Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.     

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10??). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.     

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?3 to P = 1.2 × 10?13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.     

Passive seismic experiment and ScS wave splitting in the southwestern subbasin of South China Sea

The seismic experiment of 3D array of OBS in the southwestern sub-basin of the South China Sea(SCS) is briefly introduced in this paper.The data analysis of broadband OBS shows that totally 93 earthquakes with magnitude of Ms 6.0-6.9 and 10 earthquakes with magnitude above Ms 7.0 were recorded in high quality during this experiment,especially the catastrophic earthquake Ms 9.0 occurred in the east sea area of Japan on March 11,2011.The anisotropy parameters inversion of ScS wave of four events above Ms 7.0 indicates that the fast direction of shear wave is N58°E parallel to the ceased spreading ridge of the southwestern sub-basin of SCS(the slow direction is S35°E perpendicular to the spreading ridge),which means the spreading ridge is under compressing stress at present and the cessation of seafloor spreading is related to such stress field as well.     

Au NPs decorated TiO2 nanotubes array candidate for UV photodetectors

This work reports the Au nanoparticles (NPs) deposited on TiO2 nanotubes (NTs) which were successfully synthesized by a simple two-step anodization method. This fabrication process is notable for a simple and inexpensive method for obtaining pure TiO2 NTs and Au NPs deposited TiO2 NTs. The prepared samples were characterized by field emission scanning electron microscope (FESEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and I-V curve. We found that the size of Au NPs can be controlled by changing the bias voltage during the deposition. The photodetectors of Au NPs/TiO2 devices showed good wavelength selectivity with high photocurrent as compared to pure TiO2 NTs devices. Subsequently, Au NPs deposited on TiO2 NTs at bias voltage of 70 V was potentially used in fabrication of UV photodetector. At this applied voltage, a high density of Au NPs was uniformly deposited on TiO2 NTs. As a result, it enables a high photocurrent and great responsivity in UV region. It is suggested that the Au NPs deposited TiO2 NTs device shows good promise for UV photodetectors with possibility to fine-tune properties in both UV and visible regions and is worthy of further investigation.     

Dynorphin(1-13) improves survival in cats with focal cerebral ischaemia

Since the discovery of opiate receptors in the central nervous system (CNS), it has become apparent that endogenous opiate ligands are involved in CNS function. Most attention has focused on their role in modulating pain, but they have also been implicated in various physiological functions and in disease states. We are concerned with evidence that endogenous opioid peptides may also contribute to the neurological deficits arising from cerebral ischaemia. Dynorphin, which is widely distributed in the brain and pituitary, has been reported to produce unusual motor and behavioural effects and may act as a regulatory neuropeptide, not as a classical opiate agonist or antagonist. We have therefore administered to cats in which the right middle cerebral artery had been occluded both dynorphin (1-13) and analogue and control materials. We find that dynorphin (1-13) prolongs survival.     

Transvascular delivery of small interfering RNA to the central nervous system

A major impediment in the treatment of neurological diseases is the presence of the blood-brain barrier, which precludes the entry of therapeutic molecules from blood to brain. Here we show that a short peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of small interfering RNA (siRNA) to the brain. This 29-amino-acid peptide specifically binds to the acetylcholine receptor expressed by neuronal cells. To enable siRNA binding, a chimaeric peptide was synthesized by adding nonamer arginine residues at the carboxy terminus of RVG. This RVG-9R peptide was able to bind and transduce siRNA to neuronal cells in vitro, resulting in efficient gene silencing. After intravenous injection into mice, RVG-9R delivered siRNA to the neuronal cells, resulting in specific gene silencing within the brain. Furthermore, intravenous treatment with RVG-9R-bound antiviral siRNA afforded robust protection against fatal viral encephalitis in mice. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies. Thus, RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the blood-brain barrier.     

Sortilin is essential for proNGF-induced neuronal cell death

Sortilin (approximately 95 kDa) is a member of the recently discovered family of Vps10p-domain receptors, and is expressed in a variety of tissues, notably brain, spinal cord and muscle. It acts as a receptor for neurotensin, but predominates in regions of the nervous system that neither synthesize nor respond to this neuropeptide, suggesting that sortilin has additional roles. Sortilin is expressed during embryogenesis in areas where nerve growth factor (NGF) and its precursor, proNGF, have well-characterized effects. These neurotrophins can be released by neuronal tissues, and they regulate neuronal development through cell survival and cell death signalling. NGF regulates cell survival and cell death via binding to two different receptors, TrkA and p75NTR (ref. 10). In contrast, proNGF selectively induces apoptosis through p75NTR but not TrkA. However, not all p75NTR-expressing cells respond to proNGF, suggesting that additional membrane proteins are required for the induction of cell death. Here we report that proNGF creates a signalling complex by simultaneously binding to p75NTR and sortilin. Thus sortilin acts as a co-receptor and molecular switch governing the p75NTR-mediated pro-apoptotic signal induced by proNGF.     

AOP event manager in open service gateway

The Open Service Gateway Initiative (OSGi) has played an important role in ubiquitous environments that support interoperability among embedded devices, such as home appliances and network devices. However, the OSGi does not have a common event mechanism yet, and it is difficult to communicate among services asynchronously. In the present work, a common event manager, Aspect-Oriented Event Manager (AOEM), was designed on an OSGi framework. AOEM supports services to generate and provide notification of events. This paper presents the implementation of AOEM as an OSGi bundle with AspectJ. The experiment on transferring between device service and application service demonstrate that AOEM provides good abstraction of the services and convenience.     

Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2

A human homologue of the cdc2 gene has been cloned by expressing a human cDNA library in fission yeast and selecting for clones that can complement a mutant of cdc2. The predicted protein sequence of the human homologue is very similar to that of the yeast cdc2 gene. These data indicate that elements of the mechanism by which the cell cycle is controlled are likely to be conserved between yeast and humans.