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

Nanoscale Morphological Changes at Lithium Interface, Triggered by the Electrolyte Composition and Electrochemical Cycling

Understanding the electrochemical and morphological properties of the Li-electrolyte interface plays a central role in the implementation of metallic Li in safe and efficient electrochemical energy storage. The current study explores the influence of soluble polysulfides (PS) and lithium nitrate (LiNO3) on the characteristics of the solid electrolyte interphase (SEI) layer, formed spontaneously on the Li surface, prior to electrochemical cycling. Special attention is paid to the evolution of the electrochemical impedance and nanoscale morphology of the interface, influenced by the contact time and electrolyte composition. The basic tools applied in this investigation are electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM) performed at the nanoscale, and X-ray photoelectron spectroscopy (XPS). The individual addition of polysulfides and LiNO3 increases the interface resistance, while the simultaneous application of these components is beneficial, reducing the SEI resistive behavior. The electrochemical cycling of Li in nonmodified 1,2-dimethoxy ethane (DME) and tetraethylene glycol dimethyl ether (TEGDME) based electrolytes leads to slight morphological changes, compared to the pristine Li pattern. In contrast, we found that in the presence of PS and LiNO3, the interface displays a rough and inhomogeneous morphology

Prediction of chronic lung disease, survival and need for ECMO therapy in infants with congenital diaphragmatic hernia: Additional value of fetal MRI measurements?

Introduction: The lung-to-head ratio (LHR), measured by ultrasound, and the fetal lung volume (FLV), measured by MRI, are both used to predict survival and need for extra corporeal membrane oxygenation (ECMO) in infants with congenital diaphragmatic hernia (CDH). The aim of this study is to determine whether MRI measurements of the FLV, in addition to standard ultrasound measurements of the LHR, give better prediction of chronic lung disease, mortality by day 28 and need for ECMO. Materials and methods: Patients with unilateral isolated CDH born between January 2002 and December 2008 were eligible for inclusion. LHR and FLV were expressed as observed-to-expected values (O/E LHR and O/E FLV). Univariate and multivariate analyses were performed. Receiver operating characteristic curves were constructed and areas under the curve (AUC) were calculated to determine predictive values. Results: 90 patients were included in the analysis. Combined measurement of the O/E LHR and O/E FLV gave a slightly better prediction of chronic lung disease (AUC = 0.83 and AUC = 0.87) and need for ECMO therapy (AUC = 0.77 and AUC = 0.81) than standard ultrasound measurements of the O/E LHR alone. Combined measurement of the O/E LHR and O/E FLV did not improve prediction of early mortality (AUC = 0.90) compared to measurement of the O/E LHR alone (AUC = 0.89). An intrathoracal position of the l Discussion: Chronic lung disease and need for ECMO therapy are slightly better predicted by combined measurement of the O/E LHR and the O/E FLV. Early mortality is very well predicted by measurement of the O/E LHR alone. Conclusion: Clinical relevance of additional MRI measurements may be debated. (C) 2011 Elsevier Ireland Ltd. All rights reserved