Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients

Background: Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients. Method: The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT). Results: Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning. Conclusion: VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment. Copyright (C) 2011 S. Karger AG, Base

Anchoring of proteins to lactic acid bacteria

The anchoring of proteins to the cell surface of lactic acid bacteria (LAB) using genetic techniques is an exciting and emerging research area that holds great promise for a wide variety of biotechnological applications. This paper reviews five different types of anchoring domains that have been explored for their efficiency in attaching hybrid proteins to the cell membrane or cell wall of LAB. The most exploited anchoring regions are those with the LPXTG box that bind the proteins in a covalent way to the cell wall. In recent years, two new modes of cell wall protein anchoring have been studied and these may provide new approaches in surface display. The important progress that is being made with cell surface display of chimaeric proteins in the areas of vaccine development and enzyme- or whole-cell immobilisation is highlighted.

Spatially anisotropic S=1 square-lattice antiferromagnet with single-ion anisotropy realized in a Ni(II) pyrazine- n,n′ -dioxide coordination polymer

The Ni(NCS)2(pyzdo)2 coordination polymer is found to be an S=1 spatially anisotropic square lattice with easy-axis single-ion anisotropy. This conclusion is based upon considering in concert the experimental probes x-ray diffraction, magnetic susceptibility, magnetic-field-dependent heat capacity, muon-spin relaxation, neutron diffraction, neutron spectroscopy, and pulsed-field magnetization. Long-range antiferromagnetic (AFM) order develops at TN=18.5K. Although the samples are polycrystalline, there is an observable spin-flop transition and saturation of the magnetization at ≈80T. Linear spin-wave theory yields spatially anisotropic exchanges within an AFM square lattice, Jx=0.235meV, Jy=2.014meV, and an easy-axis single-ion anisotropy D=-1.622meV (after renormalization). The anisotropy of the exchanges is supported by density functional theory

Light dark matter in the NMSSM: upper bounds on direct detection cross sections

In the Next-to-Minimal Supersymmetric Standard Model, a bino-like LSP can be as light as a few GeV and satisfy WMAP constraints on the dark matter relic density in the presence of a light CP-odd Higgs scalar. We study upper bounds on the direct detection cross sections for such a light LSP in the mass range 2-20 GeV in the NMSSM, respecting all constraints from B-physics and LEP. The OPAL constraints on e^+ e^- -> \chi^0_1 \chi^0_i (i > 1) play an important role and are discussed in some detail. The resulting upper bounds on the spin-independent and spin-dependent nucleon cross sections are ~ 10^{-42} cm^{-2} and ~ 4\times 10^{-40} cm^{-2}, respectively. Hence the upper bound on the spin-independent cross section is below the DAMA and CoGeNT regions, but could be compatible with the two events observed by CDMS-II.Comment: 17 pages, 3 figure

Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Lectin-like bacteriocins from pseudomonas spp. utilise D-rhamnose containing lipopolysaccharide as a cellular receptor

Lectin-like bacteriocins consist of tandem monocot mannose-binding domains and display a genus-specific killing activity. Here we show that pyocin L1, a novel member of this family from Pseudomonas aeruginosa, targets susceptible strains of this species through recognition of the common polysaccharide antigen (CPA) of P. aeruginosa lipopolysaccharide that is predominantly a homopolymer of d-rhamnose. Structural and biophysical analyses show that recognition of CPA occurs through the C-terminal carbohydrate-binding domain of pyocin L1 and that this interaction is a prerequisite for bactericidal activity. Further to this, we show that the previously described lectin-like bacteriocin putidacin L1 shows a similar carbohydrate-binding specificity, indicating that oligosaccharides containing d-rhamnose and not d-mannose, as was previously thought, are the physiologically relevant ligands for this group of bacteriocins. The widespread inclusion of d-rhamnose in the lipopolysaccharide of members of the genus Pseudomonas explains the unusual genus-specific activity of the lectin-like bacteriocins

A summer heat wave decreases the immunocompetence of the mesograzer, Idotea baltica

Extreme events associated with global change will impose increasing stress on coastal organisms. How strong biological interactions such as the host–parasite arms-race are modulated by environmental change is largely unknown. The immune system of invertebrates, in particular phagocytosis and phenoloxidase activity response are key defence mechanisms against parasites, yet they may be sensitive to environmental perturbations. We here simulated an extreme event that mimicked the European heat wave in 2003 to investigate the effect of environmental change on the immunocompetence of the mesograzer Idotea baltica. Unlike earlier studies, our experiment aimed at simulation of the natural situation as closely as possible by using long acclimation, a slow increase in temperature and a natural community setting including the animals’ providence with natural food sources (Zostera marina and Fucus vesiculosus). Our results demonstrate that a simulated heat wave results in decreased immunocompetence of the mesograzer Idotea baltica, in particular a drop of phagocytosis by 50%. This suggests that global change has the potential to significantly affect host–parasite interactions

Genomic analysis of the function of the transcription factor gata3 during development of the Mammalian inner ear

We have studied the function of the zinc finger transcription factor gata3 in auditory system development by analysing temporal profiles of gene expression during differentiation of conditionally immortal cell lines derived to model specific auditory cell types and developmental stages. We tested and applied a novel probabilistic method called the gamma Model for Oligonucleotide Signals to analyse hybridization signals from Affymetrix oligonucleotide arrays. Expression levels estimated by this method correlated closely (p<0.0001) across a 10-fold range with those measured by quantitative RT-PCR for a sample of 61 different genes. In an unbiased list of 26 genes whose temporal profiles clustered most closely with that of gata3 in all cell lines, 10 were linked to Insulin-like Growth Factor signalling, including the serine/threonine kinase Akt/PKB. Knock-down of gata3 in vitro was associated with a decrease in expression of genes linked to IGF-signalling, including IGF1, IGF2 and several IGF-binding proteins. It also led to a small decrease in protein levels of the serine-threonine kinase Akt2/PKB beta, a dramatic increase in Akt1/PKB alpha protein and relocation of Akt1/PKB alpha from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27(kip1), a known target of PKB/Akt, simultaneously decreased. In heterozygous gata3 null mice the expression of gata3 correlated with high levels of activated Akt/PKB. This functional relationship could explain the diverse function of gata3 during development, the hearing loss associated with gata3 heterozygous null mice and the broader symptoms of human patients with Hearing-Deafness-Renal anomaly syndrome

Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli

Gram-negative bacteria, such as Escherichia coli, expel toxic chemicals via tripartite efflux pumps spanning both the inner and outer membranes. The three parts are: 1) a membrane fusion protein connecting 2) a substrate-binding inner membrane transporter to 3) an outer membrane-anchored channel in the periplasmic space. A crystallographic model of this tripartite efflux complex has been unavailable simply because co-crystallization of different components of the system has proven to be extremely difficult. We previously described the crystal structures of both the inner membrane transporter CusA1 and membrane fusion protein CusB2 of the CusCBA efflux system3,4 from E. coli. We here report the co-crystal structure of the CusBA efflux complex, revealing the trimeric CusA efflux pump interacts with six CusB protomers at the upper half of the periplasmic domain. These six CusB molecules form a channel extending contiguously from the top of the pump. The affinity of the CusA and CusB interaction was found to be in the micromolar range. Finally, we predicted a three-dimensional structure of the trimeric CusC outer membrane channel, and develop a model of the tripartite efflux assemblage. This CusC3-CusB6-CusA3 model presents a 750 kDa efflux complex spanning the entire bacterial cell envelope to export Cu(I)/Ag(I) ions