Resonance assignments for stromelysin complexed with a β-sulfonyl hydroxamate inhibitor

The sequence specific ¹H, ¹³C, and ¹⁵N resonance assignments for stromelysin, a Matrix metalloproteinase, are reported in this article. Almost 70% of assignable backbone and side-chain atoms were assigned in this highly dynamic protein.     

Dominance and non-complementation among pink-adenineless mutants of Schizophyllum commune involving two discrete genes

Summary In Schizophyllum commune, adenineless mutations conferring pink color fell into two loosely linked loci, ad-4 and ad-7. The mutations were tested for dominance and complementation in dikaryons, and several of the ad-7 mutations were found to be partly dominant over their wild allele and noncomplementary with mutations of the ad-4 locus. The dominance and at least one case of intergenic noncomplementation were verified by quantitative tests.This research was partly supported by the U.S. Department of Agriculture Grant No. A10-CR-66.     

Experimental in vitro mechanical characterization of porcine Glisson's capsule and hepatic veins

Understanding the mechanical properties of human liver is the most critical aspect of numerical modeling for medical applications and impact biomechanics. Many researchers work on identifying mechanical properties of the liver both in vivo and in vitro considering the high liver injury percentage in abdominal trauma and for easy detection of fatal liver diseases such as viral hepatitis, cirrhosis, etc. This study is performed to characterize mechanical properties of individual parts of the liver, namely Glisson's capsule and hepatic veins, as these parts are rarely characterized separately. The long term objective of this study is to develop a realistic liver model by characterizing individual parts and later integrating them. In vitro uniaxial quasi-static tensile tests are done on fresh unfrozen porcine hepatic parts for large deformations at the rate of 0.1mm/s with a Bose Electroforce 3200 biomaterials test instrument. Results show that mean values of small strain and large strain elastic moduli are 8.22 ± 3.42 and 48.15 ± 4.5 MPa for Glisson's capsule (30 samples) and 0.62 ± 0.41 and 2.81 ± 2.23 MPa for veins (20 samples), respectively, and are found to be in good agreement with data in the literature. Finally, a non-linear hyper-elastic constitutive law is proposed for the two separate liver constituents under study.     

Impact of protein stability, cellular localization, and abundance on proteomic detection of tumor-derived proteins in plasma

Tumor-derived, circulating proteins are potentially useful as biomarkers for detection of cancer, for monitoring of disease progression, regression and recurrence, and for assessment of therapeutic response. Here we interrogated how a protein's stability, cellular localization, and abundance affect its observability in blood by mass-spectrometry-based proteomics techniques. We performed proteomic profiling on tumors and plasma from two different xenograft mouse models. A statistical analysis of this data revealed protein properties indicative of the detection level in plasma. Though 20% of the proteins identified in plasma were tumor-derived, only 5% of the proteins observed in the tumor tissue were found in plasma. Both intracellular and extracellular tumor proteins were observed in plasma; however, after normalizing for tumor abundance, extracellular proteins were seven times more likely to be detected. Although proteins that were more abundant in the tumor were also more likely to be observed in plasma, the relationship was nonlinear: Doubling the spectral count increased detection rate by only 50%. Many secreted proteins, even those with relatively low spectral count, were observed in plasma, but few low abundance intracellular proteins were observed. Proteins predicted to be stable by dipeptide composition were significantly more likely to be identified in plasma than less stable proteins. The number of tryptic peptides in a protein was not significantly related to the chance of a protein being observed in plasma. Quantitative comparison of large versus small tumors revealed that the abundance of proteins in plasma as measured by spectral count was associated with the tumor size, but the relationship was not one-to-one; a 3-fold decrease in tumor size resulted in a 16-fold decrease in protein abundance in plasma. This study provides quantitative support for a tumor-derived marker prioritization strategy that favors secreted and stable proteins over all but the most abundant intracellular proteins.     

Curcumin alleviates matrix metalloproteinase-3 and -9 activities during eradication of Helicobacter pylori infection in cultured cells and mice

Current therapy-regimens against Helicobacter pylori (Hp) infections have considerable failure rates and adverse side effects that urge the quest for an effective alternative therapy. We have shown that curcumin is capable of eradicating Hp-infection in mice. Here we examine the mechanism by which curcumin protects Hp infection in cultured cells and mice. Since, MMP-3 and -9 are inflammatory molecules associated to the pathogenesis of Hp-infection, we investigated the role of curcumin on inflammatory MMPs as well as proinflammatory molecules. Curcumin dose dependently suppressed MMP-3 and -9 expression in Hp infected human gastric epithelial (AGS) cells. Consistently, Hp-eradication by curcumin-therapy involved significant downregulation of MMP-3 and -9 activities and expression in both cytotoxic associated gene (cag)(+ve) and cag(-ve) Hp-infected mouse gastric tissues. Moreover, we demonstrate that the conventional triple therapy (TT) alleviated MMP-3 and -9 activities less efficiently than curcumin and curcumin's action on MMPs was linked to decreased pro-inflammatory molecules and activator protein-1 activation in Hp-infected gastric tissues. Although both curcumin and TT were associated with MMP-3 and -9 downregulation during Hp-eradication, but unlike TT, curcumin enhanced peroxisome proliferator-activated receptor-γ and inhibitor of kappa B-α. These data indicate that curcumin-mediated healing of Hp-infection involves regulation of MMP-3 and -9 activities.     

Effectiveness of action in India to reduce exposure of Gyps vultures to the toxic veterinary drug diclofenac

Contamination of their carrion food supply with the non-steroidal anti-inflammatory drug diclofenac has caused rapid population declines across the Indian subcontinent of three species of Gyps vultures endemic to South Asia. The governments of India, Pakistan and Nepal took action in 2006 to prevent the veterinary use of diclofenac on domesticated livestock, the route by which contamination occurs. We analyse data from three surveys of the prevalence and concentration of diclofenac residues in carcasses of domesticated ungulates in India, carried out before and after the implementation of a ban on veterinary use. There was little change in the prevalence and concentration of diclofenac between a survey before the ban and one conducted soon after its implementation, with the percentage of carcasses containing diclofenac in these surveys estimated at 10.8 and 10.7%, respectively. However, both the prevalence and concentration of diclofenac had fallen markedly 7-31 months after the implementation of the ban, with the true prevalence in this third survey estimated at 6.5%. Modelling of the impact of this reduction in diclofenac on the expected rate of decline of the oriental white-backed vulture (Gyps bengalensis) in India indicates that the decline rate has decreased to 40% of the rate before the ban, but is still likely to be rapid (about 18% year(-1)). Hence, further efforts to remove diclofenac from vulture food are still needed if the future recovery or successful reintroduction of vultures is to be feasible.     

Microbial Metabolites and Intestinal Stem Cells Tune Intestinal Homeostasis

Microorganisms that colonize the gastrointestinal tract, collectively known as the gut microbiota, are known to produce small molecules and metabolites that significantly contribute to host intestinal development, functions, and homeostasis. Emerging insights from microbiome research reveal that gut microbiota‐derived signals and molecules influence another key player maintaining intestinal homeostasis—the intestinal stem cell niche, which regulates epithelial self‐renewal. In this review, the literature on gut microbiota‐host crosstalk is surveyed, highlighting the effects of gut microbial metabolites on intestinal stem cells. The production of various classes of metabolites, their actions on intestinal stem cells are discussed and, finally, how the production and function of metabolites are modulated by aging and dietary intake is commented upon.