Brain Phenotype of Transgenic Mice Overexpressing Cystathionine β-Synthase

The cystathionine β-synthase (CBS) gene, located on human chromosome 21q22.3, is a good candidate for playing a role in the Down Syndrome (DS) cognitive profile: it is overexpressed in the brain of individuals with DS, and it encodes a key enzyme of sulfur-containing amino acid (SAA) metabolism, a pathway important for several brain physiological processes.Here, we have studied the neural consequences of CBS overexpression in a transgenic mouse line (60.4P102D1) expressing the human CBS gene under the control of its endogenous regulatory regions. These mice displayed a ∼2-fold increase in total CBS proteins in different brain areas and a ∼1.3-fold increase in CBS activity in the cerebellum and the hippocampus. No major disturbance of SAA metabolism was observed, and the transgenic mice showed normal behavior in the rotarod and passive avoidance tests. However, we found that hippocampal synaptic plasticity is facilitated in the 60.4P102D1 line.We demonstrate that CBS overexpression has functional consequences on hippocampal neuronal networks. These results shed new light on the function of the CBS gene, and raise the interesting possibility that CBS overexpression might have an advantageous effect on some cognitive functions in DS

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Etomidate anaesthesia by immersion in oriental fire-bellied toads (Bombina orientalis)

The objective of the present study was to evaluate the efficacy and the safety of etomidate anaesthesia by immersion technique in Bombina orientalis. The study comprised two phases. The first phase was carried out to identify the etomidate concentration capable of producing anaesthetic induction, as well as surgical anaesthesia, in the toads. The second phase was aimed at testing that concentration in eight additional animals. Etomidate administered via immersion at a concentration of 37.5 mg/L produced effective anaesthesia in oriental fire-bellied toads. The average duration of surgical anaesthesia was 20 min. All the toads enrolled in the study survived the anaesthesia and long-term complications did not occur. However, undesired side-effects, namely itching, myoclonus and prolonged recovery, were noticed during the perianaesthetic period. The authors concluded that etomidate anaesthesia by immersion, at a concentration of 37.5 mg/L, is suitable in oriental fire-bellied toads and produces anaesthesia of a depth and duration that is sufficient to allow the completion of various experimental procedures, without resulting in lethal complications. However, the occurrence of undesired side-effects opens a debate on the safety of this anaesthetic technique, and imposes the need for further investigation prior to proposing the latter for routine laboratory practice

Comparative electrophysiological study of word reading in French: does the P1-N1 temporal window reveal a neurodevelopmental anomaly?

International audienceBackground: Event-Related Potentials (ERPs) permit to study neuronal specialization during reading acquisition. The N170 wave was previously shown to be a surrogate of the fine tuning of reading in adults and adolescents as well. Aim: We analyzed and described the variations of the N170 wave as a function of French words with visual or phonetical similarities in 12 to 14 yearold dyslexic patients. We tested the validity and modulation of this effect by comparing different populations of normal and dyslexic patients of various severity. Methods: ERPs were recorded in seventeen dyslexic children with the same method as in normative populations in lexical decision. Stimuli consisted of frequent words chosen on the basis of near or far visemes and morphemes. Dyslexic children were compared to two control (i.e. normal readers) groups, one group of the same age (N=15) and one group of adults (N=17). N170 and P100 waves were analyzed, as well as interactions between both (i.e. P1N1) searched. Psychometric and language tests were also performed. Results were analyzed by ANOVA. Results: The results of sixteen patients are presented. All sixteen showed significant differences on all psycholinguistic items when compared to the two control groups. All groups (patients and controls) significantly differed from each other for all tests (F'(4;42)=119, 2; p<0.001). However, the heterogeneity of the ERP patterns in the dyslexic group rendered group averaging irrelevant. The N170 wave sometimes overlapped with the P100 wavelength, but was also found to be negative or absent in some patients. In the course of development, N170 variations seem dependent on characteristics of the P100. No correlation was found between the variations of the N170 and clinical measures. Analysis of the P1-N1 temporal course showed a tendency to correlate with reading speed for the entire study population, yet not reaching statistical significance. Interpretation: N170 variations during development and dyslexic pathologies are associated with P100 variations. The P1-N1 time course could reflect silent reading speed. The P1-N1 temporal course was linked with clinical measures in all three groups, which could reflect neurodevelopmentalyrelated variations of the heterogeneity of the N170 as well as a developmental pathology. Verbal stimuli permit us to test the N170 physiological heterogeneity during development but variations in response to easy tasks show low sensitivity of N170 as a marker of dyslexia

Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations

Background: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA). Methods: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set. Results: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC. Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs. Conclusions: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement