Genome-wide functional analysis reveals that autophagy is necessary for growth, sporulation, deoxynivalenol production and virulence in Fusarium graminearum

Autophagy is a conserved cellular recycling and trafficking pathway in eukaryotic cells and has been reported to be important in the virulence of a number of microbial pathogens. Here, we report genome-wide identification and characterization of autophagy-related genes (ATGs) in the wheat pathogenic fungus Fusarium graminearum. We identified twenty-eight genes associated with the regulation and operation of autophagy in F. graminearum. Using targeted gene deletion, we generated a set of 28 isogenic mutants. Autophagy mutants were classified into two groups by differences in their growth patterns. Radial growth of 18 Group 1 ATG mutants was significantly reduced compared to the wild-type strain PH-1, while 10 Group 2 mutants grew normally. Loss of any of the ATG genes, except FgATG17, prevented the fungus from causing Fusarium head blight disease. Moreover, subsets of autophagy genes were necessary for asexual/sexual differentiation and deoxynivalenol (DON) production, respectively. FgATG1 and FgATG5 were investigated in detail and showed severe defects in autophagy. Taken together, we conclude that autophagy plays a critical role in growth, asexual/sexual sporulation, deoxynivalenol production and virulence in F. graminearum

Control of a neuronal morphology program by an RNA-binding zinc finger protein, Unkempt

Cellular morphology is an essential determinant of cellular function in all kingdoms of life, yet little is known about how cell shape is controlled. Here we describe a molecular program that controls the early morphology of neurons through a metazoan-specific zinc finger protein, Unkempt. Depletion of Unkempt in mouse embryos disrupts the shape of migrating neurons, while ectopic expression confers neuronal-like morphology to cells of different nonneuronal lineages. We found that Unkempt is a sequence-specific RNA-binding protein and identified its precise binding sites within coding regions of mRNAs linked to protein metabolism and trafficking. RNA binding is required for Unkempt-induced remodeling of cellular shape and is directly coupled to a reduced production of the encoded proteins. These findings link post-transcriptional regulation of gene expression with cellular shape and have general implications for the development and disease of multicellular organisms

The Cerebrospinal Fluid Provides a Proliferative Niche for Neural Progenitor Cells

Cortical development depends on the active integration of cell autonomous and extrinsic cues, but the coordination of these processes is poorly understood. Here, we show that the apical complex protein Pals1 and Pten have opposing roles in localizing the Igf1R to the apical, ventricular domain of cerebral cortical progenitor cells. We found that the cerebrospinal fluid (CSF), which contacts this apical domain, has an age-dependent effect on proliferation, much of which is attributable to Igf2, but that CSF contains other signaling activities as well. CSF samples from patients with glioblastoma multiforme show elevated Igf2 and stimulate stem cell proliferation in an Igf2-dependent manner. Together, our findings demonstrate that the apical complex couples intrinsic and extrinsic signaling, enabling progenitors to sense and respond appropriately to diffusible CSF-borne signals distributed widely throughout the brain. The temporal control of CSF composition may have critical relevance to normal development and neuropathological conditions

A novel COMP mutation in a pseudoachondroplasia family of Chinese origin

<p>Abstract</p> <p>Background</p> <p>Pseudoachondroplasia (PSACH) is caused exclusively by mutations in the gene for cartilage oligomeric matrix protein (<it>COMP</it>). Only a small number of studies have documented the clinical phenotype and genetic basis in Chinese PSACH patients.</p> <p>Case presentation</p> <p>We investigated a four-generation PSACH pedigree of Chinese Han origin. Two patients and two unaffected individuals were recruited for clinical evaluation and molecular genetic analysis. The genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction (PCR) was adopted to amplify the 8-19 exons of <it>COMP </it>gene. Then the products were sequenced bi-directionally for screening mutation. Clinical evaluation revealed that PSACH patients in this pedigree had a severe disproportionate short stature (-10SD). A heterozygous TGTCCCTGG insertion in exon 13, between nucleotide 1352T and 1353G, were identified in the patients except the unaffected individuals, which resulted in a three-amino-acid insertion (451V_452P ins VPG) in the sixth calmodulin-like repeat of the <it>COMP </it>protein.</p> <p>Conclusion</p> <p>This c. 1352_1353ins TGTCCCTGG is a novel mutation responsible for severe familial PSACH.</p

ANS: Aberrant Neurodevelopment of the Social Cognition Network in Adolescents with Autism Spectrum Disorders

