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ojections from basal forebrain and mesopontine tegmental nuclei that contribute to sleep and wakefulness. We have demonstrated that the SCN of inbred rats in a hypothalamic brain slice is sensitive to cholinergic phase adjustment via muscarinic receptors (mAChRs) only at night. We used this paradigm to probe the muscarinic signal transduction mechanism and the site(s) gating nocturnal responsiveness. The cholinergic agonist carbachol altered the circadian rhythm of SCN neuronal activity in a pattern closely resembling that for analogs of cGMP; nocturnal gating of clock sensitivity of each is preserved in vitro. Specific inhibitors of guanylyl cyclase (GC) and cGMP-dependent protein kinase (PKG), key elements in the cGMP signal transduction cascade, blocked phase shifts induced by carbachol. Further, carbachol administration to the SCN at night increased cGMP production and PKG activity. The carbachol-induced increase in cGMP was blocked both by atropine, an mAChR antagonist, and by LY83583, a GC inhibitor. We conclude that (1) mAChR regulation of the SCN is mediated via GC-->cGMP-->PKG, (2) nocturnal gating of this pathway is controlled by the circadian clock, and (3) a gating site is positioned downstream from cGMP. This study is among the first to identify a functional context for mAChR-cGMP coupling in the CNS.

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ient and his or her relatives. We describe a case of mature onset diabetes of the young (MODY) with sufficient evidence to support the classification of a novel HNF1A (hepatocyte nuclear factor-1-alpha) mutation as a cause of MODY-3. METHODS: A 21-year-old Caucasian female presented to our office with a diagnosis of noninsulin-dependent diabetes mellitus (NIDDM) at age 10; glycemia was initially managed with oral antidiabetic (OAD) agents and insulin detemir. The patient reported a strong family history of early-onset NIDDM in both her mother and maternal grandmother, both of whom eventually required insulin therapy to control glycemia. The patient's medical and family history were highly suggestive of maturity-onset diabetes of the young (MODY), and genetic testing was performed. RESULTS: Genetic screening detected a mutation p. Arg200Trp in the HNF1A gene in the patient, her mother, and maternal grandmother, suggesting a diagnosis of MODY-3. This finding resulted in a change of antidiabetic therapy in all 3 patients, including the addition of once-daily liraglutide therapy, which helped improve their glycemic control. CONCLUSION: Our case report supports the classification of the p. Arg200Trp mutation as a cause of MODY-3. The findings also suggest that glucagon-like peptide-1 (GLP-1) receptor agonist therapy may be of value in managing glycemia in patients with MODY-3.

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ation of a novel 1.2-kb gene that encodes a Fas apoptosis inhibitory molecule (FAIM). faim-transfected BAL-17 B lymphoma cells were less sensitive by half or more to Fas-mediated apoptosis than were vector-transfected controls, using Fas ligand-bearing T cells or a cytotoxic anti-Fas antibody to trigger Fas, and this was associated with inhibition of Fas- induced poly-ADP ribose polymerase (PARP) cleavage. In primary B cells, the time course of faim mRNA and FAIM protein expression correlated with the induction of Fas resistance by surface (s)Ig engagement. Thus, FAIM is an inducible effector molecule that mediates Fas resistance produced by sIg engagement in B cells. However, faim is broadly expressed in various tissues and the faim sequence is highly conserved evolutionarily, suggesting that its role extends beyond lymphocyte homeostasis. As FAIM has no significant regions of homology to other gene products that modulate Fas killing, it appears to represent a distinct, new class of antiapoptotic protein.

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moker without COPD(S), smoker with stable COPD(S-COPD) and smoker with acute exacerbation COPD(AE-COPD) was observed by quantitative real-time PCR. By bioinformatics prediction, Fas apoptotic inhibitory molecule 2 (FAIM2) was identified as a potential target of miR-3202. In vitro, human bronchial epithelial (HBE) cells and cigarette smoke extract (CSE) stimulated T lymphocytes were co-cultured. Cell proliferation and apoptosis of HBE cells were determinated. In vivo, rats were exposed in cigarette smoke for 30 days and expression of miR-3202 and FAIM2 in bronchia were detected. Results showed that The miR-3202 was down-regulated in S, S-COPD and AE-COPD group when compared with C group. Decreased level of miR-3202 was also observed in CSE treated T lymphocyte. Additionally, CSE stimulation increased INF-γ and TNF-α levels and FAIM2 expression whereas inhibited Fas and FasL expressions in T lymphocytes. However, these effects were significantly suppressed by miR-3202 overexpression and enhanced by miR-3202 inhibitor. Likely to exogenous miR-3202, FAIM2 knockdown significantly inhibited HBE cells apoptosis, as well as inhibited INF-γ and TNF-α levels. In COPD rats model, miR-3202 was reduced while FAIM2 was up-regulated accordingly. Here, results suggest that high level miR-3202 in T lymphocytes may protect epithelial cells through targeting FAIM2. MiR-3202 might be used as a notable biomarker of COPD.