endocrine-disrupting effects. However, the association between OPs metabolites and sex hormones remains unclear. OBJECTIVE: To investigate the association between OPs metabolites and sex hormones. METHODS: Data of 1438 participants from NHANES 2015-2016 was applied. Urinary OPs metabolites, dialkyl phosphates (DAPs), and serum sex hormones (total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG)) were measured. Free androgen index (FAI) and TT/E2 ratio were also calculated. The generalized linear regression model and restricted cubic spline (RCS) model were employed to evaluate the association and exposure-response curve of DAPs and sex hormones in males and females. The modulation effect of age on their associations in female participants was also explored. RESULTS: After adjusting for confounding factors, DETP was negatively associated with E2 (ß = -0.03; 95% CI: -0.05, -0.01) and FAI (ß = -0.03; 95% CI: -0.06, -0.001) in males. In females, all the four DAP metabolites (DMP, DEP, DMTP, and DETP) were negatively associated with FAI (DMP: ß = -0.06, 95% CI: -0.11, -0.01; DEP: ß = -0.06, 95% CI: -0.12, -0.01; DMTP: -0.05, 95% CI: -0.09, -0.02; DETP: -0.09, 95% CI: -0.14, -0.04). DETP was also found negatively associated with TT and TT/E2 ratio in females. The associations between DETP and TT, FAI, and TT/E2 ratio were modified by gender (Pinteraction<0.05). RCS analysis found these associations were in linear decreased exposure-response curves. For females of different age groups, the inverse associations of DETP with TT and FAI remained stable. Decreased FAI with DMP and DMTP was also found in females ≤50 years old. CONCLUSIONS: Our study indicates OPs metabolites had negative associations with androgen indicators, which was characterized as decreased FAI and E2 in males and decreased TT, FAI, and TT/E2 ratio in females, particularly among females ≤50 years old. Further studies are warranted in larger-scale populations.

The receptor tyrosine kinase EPHB6 regulates catecholamine exocytosis in adrenal gland chromaffin cells.

The erythropoietin-producing human hepatocellular receptor EPH receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosterone-dependent fashion. EPHB6 also has a role in regulating blood pressure, but several facets of this regulation remain unclear. Using amperometry recordings, we now found that catecholamine secretion by AGCCs is compromised in the absence of EPHB6. AGCCs from male knockout (KO) mice displayed reduced cortical F-actin disassembly, accompanied by decreased catecholamine secretion through exocytosis. This phenotype was not observed in AGCCs from female KO mice, suggesting that testosterone, but not estrogen, contributes to this phenotype. Of note, reverse signaling from EPHB6 to ephrin B1 (EFNB1) and a 7-amino acid-long segment in the EFNB1 intracellular tail were essential for the regulation of catecholamine secretion. Further downstream, the Ras homolog family member A (RHOA) and FYN proto-oncogene Src family tyrosine kinase (FYN)-proto-oncogene c-ABL-microtubule-associated monooxygenase calponin and LIM domain containing 1 (MICAL-1) pathways mediated the signaling from EFNB1 to the defective F-actin disassembly. We discuss the implications of EPHB6's effect on catecholamine exocytosis and secretion for blood pressure regulation.

EPHB6 controls catecholamine biosynthesis by up-regulating tyrosine hydroxylase transcription in adrenal gland chromaffin cells.

EPHB6 is a member of the erythropoietin-producing hepatocellular kinase (EPH) family and a receptor tyrosine kinase with a dead kinase domain. It is involved in blood pressure regulation and adrenal gland catecholamine (CAT) secretion, but several facets of EPHB6-mediated CAT regulation are unclear. In this study, using biochemical, quantitative RT-PCR, immunoblotting, and gene microarray assays, we found that EPHB6 up-regulates CAT biosynthesis in adrenal gland chromaffin cells (AGCCs). We observed that epinephrine content is reduced in the AGCCs from male Ephb6-KO mice, caused by decreased expression of tyrosine hydroxylase, the rate-limiting enzyme in CAT biosynthesis. We demonstrate that the signaling pathway from EPHB6 to tyrosine hydroxylase expression in AGCCs involves Rac family small GTPase 1 (RAC1), MAP kinase kinase 7 (MKK7), c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, activator protein 1 (AP1), and early growth response 1 (EGR1). On the other hand, signaling via extracellular signal-regulated kinase (ERK1/2), p38 mitogen-activated protein kinase, and ELK1, ETS transcription factor (ELK1) was not affected by EPHB6 deletion. We further report that EPHB6's effect on AGCCs was via reverse signaling through ephrin B1 and that EPHB6 acted in concert with the nongenomic effect of testosterone to control CAT biosynthesis. Our findings elucidate the mechanisms by which EPHB6 modulates CAT biosynthesis and identify potential therapeutic targets for diseases, such as hypertension, caused by dysfunctional CAT biosynthesis.

