Genome-wide association (GWA) studies have identified a large number of single-nucleotide polymorphisms (SNPs) associated with disease phenotypes. As most GWA studies have been performed primarily in populations of European descent, this review examines the issues involved in extending consideration of GWA studies to diverse worldwide populations. Although challenges exist with such issues as imputation, admixture, and replication, investigation of diverse populations in GWA studies has significant potential to advance the project of mapping the genetic determinants of complex diseases for the human population as a whole.In the last few years, genome-wide association (GWA) studies have produced numerous successes in identifying genetic variants that contribute to complex human traits1 , 2. Several factors are recognized3 , 4 as having dramatically enlarged the number of genotypephenotype associations documented for a wide range of phenotypes5 , 6. These include: increasingly dense sets of genetic markers, increasingly large sample sizes, improved resources on genomic variation, and new statistical techniques for genotype imputation 7 , 8 and meta-analysis9 , 10 that leverage these resources.With few exceptions, however, GWA studies have been centered in populations of European descent (Box 1), and the degree to which knowledge gained from these studies is transferrable to other populations has not been extensively investigated. Recent reports such populations as Chinese11 , 12, Japanese13 , 14, Koreans15 , 16, and Pacific islanders from Kosrae17 , 18 represent some of the first in a new wave of GWA studies in non-European populations, as researchers seek to search additional groups for new findings on widely distributed phenotypes, to consider new phenotypes that are more prevalent in non-European populations, and to establish the generality of findings obtained initially in Europeans and European Americans. NIH Public Access Author ManuscriptNat Rev Genet. Author manuscript; available in PMC 2011 May 1. Populations in past GWA studiesTo assess the extent to which non-European populations have been incorporated into GWA studies, we examined the distribution of study populations across 492 GWA articles in the National Human Genome Research Institute catalog of GWA results6 , 130. This database provides a manually curated list of SNP-phenotype associations (P < 10 −5 ) identified in studies with at least 100,000 SNPs. Article classifications were assessed independently by two raters, with discrepancies resolved by consensus in discussions with a third rater. The figure on the right tabulates classifications based on whether articles used individuals of European descent, individuals of non-European descent, or a combination of individuals of European and non-European descent. Eight articles that provided insufficient information about study subjects are omitted, so that each bar represents 80 or 81 articles, grouped by date. The later date ranges are narrower, indicating that in more recent time periods, ...

Disturbance of the tight junction (TJ) complexes between brain endothelial cells leads to increased paracellular permeability, allowing leukocyte entry into inflamed brain tissue and also contributing to edema formation. The current study dissects the mechanisms by which a chemokine, CCL2, induces TJ disassembly. It investigates the potential role of selective internalization of TJ transmembrane proteins (occludin and claudin-5) in increased permeability of the brain endothelial barrier in vitro. To map the internalization and intracellular fate of occludin and claudin-5, green fluorescent protein fusion proteins of these TJ proteins were generated and imaged by fluorescent microscopy with simultaneous measurement of transendothelial electrical resistance. During CCL2-induced reductions in transendothelial electrical resistance, claudin-5 and occludin became internalized via caveolae and further processed to early (EEA1؉) and recycling (Rab4؉) endosomes but not to late endosomes. Western blot analysis of fractions collected from a sucrose gradient showed the presence of claudin-5 and occludin in the same fractions that contained caveolin-1. For the first time, these results suggest an underlying molecular mechanism by which the pro-inflammatory chemokine CCL2 mediates brain endothelial barrier disruption during CNS inflammation.

The PROSPECT study validates that despite having more comorbid risk factors than men, women have less extensive coronary artery disease by both angiographic and IVUS measures, and that lesions in women compared with men have less plaque rupture, less necrotic core and calcium, similar plaque burden, and smaller lumens. TCFA may also be a stronger marker of plaque vulnerability in women than men.

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We have identified and sequenced the genes encoding the aggregation-promoting factor (APF) protein from six different strains of Lactobacillus johnsonii and Lactobacillus gasseri. Both species harbor two apf genes, apf1 and apf2, which are in the same orientation and encode proteins of 257 to 326 amino acids. Multiple alignments of the deduced amino acid sequences of these apf genes demonstrate a very strong sequence conservation of all of the genes with the exception of their central regions. Northern blot analysis showed that both genes are transcribed, reaching their maximum expression during the exponential phase. Primer extension analysis revealed that apf1 and apf2 harbor a putative promoter sequence that is conserved in all of the genes. Western blot analysis of the LiCl cell extracts showed that APF proteins are located on the cell surface. Intact cells of L. johnsonii revealed the typical cell wall architecture of S-layer-carrying gram-positive eubacteria, which could be selectively removed with LiCl treatment. In addition, the amino acid composition, physical properties, and genetic organization were found to be quite similar to those of S-layer proteins. These results suggest that APF is a novel surface protein of the Lactobacillus acidophilus B-homology group which might belong to an S-layer-like family.Lactic acid bacteria (LAB) constitute a large family of grampositive bacteria which are extensively applied in the fermentation of raw agricultural products and in the manufacture of a wide variety of food products (43, 44). The amount of published information concerning LAB genetics and metabolism has opened the door for new food as well as nonfood applications of these bacteria. The utilization of LAB as in vivo delivery vectors for biologically active molecules has become increasingly attractive due to their nonpathogenicity (12, 46) and their ability to survive passage through the gastrointestinal tract (12,46). The fulfillment of these objectives requires an adequate delivery system and knowledge of the cell surface components of LAB. The cell surfaces of gram-positive bacteria cover a variety of functions, and many molecules are considered to be linked to it by different modes of anchoring (for a review, see reference 18). The lack of an outer membrane and the presence of multiple peptidoglycan layers in the cell walls of these bacteria have resulted in the use of a number of different targeting strategies that link proteins to the membrane or cell wall (10, 41). Three main strategies for anchoring on the cell surface have been identified: covalent attachment (e.g., the LPXTG-containing protein [27]), charge interactions (e.g., the S-layer protein [23]), and hydrophobic interaction (18).The probiotic properties of LAB have stimulated various types of research on the possible roles of surface proteins in adherence to human intestinal cells (e.g., Caco2 cells). In particular, the involvement of proteinaceous bacterial surface compounds in adhesion to enterocytes has been demonstrated for many Lact...

