Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site

Common fragile sites have long been identified by cytogeneticists as chromosomal regions prone to breakage upon replication stress. They are increasingly recognized to be preferential targets for oncogene-induced DNA damage in pre-neoplastic lesions and hotspots for chromosomal rearrangements in various cancers. Common fragile site instability was attributed to the fact that they contain sequences prone to form secondary structures that may impair replication fork movement, possibly leading to fork collapse resulting in DNA breaks. Here we show, in contrast to this view, that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kilobases, which forces forks coming from flanking regions to cover long distances in order to complete replication. We also show that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability we observed. Thus, we propose that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates.     

The circadian molecular clock creates epidermal stem cell heterogeneity

Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.     

The unusual minimum of sunspot cycle 23 caused by meridional plasma flow variations

Direct observations over the past four centuries show that the number of sunspots observed on the Sun's surface varies periodically, going through successive maxima and minima. Following sunspot cycle 23, the Sun went into a prolonged minimum characterized by a very weak polar magnetic field and an unusually large number of days without sunspots. Sunspots are strongly magnetized regions generated by a dynamo mechanism that recreates the solar polar field mediated through plasma flows. Here we report results from kinematic dynamo simulations which demonstrate that a fast meridional flow in the first half of a cycle, followed by a slower flow in the second half, reproduces both characteristics of the minimum of sunspot cycle 23. Our model predicts that, in general, very deep minima are associated with weak polar fields. Sunspots govern the solar radiative energy and radio flux, and, in conjunction with the polar field, modulate the solar wind, the heliospheric open flux and, consequently, the cosmic ray flux at Earth.     

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.     

A Pluto-like radius and a high albedo for the dwarf planet Eris from an occultation

The dwarf planet Eris is a trans-Neptunian object with an orbital eccentricity of 0.44, an inclination of 44 degrees and a surface composition very similar to that of Pluto. It resides at present at 95.7 astronomical units (1?AU is the Earth-Sun distance) from Earth, near its aphelion and more than three times farther than Pluto. Owing to this great distance, measuring its size or detecting a putative atmosphere is difficult. Here we report the observation of a multi-chord stellar occultation by Eris on 6 November 2010 UT. The event is consistent with a spherical shape for Eris, with radius 1,163?±?6?kilometres, density 2.52?±?0.05 grams per cm(3) and a high visible geometric albedo, Pv = 0.96(+0.09)(-0.04). No nitrogen, argon or methane atmospheres are detected with surface pressure larger than ～1?nanobar, about 10,000 times more tenuous than Pluto's present atmosphere. As Pluto's radius is estimated to be between 1,150 and 1,200 kilometres, Eris appears as a Pluto twin, with a bright surface possibly caused by a collapsed atmosphere, owing to its cold environment. We anticipate that this atmosphere may periodically sublimate as Eris approaches its perihelion, at 37.8 astronomical units from the Sun.     

Role of sulphuric acid, ammonia and galactic cosmic rays in atmospheric aerosol nucleation

Atmospheric aerosols exert an important influence on climate through their effects on stratiform cloud albedo and lifetime and the invigoration of convective storms. Model calculations suggest that almost half of the global cloud condensation nuclei in the atmospheric boundary layer may originate from the nucleation of aerosols from trace condensable vapours, although the sensitivity of the number of cloud condensation nuclei to changes of nucleation rate may be small. Despite extensive research, fundamental questions remain about the nucleation rate of sulphuric acid particles and the mechanisms responsible, including the roles of galactic cosmic rays and other chemical species such as ammonia. Here we present the first results from the CLOUD experiment at CERN. We find that atmospherically relevant ammonia mixing ratios of 100 parts per trillion by volume, or less, increase the nucleation rate of sulphuric acid particles more than 100-1,000-fold. Time-resolved molecular measurements reveal that nucleation proceeds by a base-stabilization mechanism involving the stepwise accretion of ammonia molecules. Ions increase the nucleation rate by an additional factor of between two and more than ten at ground-level galactic-cosmic-ray intensities, provided that the nucleation rate lies below the limiting ion-pair production rate. We find that ion-induced binary nucleation of H(2)SO(4)-H(2)O can occur in the mid-troposphere but is negligible in the boundary layer. However, even with the large enhancements in rate due to ammonia and ions, atmospheric concentrations of ammonia and sulphuric acid are insufficient to account for observed boundary-layer nucleation.     

Modulation of protein biophysical properties by chemical glycosylation: biochemical insights and biomedical implications

Glycosylation constitutes one of the most important posttranslational modifications employed by biological systems to modulate protein biophysical properties. Due to the direct biochemical and biomedical implications of achieving control over protein stability and function by chemical means, there has been great interest in recent years towards the development of chemical strategies for protein glycosylation. Since current knowledge about glycoprotein biophysics has been mainly derived from the study of naturally glycosylated proteins, chemical glycosylation provides novel insights into its mechanistic understanding by affording control over glycosylation parameters. This review presents a survey of the effects that natural and chemical glycosylation have on the fundamental biophysical properties of proteins (structure, dynamics, stability, and function). This is complemented by a mechanistic discussion of how glycans achieve such effects and discussion of the implications of employing chemical glycosylation as a tool to exert control over protein biophysical properties within biochemical and biomedical applications. Received 15 December 2006; received after revision 28 March 2007; accepted 25 April 2007     

Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia

Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL), caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER). Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia.