Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

Propriétés tensioactives de phosphobétaïnes neutres à distance intercharge modulée

Une famille de phosphobétaïnes neutres (I) à caractères structuraux variés - chaînes lipophiles R = C12H25 et C18H37; distances intercharges définies par un nombre de groupe méthylène n entre têtes polaires (2 < n < 6); substituants R3 = éthoxy et phényle sur l'atome de phosphore - ont été étudiés comme agents tensioactifs associés au pentanol dans la formation de micro émulsions. Des diagrammes pseudo-ternaires ont été dressés qui indiquent la formation des différentes phases Wl, II, III et monophasique. Des évolutions sensibles sont observées en fonction des divers paramètres moléculaires. L'effet de distance intercharge se traduit par l'augmentation de la surface par tête polaire augmentant régulièrement les surfaces Wl et WIII tandis que le facteur HLB suggère la présence de structures différemment ordonnées. L'hydrophilie des phosphobétaïnes peut être contrôlée par la nature du substituant R2 placé sur l'atome de phosphore. Un remarquable maintien des propriétés est obtenu dans les différentes conditions de salinité et de température. Sur la base de ces résultats, il est possible de définir les paramètres moléculaires utiles à ces tensioactifs pour leur utilisation comme agent dopant des produits de la récupération assistée du pétrole

Simplified gyral pattern in severe developmental microcephalies? New insights from allometric modeling for spatial and spectral analysis of gyrification

The strong positive-allometric relationship between brain size, cortical extension and gyrification complexity, recently highlighted in the general population, could be modified by brain developmental disorders. Indeed, in case of brain growth insufficiency, the pathophysiological relevance of the "simplified gyral pattern" phenotype is strongly disputed since almost no genotype-phenotype correlations have been found in primary microcephalies. Using surface scaling analysis and newly-developed spectral analysis of gyrification (Spangy), we tested whether the gyral simplification in groups of severe microcephalies related to ASPM, PQBP1 or fetal-alcohol-syndrome could be fully explained by brain size reduction according to the allometric scaling law established in typically-developing control groups, or whether an additional disease effect was to be suspected. We found the surface area reductions to be fully explained by scaling effect, leading to predictable folding intensities measured by gyrification indices. As for folding pattern assessed by spectral analysis, scaling effect also accounted for the majority of the variations, but an additional negative or positive disease effect was found in the case of ASPM and PQBP1-linked microcephalies, respectively. Our results point out the necessity of taking allometric scaling into account when studying the gyrification variability in pathological conditions. They also show that the quantitative analysis of gyrification complexity through spectral analysis can enable distinguishing between even (predictable, non-specific) and uneven (unpredictable, maybe disease-specific) gyral simplifications

Recherche sur de nouveaux tensio-actifs zwitterioniques

Available at INIST (FR), Document Supply Service, under shelf-number : AR 13898 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc

CCDC22: a novel candidate gene for syndromic X-linked intellectual disability

Letter to the editorI Voineagu, L Huang, K Winden, M Lazaro, E Haan, J Nelson, J McGaughran, LS Nguyen, K Friend, A Hackett, M Field, J Gecz and D Geschwin

Decentralised paediatric HIV care in Ethiopia: a comparison between outcomes of patients managed in health centres and in a hospital clinic

Background: In order to increase access to antiretroviral therapy (ART) in HIV-infected children, paediatric HIV care has been introduced in health centres in Ethiopia, where patients are managed by health professionals with limited training. Objective: To compare outcomes of paediatric HIV care in hospital and health centre clinics and to determine risk factors for death and loss to follow-up (LTFU). Design: Retrospective comparison of patient characteristics and outcomes among children managed in a public hospital and all five public health centres in the uptake area. Results: Among 1,960 patients (health centres 572, hospital clinic 1,388), 34% were lost to follow-up, 2% died, 14% were transferred out, and 46% remained in care. Children initiating ART in the hospital clinic had lower median CD4 cell counts (age &#60;1 year: 575 vs. 1,183 cells/mm3, p=0.024; age 1&#x2013;5 years: 370 vs. 598 cells/mm3, p&#60;0.001; age &#x003E;5 years: 186 vs. 259 cells/mm3, p&#60;0.001), and a higher proportion were &#60;1 year of age (22% vs. 15%, p=0.025). ART initiation rates and retention in care were similar between children managed in health centres and in the hospital clinic (36% vs. 37% and 47% vs. 46%, respectively). Among patients starting ART, mortality was associated with age &#60;1 year [hazard ratio (HR) 12.0; 95% confidence interval (CI): 3.5, 41]. LTFU was associated with CD4 cell counts &#60;350 cells/mm3 (HR 1.8; 95% CI: 1.2, 3.0), weight-for-age z-scores below &#x2212;4 (HR 2.8; 95% CI: 1.4, 5.6), and age &#60;5 years (1&#x2013;5 years: HR 1.6; 95% CI: 1.0, 2.5; &#60;1 year: HR 3.3; 95% CI: 1.6, 6.6). Conclusions: Outcomes of HIV care were similar for Ethiopian children managed in a hospital clinic or in health centres. However, patients treated at the hospital clinic had characteristics of more advanced disease. Rates of LTFU were high in both types of health facility

On the growth and form of cortical convolutions

International audienceThe rapid growth of the human cortex during development is accompanied by the folding of the brain into a highly convoluted structure1-3. Recent studies have focused on the genetic and cellular regulation of cortical growth4-8, but understanding the formation of the gyral and sulcal convolutions also requires consideration of the geometry and physical shaping of the growing brain9-15. To study this, we use magnetic resonance images to build a 3D-printed layered gel mimic of the developing smooth fetal brain; when immersed in a solvent, the outer layer swells relative to the core, mimicking cortical growth. This relative growth puts the outer layer into mechanical compression and leads to sulci and gyri similar to those in fetal brains. Starting with the same initial geometry, we also build numerical simulations of the brain modelled as a soft tissue with a growing cortex, and show that this also produces the characteristic patterns of convolutions over a realistic developmental course. All together, our results show that although many molecular determinants control the tangential expansion of the cortex, the size, shape, placement and orientation of the folds arise through iterations and variations of an elementary mechanical instability modulated by early fetal brain geometry