A somitic Wnt16/Notch pathway specifies haematopoietic stem cells

Haematopoietic stem cells (HSCs) are a self-renewing population of cells that continuously replenish all blood and immune cells during the lifetime of an individual. HSCs are used clinically to treat a wide array of diseases, including acute leukaemias and congenital blood disorders, but obtaining suitable numbers of cells and finding immune-compatible donors remain serious problems. These difficulties have led to an interest in the conversion of embryonic stem cells or induced pluripotent stem cells into HSCs, which is not possible using current methodologies. To accomplish this goal, it is critical to understand the native mechanisms involved in the specification of HSCs during embryonic development. Here we demonstrate in zebrafish that Wnt16 controls a novel genetic regulatory network required for HSC specification. Non-canonical signalling by Wnt16 is required for somitic expression of the Notch ligands deltaC (dlc) and deltaD (dld), and these ligands are, in turn, required for the establishment of definitive haematopoiesis. Notch signalling downstream of Dlc and Dld is earlier than, and distinct from, known cell-autonomous requirements for Notch, strongly suggesting that novel Notch-dependent relay signal(s) induce the first HSCs in parallel to other established pathways. Our results demonstrate that somite-specific gene expression is required for the production of haemogenic endothelium.     

Exome sequencing of liver fluke-associated cholangiocarcinoma

Opisthorchis viverrini-related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini-related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8-3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini-related CCA.     

Superconductivity in the non-oxide perovskite MgCNi3

The interplay of magnetic interactions, the dimensionality of the crystal structure and electronic correlations in producing superconductivity is one of the dominant themes in the study of the electronic properties of complex materials. Although magnetic interactions and two-dimensional structures were long thought to be detrimental to the formation of a superconducting state, they are actually common features of both the high transition-temperature (Tc) copper oxides and low-Tc material Sr2RuO4, where they appear to be essential contributors to the exotic electronic states of these materials. Here we report that the perovskite-structured compound MgCNi3 is superconducting with a critical temperature of 8 K. This material is the three-dimensional analogue of the LnNi2B2C family of superconductors, which have critical temperatures up to 16 K (ref. 2). The itinerant electrons in both families of materials arise from the partial filling of the nickel d-states, which generally leads to ferromagnetism as is the case in metallic Ni. The high relative proportion of Ni in MgCNi3 suggests that magnetic interactions are important, and the lower Tc of this three-dimensional compound-when compared to the LnNi2B2C family-contrasts with conventional ideas regarding the origins of superconductivity.     

Vortex-like excitations and the onset of superconducting phase fluctuation in underdoped La(2-x)Sr(x)CuO4

Two general features of a superconductor, which appear at the critical temperature, are the formation of an energy gap and the expulsion of magnetic flux (the Meissner effect). In underdoped copper oxides, there is strong evidence that an energy gap (the pseudogap) opens up at a temperature significantly higher than the critical temperature (by 100-220 K). Certain features of the pseudogap suggest that it is closely related to the gap that appears at the critical temperature (for example, the variation of the gap magnitudes around the Fermi surface and their maximum amplitudes are very similar). However, the Meissner effect is absent in the pseudogap state. The nature of the pseudogap state, and its relation (if any) to the superconducting state are central issues in understanding copper oxide superconductivity. Recent evidence suggests that, in the underdoped regime, the Meissner state is destroyed above the critical temperature by strong phase fluctuations (as opposed to a vanishing of the superfluid density). Here we report evidence for vortices (or vortex-like excitations) in La(2-x)Sr(x)CuO4 at temperatures significantly above the critical temperature. A thermal gradient is applied to the sample in a magnetic field. Vortices are detected by the large transverse electric field produced as they diffuse down the gradient (the Nernst effect). We find that the Nernst signal is anomalously enhanced at temperatures as high as 150 K.     

面向飞机PHM的大数据分析与人工智能应用

针对新一代电子产品密集型的飞机,其系统结构和失效机理复杂、失效模式多样,传统的方法难以对其进行有效健康管理的现状,因此提出了基于海量数据挖掘的飞机PHM研究。首先从系统结构、服役环境、数据来源与存储方式等角度分析了新一代飞机对海量数据挖掘的应用需求;其次论述了基于海量数据挖掘的关键技术,包括数据的预处理、集成管理、聚类、分类、关联、预测等;最后提出了一种基于私有云的飞机PHM海量数据挖掘平台,详细阐述了该平台的总体框架和软硬件结构,该平台为飞机PHM提供了验证平台,对促进飞机PHM的集成与工程化实现具有重大的军事应用意义。     

The c-erb-A gene encodes a thyroid hormone receptor

The cDNA sequence of human c-erb-A, the cellular counterpart of the viral oncogene v-erb-A, indicates that the protein encoded by the gene is related to the steroid hormone receptors. Binding studies with the protein show it to be a receptor for thyroid hormones.     

Two functionally distinct calcium pools in the excitation-contraction coupling process

Zusammenfassung Es wird angenommen, dass mindestens zwei Fraktionen von intrazellulärem Kalzium am Kupplungsprozess zwischen Reizung und Kontraktion des Herzens beteiligt sind.

---

---

This work was supported by grants from the Manitoba Heart Foundation and the Medical Research Council of Canada. We thank Mr.Stan Vivian for development of the PDP8/I computer program to analyze the calcium uptake curves.     

Compensatory caspase activation in MPP+-induced cell death in dopaminergic neurons

Many have hypothesized that cell death in Parkinsons disease is via apoptosis and, specifically, by the mitochondrial-mediated apoptotic pathway. We tested this hypothesis using a mouse dopaminergic cell line of mesencephalic origin, MN9D, challenged with the Parkinsonism-causing neurotoxin MPP⁺ (1-methyl-4-phenylpyridinium ion). Apoptosis was the main mode of cell death when the cells were subjected to MPP⁺ treatment under serum-free conditions for 24 h. Caspase-3 and caspase-9, however, were not activated, thus indicating the existence of alternate or compensatory cell death pathway(s) in dopaminergic neuronal cells. Using caspase inhibitors, we demonstrated that these pathways involve caspase-2, –8, –6 and –7. A time-course study indicated that activation of caspase-2 and –8 occurred upstream of caspase-6 and caspase-7. Upon MPP⁺ challenge, the apoptosis-inducing factor was translocated from the mitochondria into the MN9D cytosol and nucleus. These results suggest the existence of alternative apoptotic pathways in dopaminergic neurons.Received 20 September 2004; received after revision 5 November 2004; accepted 22 November 2004