Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy

Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.     

Distribution, movements, and habitat use of razorback sucker ( Xyrauchen texanus ) in a lower Colorado River reservoir, Arizona-Nevada

Distribution, movements, and habitat use of 10 wild adult razorback suckers ( Xyrauchen texanus ) were examined in Lake Mohave, Arizona-Nevada, from November 1994 through July 1997. Movement rates (0.00-17.35 km d -1 ) and ranges ( x = 39 km) were similar to those for riverine populations. All study fish returned to spawning sites used in previous years, but they also visited other spawning areas. Spawning females were significantly ( P = 0.031) more active than males (480 vs. 87 m d -1 ) and moved substantial distances between spawning sites during peak reproduction (1-28 February). Fish became most active (m d -1 , km month -1 ) after spawning and moved to areas known to support higher algal production. Fish were typically within 50 m ( P 30.0 m). Adults were detected throughout the available thermal gradient (12°-30°C), but during summer typically had body temperatures between 18° and 22°C. Vertical movements within the water column showed no correlation with depth or time of day, but seasonal shifts suggest fish may regulate body temperature by seeking specific temperatures during reservoir stratification.     

Expression and functional importance of innate immune receptors by intestinal epithelial cells

Pattern recognition receptors are somatically encoded and participate in the innate immune responses of a host to microbes. It is increasingly acknowledged that these receptors play a central role both in beneficial and pathogenic interactions with microbes. In particular, these receptors participate actively in shaping the gut environment to establish a fruitful life-long relationship between a host and its microbiota. Commensal bacteria engage Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs) to induce specific responses by intestinal epithelial cells such as production of antimicrobial products or of a functional mucus layer. Furthermore, a complex crosstalk between intestinal epithelial cells and the immune system is initiated leading to a mature gut-associated lymphoid tissue to secrete IgA. Impairment in NLR and TLR functionality in epithelial cells is strongly associated with chronic inflammatory diseases such as Crohn’s disease, cancer, and with control of the commensal microbiota creating a more favorable environment for the emergence of new infections.     

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.     

microRNA-122 target sites in the hepatitis C virus RNA NS5B coding region and 3′ untranslated region: function in replication and influence of RNA secondary structure

We have analyzed the binding of the liver-specific microRNA-122 (miR-122) to three conserved target sites of hepatitis C virus (HCV) RNA, two in the non-structural protein 5B (NS5B) coding region and one in the 3′ untranslated region (3′UTR). miR-122 binding efficiency strongly depends on target site accessibility under conditions when the range of flanking sequences available for the formation of local RNA secondary structures changes. Our results indicate that the particular sequence feature that contributes most to the correlation between target site accessibility and binding strength varies between different target sites. This suggests that the dynamics of miRNA/Ago2 binding not only depends on the target site itself but also on flanking sequence context to a considerable extent, in particular in a small viral genome in which strong selection constraints act on coding sequence and overlapping cis-signals and model the accessibility of cis-signals. In full-length genomes, single and combination mutations in the miR-122 target sites reveal that site 5B.2 is positively involved in regulating overall genome replication efficiency, whereas mutation of site 5B.3 showed a weaker effect. Mutation of the 3′UTR site and double or triple mutants showed no significant overall effect on genome replication, whereas in a translation reporter RNA, the 3′UTR target site inhibits translation directed by the HCV 5′UTR. Thus, the miR-122 target sites in the 3′-region of the HCV genome are involved in a complex interplay in regulating different steps of the HCV replication cycle.     

Der Mathematiker Abraham de Moivre (1667–1754)

Summary Before examining de Moivre's contributions to the science of mathematics, this article reviews the source materials, consisting of the printed works and the correspondence of de Moivre, and constructs his biography from them.The analytical part examines de Moivre's contributions and achievements in the study of equations, series, and the calculus of probability. De Moivre contributed to the continuing development from Viète to Abel and Galois of the theory of solving equations by means of constructing particular equations, the roots of which can be written in the form . He also discovered the reciprocal equations. In the course of this work de Moivre discovered an expression equivalent to (cos +i sin ) ⁿ =cos n +i sin n and, following Cotes, he succeeded in expressing the nth roots of unity in trigonometric form.In the theory of series, de Moivre developed a polynomial theorem encom-passing Newton's binomial theorem and, in particular, a theorem of recurrent series useful in the calculus of probability.The demands of the calculus of probability led de Moivre to an approximation for the binomial coefficients for large values of n. The interaction between de Moivre and James Stirling, particularly in regard to the asymptotic series for log (n!), is treated at length. This work supplied the foundation for de Moivre's limit theorem for the binomial distribution.The calculus of probability, which occupied him from 1708 onward, became in time ever more the center of de Moivre's inquiries. Proceeding from contemporary collections of gambling exercises, de Moivre, by introducing an explicit measure of probability for the so-called Laplace experiments, found the beginnings of a theory of probability. De Moivre expanded the classic application of probability calculus to games of chance by addressing himself to the problem of annuities and by adopting Halley's work with its conception of Probability of life. De Moivre was the first to publish a mathematically formulated law for the decrements of life derived from mortality tables.

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Abkürzungen a.a.O. am angegebenen Ort = Verweis auf das nach Verfassern alphabetisch geordnete Literaturverzeichnis. Eine vor a.a.O. in runden Klammern angegebene Zahl kennzeichnet die entsprechende Nummer der im Literaturverzeichnis aufgeführten Arbeiten eines Autors. - AC Ars conjectandi = Jakob Bernoulli (4) a.a.O. - AE Acta Eruditorum - a.S. alter Stil⁴⁷ - BM Bibliotheca Mathematica - DMV Deutsche Mathematiker-Vereinigung - JL Journal Literaire - MA Miscellanea Analytica, London 1730 - n.S. neuer Stil⁴⁷ - PT Philosophical Transactions of the Royal Society of London - r.F. rekurrente Folge - r.R. rekurrente Reihe - SMA Miscellaneis Analyticis Supplementum, London 1730 - v. veröffentlicht (nur im Briefverzeichnis verwendet) Prof. Dr. Kurt Vogel zum 80. Geburtstag Vorgelegt von J. E. Hofmann     

Reversible lenticular opacities induced in rats by emotional stress

Zusammenfassung Ratten (20 Tiere, 45 Tage alt) erhielten 150 mg/kg paraglynes Hydrochlorid s.c. injiziert. Akustischer Schock (2 h später) ergab bei 16 von 20 Tieren eine reversible subkapsuläre Linsentrübung.

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The authors wish to thank Mr. R. D.Lock for technical assistance.     

Glassy particles in lunar fines

Most of the Apollo 11 glassy particles differ from those generated by terrestrial volcanism, by meteoritic impacts, or by the condensation of the parent bodies of meteorites. Some of the particles may have been formed by the action of solar flares on the lunar surface.