The aim of this study was to determine the effect of RNA interference inhibition of mineralocorticoid receptor (MR) on cold-induced hypertension (CIH) and renal damage. Recombinant adeno-associated virus (AAV) carrying short hairpin small interference (si)RNA for MR (AAV.MR-shRNA) was constructed and tested for the ability to inhibit renal MR and to control CIH. Three groups of rats with CIH received AAV.MR-shRNA (1.25 Â 10 9 particles/rat, intravenous), AAV carrying scrambled shRNA (AAV.Control-shRNA) (1.25 Â 10 9 particles/rat, intravenous) and phosphate buffer solution (PBS), respectively. All rats were kept in a cold chamber (6.71C) throughout the experiment. Adeno-associated virus delivery of MR-shRNA prevented progression of CIH. Blood pressure (BP) of the AAV.MR-shRNA-treated group did not increase and remained at 14573 mm Hg, whereas BP of the AAV.Control-shRNA-treated and PBStreated group increased to 16774 and 16173 mm Hg, respectively, at 3 weeks after gene delivery. Thus, the antihypertensive effect of a single injection of AAV.MRshRNA lasted for at least 3 weeks (length of the study). Adeno-associated virus carrying short hairpin siRNA for MR significantly increased urinary sodium excretion and decreased proteinuria. It also decreased serum creatinine and blood urea nitrogen, suggesting enhanced renal function. Both Western blot and immunohistochemical analysis showed that MR expression was decreased significantly in the kidney in the AAV.MR-shRNA-treated rats, confirming that renal MR is effectively inhibited by AAV.MR-shRNA. Adeno-associated virus carrying short hairpin siRNA for MR also significantly attenuated renal hypertrophy. In addition, AAV delivery of MR-shRNA prevented atrophy and dilation of renal tubules and abolished tubular deposition of proteinaceous material seen in CIH rats. Conclusions: (1) AAV delivery of MR-shRNA effectively silenced MR in vivo. (2) RNA interference inhibition of MR may open a new avenue for the long-term control of hypertension and renal damage.
We report the results of an extensive study employing numerous methods to characterize carrier transport within copper indium gallium sulfoselenide (CIGSS) photovoltaic devices, whose absorber layers were fabricated by diverse process methods in multiple laboratories. This collection of samples exhibits a wide variation of morphologies, compositions, and solar power conversion efficiencies. An extensive characterization of transport properties is reported here -including those derived from capacitance-voltage, admittance spectroscopy, deep level transient spectroscopy, time-resolved photoluminescence, Auger emission profiling, Hall effect, and drive level capacitance profiling. Data from each technique were examined for correlation with device performance, and those providing indicators of related properties were compared to determine which techniques and interpretations provide credible values for transport properties. Although these transport properties are not sufficient to predict all aspects of current-voltage characteristics, we have identified specific physical and transport characterization methods that can be combined using a model-based analysis algorithm to provide a quantitative prediction of voltage loss within the absorber. The approach has potential as a tool to optimize and understand device performance irrespective of the specific
We present results of detailed investigations of light emission from semiconductor multiple quantum wells at low temperatures and high magnetic fields excited by intense femtosecond laser pulses. The intensity and linewidth as well as the directional and statistical properties of photoemission strongly depended on the magnetic field strength and pump laser fluence. We also investigated the effects of spot size, temperature, excitation geometry, and excitation pulse width on the emission properties. The results suggest that the initially incoherent photoexcited electron-hole pairs spontaneously form a macroscopic coherent state upon relaxation into the low-lying magnetoexcitonic states, followed by the emission of a superfluorescent burst of radiation. We have developed a theoretical model for superfluorescent emission from semiconductor quantum wells, which successfully explained the observed characteristics.
Improvements in high-throughput sequencing technologies have spurred a large number of studies aimed at obtaining a better understanding of the composition and the dynamics in gut microbiota and its associations with various human diseases, especially those in the intestinal tract. Here we briefly summarize results from three different such studies from our group, all of which used 454 based high-throughput 16S rRNA sequence analysis combined with other microbiota profiling methods to determine faecal microbiota composition. In the first study, a controlled feeding trial, we establish that energy gain from the consumption of up to 50 g/day of a resistant maltodextrin depends on the prevalent microbiota composition. Over time, resistant maltodextrin supplementation increased the proportion of total faecal bacteria as well as potentially beneficial bifidobacteria. Thus, energy gain from resistant maltodextrin in an individual appears to vary over time and depend on the adaptation of gut microbiota. We then illustrate the power of molecular tools for identifying (i) distortions in early microbiota development in pre-term infants and the presence of potentially novel pathogens contributing to necrotizing enterocolitis and (ii) a specific microbiota signature, based on discriminant analysis of the 16S rRNA sequences, that correlates with the prevalence of an early risk marker associated with colorectal carcinogenesis, intestinal adenoma, in elderly adults.
Our laboratory develops protocols to prevent or reverse ongoing anti-hFIX IgG inhibitors in haemophilia B mice with a F9 gene deletion on BALB/c and C3H/HeJ backgrounds. C3H/HeJ F9−/Y mice develop high titre anti-hFIX IgG1 inhibitors and anaphylaxis, whereas most BALB/c F9−/Y mice have mild anti-hFIX IgG1 inhibitors and no anaphylaxis. Our aim was to determine if hFIX-specific B- and T-cell responses in BALB/c and C3H/HeJ F9−/Y mice trigger the difference in anti-hFIX immune responses. BALB/c and C3H/HeJ F9−/Y mice were challenged weekly with recombinant hFIX protein. Humoral immune responses were determined by IgG1 and IgG2a anti-hFIX ELISA, Bethesda assay for inhibitors and B-cell ELISpot on bone marrow and spleen cells. T-cell studies measured the TH1 (IFN-γ) and TH2 (IL-4) cytokine responses in splenocytes at the mRNA and protein level in response to hFIX protein. Antibody responses were also measured in C3H/HeJ/OuJ F9−/Y mice with restored toll-like receptor 4 (TLR4) function. BALB/c F9−/Y mice have a TH2 skewed response and a reduction in anti-hFIX secreting plasma cells in the bone marrow. Independent antigen challenge revealed both strains generated equivalent IgG1 antibody titres to an intravenously delivered antigen. C3H/HeJ F9−/Y mice have a mixed TH1 and TH2 response (mainly TH2). Importantly, TLR4 signalling has a modulatory role in the C3H background on the levels of anti-hFIX IgG1 and incidence of anaphylaxis. The background strain strongly impacts the immune response to hFIX, which can be significantly impacted by mutations in innate immune sensors.
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