ATP-sensitive potassium channels mediate survival during infection in mammals and insects

Specific homeostatic mechanisms confer stability in innate immune responses, preventing injury or death from infection. Here we identify, from a screen of N-ethyl-N-nitrosourea-mutagenized mice, a mutation causing both profound susceptibility to infection by mouse cytomegalovirus and approximately 20,000-fold sensitization to lipopolysaccharide (LPS), poly(I.C) and immunostimulatory (CpG) DNA. The LPS hypersensitivity phenotype is not suppressed by mutations in Myd88, Trif, Tnf, Tnfrsf1a, Ifnb, Ifng or Stat1, genes contributing to LPS responses, and results from an abnormality extrinsic to hematopoietic cells. The phenotype is due to a null allele of Kcnj8, encoding Kir6.1, a protein that combines with SUR2 to form an ATP-sensitive potassium channel (K(ATP)) expressed in coronary artery smooth muscle and endothelial cells. In Drosophila melanogaster, suppression of dSUR by RNA interference similarly causes hypersensitivity to infection by flock house virus. Thus, K(ATP) evolved to serve a homeostatic function during infection, and in mammals it prevents coronary artery vasoconstriction induced by cytokines dependent on TLR and/or MDA5 immunoreceptors.     

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy

Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.     

微量硼对形变TiAl

以形变     

萨尔短简

这是萨尔区域世界语同志寄来的通信。由亦文先生译出发表。国内杂志登载世界语通信这是第一次。以後还打算组织世界语通信网,每期登载些各地世界语通信,特此预告。编者一九三四年已过去了四分之三,一九三五年转瞬将届,决定萨     

加拿大 枫叶国度的直销兴起

在加拿大，随着直销业的持续发展，新办公司如雨后春笋一般。加拿大人对直销并不陌生，直销在新移民团体及其年轻一代人之中也开始渗透交融。这其中，加拿大直销协会起到了非常重要的作用。     

纳粹为何造不出原子弹?

英美当局确实晓得了在一九四五年有造成原子弹的可能,当然是立刻要想知道,德国人有没有抢在他们的前面。希特勒的周期性地誇耀秘密武器,加重了他们的恐懼。于是美国人成立一个机构,叫做阿尔沙斯(Alsos),探听德国人在造些     

新型航天材料太空诞生记

美国《选萃》杂志组织人员在一次航天飞行任务中,充分利用地球外空轨道的“零重力”条件,试验诞生了一种前景广阔的新型航天材料——超轻金属泡沫合金。     

法共三巨頭

法国共产党是法国三大政党之一,也是欧洲(除了苏联)的最大最成功的共产党。战後的欧洲,在政治上可以说已普遍地向左倾。在这种情形之下,法国共产党的成败,不特可以决定法国的命运,也足以左右今後整个欧洲的政治动向。所以,法共的首脑人物和它的发展情形,是我们研究欧洲政治问题时所不能忽略的。     

政策研究的摇篮——纪念兰德公司成立四十周年

兰德公司是一个私营的、非赢利性研究和培训机构,今年是兰德公司成立四十周年。我们的工作是从研究技术挑战和加速多学科研究领域发展开始的,今天我们致力于广泛的公共政策问题的研究。在开始的两年里,美国空军是我们仅有的委托者。今天我们设立了许多联邦政府资助的研究发展中心,为美国空军,     

21世纪的能源

未来的能源要求能以热和电两种形式满足消费者.全世界一半以上的电力由矿物燃料的热能转化而获得(图1),其平均转化效率为35%,产生1千瓦时电能约需3千瓦时的热能.一特定量的非矿物燃料(如水力、核能)所发电力的初级当量相当于在矿物燃