Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees

OBJECTIVE The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). METHOD The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs. RESULTS No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10-17, explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families. CONCLUSIONS Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

Identification of the F1-ATPase at the cell surface of colonic epithelial cells:role in mediating cell proliferation

F1F0-ATPase was initially believed to be strictly expressed in the mitochondrial membrane. Interestingly, recent reports have shown that the F1 complex can serve as a cell surface receptor for apparently unrelated ligands. Here, we show for the first time the presence of the F1-ATPase at the cell surface of normal or cancerous colonic epithelial cells. Using Surface Plasmon Resonance technology and mass spectrometry, we identified a peptide hormone product of the gastrin gene (glycine-extended gastrin, G-gly), as a new ligand for the F1-ATPase. By molecular modeling, we identified the motif in the peptide sequence (EE/DxY), which directly interacts with the F1-ATPase and the amino-acids in the F1-ATPase which bind this motif. Replacement of the E9 residue by an alanine in the EE/DxY motif resulted in a strong decrease of G-gly binding to the F1-ATPase and the loss of its biological activity. In addition we demonstrated that F1-ATPase mediates the growth effects of the peptide. Indeed, blocking ATPase activity decreases G-gly-induced cell growth. The mechanism likely involves ADP production by the membrane F1-ATPase which is induced by G-gly. These results suggest an important contribution of cell surface ATPase in the pro-proliferative action of this gastrointestinal peptide.

Force-induced activation of covalent bonds in mechanoresponsive polymeric materials

Mechanochemical transduction enables an extraordinary range of physiological processes such as the sense of touch, hearing, balance, muscle contraction, and the growth and remodelling of tissue and
bone1–6. Although biology is replete with materials systems that actively and functionally respond to mechanical stimuli, the default mechanochemical reaction of bulk polymers to large external stress is the unselective scission of covalent bonds, resulting in damage or failure7. An alternative to this degradation process is the rational molecular design of synthetic materials such that mechanical stress
favourably altersmaterial properties. A few mechanosensitive polymers with this property have been developed8–14; but their active response is mediated through non-covalent processes, which may
limit the extent to which properties can be modified and the longterm stability in structural materials. Previously, we have shown with dissolved polymer strands incorporating mechanically sensitive chemical groups—so-called mechanophores—that the directional nature of mechanical forces can selectively break and re-form covalent bonds15,16. We now demonstrate that such forceinduced covalent-bond activation can also be realized with mechanophore-linked elastomeric and glassy polymers, by using a mechanophore that changes colour as it undergoes a reversible electrocyclic ring-opening reaction under tensile stress and thus allows us to directly and locally visualize the mechanochemical reaction. We find that pronounced changes in colour and fluorescence emerge with the accumulation of plastic deformation, indicating that in these polymeric materials the transduction of mechanical force into the ring-opening reaction is an activated process. We anticipate that force activation of covalent bonds can serve as a general strategy for the development of new mechanophore building blocks that impart polymeric materials with desirable functionalities ranging from damage sensing to fully regenerative self-healing.

Mitigation of Fatigue Damage in Self-Healing Vascular Materials

The fatigue response of an epoxy matrix containing vasculature for the delivery of liquid healing agents is investigated. The release of a rapidly curing, two-part epoxy healing chemistry into the wake of a propagating crack reduces the rate of crack extension by shielding the crack tip from the full range of applied stress intensity factor. Crack propagation is studied for a variety of loading conditions, with the maximum applied stress intensity factor ranging from 62 to 84% of the quasi-static fracture toughness of the material. At the highest level of applied load, the rate of mechanical damage is so fast that the healing agents do not fully mix and polymerize, and the effect of healing is minimal. The self-healing response is most effective at impeding the slower propagating cracks, with complete crack arrest occurring at the lowest level of applied load, and reductions of 79–84% in the rate of crack extension at intermediate loads.

Genome-wide association study of Alzheimer's disease with psychotic symptoms

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.Molecular Psychiatry advance online publication, 18 October 2011; doi:10.1038/mp.2011.125.