Contaminant-related oxidative distress in common kingfisher (Alcedo atthis) breeding at an e-waste site in South China.

The crude electronic waste (e-waste) recycling has caused severe contamination of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the local environment, begging the question of whether wildlife like birds living at e-waste sites are suffering from adverse effects. We examined several oxidative status markers and their relationships with hepatic concentrations of PCBs and PBDEs in common kingfisher (Alcedo atthis) that inhabit an e-waste site in South China. The results showed that the mean concentrations of ∑PCBs (19100 ng/g) and ∑PBDEs (507 ng/g) in kingfishers from e-waste site were several orders of magnitude higher than those in the species from a reference site. Correspondingly, hepatic concentrations of malondialdehyde (MDA) and reactive oxygen species (ROS) in kingfishers from the e-waste site were significantly higher than those detected in the reference population, suggesting oxidative distress in the birds breeding at the e-waste site. The activities of superoxide dismutase (SOD) and catalase (CAT) in the liver from the exposed group were significantly lower compared with the reference group, while the opposite trend was observed for glutathione peroxidase (GPx). Significantly positive correlations were observed between PCB or PBDE concentrations and the levels of MDA and ROS; while negative correlations were found for enzymatic activities of SOD and CAT. Overall, our results may suggest a potential linkage between exposure to e-waste-derived pollutants and elevated oxidative stress, thereby indicating a potential oxidative stress-related health effects in common kingfisher breeding at the e-waste site.

Evaluation of Factors Associated with Anxiety and Depression in Chinese Visiting Scholars in the United States During the COVID-19 Pandemic Assessed by Online Questionnaires.

BACKGROUND This study aimed to use online questionnaires to evaluate the factors associated with anxiety and depression in Chinese visiting scholars in the United States during the COVID-19 pandemic. MATERIAL AND METHODS Using a cross-sectional design, 311 Chinese scholars visiting 41 states in the United States were interviewed on 20 and 21 April 2020 through WeChat using the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7) questionnaire. RESULTS Of these 311 visiting scholars, 69 (22.2%) reported no symptoms of anxiety or depression, whereas 63 (20.3%) reported severe anxiety and 67 (21.5%) reported severe depression. Risk of anxiety was 93% higher in visiting scholars with than without accompanying parents in the US (odds ratio [OR], 1.93; 95% confidence interval [CI], 1.01-3.68) and was 1.72-fold (95% CI, 1.04-2.84) higher in those experiencing stress about family members with COVID-19. Stresses about personal security and return to China on schedule were associated with 1.73-fold (95% CI, 1.03-2.92) and 3.00-fold (95% CI, 1.51-5.95) higher risks of anxiety, respectively. Risks of depression were 1.86-fold (95% CI, 1.14-3.05), 1.84-fold (95% CI, 1.10-3.07), and 3.45-fold (95% CI, 1.72-6.92) higher in visiting Chinese scholars who were than were not experiencing stresses about financial support, personal security and return to China on schedule, respectively. CONCLUSIONS Chinese scholars visiting the United States during the COVID-19 pandemic experienced severe psychological distress. Surveys that include larger numbers of visiting scholars are warranted.

Decarbromodiphenyl ether (BDE-209) promotes monocyte-endothelial adhesion in cultured human aortic endothelial cells through upregulating intercellular adhesion molecule-1.

