Posttraumatic stress disorder (PTSD) is a common and debilitating psychiatric disease. Estimates of the prevalence of PTSD in populations experiencing potentially traumatic events range from 1% to ...15% for current PTSD and 10% to 39% for lifetime PTSD (1) indicating that although a substantial amount of individuals exposed to a traumatic event develop PTSD, most individuals do not. Beside the severity of trauma and the extent of peritraumatic social support, inborn or acquired constitutional factors could explain why only some exposed individuals develop PTSD. Latter assumption fueled the performance of several genetic association studies in patients and animal models that revealed a set of interesting candidate genes mostly linked to either the fields of neurotransmission, neurode-/regeneration or HPA-axis modulation. Nevertheless, some of these trials achieved contradictory findings possibly resulting from confounding variables like co-morbidities, types of trauma and, supposedly, yet unknown non – genomic constitutional variables. These discrepancies demand the need for further and more comprehensive clinical research trials hopefully contributing to the improvement of current therapeutic options. Here we present the conceptual design of the Munich PTSD Biomarker Research Study – a clinical research trial started in March 2009at the Max Planck Institute of Psychiatry. 1. Neurocognitive risk factors for PTSD, Orr S.P., Pitman R., in: Risk Factors for PTSD, 1999, p.125–43
There are two isochorismate synthase genes
entC and
menF in
Escherichia coli. They encode enzymes (isochorismate synthase, EC 5.4.99.6) which reversibly synthesize isochorismic acid from chorismic ...acid. The genes share a 24.2% identity but are differently regulated. Activity of the MenF isochorismate synthase is significantly increased under anaerobic conditions whereas the activity of the EntC isochorismate synthase is greatly stimulated during growth in an iron deficient medium. Isochorismic acid synthesized by EntC is mainly channeled into enterobactin synthesis whereas isochorismic acid synthesized by MenF is mainly channeled into menaquinone synthesis. When
menF or
entC were separately placed onto overexpression plasmids and the plasmids introduced into a
menF
−/
entC
− double mutant in two separate experiments, the isochorismate formed was fed into both, the menaquinone and the enterobactin pathway. Moreover, in spite of a high isochorismate synthase activity menaquinone and enterobactin formation were not fully restored, indicating that isochorismate was lost by diffusion. Thus, under these conditions channeling was not observed. We conclude that in
E. coli the chromosomal position of both
menF and
entC in their respective clusters is a prerequisite for channeling of isochorismate in both pathways.
Voltage-dependent sodium channels consist of a pore-forming alpha-subunit and regulatory beta-subunits. Alterations in these channels have been implicated in temporal lobe epilepsy (TLE) and several ...genetic epilepsy syndromes. Recently we identified Na(v)beta3 as a TLE-regulated gene. Here we performed a detailed analysis of the hippocampal expression of Na(v)beta3 in TLE patients with hippocampal sclerosis (HS) and without HS (non-HS) and compared expression with autopsy controls (ACs). Immunoblot analysis showed that Na(v)beta3 levels were dramatically reduced in the hippocampus, but not in the cortex of non-HS patients when compared to HS patients. This was confirmed by immunohistochemistry showing reduced Na(v)beta3 expression in all principal neurons of the hippocampus proper. Sequence analysis revealed no Na(v)beta3 mutations. The functional consequences of the reduced Na(v)beta3 expression in non-HS patients are unknown. Altered Na(v)beta3 expression might influence microcircuitry in the hippocampus, affecting excitability and contributing to epileptogenesis in non-HS patients. Further experiments are required to elucidate these functional possibilities.
Purpose This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods Variants were identified and de novo origins were ...confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. Conclusion Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.
Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the ...quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immuneregulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.
We examined the chromosome set of the aphid species Sitobion avenae, Schizaphis graminum and Methopolophium dirhodum by means of conventional staining and C, NOR, AluI and HaeIII banding methods. ...These species are considered important pests to several plants of economic interest in Brazil. No variation was observed in the number of chromosomes of S. avenae, whereas there was intraspecific variation in the other two species. Interspecific differences in the response to the banding treatments were observed. Whereas these techniques allowed the identification of several S. graminum chromosome pairs, only the AluI treatment was capable of inducing differential staining in the M. dirhodum chromosomes and no clear patterns emerged when the S. avenae preparations were treated
Por meio de coloração convencional e de métodos de bandamento C, NOR, AluI e HaeIII, foi feita uma tentativa de caracterizar o cariótipo e a variação no número cromossômico das espécies de afídeos Sitobion avenae, Schizaphis graminum e Methopolophium dirhodum, que são considerados como pragas importantes para várias plantas de interesse econômico no Brasil. Não foi encontrada variação no número cromossômico de S. avenae, enquanto que as outras duas espécies apresentaram variação numérica intra-específica. Diferenças interespecíficas quanto à resposta aos tratamentos de bandamento foram observadas. Através dos métodos utilizados, foi possível a identificação de vários pares cromossômicos de S. graminum, mas só o tratamento com AluI foi capaz de induzir coloração diferencial nos cromossomos de M. dirhodum, enquanto que nenhum padrão claro de bandamento apareceu nos preparados de S. avenae
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