Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.

Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQβ1 position 57 (previously known; P = 1 × 10(-1,355)) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 positions 13 (P = 1 × 10(-721)) and 71 (P = 1 × 10(-95)) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1-HLA-DQA1-HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1-HLA-DQA1-HLA-DQB1 haplotypes (P = 1.6 × 10(-64)). HLA-DRβ1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket.This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. This work is supported in part by funding from the National Institutes of Health (5R01AR062886-02 (PIdB), 1R01AR063759 (SR), 5U01GM092691-05 (SR), 1UH2AR067677-01 (SR), R01AR065183 (PIWdB)), a Doris Duke Clinical Scientist Development Award (SR), the Wellcome Trust (JAT) and the National Institute for Health Research (JAT and JMMH), and a Vernieuwingsimpuls VIDI Award (016.126.354) from the Netherlands Organization for Scientific Research (PIWdB). TLL was supported by the German Research Foundation (LE 2593/1-1 and LE 2593/2-1).This is the accepted manuscript. The final version is available at http://www.nature.com/ng/journal/v47/n8/full/ng.3353.html

Cross-cultural investigation of the link between identity processing styles and the actual work of identity in the career domain

The current study investigated and compared the associations between identity processing styles and the actual work of identity formation in the career domain in two national contexts, the US and Turkey. Identity styles represent individuals' orientations to identity work, and were measured by the Identity Processing Styles Q-Sort (IPSQ). The actual work of identity indicates engagement in exploration and commitment activities at multiple levels; and was measured by an adapted version of the Dimensions of Identity Development Scale (DIDS). In the current study, the actual work of identity was examined in the career domain only. The effects of gender and work status while in school on identity formation process in two national contexts also were examined. Results of the current study showed that the associations between identity processing styles and the actual work of identity are consistent across the two contexts, except that there is a stronger relation between informational style and identity work in Turkey; the impact of gender and work status on the actual work of identity also differed across contexts. The similarities and differences across the American and Turkish samples are discussed within the framework of broader contextual differences

Analysis of beta3 adrenergic receptor gene polymorphism using noninvasive samples obtained at scheduled infant health checkups.

Obesity is a risk factor for life-style-related diseases, and is based on three factors: genetic, environmental, and life-style. In adults, it is difficult to achieve and maintain normal body weight, so it is more effective to intervene from infancy to establish weight control. Legally required health checkups in infants of 18 and 36 months present important opportunities for obesity prevention. We consider genetic analysis to be a very important factor for obesity prevention in infancy. However, since health checkups don’t involve the collection of blood, genetic analysis is considered difficult. In this study, we attempted the typing of beta3 adrenergic receptor gene polymorphism as a genetic factor from non-invasively obtained samples, buccal mucosa, hair and cerumen in 96 infants at their 18- and 36-month health checkups. Sampling buccal mucosa, hair and cerumen instead of blood caused almost no anxiety to the child or parent, so 94.1% cooperation with sampling was obtained. From buccal mucosa, about 76% of the samples could be used for the typing of polymorphism (81% by enzyme method, 59% by kit method). From hair, about 44% of the samples permitted typing of polymorphism, but from cerumen only about 4% of the samples could be used. Results from buccal mucosa and hair typed about 90% of infant polymorphism. These results suggest that this method would be practical at periodic health checkups, and would probably be applicable to mass screenings for genetic factor analysis for other diseases

Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure–activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL–carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models