There is growing evidence that exposure to persistent organic pollutants (POPs) is statistically associated with incidence of cardiovascular disease (CVD) or its risk factors. Decarbromodiphenyl ether (BDE-209) is a new POP which exists extensively in human tissues, but its potential effects on CVD have so far received less focus. The adhesion of circulating monocytes to endothelial cells is one of the critical underlying steps in the initiation and development of CVD. In the present study, we investigated the effect of BDE-209 on the adhesion of THP-1 monocytes to human aortic endothelial cells (HAECs) and identified the molecular mechanisms involved. Our results showed that 6.25, 12.5 and 25 µM of BDE-209 exposures caused significant increases in monocyte-endothelial cell adhesion, in a dose-dependent manner. Mechanistically, BDE-209 exposure increased the expression of intercellular adhesion molecule-1 (ICAM-1). Moreover, the up-regulation of ICAM-1 was accompanied by a decrease in the expression of microRNA-141 (miR-141). Furthermore, the up-regulation of ICAM-1 and the increased adhesion induced by BDE-209 could be reversed by miR-141 supplement. Taken together, our results show that BDE-209 potentiates monocyte-endothelial cell interaction via miR-141/ICAM-1 pathway in HAECs.

Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors.

Purpose: To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors.Materials and methods: Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT + ACT (n = 10), HT + ACT + anti-PD-1 inhibitor (pembrolizumab) (n = 11) and HT + ACT + CT (n = 12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment.Results: The objective response rate (ORR) was 30% (10/33), including three complete responses (CR) (9.1%) and seven partial responses (PR) (21.2%) and a disease control rate (DCR = CR + PR + SD) of 66.7% (22 of 33). The most common adverse reactions, blistering, subcutaneous fat induration, local heat-related pain, vomiting and sinus tachycardia, were observed in association with HT. IL-2, IL-4, TNF-α, and IFN-γ levels in peripheral blood were significantly increased among the clinical responders (p < 0.05) while IL-6 and IL-10 were elevated among those with progressive disease (p < 0.05). Peripheral blood CD8+/CD28+ T cells increased (p = 0.002), while the CD4+/CD25+/CD127+Treg cells decreased after therapy (p = 0.012). TCR diversity was substantially increased among the clinical responders.Conclusions: Combining HT with ACT plus either CT or anti-PD-1 antibody was safe, generated clinical responses in previously treated advanced cancers, and promoted TCR repertoire diversity and favorable changes in serum IL-2, IL-4, TNF-α, and IFN-γ levels in clinical responders.

Sleep patterns in Parkinson's disease: direct recordings from the subthalamic nucleus.

Sleep is a fundamental homeostatic process, and disorders of sleep can greatly affect quality of life. Parkinson's disease (PD) is highly comorbid for a spectrum of sleep disorders and deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been reported to improve sleep architecture in PD. We studied local field potential (LFP) recordings in PD subjects undergoing STN-DBS over the course of a full-night's sleep. We examined the changes in oscillatory activity recorded from STN between ultradian sleep states to determine whether sleep-stage dependent spectral patterns might reflect underlying dysfunction. For this study, PD (n=10) subjects were assessed with concurrent polysomnography and LFP recordings from the DBS electrodes, for an average of 7.5 hours in 'off' dopaminergic medication state. Across subjects, we found conserved spectral patterns among the canonical frequency bands (delta 0-3 Hz, theta 3-7 Hz, alpha 7-13 Hz, beta 13-30 Hz, gamma 30-90 Hz and high frequency 90-350 Hz) that were associated with specific sleep cycles: delta (0-3 Hz) activity during non-rapid eye movement (NREM) associated stages was greater than during Awake, whereas beta (13-30 Hz) activity during NREM states was lower than Awake and rapid eye movement (REM). In addition, all frequency bands were significantly different between NREM states and REM. However, each individual subject exhibited a unique mosaic of spectral interrelationships between frequency bands. Our work suggests that LFP recordings from human STN differentiate between sleep cycle states, and sleep-state specific spectral mosaics may provide insight into mechanisms underlying sleep pathophysiology.

Oleiferoside W from the roots of Camellia oleifera C. Abel, inducing cell cycle arrest and apoptosis in A549 cells.

Camellia oleifera C. Abel has been widely cultivated in China, and a group of bioactive constituents such as triterpeniod saponin have been isolated from C. oleifera C. Abel. In the current study, a new triterpeniod saponin was isolated from the EtOH extract of the roots of C. oleifera C. Abel, named as oleiferoside W, and the cytotoxic properties of oleiferoside W were evaluated in non-small cell lung cancer A549 cells. At the same time the inducing apoptosis, the depolarization of mitochondrial membrane potential (Δψ), the up-regulation of related pro-apoptotic proteins, such as cleaved-PARP, cleaved-caspase-3, and the down-regulation of anti-apoptotic marker Bcl-2/Bax were measured on oleiferoside W. Furthermore, the function, inducing the generation of reactive oxygen species (ROS) and apoptosis, of oleiferoside W could be reversed by N-acetylcysteine (NAC). In conclusion, our findings showed that oleiferoside W induced apoptosis involving mitochondrial pathway and increasing intracellular ROS production in the A549 cells, suggesting that oleiferoside W may have the possibility to be a useful anticancer agent for therapy in lung cancer.