Here we present the complement of the carbohydrate uptake systems of the strictly anaerobic probiotic Bifidobacterium longum NCC2705. The genome analysis of this bacterium predicts that it has 19 permeases for the uptake of diverse carbohydrates. The majority belongs to the ATP-binding cassette transporter family with 13 systems identified. Among them are permeases for lactose, maltose, raffinose, and fructooligosaccharides, a commonly used prebiotic additive. We found genes that encode a complete phosphotransferase system (PTS) and genes for three permeases of the major facilitator superfamily. These systems could serve for the import of glucose, galactose, lactose, and sucrose. Growth analysis of NCC2705 cells combined with biochemical characterization and microarray data showed that the predicted substrates are consumed and that the corresponding transport and catabolic genes are expressed. Biochemical analysis of the PTS, in which proteins are central in regulation of carbon metabolism in many bacteria, revealed that B. longum has a glucose-specific PTS, while two other species (Bifidobacterium lactis and Bifidobacterium bifidum) have a fructose-6-phosphate-forming fructose-PTS instead. It became obvious that most carbohydrate systems are closely related to those from other actinomycetes, with a few exceptions. We hope that this report on B. longum carbohydrate transporter systems will serve as a guide for further in-depth analyses on the nutritional lifestyle of this beneficial bacterium.

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Analysis of culture supernatants obtained from Bifidobacterium longum NCC2705 grown on glucose and lactose revealed that glucose utilization is impaired until depletion of lactose. Thus, unlike many other bacteria, B. longum preferentially uses lactose rather than glucose as the primary carbon source. Glucose uptake experiments with B. longum cells showed that glucose transport was repressed in the presence of lactose. A comparative analysis of global gene expression profiling using DNA arrays led to the identification of only one gene repressed by lactose, the putative glucose transporter gene glcP. The functionality of GlcP as glucose transporter was demonstrated by heterologous complementation of a glucose transport-deficient Escherichia coli strain. Additionally, GlcP exhibited the highest substrate specificity for glucose. Primer extension and real-time PCR analyses confirmed that expression of glcP was mediated by lactose. Hence, our data demonstrate that the presence of lactose in culture medium leads to the repression of glucose transport and transcriptional down-regulation of the glucose transporter gene glcP. This may reflect the highly adapted life-style of B. longum in the gastrointestinal tract of mammals.Bifidobacteria are strictly anaerobic microorganisms that are found as commensals in the mammalian gastrointestinal tract (2). They predominate in infants' intestines and can represent up to 3% of the gut microbiota in adult humans (2). Together with lactobacilli, bifidobacteria are considered health-promoting bacteria and thus are used as food additives in the dairy industry (1, 9).Bifidobacteria can utilize a wide range of carbon sources. Some of them, such as oligofructose, inulin, and raffinose, have been identified as growth-promoting, bifidogenic compounds (8,10). This is further substantiated by sequence information from Bifidobacterium longum NCC2705, whose chromosome encodes a large variety of carbohydrate utilization genes (22). Nevertheless, little is known about the mechanisms of simple sugar transport, utilization, and regulation in bifidobacteria. Biochemical analyses of glucose transport revealed that a glucose-specific phosphotransferase system (PTS) is present in Bifidobacterium breve, and a potassium-dependent glucose permease, a facilitator for galactose, and a proton-driven symporter for lactose were described in Bifidobacterium bifidum (5,12,13). A sucrose permease gene from Bifidobacterium lactis was found as part of an operon that is induced by sucrose and raffinose and is subject to glucose repression (23). The isolation of a fructose kinase gene, frk, which is also repressed by glucose, has been related to fructose utilization in B. longum (3).In this report, we demonstrate that B. longum NCC2705 preferentially uses lactose over glucose when grown in the presence of both sugars. We further show that glucose transport is down-regulated by lactose, and we identify a glucose transporter gene that undergoes lactose repression. MATERIALS AND METHODSBacterial strains and culture ...