Orai1 is an essential pore subunit of the CRAC channel

Stimulation of immune cells causes depletion of Ca2+ from endoplasmic reticulum (ER) stores, thereby triggering sustained Ca2+ entry through store-operated Ca2+ release-activated Ca2+ (CRAC) channels, an essential signal for lymphocyte activation and proliferation. Recent evidence indicates that activation of CRAC current is initiated by STIM proteins, which sense ER Ca2+ levels through an EF-hand located in the ER lumen and relocalize upon store depletion into puncta closely associated with the plasma membrane. We and others recently identified Drosophila Orai and human Orai1 (also called TMEM142A) as critical components of store-operated Ca2+ entry downstream of STIM. Combined overexpression of Orai and Stim in Drosophila cells, or Orai1 and STIM1 in mammalian cells, leads to a marked increase in CRAC current. However, these experiments did not establish whether Orai is an essential intracellular link between STIM and the CRAC channel, an accessory protein in the plasma membrane, or an actual pore subunit. Here we show that Orai1 is a plasma membrane protein, and that CRAC channel function is sensitive to mutation of two conserved acidic residues in the transmembrane segments. E106D and E190Q substitutions in transmembrane helices 1 and 3, respectively, diminish Ca2+ influx, increase current carried by monovalent cations, and render the channel permeable to Cs+. These changes in ion selectivity provide strong evidence that Orai1 is a pore subunit of the CRAC channel.     

Occurrence of DDT and BHC residues in human milk in India

Summary Samples of human milk from Punjab, India have shown the presence of DDT and BHC residues in amounts greater than those reported from most of the other countries.This research has been financed in part by a grant made by the United States Department of Agriculture, Agricultural Research Service authorized by Public Law 480.     

Occurrence of DDT and BHC residues in human milk in India

The presence of pesticide residue of DDT and of BHC were determined in 1979 in samples of milk from 75 lactating mothers from Punjab, within a week after delivery. DDT and BHC residues were found present in all 75 samples collected. Recovery of isomers of BHC and metabolites/isomers of p.p'-DDT from the spiked samples was above 80%. The mean level of DDT residue was 0.51 ppm, which is more than the level reported from the U.S., Canada, Europe and Australia, but less than the level found in Guatemala. BHC residues also were higher than those found in other countries, with the exception of Japan. DDT level of 0.5 ppm in milk represents an infant intake of 0.09 mg/kg/day, which is 18 times the acceptable daily intake (0.005 mg/kg/day) recommended by the WHO. Acceptable daily intake of BHC has not yet been established.     

Activation of nisin production by UV-irradiation in a nisin-producing strain ofStreptococcus lactis

Zusammenfassung Isolierung von Mutanten mit erhöhter Nisin-Produktion aus einem weiterenStreptococcus lactis-6 Stamm durch UV-Bestrahlung (9000 erg/mm²). Die Produktion des Antibiotikums nahm nach der ersten Bestrahlung im 50%, nach der zweiten Bestrahlung um 100% zu, während nach der dritten eine Abnahme beobachtet wurde.

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NDRI Publication     

Positional cloning of the combined hyperlipidemia gene Hyplip1.

Familial combined hyperlipidemia (FCHL, MIM-144250) is a common, multifactorial and heterogeneous dyslipidemia predisposing to premature coronary artery disease and characterized by elevated plasma triglycerides, cholesterol, or both. We identified a mutant mouse strain, HcB-19/Dem (HcB-19), that shares features with FCHL, including hypertriglyceridemia, hypercholesterolemia, elevated plasma apolipoprotein B and increased secretion of triglyceride-rich lipoproteins. The hyperlipidemia results from spontaneous mutation at a locus, Hyplip1, on distal mouse chromosome 3 in a region syntenic with a 1q21-q23 FCHL locus identified in Finnish, German, Chinese and US families. We fine-mapped Hyplip1 to roughly 160 kb, constructed a BAC contig and sequenced overlapping BACs to identify 13 candidate genes. We found substantially decreased mRNA expression for thioredoxin interacting protein (Txnip). Sequencing of the critical region revealed a Txnip nonsense mutation in HcB-19 that is absent in its normolipidemic parental strains. Txnip encodes a cytoplasmic protein that binds and inhibits thioredoxin, a major regulator of cellular redox state. The mutant mice have decreased CO2 production but increased ketone body synthesis, suggesting that altered redox status down-regulates the citric-acid cycle, sparing fatty acids for triglyceride and ketone body production. These results reveal a new pathway of potential clinical significance that contributes to plasma lipid metabolism.     

印度国家网站:India.gov.in

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Resveratrol improves health and survival of mice on a high-calorie diet

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.