Work stress, family stress and asthma: a cross-sectional study among women in China.

PURPOSE: Research addressing links of work stress or family stress with asthma is constrained by (1) inconsistent evidence, (2) failure to consider the combined exposure to work stress and family stress, and (3) its primary focus on Western study populations. We aimed to address these knowledge gaps. METHODS: We used cross-sectional data collected in 2015 among 7816 women from five professional groups in five Chinese cities. Work stress was measured by the 10-item effort-reward imbalance (ERI) questionnaire. Family stress was assessed by a psychometrically evaluated instrument comprising five items on, e.g., familial conflicts or domestic workload. Asthma was operationalized by self-reports of a physician diagnosis. Associations were examined by multivariable logistic regression estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Both high work stress (i.e., ERI score >1) and high family stress (i.e., score above the median) were associated with asthma (OR 1.66, 95% CI 1.22-2.27 and OR 1.48, 95% CI 1.10-1.99, respectively). Women with combined exposure (versus none) had somewhat higher odds of asthma (OR 2.13, 95% CI 1.42-3.19) than those with sole exposure to either work stress (OR 1.89, 95% CI 1.20-2.96) or family stress (OR 1.71, 95% CI 1.03-2.84). Interaction terms were significant for continuous variables (p = 0.046), but not for dichotomized variables (p = 0.199). CONCLUSIONS: The present study suggests that both work stress and family stress are positively associated with asthma in women in China. Further, the combined exposure may be associated with a further excess of asthma occurrence. Longitudinal studies are needed to confirm our findings and to explore potential temporal relationships.

EPHB4 Protein Expression in Vascular Smooth Muscle Cells Regulates Their Contractility, and EPHB4 Deletion Leads to Hypotension in Mice.

EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure.

EphrinB1 and EphrinB2 regulate T cell chemotaxis and migration in experimental autoimmune encephalomyelitis and multiple sclerosis.

T cells are believed to be key effector cells in multiple sclerosis (MS). In this study, we examined the roles of T cell ephrinB1 (EFNB1) and ephrinB2 (EFNB2) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and MS. We provide evidence that animals with T cell specific double deletion of EFNB1 and EFNB2 (dKO) have reduced proliferation in response to MOG35-55, defective Th1 and Th17 differentiations and significantly lower scores of MOG-induced EAE. We further demonstrate that dKO T cells are compromised in their ability to migrate into the CNS of EAE animals in vivo and towards multiple chemokines in vitro. Using deletion mutations, we identified a critical 11-aa EFNB1 intracellular domain segment that controls T cell chemotaxis towards CCL21. In humans, EFNB1 and EFNB2 are highly expressed in Th1 and Th17 cells and EFNB1- and EFNB2-expressing T cells are found among immune cell infiltrates in MS lesions. Reverse signaling through EFNB1 and EFNB2 in human Th17 cells enhances their migration through a monolayer of blood brain barrier endothelial cells. Our study demonstrates that expression of EFNB1 and EFNB2 is implicated in Th cell differentiation and migration to inflammatory sites in both EAE and MS.

TGFBI (ßIG-H3) is a diabetes-risk gene based on mouse and human genetic studies.

