Mutant deoxynucleotide carrier is associated with congenital microcephaly

The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth.     

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.     

The genome sequence of the filamentous fungus Neurospora crassa

Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000 protein-coding genes--more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism, and important differences in Ca2+ signalling as compared with plants and animals. Neurospora possesses the widest array of genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes.     

Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis

The pattern of blood flow in the developing heart has long been proposed to play a significant role in cardiac morphogenesis. In response to flow-induced forces, cultured cardiac endothelial cells rearrange their cytoskeletal structure and change their gene expression profiles. To link such in vitro data to the intact heart, we performed quantitative in vivo analyses of intracardiac flow forces in zebrafish embryos. Using in vivo imaging, here we show the presence of high-shear, vortical flow at two key stages in the developing heart, and predict flow-induced forces much greater than might have been expected for micro-scale structures at low Reynolds numbers. To test the relevance of these shear forces in vivo, flow was occluded at either the cardiac inflow or outflow tracts, resulting in hearts with an abnormal third chamber, diminished looping and impaired valve formation. The similarity of these defects to those observed in some congenital heart diseases argues for the importance of intracardiac haemodynamics as a key epigenetic factor in embryonic cardiogenesis.     

Na+,K+-ATPase as a docking station: protein–protein complexes of the Na+,K+-ATPase

The Na⁺,K⁺-ATPase, or sodium pump, is well known for its role in ion transport across the plasma membrane of animal cells. It carries out the transport of Na⁺ ions out of the cell and of K⁺ ions into the cell and thus maintains electrolyte and fluid balance. In addition to the fundamental ion-pumping function of the Na⁺,K⁺-ATPase, recent work has suggested additional roles for Na⁺,K⁺-ATPase in signal transduction and biomembrane structure. Several signaling pathways have been found to involve Na⁺,K⁺-ATPase, which serves as a docking station for a fast-growing number of protein interaction partners. In this review, we focus on Na⁺,K⁺-ATPase as a signal transducer, but also briefly discuss other Na⁺,K⁺-ATPase protein–protein interactions, providing a comprehensive overview of the diverse signaling functions ascribed to this well-known enzyme.     

Probability in 1919/20: the von Mises-Pólya-Controversy

The correspondence between Richard von Mises and George Pólya of 1919/20 contains reflections on two well-known articles by von Mises on the foundations of probability in the Mathematische Zeitschrift of 1919, and one paper from the Physikalische Zeitschrift of 1918. The topics touched on in the correspondence are: the proof of the central limit theorem of probability theory, von Mises' notion of randomness, and a statistical criterion for integer-valuedness of physical data. The investigation will hint at both the fruitfulness and the limits of several of von Mises' notions such as ``collective', ``distribution' and ``complex adjuncts' (characteristic functions) for further developments in probability theory and in ``directional statistics'. By pointing to the selectiveness of Pólya's criticism, the historical analysis shows the differing expectations of the two men with respect to the further development of the theory of probability and its applications. The paper thus gives a glimpse of the provisional state of the theory around 1920, before others such as P. Lévy (1886–1971) and A. N. Kolmogorov (1903–1987) stepped in and created a new paradigm for probability theory.     

水玻璃旧砂中的Na_2O

水玻璃砂铸型因受不同温度的作用，其断面浇注后变成７种不同的颜色．通过对７种不同色层旧砂的再生处理、化学分析和电性能测试，揭示了水玻璃砂型中的Ｎａ２Ｏ经高温浇注后的行为、在旧砂中的分布及其对水玻璃砂再生和再生砂性能的影响     

Influence of chronic treatment with 2-bromo-α-ergocryptine (CB-154) on the reproductive and lactational performance of the C3H/HeJ female mouse

Zusammenfassung C3H/HeJ-weibliche Mäuse, die vor der Paarung dauernd mit CB-154, einem stark wirkenden Mittel zur Unterdrückung der Prolactinsekretion, behandelt wurden, wiesen keine bedeutsame Schädigung ihrer Fortpflanzungsfähigkeit auf. CB-154 Dauerbehandlung von weiblichen Mäusen sowohl während der Paarung als auch während der Laktation führte zu einer bedeutsamen Herabsetzung der Fruchtbarkeit und Milchabsonderung.

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Supported by NIH research grant No. CA-13777 and American Cancer Society research grant No. ET-59.

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NIH Research Career Development Awardee No. CA-35027

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CB-154 was provided through the courtesy of Dr.Richard Elton, Sandoz Pharmaceuticals, East Hanover, N. J., USA.

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Thanks are given toMs. Carol Gribler for her assistance in this study.     

Versuche zum enzymatischen Abbau der «gebundenen» gibberelline vonPharbitis purpurea

Summary Seeds and fruit walls ofPharbitis purpurea contain in addition to the free gibberellins A₈, A₃, A₅, more polar gibberellin-like substances, so-called bound gibberellins tentatively namedPharbitis and. After purification by thin layer chromatography, these 2 substances were treated with both Ficin and Emulsin in buffered solutions of pH 6.2. After treatment with Emulsin, the free gibberellins A₈ and A₅, after treatment with Ficin the gibberellins A₃ and A₅, were detectable in thin layer chromatograms.