The rockefeller university

A study reports a new method for wholesale labeling of neuronal proteins in situ that can visualize newly synthesized protein in a manner compatible with standard immunostaining techniques.

Persistent hepatitis C virus (HCV) infection is a primary etiological factor for the development of chronic liver disease, including cirrhosis and cancer. A recent study identified occludin (OCLN), an integral tight junction protein, as one of the key factors for HCV entry into cells. We explored the splicing diversity of OCLN in normal human liver and observed variable expression of alternative splice variants, including two known forms (WT-OCLN and OCLN-ex4del) and six novel forms (OCLN-ex7ext, OCLN-ex3pdel, OCLN-ex3del, OCLN-ex3-4del, OCLN-ex3p-9pdel, and OCLN-ex3p-7pdel). Recombinant protein isoforms WT-OCLN and OCLN-ex7ext, which retained the HCV-interacting MARVEL domain, were expressed on the cell membrane and were permissive for HCV infection in in vitro infectivity assays. All other forms lacked the MARVEL domain, were expressed in the cytoplasm, and were nonpermissive for HCV infection. Additionally, we observed variable expression of OCLN splicing forms across human tissues and cell lines. Our study suggests that the remarkable natural splicing diversity of OCLN might contribute to HCV tissue tropism and possibly modify the outcome of HCV infection in humans. Genetic factors crucial for regulation of OCLN expression and susceptibility to HCV infection remain to be elucidated.

During vertebrate embryogenesis, the expression of Hox genes that define anterior-posterior identity follows general rules: temporal colinearity and posterior prevalence. A mathematical measure for the quality or fitness of the embryonic pattern produced by a gene regulatory network is derived. Using this measure and in silico evolution we derive gene interaction networks for anterior-posterior ( AP) patterning under two developmental paradigms. For patterning during growth ( paradigm I), which is appropriate for vertebrates and short germ-band insects, the algorithm creates gene expression patterns reminiscent of Hox gene expression. The networks operate through a timer gene, the level of which measures developmental progression ( a candidate is the widely conserved posterior morphogen Caudal). The timer gene provides a simple mechanism to coordinate patterning with growth rate. The timer, when expressed as a static spatial gradient, functions as a classical morphogen ( paradigm II), providing a natural way to derive the AP patterning, as seen in long germ-band insects that express their Hox genes simultaneously, from the ancestral short germ-band system. Although the biochemistry of Hox regulation in higher vertebrates is complex, the actual spatiotemporal expression phenotype is not, and simple activation and repression by Hill functions suffices in our model. In silico evolution provides a quantitative demonstration that continuous positive selection can generate complex phenotypes from simple components by incremental evolution, as Darwin proposed.

We combine results from searches by the CDF and D0 collaborations for a standard model Higgs boson (H) in the process gg -> H -> W+W- in p (p) over bar collisions at the Fermilab Tevatron Collider at root s = 1.96 TeV. With 4.8 fb(-1) of integrated luminosity analyzed at CDF and 5.4 fb(-1) at D0, the 95% confidence level upper limit on sigma(gg -> H) x B(H -> W+W-) is 1.75 pb at m(H) = 120 GeV, 0.38 pb at m(H) = 165 GeV, and 0.83 pb at m(H) = 200 GeV. Assuming the presence of a fourth sequential generation of fermions with large masses, we exclude at the 95% confidence level a standard-model-like Higgs boson with a mass between 131 and 204 GeV.

We report a measurement of the ratio of the t (t) over bar to Z/gamma* production cross sections in root s = 1.96 TeV p (p) over bar collisions using data corresponding to an integrated luminosity of up to 4.6 fb(-1), collected by the CDF II detector. The t (t) over bar cross section ratio is measured using two complementary methods, a b-jet tagging measurement and a topological approach. By multiplying the ratios by the well-known theoretical Z/gamma* -> ll cross section predicted by the standard model, the extracted t (t) over bar cross sections are effectively insensitive to the uncertainty on luminosity. A best linear unbiased estimate is used to combine both measurements with the result sigma(t (t) over bar) = 7.70 +/- 0.52 pb, for a top-quark mass of 172.5 GeV/c(2).

Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition to its well-characterized functions in malignancy, recent evidence from several laboratories suggests a role for Hsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated or over-activated, allowing and sustaining the accumulation of toxic aggregates. In addition, Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1), the master regulator of the heat shock response, mechanism that cells use for protection when exposed to conditions of stress. These biological functions therefore propose Hsp90 inhibition as a dual therapeutic modality in neurodegenerative diseases. First, by suppressing aberrant neuronal activity, Hsp90 inhibitors may ameliorate protein aggregation and its associated toxicity. Second, by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity. This mini-review will summarize our current knowledge on Hsp90 in neurodegeneration and will focus on the potential beneficial application of Hsp90 inhibitors in neurodegenerative diseases.

The putative role of the endocannabinoid system and the effects of cannabis use in male and female sexual functioning are summarized. The influence of cannabis intake on sexual behavior and arousability appear to be dose-dependent in both men and women, although women are far more consistent in reporting facilitatory effects. Furthermore, evidence from nonhuman species indicate somewhat more beneficial than debilitating effects of cannabinoids on female sexual proceptivity and receptivity while suggesting predominantly detrimental effects on male sexual motivation and erectile functioning. Data from human and nonhuman species converge on the ephemeral nature of THC-induced testosterone decline. However, it is clear that cannabinoid-induced inhibition of male sexual behavior is independent of concurrent declines in testosterone levels. Investigations also reveal a suppression of gonadotropin release by cannabinoids across various species. Historical milestones and promising future directions in the area of cannabinoid and sexuality research are also outlined in this review. (C) 2009 Elsevier Inc. All rights reserved.