Association between tortilla consumption and human urinary fumonisin B1 levels in a Mexican population

Fumonisins are mycotoxins produced by Fusarium spp. and commonly contaminate maize and maize products worldwide. Fumonisins are rodent carcinogens and have been associated with human esophageal cancer. However, the lack of a valid exposure biomarker has hindered both the assessment of human exposure and the evaluation of disease risk. A sensitive liquid chromatography-mass spectrometry method to measure urinary fumonisin B1 (FB1) following extraction on Oasis MAX cartridges was established and applied to urine samples from women in a cohort recruited in Morelos County, Mexico. Urinary FB1 was compared with dietary information on tortilla consumption. FB1 recovery in spiked samples averaged 94% as judged by deuterium-labeled FB1 internal standard. Urinary FB1 was determined in 75 samples from women selected based on low, medium, or high consumption of maize-based tortillas. The geometric mean (95% confidence interval) of urinary FB1 was 35.0 (18.8-65.2), 63.1 (36.8-108.2), and 147.4 (87.6-248.0) pg/mL and the frequency of samples above the detection limit (set at 20 pg FB1/mL urine) was 45%, 80%, and 96% for the low, medium, and high groups, respectively. Women with high intake had a 3-fold higher average FB1 levels compared with the "low intake" group (F = 7.3; P = 0.0015). Urinary FB1 was correlated with maize intake (P-trend = 0.001); the correlation remained significant after adjusting for age, education, and place of residence. This study suggests that measurement of urinary FB1 is sufficiently sensitive for fumonisin exposure assessment in human populations and could be a valuable tool in investigating the associated health effects of exposure.

Dam Methylation Participates in the Regulation of PmrA/PmrB and RcsC/RcsD/RcsB Two Component Regulatory Systems in Salmonella enterica Serovar Enteritidis

The absence of Dam in Salmonella enterica serovar Enteritidis causes a defect in lipopolysaccharide (LPS) pattern associated to a reduced expression of wzz gene. Wzz is the chain length regulator of the LPS O-antigen. Here we investigated whether Dam regulates wzz gene expression through its two known regulators, PmrA and RcsB. Thus, the expression of rcsB and pmrA was monitored by quantitative real-time RT-PCR and Western blotting using fusions with 3×FLAG tag in wild type (wt) and dam strains of S. Enteritidis. Dam regulated the expression of both rcsB and pmrA genes; nevertheless, the defect in LPS pattern was only related to a diminished expression of RcsB. Interestingly, regulation of wzz in serovar Enteritidis differed from that reported earlier for serovar Typhimurium; RcsB induces wzz expression in both serovars, whereas PmrA induces wzz in S. Typhimurium but represses it in serovar Enteritidis. Moreover, we found that in S. Enteritidis there is an interaction between both wzz regulators: RcsB stimulates the expression of pmrA and PmrA represses the expression of rcsB. Our results would be an example of differential regulation of orthologous genes expression, providing differences in phenotypic traits between closely related bacterial serovars.

Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding

To compare the disposition of fluoxetine and norfluoxetine enantiomers in the mother, foetus and infant.

Pre-storage of gelified reagents in a lab-on-a-foil system for rapid nucleic acid analysis

Reagent pre-storage in a microfluidic chip can enhance operator convenience, simplify the system design, reduce the cost of storage and shipment, and avoid the risk of cross-contamination. Although dry reagents have long been used in lateral flow immunoassays, they have rarely been used for nucleic acid-based point-of-care (POC) assays due to the lack of reliable techniques to dehydrate and store fragile molecules involved in the reaction. In this study, we describe a simple and efficient method for prolonged on-chip storage of PCR reagents. The method is based on gelification of all reagents required for PCR as a ready-to-use product. The approach was successfully implemented in a lab-on-a-foil system, and the gelification process was automated for mass production. Integration of reagents on-chip by gelification greatly facilitated the development of easy-to-use lab-on-a-chip (LOC) devices for fast and cost-effective POC analysis.