The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci

Sm and Sm-like (LSm) proteins form heptameric complexes that are involved in various steps of RNA metabolism. In yeast, the Lsm1-7 complex functions in mRNA degradation and is associated with several enzymes of this pathway, while the complex LSm2-8, the composition of which largely overlaps with that of LSm1-7, has a role in pre-mRNA splicing. A human gene encoding an LSm1 homolog has been identified, but its role in mRNA degradation has yet to be elucidated. We performed subcellular localization studies and found hLSm1 predominantly in the cytoplasm. However, it is not distributed evenly; rather, it is highly enriched in small, discrete foci. The endogenous hLSm4 is similarly localized, as are the overexpressed proteins hLSm1-7, but not hLSm8. The foci also contain two key factors in mRNA degradation, namely the decapping enzyme hDcp1/2 and the exonuclease hXrn1. Moreover, coexpression of wild-type and mutant LSm proteins, as well as fluorescence resonance energy transfer (FRET) studies, indicate that the mammalian proteins hLSm1-7 form a complex similar to the one found in yeast, and that complex formation is required for enrichment of the proteins in the cytoplasmic foci. Therefore, the foci contain a partially or fully assembled machinery for the degradation of mRNA.     

Role of cytokines and testosterone in regulating lean body mass and resting energy expenditure in HIV-infected men

Although catastrophic weight loss is no longer common in HIV-infected men, we hypothesized that a more gradual process of cachexia [loss of lean body mass (LBM) without severe weight loss, often accompanied by elevated resting energy expenditure (REE)] is still common and is driven by excessive production of the catabolic cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). We performed a longitudinal analysis of an ongoing cohort study of nutritional status in 172 men with HIV infection. LBM loss of >1 kg occurred in 35% of the cohort, and LBM loss of >5% occurred in 12.2% over 8 mo of observation, but classical wasting (loss of approximately 10% of weight) was rare (2%). Both TNF-alpha (-150 g LBM. ng(-1) x ml(-1), P < 0.02) and IL-1 beta production (-130 g LBM x ng(-1) x ml(-1), P < 0.01) by peripheral blood mononuclear cells predicted loss of LBM. A rise in REE of >200 kcal/day was found in 17.7% of the subjects regardless of weight change. IL-1 beta (+9 kcal/day per ng/ml, P < 0.002) and TNF-alpha (+10 kcal/day per ng/ml, P < 0.02) production predicted Delta REE. Serum free testosterone was inversely associated with TNF-alpha production and was not an independent predictor of either Delta LBM or Delta REE after adjustment for cytokine production. Even though weight loss was rare in this cohort of patients treated with highly active antiretroviral therapy, loss of LBM was common and was driven by catabolic cytokines and not by inadequate dietary intake or hypogonadism.     

Hepatoimmunology: a perspective

Premises for the subspecialty of hepatoimmunology include the recognition that the liver is a lymphoid organ with unique immunological properties. These properties ensure efficient innate defence against intestinal microbes and toxins, confer a particular capacity for induction of tolerance, and provide for apoptotic disposal of redundant lymphocytes. Pathological responses within the liver are elicited when: (i) hepatotropic viruses (hepatitis virus B and C) escape immune elimination and reside in hepatocytes; (ii) the liver becomes the site of autoimmune responses directed against either hepatocytes (autoimmune hepatitis) or biliary ductules (primary biliary cirrhosis); or (iii) the liver in the course of disposal of drugs generates neoantigens that provoke adverse allergic responses. Recent advances in the understanding of the immunopathogenesis of these entities are reviewed.     

Bayesian modeling of incidence and progression of disease from cross-sectional data

In the absence of longitudinal data, the current presence and severity of disease can be measured for a sample of individuals to investigate factors related to disease incidence and progression. In this article, Bayesian discrete-time stochastic models are developed for inference from cross-sectional data consisting of the age at first diagnosis, the current presence of disease, and one or more surrogates of disease severity. Semiparametric models are used for the age-specific hazards of onset and diagnosis, and a normal underlying variable approach is proposed for modeling of changes with latency time in disease severity. The model accommodates multiple surrogates of disease severity having different measurement scales and heterogeneity among individuals in disease progression. A Markov chain Monte Carlo algorithm is described for posterior computation, and the methods are applied to data from a study of uterine leiomyoma.     

Strategies used by rhizobia to lower plant ethylene levels and increase nodulation

Agriculture depends heavily on biologically fixed nitrogen from the symbiotic association between rhizobia and plants. Molecular nitrogen is fixed by differentiated forms of rhizobia in nodules located on plant roots. The phytohormone, ethylene, acts as a negative factor in the nodulation process. Recent discoveries suggest several strategies used by rhizobia to reduce the amount of ethylene synthesized by their legume symbionts, decreasing the negative effect of ethylene on nodulation. At least one strain of rhizobia produces rhizobitoxine, an inhibitor of ethylene synthesis. Active 1-aminocyclopropane-1-carboxylate (ACC) deaminase has been detected in a number of other rhizobial strains. This enzyme catalyzes the cleavage of ACC to alpha-ketobutyrate and ammonia. It has been shown that the inhibitory effect of ethylene on plant root elongation can be reduced by the activity of ACC deaminase.     

Effects of interleukin-8 on granulation tissue maturation

The inflammatory alpha-chemokine, interleukin-8 (IL-8), affects the function and recruitment of various inflammatory cells, fibroblasts, and keratinocytes. Gap junctions are anatomical channels that facilitate the direct passage of small molecules between cells. The hypothesis is that IL-8 enhances gap junctional intercellular communication (GJIC) between fibroblasts in granulation tissue, which increases the rate of granulation tissue maturation. In vitro, human dermal fibroblasts were incubated with IL-8 prior to scrape loading, a technique that quantifies GJIC. Polyvinyl alcohol (PVA) sponges were implanted within subcutaneous pockets in rats and received local injections of either IL-8 or saline and were harvested on day 11. In vitro, IL-8 treated fibroblasts demonstrated an increase in GJIC by scrape loading compared to saline treated controls. In vivo, IL-8 treated PVA sponges demonstrated a decrease in cell density and an increase in vascularization compared to saline controls by H&E staining. Polarized light viewed Sirius red-stained specimens demonstrated greater collagen birefringence intensity, indicating thicker, more-mature collagen fibers. IL-8 increases GJIC in cultured fibroblasts and induces a more rapid maturation of granulation tissue.     

Pedstrip: extracting a maximal subset of available,unrelated individuals from a pedigree

SUMMARY: Certain types of genetic analysis are simplified by assembling a collection of unrelated individuals, e.g. case-control experiments. If a family study is being performed then it will be necessary to extract subsets of unrelated, available individuals from pedigress. Our program provides an optimal method for performing this task. AVAILABILITY: The software is available, free of charge, on request from Oxagen Ltd. SUPPLEMENTARY INFORMATION: http://www.oxagen.co.uk