These data demonstrate that vaginal mucosal immunization can enhance resistance to urinary tract infections in susceptible patients.

BackgroundEpigenetic mechanisms, including DNA methylation, histone modification, and microRNAs, play pivotal roles in stem cell biology. Methyl-CpG binding protein 1 (MBD1), an important epigenetic regulator of adult neurogenesis, controls the proliferation and differentiation of adult neural stem/progenitor cells (aNSCs). We recently demonstrated that MBD1 deficiency in aNSCs leads to altered expression of several noncoding microRNAs (miRNAs).Methodology/Principal FindingsHere we show that one of these miRNAs, miR-195, and MBD1 form a negative feedback loop. While MBD1 directly represses the expression of miR-195 in aNSCs, high levels of miR-195 in turn repress the expression of MBD1. Both gain-of-function and loss-of-function investigations show that alterations of the MBD1–miR-195 feedback loop tip the balance between aNSC proliferation and differentiation.Conclusions/SignificanceTherefore the regulatory loop formed by MBD1 and miR-195 is an important component of the epigenetic network that controls aNSC fate.

(7), and phosphate (P) (1). In contrast, calcitonin (CT)-stimulated 25(OH)D-1␣-hydroxylase activity in the proximal straight tubule is normally responsive (9). At present, the mechanism underlying such localized enzyme unresponsiveness in XLH remains unclear. Although recent studies indicate that modulation of renal 25(OH)D-1␣-hydroxylase activity occurs secondary to transcriptional regulation of the 1␣-hydroxylase gene, CYP27B1 (10 -12), we have previously reported that the abnormal regulation of 25(OH)D-1␣-hydroxylase in the proximal convoluted tubule of hyp-mice manifests despite normal PTH-and P-mediated control of gene expression (13). These observations affirm the presence of a dissociation between mRNA expression and renal 25(OH)D-1␣-hydroxylase activity in hyp-mice and suggest that abnormal modulation of enzyme function occurs secondary to a posttranscriptional defect.Thus, in this study, we investigated whether the aberrant P-and PTH-mediated regulation of vitamin D metabolism in hyp-mice results from abnormal translation of 25(OH)D-1␣-hydroxylase mRNA. In the experiments performed, we assessed renal enzyme activity, mRNA expression, and 25(OH)D-1␣-hydroxylase protein content in response to hypophosphatemia and PTH (as well as CT) in hyp-mice and age-matched normals, using a sensitive in vitro assay of murine enzyme function, real-time RT-PCR for assessment of 25(OH)D-1␣-hydroxylase cytochrome P450 mRNA, and Western blotting to measure 25(OH)D-1␣-hydroxylase protein content in renal tissue.

In both the embryonic and adult brain, a critical step in neurogenesis is neuronal maturation. Deficiency of MeCP2 leads to Rett syndrome, a severe neurodevelopmental disorder. We have previously shown that MeCP2 plays critical roles in the maturation step of new neurons during neurogenesis. MeCP2 is known to regulate the expression of brain-derived neurotrophic factor (BDNF), a potent neurotrophic factor for neuronal maturation. Nevertheless, how MeCP2 regulates BDNF expression and how MeCP2 deficiency leads to reduced BDNF expression remain unclear. Here we show that MeCP2 regulates the expression of a microRNA, miR-15a. We find that miR-15a plays a significant role in the regulation of neuronal maturation. Overexpression of miR-15a inhibits dendritic morphogenesis in immature neurons. On the other hand, a reduction in miR-15a has the opposite effect. We further show that miR-15a regulates expression levels of BDNF, and exogenous BDNF could partially rescue the neuronal maturation deficits resulting from miR-15a overexpression. Finally, inhibition of miR-15a could rescue neuronal maturation deficits in MeCP2-deficient adult-born new neurons. These results demonstrate a novel role for miR-15a in neuronal development and provide a missing link in the regulation of BDNF by MeCP2.

Infections with the picornavirus, human rhinovirus (HRV), are a major cause of wheezing illnesses and asthma exacerbations. In developing a murine model of picornaviral airway infection, we noted the absence of murine rhinoviruses and that mice are not natural hosts for HRV. The picornavirus, mengovirus, induces lethal systemic infections in its natural murine hosts, but small genetic differences can profoundly affect picornaviral tropism and virulence. We demonstrate that inhalation of a genetically attenuated mengovirus, vMC0, induces lower respiratory tract infections in mice. After intranasal vMC0 inoculation, lung viral titers increased, peaking at 24 h postinoculation with viral shedding persisting for 5 days, whereas HRV-A01a lung viral titers decreased and were undetectable 24 h after intranasal inoculation. Inhalation of vMC0, but not vehicle or UV-inactivated vMC0, induced an acute respiratory illness, with body weight loss and lower airway inflammation, characterized by increased numbers of airway neutrophils and lymphocytes and elevated pulmonary expression of neutrophil chemoattractant CXCR2 ligands (CXCL1, CXCL2, CXCL5) and interleukin-17A. Mice inoculated with vMC0, compared with those inoculated with vehicle or UV-inactivated vMC0, exhibited increased pulmonary expression of interferon (IFN-α, IFN-β, IFN-λ), viral RNA sensors [toll-like receptor (TLR)3, TLR7, nucleotide-binding oligomerization domain containing 2 (NOD2)], and chemokines associated with HRV infection in humans (CXCL10, CCL2). Inhalation of vMC0, but not vehicle or UV-inactivated vMC0, was accompanied by increased airway fluid myeloperoxidase levels, an indicator of neutrophil activation, increased MUC5B gene expression, and lung edema, a sign of infection-related lung injury. Consistent with experimental HRV inoculations of nonallergic, nonasthmatic human subjects, there were no effects on airway hyperresponsiveness after inhalation of vMC0 by healthy mice. This novel murine model of picornaviral airway infection and inflammation should be useful for defining mechanisms of HRV pathogenesis in humans.