Replication of fifteen loci involved in human plasma protein N-glycosylation in 4,802 samples from four cohorts

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4,802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the sixteen loci reported previously, fifteen were replicated in our study. For the remaining locus (near the KREMEN1 gene) the replication power was low, and hence replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The fifteen replicated loci present a good target for further functional studies. Among these, eight genes encode glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4, and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo

Multiple Chronic Conditions: Prevalence, Health Consequences, and Implications for Quality, Care Management, and Costs

Persons with multiple chronic conditions are a large and growing segment of the US population. However, little is known about how chronic conditions cluster, and the ramifications of having specific combinations of chronic conditions. Clinical guidelines and disease management programs focus on single conditions, and clinical research often excludes persons with multiple chronic conditions. Understanding how conditions in combination impact the burden of disease and the costs and quality of care received is critical to improving care for the 1 in 5 Americans with multiple chronic conditions. This Medline review of publications examining somatic chronic conditions co-occurring with 1 or more additional specific chronic illness between January 2000 and March 2007 summarizes the state of our understanding of the prevalence and health challenges of multiple chronic conditions and the implications for quality, care management, and costs

Gold and silver diffusion in germanium: a thermodynamic approach

Diffusion properties are technologically important in the understanding of semiconductors for the efficent formation of defined nanoelectronic devices. In the present study we employ experimental data to show that bulk materials properties (elastic and expansivity data) can be used to describe gold and silver diffusion in germanium for a wide temperature range (702–1177 K). Here we show that the so-called cBΩ model thermodynamic model, which assumes that the defect Gibbs energy is proportional to the isothermal bulk modulus and the mean volume per atom, adequately metallic diffusion in germanium

Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120

A substantial fraction of broadly neutralizing antibodies (bnAbs) in certain HIV-infected donors recognizes glycan-dependent epitopes on HIV-1 gp120. Here, we elucidate how bnAb PGT 135 recognizes its Asn332 glycan-dependent epitope from its crystal structure with gp120, CD4 and Fab 17b at 3.1 Å resolution. PGT 135 interacts with glycans at Asn332, Asn392 and Asn386, using long CDR loops H1 and H3 to penetrate the glycan shield to access the gp120 protein surface. Electron microscopy reveals PGT 135 can accommodate the conformational and chemical diversity of gp120 glycans by altering its angle of engagement. The combined structural studies of PGT 135, PGT 128 and 2G12 show this Asn332-dependent epitope is highly accessible and much more extensive than initially appreciated, allowing for multiple binding modes and varied angles of approach, thereby representing a supersite of vulnerability for antibody neutralization

The regulatory role of long-term depression in juvenile and adult mouse ocular dominance plasticity

The study of experience-dependent ocular dominance (OD) plasticity has greatly contributed to the understanding of visual development. During the critical period, preventing input from one eye results in a significant impairment of vision, and loss of cortical responsivity via the deprived eye. Residual ocular dominance plasticity has recently been observed in adulthood. Accumulating evidence suggests that OD plasticity involves N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD). Here we report that the administration of a selective LTD antagonist prevented the ocular dominance shift during the critical period. The NMDAR co-agonist D-serine facilitated adult visual cortical LTD and the OD shift in short-term monocularly deprived (MD) adult mice. When combined with reverse suture, D-serine proved effective in restoring a contralaterally-dominated visual input pattern in long-term MD mice. This work suggests LTD as a key mechanism in both juvenile and adult ocular dominance plasticity, and D-serine as a potential therapeutic in human amblyopic subjects

Loss of Guanylyl Cyclase C (GCC) Signaling Leads to Dysfunctional Intestinal Barrier

Guanylyl Cyclase C (GCC) signaling via uroguanylin (UGN) and guanylin activation is a critical mediator of intestinal fluid homeostasis, intestinal cell proliferation/apoptosis, and tumorigenesis. As a mechanism for some of these effects, we hypothesized that GCC signaling mediates regulation of intestinal barrier function.Paracellular permeability of intestinal segments was assessed in wild type (WT) and GCC deficient (GCC-/-) mice with and without lipopolysaccharide (LPS) challenge, as well as in UGN deficient (UGN-/-) mice. IFNγ and myosin light chain kinase (MLCK) levels were determined by real time PCR. Expression of tight junction proteins (TJPs), phosphorylation of myosin II regulatory light chain (MLC), and STAT1 activation were examined in intestinal epithelial cells (IECs) and intestinal mucosa. The permeability of Caco-2 and HT-29 IEC monolayers, grown on Transwell filters was determined in the absence and presence of GCC RNA interference (RNAi). We found that intestinal permeability was increased in GCC-/- and UGN-/- mice compared to WT, accompanied by increased IFNγ levels, MLCK and STAT1 activation in IECs. LPS challenge promotes greater IFNγ and STAT1 activation in IECs of GCC-/- mice compared to WT mice. Claudin-2 and JAM-A expression were reduced in GCC deficient intestine; the level of phosphorylated MLC in IECs was significantly increased in GCC-/- and UGN-/- mice compared to WT. GCC knockdown induced MLC phosphorylation, increased permeability in IEC monolayers under basal conditions, and enhanced TNFα and IFNγ-induced monolayer hyperpermeability.GCC signaling plays a protective role in the integrity of the intestinal mucosal barrier by regulating MLCK activation and TJ disassembly. GCC signaling activation may therefore represent a novel mechanism in maintaining the small bowel barrier in response to injury

