Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors

Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.     

Survey of Neodohrniphora spp. (Diptera: Phoridae) at colonies of Atta sexdens rubropilosa (FOREL) and specificity of attack behaviour in relation to their hosts

Atta sexdens rubropilosa is a leaf-cutting ant that is a significant agricultural and forestry pest in the Neotropical region. This ant is parasitized by flies from the genera Neodohrniphora spp., Apocephalus spp. and Myrmosicarius spp. This study was carried out to determine which species of Neodohrniphora spp. are found near foraging trails of Atta sexdens rubropilosa and to evaluate the specificity of attack behaviour of these parasitoids. From May 2002 to April 2004, we sampled Neodohrniphora spp. hovering over foraging trails of Atta sexdens rubropilosa between 8:00 and 11:00 h and between 15:00 and 18:00 h. To investigate the attacking behaviour against the ants, flies were released individually inside an observation chamber containing a single leaf-cutting ant worker. Each parasitoid was confronted successively with a worker ant of A. sexdens rubropilosa, Atta laevigata Smith, Acromyrmex crassispinus Forel and Acromyrmex subterraneus molestans Santschi. Phorids of three species were identified: Neodohrniphora elongata Brown, Neodohrniphora declinata Borgmeier and Neodohrniphora tonhascai Brown. The three phorid species were active throughout the year and often along the same foraging trails, but N. elongata was the most frequent species. In the laboratory assay, N. elongata, N. declinata and N. tonhascai attacked workers of A. sexdens rubropilosa, A. laevigata and A. crassispinus, but not of A. subterraneus molestans.     

Evidence of gene–environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate

Although multiple genes have been identified as genetic risk factors for isolated, non-syndromic cleft lip with/without cleft palate (CL/P), a complex and heterogeneous birth defect, interferon regulatory factor 6 gene (IRF6) is one of the best documented genetic risk factors. In this study, we tested for association between markers in IRF6 and CL/P in 326 Chinese case–parent trios, considering gene–environment interaction for two common maternal exposures, and parent-of-origin effects. CL/P case–parent trios from three sites in mainland China and Taiwan were genotyped for 22 single nucleotide polymorphisms (SNPs) in IRF6. The transmission disequilibrium test was used to test for marginal effects of individual SNPs. We used PBAT to screen the SNPs and haplotypes for gene–environment (G × E) interaction and conditional logistic regression models to quantify effect sizes for SNP–environment interaction. After Bonferroni correction, 14 SNPs showed statistically significant association with CL/P. Evidence of G × E interaction was found for both maternal exposures, multivitamin supplementation and environmental tobacco smoke (ETS). Two SNPs showed evidence of interaction with multivitamin supplementation in conditional logistic regression models (rs2076153 nominal P = 0.019, rs17015218 nominal P = 0.012). In addition, rs1044516 yielded evidence for interaction with maternal ETS (nominal P = 0.041). Haplotype analysis using PBAT also suggested interaction between SNPs in IRF6 and both multivitamin supplementation and ETS. However, no evidence for maternal genotypic effects or significant parent-of-origin effects was seen in these data. These results suggest IRF6 gene may influence risk of CL/P through interaction with multivitamin supplementation and ETS in the Chinese population.     

Thaimycins,new anthelmintic and antiprotozoal antibiotics produced by Streptomyces michiganensis var. amylolyticus var. nova

Summary A new microorganism, isolated in our laboratories and identified as Streptomyces michiganensis var. amylolyticus var. nova is described.Thaimycins can be obtained by submerged fermentation of this microorganism on a suitable culture medium.Three new related compounds, thaimycins A, B and C have been obtained and characterized by their physical and chemical properties.Data on the antiprotozoal and anthelmintic activities in vitro as well as in vivo are reported.     

IL-7 withdrawal induces a stress pathway activating p38 and Jun N-terminal kinases

IL-7 delivers survival signals to cells at an early stage in lymphoid development. In the absence of IL-7, pro-T cells undergo programmed cell death, which has previously been associated with a decline in Bcl-2 and translocation of Bax from cytosol to mitochondria. A new, earlier feature of IL-7 withdrawal was identified using an IL-7-dependent thymocyte line. We observed that withdrawal of IL-7 induced increased expression of jun and fos family member genes including c-jun, junB, junD, c-fos and fra2. This transient response peaked 3-4 h after IL-7 was withdrawn and resulted in increased DNA-binding activity of AP-1 and in a change in the composition of the Jun/Fos family dimers shown by electrophoretic mobility shift and supershift assays. Induction of jun and fos genes and the increased DNA-binding activity of AP-1 were attributable to the phosphorylation-induced activation of the stress kinases p38 and JNK and were blocked by the chemical kinase inhibitors SB203580 and SB202190. The stress response contributed to cell death following IL-7 withdrawal as shown by blocking the activity of the stress (MAP) kinases or by blocking the production of c-Jun and c-Fos using antisense oligonucleotides.     

Cloning vectors for Streptococcus thermophilus derived from a native plasmid

Marine sponges frequently contain a complex mixture of bacteria, fungi, unicellular algae and cyanobacteria. Epifluorescent microscopy showed that Mycale (Carmia) hentscheli contained coccoid cyanobacteria. The 16S rRNA gene was amplified, fragments cloned and analysed using amplified rRNA gene restriction analysis. The nearly complete 16S rRNA gene of distinct clones was sequenced and aligned using ARB. The phylogenetic analysis indicated the presence of four closely related clones which have a high (8%) sequence divergence from known cyanobacteria, Cyanobacterium stanieri being the closest, followed by Prochloron sp. and Synechocystis sp. All belong to the order Chroococcales. The lack of non-molecular evidence prevents us from proposing a new genus.     

Isolating Potentiated Hsp104 Variants Using Yeast Proteinopathy Models

Many protein-misfolding disorders can be modeled in the budding yeast Saccharomyces cerevisiae. Proteins such as TDP-43 and FUS, implicated in amyotrophic lateral sclerosis, and α-synuclein, implicated in Parkinson’s disease, are toxic and form cytoplasmic aggregates in yeast. These features recapitulate protein pathologies observed in patients with these disorders. Thus, yeast are an ideal platform for isolating toxicity suppressors from libraries of protein variants. We are interested in applying protein disaggregases to eliminate misfolded toxic protein conformers. Specifically, we are engineering Hsp104, a hexameric AAA+ protein from yeast that is uniquely capable of solubilizing both disordered aggregates and amyloid and returning the proteins to their native conformations. While Hsp104 is highly conserved in eukaryotes and eubacteria, it has no known metazoan homologue. Hsp104 has only limited ability to eliminate disordered aggregates and amyloid fibers implicated in human disease. Thus, we aim to engineer Hsp104 variants to reverse the protein misfolding implicated in neurodegenerative disorders. We have developed methods to screen large libraries of Hsp104 variants for suppression of proteotoxicity in yeast. As yeast are prone to spontaneous nonspecific suppression of toxicity, a two-step screening process has been developed to eliminate false positives. Using these methods, we have identified a series of potentiated Hsp104 variants that potently suppress the toxicity and aggregation of TDP-43, FUS, and α-synuclein. Here, we describe this optimized protocol, which could be adapted to screen libraries constructed using any protein backbone for suppression of toxicity of any protein that is toxic in yeast.