使蛋白质特性和结构散发光芒的三重奖诺贝尔化学奖纵横光谱

继基因革命而来的时髦新词是蛋白质学(PRO-TEOMICS)——研究从活细胞产生的蛋白质的多样性的学说。今年的诺贝尔化学奖颁发给三位研究人员——他们研制出了用于分析蛋白质的二项关键工具。     

Retardation of murine viral leukemogenesis by prolonged antigenic stimulation

Zusammenfassung Die Mortalität an Leukämie bei BALB/c-Mäusen wurde durch wöchentliche i.p. Injektionen mit menschlichen Erythrozyten herabgesetzt, wenn sie während 8 Monaten vor der Impfung mitRauscher-Leukämievirus vorbehandelt waren. 7 Monate nach der Virusinfektion zeigten 20% dieser Mäuse keine Zeichen von Leukämie. Kontrollversuche mit der gleichen Serie von Injektionen von Ochsenserumalbumin zeigten keinen Schutz.     

Neural correlates, computation and behavioural impact of decision confidence

Humans and other animals must often make decisions on the basis of imperfect evidence. Statisticians use measures such as P values to assign degrees of confidence to propositions, but little is known about how the brain computes confidence estimates about decisions. We explored this issue using behavioural analysis and neural recordings in rats in combination with computational modelling. Subjects were trained to perform an odour categorization task that allowed decision confidence to be manipulated by varying the distance of the test stimulus to the category boundary. To understand how confidence could be computed along with the choice itself, using standard models of decision-making, we defined a simple measure that quantified the quality of the evidence contributing to a particular decision. Here we show that the firing rates of many single neurons in the orbitofrontal cortex match closely to the predictions of confidence models and cannot be readily explained by alternative mechanisms, such as learning stimulus-outcome associations. Moreover, when tested using a delayed reward version of the task, we found that rats' willingness to wait for rewards increased with confidence, as predicted by the theoretical model. These results indicate that confidence estimates, previously suggested to require 'metacognition' and conscious awareness are available even in the rodent brain, can be computed with relatively simple operations, and can drive adaptive behaviour. We suggest that confidence estimation may be a fundamental and ubiquitous component of decision-making.     

带非齐次项和Sobolev-Hardy临界指数的奇异椭圆方程的多解

设2*=2(N α)(N-2 β),N≥3,是极限Sobolev指数,ΩRN是RN中的开子集.在f(x)∈Hβ-1满足合适的条件且f(x)≠0下,讨论了一个带非齐次项和Sobolev-Hardy临界指数的含权的椭圆型问题:{-div(|x|β▽u)=|x|αup*-1 εf(x),x∈Ω,u>0,x∈Ω,u=0,x∈Ω,,存在两个解u和-u在H01,,βp(Ω)中,且有u≥0,u-≥0对所有的f(x)≥0.值得注意的是,当f(x)=0时一般不成立.     

Variants conferring risk of atrial fibrillation on chromosome 4q25

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.     

RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels

Therapeutics that discriminate between the genetic makeup of normal cells and tumour cells are valuable for treating and understanding cancer. Small molecules with oncogene-selective lethality may reveal novel functions of oncoproteins and enable the creation of more selective drugs. Here we describe the mechanism of action of the selective anti-tumour agent erastin, involving the RAS-RAF-MEK signalling pathway functioning in cell proliferation, differentiation and survival. Erastin exhibits greater lethality in human tumour cells harbouring mutations in the oncogenes HRAS, KRAS or BRAF. Using affinity purification and mass spectrometry, we discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs)--a novel target for anti-cancer drugs. We show that erastin treatment of cells harbouring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin, implicating these two VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, we found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabelled analogue and a filter-binding assay, we show that erastin binds directly to VDAC2. These results demonstrate that ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway.     

Two distinct modes of guidance signalling during collective migration of border cells

Although directed migration is a feature of both individual cells and cell groups, guided migration has been studied most extensively for single cells in simple environments. Collective guidance of cell groups remains poorly understood, despite its relevance for development and metastasis. Neural crest cells and neuronal precursors migrate as loosely organized streams of individual cells, whereas cells of the fish lateral line, Drosophila tracheal tubes and border-cell clusters migrate as more coherent groups. Here we use Drosophila border cells to examine how collective guidance is performed. We report that border cells migrate in two phases using distinct mechanisms. Genetic analysis combined with live imaging shows that polarized cell behaviour is critical for the initial phase of migration, whereas dynamic collective behaviour dominates later. PDGF- and VEGF-related receptor and epidermal growth factor receptor act in both phases, but use different effector pathways in each. The myoblast city (Mbc, also known as DOCK180) and engulfment and cell motility (ELMO, also known as Ced-12) pathway is required for the early phase, in which guidance depends on subcellular localization of signalling within a leading cell. During the later phase, mitogen-activated protein kinase and phospholipase Cgamma are used redundantly, and we find that the cluster makes use of the difference in signal levels between cells to guide migration. Thus, information processing at the multicellular level is used to guide collective behaviour of a cell group.