SummaryThe cerebral cortex underwent rapid expansion and increased complexity during recent hominid evolution. Gene duplications constitute a major evolutionary force, but their impact on human brain development remains unclear. Using tailored RNA sequencing (RNA-seq), we profiled the spatial and temporal expression of hominid-specific duplicated (HS) genes in the human fetal cortex and identified a repertoire of 35 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among them NOTCH2NL, human-specific paralogs of the NOTCH2 receptor, stood out for their ability to promote cortical progenitor maintenance. NOTCH2NL promote the clonal expansion of human cortical progenitors, ultimately leading to higher neuronal output. At the molecular level, NOTCH2NL function by activating the Notch pathway through inhibition of cis Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes active during human corticogenesis and reveals how human-specific NOTCH paralogs may have contributed to the expansion of the human cortex.

Autosomal recessive ataxias affect about 1 person in 20,000. Friedreich ataxia accounts for one-third of the cases in Caucasians; the others are due to a growing list of very rare molecular defects, including mild forms of metabolic diseases. In nearly 50%, the genetic cause remains undetermined.

Abnormal homeostasis of heavy metals is a well-documented physiopathological mechanism in Alzheimer's disease. An exacerbation of these abnormalities is best illustrated in the amyloid plaques in Alzheimer's disease brain tissue, in which zinc reaches the enormous concentration of 1000 microM. Zinc in the plaques is thought to originate from impaired glutamatergic neurons distributed in the associative cortex and limbic structures of normal brain. Although the characteristics of zinc binding to Abeta and its role in promotion of Abeta aggregation have been intensively studied, the contribution of zinc to the development of tau pathology remains elusive. To further document the effect of zinc we have investigated the modifications of tau phosphorylation, conformation and association to microtubules induced by zinc in clonal cell lines expressing a human tau isoform. A bimodal dose dependent effect of zinc was observed. At 100 microM zinc induced a tau dephosphorylation on the PHF-1 epitope, and at higher zinc concentrations induced the appearance of the abnormal tau conformational epitope MC1 and reduced the electrophoretic mobility of tau, known to be associated to increased tau phosphorylation. High zinc concentrations also increased glycogen synthase kinase-3beta (GSK-3beta) phosphorylation on tyrosine 216, a phosphorylation associated with increased activity of this tau kinase. Live imaging of tau-EGFP expressing cells demonstrated that high zinc concentrations induced a release of tau from microtubules. These results suggest that zinc plays a significant role in the development of tau pathology associated to Alzheimer's disease.

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Purpose: Hearing loss is characterized by an extensive genetic heterogeneity and remains a common disorder in children. Molecular diagnosis is of particular benefit in children, and permits the early identification of clinically-unrecognized hearing loss syndromes, which permits effective clinical management and follow-up, including genetic counselling. Methods: We performed whole-exome sequencing with the analysis of a panel of 189 genes associated with hearing loss in a prospective cohort of 61 children and 9 adults presenting mainly with isolated hearing loss. Results: The overall diagnostic rate using exome sequencing was 47.2% (52.5% in children; 22% in adults). In children with confirmed molecular results, 17/32 (53.2%) showed autosomal recessive inheritance patterns, 14/32 (43.75%) showed an autosomal dominant condition, and one case had X-linked hearing loss. In adults, the two patients showed an autosomal dominant inheritance pattern. Among the 32 children, 17 (53.1%) had nonsyndromic hearing loss and 15 (46.7%) had syndromic hearing loss. One adult was diagnosed with syndromic hearing loss and one with nonsyndromic hearing loss. The most common causative genes were STRC (5 cases), GJB2 (3 cases), COL11A1 (3 cases), and ACTG1 (3 cases). Conclusions: Exome sequencing has a high diagnostic yield in children with hearing loss and can reveal a syndromic hearing loss form before other organs/systems become involved, allowing the surveillance of unrecognized present and/or future complications associated with these syndromes.

This study illustrates the growing epidemic of MDR and XDR-TB, it emphasizes the importance of proper diagnosis and adequate management of TB in patients at risk for resistance and stresses the need for new therapies.

SummaryThe human cerebral cortex has undergone rapid expansion and increased complexity during recent evolution. Hominid-specific gene duplications represent a major driving force of evolution, but their impact on human brain evolution remains unclear. Using tailored RNA sequencing (RNAseq), we profiled the spatial and temporal expression of Hominid-specific duplicated (HS) genes in the human fetal cortex, leading to the identification of a repertoire of 36 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among these we focused on NOTCH2NL, previously uncharacterized HS paralogs of NOTCH2. NOTCH2NL promote the clonal expansion of human cortical progenitors by increasing self-renewal, ultimately leading to higher neuronal output. NOTCH2NL function by activating the Notch pathway, through inhibition of Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes linking genomic evolution to human brain development, and reveals how hominin-specific NOTCH paralogs may have contributed to the expansion of the human cortex.All rights reserved. No reuse allowed without permission.