Transforming growth factor beta-induced (TGFBI/ßIG-H3), also known as ßig-H3, is a protein inducible by TGFß1 and secreted by many cell types. It binds to collagen, forms part of the extracellular matrix and interacts with integrins on the cell surface. Recombinant TGFBI and transgenic TGFBI overexpression can promote both islet survival and function. In this study, we generated TGFBI KO mice and further assessed TGFBI function and signaling pathways in islets. Islets from KO mice were of normal size and quantity, and these animals were normoglycemic. However, KO islet survival and function was compromised in vitro. In vivo, KO donor islets became inferior to wild-type donor islets in achieving normoglycemia when transplanted into KO diabetic recipients. TGFBI KO mice were more prone to straptozotocin-induced diabetes than the wild-type counterpart. Phosphoprotein array analysis established that AKT1S1, a molecule linking the AKT and mTORC1 signaling pathways, was modulated by TGFBI in islets. Phosphorylation of four molecules in the AKT and mTORC1 signaling pathway, i.e. AKT, AKT1S1, RPS6 and EIF4EBP1, was upregulated in islets upon TGFBI stimulation. Suppression of AKT activity by a chemical inhibitor, or knockdown of AKT1S1, RPS6 and EIF4EBP1 expression by small interfering RNA, modulated islet survival, proving the relevance of these molecules in TGFBI-triggered signaling. Human genetic studies revealed that in the TGFBI gene and its vicinity, three single-nucleotide polymorphisms were significantly associated with type 1 diabetes risks, and one with type 2 diabetes risks. Our study suggests that TGFBI is a potential risk gene for human diabetes.

Estrogen and testosterone in concert with EFNB3 regulate vascular smooth muscle cell contractility and blood pressure.

EPH kinases and their ligands, ephrins (EFNs), have vital and diverse biological functions, although their function in blood pressure (BP) control has not been studied in detail. In the present study, we report that Efnb3 gene knockout (KO) led to increased BP in female but not male mice. Vascular smooth muscle cells (VSMCs) were target cells for EFNB3 function in BP regulation. The deletion of EFNB3 augmented contractility of VSMCs from female but not male KO mice, compared with their wild-type (WT) counterparts. Estrogen augmented VSMC contractility while testosterone reduced it in the absence of EFNB3, although these sex hormones had no effect on the contractility of VSMCs from WT mice. The effect of estrogen on KO VSMC contractility was via a nongenomic pathway involving GPER, while that of testosterone was likely via a genomic pathway, according to VSMC contractility assays and GPER knockdown assays. The sex hormone-dependent contraction phenotypes in KO VSMCs were reflected in BP in vivo. Ovariectomy rendered female KO mice normotensive. At the molecular level, EFNB3 KO in VSMCs resulted in reduced myosin light chain kinase phosphorylation, an event enhancing sensitivity to Ca(2+)flux in VSMCs. Our investigation has revealed previously unknown EFNB3 functions in BP regulation and show that EFNB3 might be a hypertension risk gene in certain individuals.

Cytokine-induced killer cell infusion combined with conventional treatments produced better prognosis for hepatocellular carcinoma patients with barcelona clinic liver cancer B or earlier stage: A systematic review and meta-analysis.

BACKGROUND AIMS: To investigate the clinical benefits of cytokine-induced killer (CIK) cell infusions on hepatocellular carcinoma (HCC) patients, combined with other conventional treatments. METHODS: This was a systematic review and meta-analysis conducted among phase II and III randomized control trials worldwide. Review manager 5.2 version was used to pool the effect size across studies. Sensitivity analyses and risk of bias were estimated among included studies. Egger's test was used to characterize the publication bias. RESULTS: Eight randomized controlled trials and 945 patients with HCC were included in the study. CIK infusion reduced cancer recurrence risk to 0.74 (95% confidence interval [CI] 0.5-0.92), I2 75% (P <0.001), and reduced cancer death risk to 0.76 (95% CI 0.65-0.88), I2 50% (P = 0.09). Among studies blinded for outcome assessment and Barcelona Clinic Liver Cancer stages of 0, A and B, CIK infusion reduced recurrence risk by 18% (relative risk [RR] = 0.82, 95% CI 0.70-0.96) and death risk by 37% (RR = 0.63, 95% CI 0.47-0.85); heterogeneity was 0% and 39%, respectively (P > 0.05). The intercepts of linear regressions for recurrence and death were -2.17 and -2.07, respectively, but the P value was 0.17 and 0.38; no significant publication bias was observed with Egger's test. DISCUSSION: Among hepatocellular carcinoma patients with Barcelona Clinic Liver Cancer score of B or less, CIK cell infusions combined with conventional treatments significantly prolonged recurrence-free and overall survival. This adoptive immunotherapy could be recommended to HCC patients.

An Enantioselective Synthesis of an 11-ß-HSD-1 Inhibitor via an Asymmetric Methallylation Catalyzed by (S)-3,3'-F2-BINOL.

An efficient asymmetric synthesis of 11-ß-HSD inhibitor 1 has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (S)-3,3'-F2-BINOL under solvent-free and metal-free conditions.