Background: Autism spectrum disorders (ASD) are characterized by aberrant neurodevelopment. Although the ASD brain undergoes precocious growth followed by decelerated maturation during early postnatal period of childhood, the neuroimaging approach has not been empirically applied to investigate how the ASD brain develops during adolescence. Methodology/Principal Findings: We enrolled 25 male adolescents with high functioning ASD and 25 typically developing controls for voxel-based morphometric analysis of structural magnetic resonance image. Results indicate that there is an imbalance of regional gray matter volumes and concentrations along with no global brain enlargement in adolescents with high functioning ASD relative to controls. Notably, the right inferior parietal lobule, a role in social cognition, have a significant interaction of age by groups as indicated by absence of an age-related gain of regional gray matter volume and concentration for neurodevelopmental maturation during adolescence. Conclusions/Significance: The findings indicate the neural correlates of social cognition exhibits aberrant neurodevelopment during adolescence in ASD, which may cast some light on the brain growth dysregulation hypothesis. The period of abnormal brain growth during adolescence may be characteristic of ASD. Age effects must be taken into account while measures of structural neuroimaging have been clinically put forward as potential phenotypes for ASD

ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss

Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.Peer reviewe

Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci

Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12 014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case–control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10−16). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10−75). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10−18). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42

Association between TCF7L2 gene polymorphisms and susceptibility to Type 2 Diabetes Mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Transcription factor 7-like 2 (<it>TCF7L2</it>) has been shown to be associated with type 2 diabetes mellitus (T2MD) in multiple ethnic groups in the past two years, but, contradictory results were reported for Chinese and Pima Indian populations. The authors then performed a large meta-analysis of 36 studies examining the association of type 2 diabetes mellitus (T2DM) with polymorphisms in the <it>TCF7L2 </it>gene in various ethnicities, containing rs7903146 C-to-T (IVS3C>T), rs7901695 T-to-C (IVS3T>C), a rs12255372 G-to-T (IVS4G>T), and rs11196205 G-to-C (IVS4G>C) polymorphisms and to evaluate the size of gene effect and the possible genetic mode of action.</p> <p>Methods</p> <p>Literature-based searching was conducted to collect data and three methods, that is, fixed-effects, random-effects and Bayesian multivariate mete-analysis, were performed to pool the odds ratio (<it>OR</it>). Publication bias and study-between heterogeneity were also examined.</p> <p>Results</p> <p>The studies included 35,843 cases of T2DM and 39,123 controls, using mainly primary data. For T2DM and IVS3C>T polymorphism, the Bayesian <it>OR </it>for TT homozygotes and TC heterozygotes versus CC homozygote was 1.968 (95% credible interval (<it>CrI</it>): 1.790, 2.157), 1.406 (95% <it>CrI</it>: 1.341, 1.476), respectively, and the population attributable risk (PAR) for the TT/TC genotypes of this variant is 16.9% for overall. For T2DM and IVS4G>T polymorphism, TT homozygotes and TG heterozygotes versus GG homozygote was 1.885 (95%<it>CrI</it>: 1.698, 2.088), 1.360 (95% <it>CrI</it>: 1.291, 1.433), respectively. Four <it>OR</it>s among these two polymorphisms all yielded significant between-study heterogeneity (P < 0.05) and the main source of heterogeneity was ethnic differences. Data also showed significant associations between T2DM and the other two polymorphisms, but with low heterogeneity (<it>P </it>> 0.10). Pooled <it>OR</it>s fit a codominant, multiplicative genetic model for all the four polymorphisms of <it>TCF7L2 </it>gene, and this model was also confirmed in different ethnic populations when stratification of IVS3C>T and IVS4G>T polymorphisms except for Africans, where a dominant, additive genetic mode is suggested for IVS3C>T polymorphism.</p> <p>Conclusion</p> <p>This meta-analysis demonstrates that four variants of <it>TCF7L2 </it>gene are all associated with T2DM, and indicates a multiplicative genetic model for all the four polymorphisms, as well as suggests the <it>TCF7L2 </it>gene involved in near 1/5 of all T2MD. Potential gene-gene and gene-environmental interactions by which common variants in the <it>TCF7L2 </it>gene influence the risk of T2MD need further exploration.</p

The Efficacy of Trastuzumab in Animal Models of Breast Cancer:A Systematic Review and Meta-Analysis

BACKGROUND:Breast cancer is the most frequent cancers and is the second leading cause of cancer death among women. Trastuzumab is an effective treatment, the first monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). To inform the development of other effective treatments we report summary estimates of efficacy of trastuzumab on survival and tumour volume in animal models of breast cancer. METHODS:We searched PubMed and EMBASE systematically to identify publications testing trastuzumab in animal models of breast cancer. Data describing tumour volume, median survival and animal features were extracted and we assessed quality using a 12-item checklist. We analysed the impact of study design and quality and evidence for publication bias. RESULTS:We included data from 83 studies reporting 169 experiments using 2076 mice. Trastuzumab treatment caused a substantial reduction in tumour growth, with tumours in treated animals growing to 32.6% of the volume of tumours in control animals (95%CI 27.8%-38.2%). Median survival was prolonged by a factor of 1.45 (1.30-1.62). Many study design and quality features accounted for between-study heterogeneity and we found evidence suggesting publication bias. CONCLUSION:We have found trastuzumab to be effective in animal breast cancer models across a range of experimental circumstances. However the presence of publication bias and a low prevalence of measures to reduce bias provide a focus for future improvements in preclinical breast cancer research