Between a Rock and a Hard Place: Habitat Selection in Female-Calf Humpback Whale (Megaptera novaeangliae) Pairs on the Hawaiian Breeding Grounds

The Au'au Channel between the islands of Maui and Lanai, Hawaii comprises critical breeding habitat for humpback whales (Megaptera novaeangliae) of the Central North Pacific stock. However, like many regions where marine mega-fauna gather, these waters are also the focus of a flourishing local eco-tourism and whale watching industry. Our aim was to establish current trends in habitat preference in female-calf humpback whale pairs within this region, focusing specifically on the busy, eastern portions of the channel. We used an equally-spaced zigzag transect survey design, compiled our results in a GIS model to identify spatial trends and calculated Neu's Indices to quantify levels of habitat use. Our study revealed that while mysticete female-calf pairs on breeding grounds typically favor shallow, inshore waters, female-calf pairs in the Au'au Channel avoided shallow waters (<20 m) and regions within 2 km of the shoreline. Preferred regions for female-calf pairs comprised water depths between 40–60 m, regions of rugged bottom topography and regions that lay between 4 and 6 km from a small boat harbor (Lahaina Harbor) that fell within the study area. In contrast to other humpback whale breeding grounds, there was only minimal evidence of typical patterns of stratification or segregation according to group composition. A review of habitat use by maternal females across Hawaiian waters indicates that maternal habitat choice varies between localities within the Hawaiian Islands, suggesting that maternal females alter their use of habitat according to locally varying pressures. This ability to respond to varying environments may be the key that allows wildlife species to persist in regions where human activity and critical habitat overlap

Gene Expression in a Drosophila Model of Mitochondrial Disease

Background A point mutation in the Drosophila gene technical knockout (tko), encoding mitoribosomal protein S12, was previously shown to cause a phenotype of respiratory chain deficiency, developmental delay, and neurological abnormalities similar to those presented in many human mitochondrial disorders, as well as defective courtship behavior. Methodology/Principal Findings Here, we describe a transcriptome-wide analysis of gene expression in tko25t mutant flies that revealed systematic and compensatory changes in the expression of genes connected with metabolism, including up-regulation of lactate dehydrogenase and of many genes involved in the catabolism of fats and proteins, and various anaplerotic pathways. Gut-specific enzymes involved in the primary mobilization of dietary fats and proteins, as well as a number of transport functions, were also strongly up-regulated, consistent with the idea that oxidative phosphorylation OXPHOS dysfunction is perceived physiologically as a starvation for particular biomolecules. In addition, many stress-response genes were induced. Other changes may reflect a signature of developmental delay, notably a down-regulation of genes connected with reproduction, including gametogenesis, as well as courtship behavior in males; logically this represents a programmed response to a mitochondrially generated starvation signal. The underlying signalling pathway, if conserved, could influence many physiological processes in response to nutritional stress, although any such pathway involved remains unidentified. Conclusions/Significance These studies indicate that general and organ-specific metabolism is transformed in response to mitochondrial dysfunction, including digestive and absorptive functions, and give important clues as to how novel therapeutic strategies for mitochondrial disorders might be developed.Public Library of Scienc

The Herschel-SPIRE Legacy Survey (HSLS): the scientific goals of a shallow and wide submillimeter imaging survey with SPIRE

A large sub-mm survey with Herschel will enable many exciting science opportunities, especially in an era of wide-field optical and radio surveys and high resolution cosmic microwave background experiments. The Herschel-SPIRE Legacy Survey (HSLS), will lead to imaging data over 4000 sq. degrees at 250, 350, and 500 micron. Major Goals of HSLS are: (a) produce a catalog of 2.5 to 3 million galaxies down to 26, 27 and 33 mJy (50% completeness; 5 sigma confusion noise) at 250, 350 and 500 micron, respectively, in the southern hemisphere (3000 sq. degrees) and in an equatorial strip (1000 sq. degrees), areas which have extensive multi-wavelength coverage and are easily accessible from ALMA. Two thirds of the of the sources are expected to be at z > 1, one third at z > 2 and about a 1000 at z > 5. (b) Remove point source confusion in secondary anisotropy studies with Planck and ground-based CMB data. (c) Find at least 1200 strongly lensed bright sub-mm sources leading to a 2% test of general relativity. (d) Identify 200 proto-cluster regions at z of 2 and perform an unbiased study of the environmental dependence of star formation. (e) Perform an unbiased survey for star formation and dust at high Galactic latitude and make a census of debris disks and dust around AGB stars and white dwarfs