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.     

Human metabolic individuality in biomedical and pharmaceutical research

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.     

FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR

Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.     

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.     

Decentralized Bezout Identity and a Parametrization of Decentralized Controllers for Singular Systems

1　 IntroductionConsider a singular decentralized control system of the formEx(t) =Ax(t) ∑Ni=1Biui(t)yi =Cix(t) ,i∈ N ={ 1 ,2 ,… ,N}(1 )where x(t)∈ Rn is the state vector,ui(t)∈ Rmi and yi(t)∈ Rpi are respectively the localcontrol input and measure outputvectors of the ith control channel.The matrix E may besingular,i.e.,rank(E) 相似文献   

膜基质金属蛋白酶和金属蛋白酶抑制因子-1 在早期胎盘中的表达及其功能的研究

用原位杂交方法研究了人早期胎盘中膜型金属蛋白酶（ＭＴ－ＭＭＰ－１）和金属蛋白酶抑制因子－１（ＴＩＭＰ－１）的分布。结果表明：（１）在绒毛滋养层细胞和与其邻近的蜕膜细胞中ＭＴ－ＭＭＰ－１和ＴＩＭＰ－１的表达量相对较高;（２）在基底盘,Ｒｏｈｒｓ和Ｎｉｔａｂｕｃｈ纹间的外绒毛膜滋养细胞,滋养层和蜕膜的腺体细胞表达最高;（３）胎膜分离层和绒毛干的少量细胞滋养层细胞以及蜕膜和绒毛干的血管壁上有明显的ＭＴ－     

纤溶酶原激活因子和抑制因子在早期胎盘中的表达及其功能

用原位杂交方法研究了人早期胎盘中组织型（ｔ）和尿激酶型（ｕ）纤溶酶原激活因子（ＰＡ）与其相应的抑制因子１型（ＰＡＩ－１）和２型（ＰＡＩ－２）ｍＲＮＡ的分布。结果表明：（１）在绒毛和蜕膜的血管壁,Ｒｏｈｒｓ和Ｎｉｔａｂｕｃｈ纹间的蜕膜中的大部分外细胞滋养层细胞沿绒毛盘、基底盘、绒毛叶间隔和绒毛膜的细胞滋养层细胞以及蜕膜的腺体细胞中都检测到ｔＰＡ、ｕＰＡ、ＰＡＩ－１和ＰＡＩ－２ｍＲＮＡ;（２）在基底绒     

Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11

The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration.