The knockout mouse project

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.     

Observation of Hanbury Brown-Twiss anticorrelations for free electrons

Fluctuations in the counting rate of photons originating from uncorrelated point sources become, within the coherently illuminated area, slightly enhanced compared to a random sequence of classical particles. This phenomenon, known in astronomy as the Hanbury Brown-Twiss effect, is a consequence of quantum interference between two indistinguishable photons and Bose Einstein statistics. The latter require that the composite bosonic wavefunction is a symmetric superposition of the two possible paths. For fermions, the corresponding two-particle wavefunction is antisymmetric: this excludes overlapping wave trains, which are forbidden by the Pauli exclusion principle. Here we use an electron field emitter to coherently illuminate two detectors, and find anticorrelations in the arrival times of the free electrons. The particle beam has low degeneracy (about 10(-4) electrons per cell in phase space); as such, our experiment represents the fermionic twin of the Hanbury Brown-Twiss effect for photons.     

High-throughput retroviral tagging to identify components of specific signaling pathways in cancer

Genetic screens carried out in lower organisms such as yeast, Drosophila melanogaster and Caenorhabditis elegans have revealed many signaling pathways. For example, components of the RAS signaling cascade were identified using a mutant eye phenotype in D. melanogaster as a readout. Screening is usually based on enhancing or suppressing a phenotype by way of a known mutation in a particular signaling pathway. Such in vivo screens have been difficult to carry out in mammals, however, owing to their relatively long generation times and the limited number of animals that can be screened. Here we describe an in vivo mammalian genetic screen used to identify components of pathways contributing to oncogenic transformation. We applied retroviral insertional mutagenesis in Myc transgenic (E mu Myc) mice lacking expression of Pim1 and Pim2 to search for genes that can substitute for Pim1 and Pim2 in lymphomagenesis. We determined the chromosomal positions of 477 retroviral insertion sites (RISs) derived from 38 tumors from E mu Myc Pim1(-/-) Pim2(-/-) mice and 27 tumors from E mu Myc control mice using the Ensembl and Celera annotated mouse genome databases. There were 52 sites occupied by proviruses in more than one tumor. These common insertion sites (CISs) are likely to contain genes contributing to tumorigenesis. Comparison of the RISs in tumors of Pim-null mice with the RISs in tumors of E mu Myc control mice indicated that 10 of the 52 CISs belong to the Pim complementation group. In addition, we found that Pim3 is selectively activated in Pim-null tumor cells, which supports the validity of our approach.     

Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)

Pelger-Hu?t anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape.     

Strong correlation between levels of tropospheric hydroxyl radicals and solar ultraviolet radiation

The most important chemical cleaning agent of the atmosphere is the hydroxyl radical, OH. It determines the oxidizing power of the atmosphere, and thereby controls the removal of nearly all gaseous atmospheric pollutants. The atmospheric supply of OH is limited, however, and could be overcome by consumption due to increasing pollution and climate change, with detrimental feedback effects. To date, the high variability of OH concentrations has prevented the use of local observations to monitor possible trends in the concentration of this species. Here we present and analyse long-term measurements of atmospheric OH concentrations, which were taken between 1999 and 2003 at the Meteorological Observatory Hohenpeissenberg in southern Germany. We find that the concentration of OH can be described by a surprisingly linear dependence on solar ultraviolet radiation throughout the measurement period, despite the fact that OH concentrations are influenced by thousands of reactants. A detailed numerical model of atmospheric reactions and measured trace gas concentrations indicates that the observed correlation results from compensations between individual processes affecting OH, but that a full understanding of these interactions may not be possible on the basis of our current knowledge of atmospheric chemistry. As a consequence of the stable relationship between OH concentrations and ultraviolet radiation that we observe, we infer that there is no long-term trend in the level of OH in the Hohenpeissenberg data set.     

JPEG2000在空间太阳望远镜中的改进应用

对JPEG2000算法提出了一种新的改进,以提高它的编码效率.通过修改编码顺序,使得在每个Tile中,数据按照其重要性降序编码.从而,码流截断方法也随之简化,并可以提前终止编码,而率失真效果仍接近最优.最后,给出一个可行的并行化方案,可大大缩短运行时间.改进后的JPEG2000更适用于计算资源有限的星上系统,满足了空间太阳望远镜的压缩需求.     

载荷累积频次谱最大穿越频数及其确定问题

载荷累积频次谱的形状和最大穿越频数对计算疲劳寿命有很大影响。为寻求和认识其中规律,本文分析了载荷累积频次谱的形状和最大穿越频数对计算疲劳寿命的作用效果,指出了针对具体情况区分最大穿越频数的必要性。在此基础上,提出了以累积损伤率为准则的确定最大穿越频数的设想。并对其计算实拖进行了初步探索。     

大庆减压渣油馏分油水界面张力的研究

采用超临界萃取分离技术 ,将大庆减压渣油按相对分子质量分割为 17个馏分 ,并对各馏分进行了化学组成分析和紫外光谱测定。在此基础上 ,采用吊环法对各馏分在不同条件 (馏分质量分数、油相组成、盐的种类及质量分数、水相 pH值 )下的油水界面张力进行了研究。结果表明 ,大庆减渣馏分相对分子质量逐渐增大 ,氢碳原子比逐渐下降 ,芳香共轭结构逐渐增多 ;随着馏分在油相中质量分数的增大 ,界面张力下降 ,且下降趋势相似 ,总体降幅不大 ;随着油相中庚烷的增多 ,界面张力降低。水相中CaCl2 使得油水界面张力上升 ,而NaCl或KCl对油水界面张力影响较小。水相 pH值在酸性范围内变化时 ,基本不影响油水界面张力 ,pH值在碱性范围内增大时 ,界面张力降低。     

Peirescs Nebel im Sternbild Orion—eine neue Textgrundlage für die Geschichte von M42

Nicolas Claude Fabri de Peiresc (1580–1637) gilt als Entdecker des Orion-Nebels (M42). Als solcher ist er seit neunzig Jahren bekannt. Der französische Astronom und Wissenschaftshistoriker Guillaume Bigourdan zog diesen Schluss aus Aufzeichnungen, die er in Peirescs unveröffentlichtem Journal des observations entdeckt und 1916 veröffentlicht hatte. Demnach soll Peiresc den Orion-Nebel im November 1610 beobachtet haben. Peirescs Zeitgenossen jedoch war diese Beobachtung verborgen geblieben, und niemandem sonst gelang sie so früh nach Einführung des Teleskops. Mittlerweile sind Zweifel an Peirescs Entdeckung angemeldet worden. Die von Bigourdan veröffentlichten Notizen sind bislang keiner eingehenden Prüfung unterzogen worden. Der vorliegende Aufsatz liefert eine neue Transkription sowie erstmals eine Übersetzung der lateinischen Handschrift. Im Vergleich dazu erweist sich die Bigourdansche Edition häufig als nicht korrekt. Peirescs Orion-Bericht, der hier erstmals in Gänze lesbar vorliegt, wirft neue Fragen auf. Denn aus ihm geht nicht hervor, welche Region im Sternbild Orion, welche Sterne und welche Nebelobjekte Peiresc 1610 beobachtete. Die vollständige Lektüre von Peirescs Notizen verlangt nach einer neuen Interpretation seiner Beobachtungen im Sternbild Orion. Nur so ließe sich klären, ob tatsächlich schon Peiresc den Orion-Nebel sehen konnte oder ob womöglich M42 erst später sichtbar wurde.     

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.