Identification of the structure of large-scale MHD perturbations in a tokamak from Mirnov signals

An algorithm is proposed that allows one to identify the MHD mode structure in toroidal plasmas by processing signals from Mirnov probes measuring plasma MHD activity. The algorithm differs fundamentally from the diagnostic methods presently used in tokamaks, being simpler and more efficient. The algorithm is based on constructing an analytic signal using the Hilbert transformation of the Mirnov signals at a given instant. The phase and amplitude dependences obtained take into account the toroidal effects and allow one to determine the number and amplitude of the excited MHD mode. The algorithm was approbated with both test signals and actual signals from MHD diagnostics in the T-10 tokamak. It is demonstrated that the algorithm can be used to analyze single-mode MHD instabilities in toroidal plasmas.     

Physical and functional interaction between Pes1 and Bop1 in mammalian ribosome biogenesis

Molecular mechanisms of mammalian ribosome biogenesis remain largely unexplored. Here we develop a series of transposon-derived dominant mutants of Pes1, the mouse homolog of the zebrafish Pescadillo and yeast Nop7p implicated in ribosome biogenesis and cell proliferation control. Six Pes1 mutants selected by their ability to reversibly arrest the cell cycle also impair maturation of the 28S and 5.8S rRNAs in mouse cells. We show that Pes1 physically interacts with the nucleolar protein Bop1, and both proteins direct common pre-rRNA processing steps. Interaction with Bop1 is essential for the efficient incorporation of Pes1 into nucleolar preribosomal complexes. Pes1 mutants defective for the interaction with Bop1 lose the ability to affect rRNA maturation and the cell cycle. These data show that coordinated action of Pes1 and Bop1 is necessary for the biogenesis of 60S ribosomal subunits.     

Testosterone regulates 25-hydroxycholesterol production in testicular macrophages

Recently, we found that testicular macrophages produce 25-hydroxycholesterol (25-HC) and express 25-hydroxylase, the enzyme that converts cholesterol to 25-HC. In addition, 25-HC may be an important paracrine factor mediating the known interactions between macrophages and neighboring Leydig cells, because it is efficiently converted to testosterone by Leydig cells. The purpose of the present study was to determine if testosterone can regulate the production of 25-HC in rat testicular macrophages, representing a potential negative-feedback loop from Leydig cells. We found that expression of 25-hydroxylase mRNA and production of 25-HC by cultured testicular macrophages were significantly inhibited by testosterone at 10 micro g/ml. This dose of testosterone did not have an effect on cell viability and did not change the rate of mRNA degradation in the presence of actinomycin D. These studies indicate that production of 25-HC is negatively regulated by testosterone, which may be representative of a paracrine negative-feedback loop.     

N-terminal sequences direct the autophosphorylation states of the FER tyrosine kinases in vivo

p94(fer) and p51(ferT) are two tyrosine kinases which share identical SH2 and kinase domains but differ in their N-terminal regions. While p94(fer) is expressed in most mammalian cells, the accumulation of p51(ferT) is restricted to meiotic spermatocytes. Here we show that the different N-terminal tails of p94(fer) and p51(ferT) direct different autophosphorylation states of these two kinases in vivo. N-terminal coiled-coil domains cooperated to drive the oligomerization and autophosphorylation in trans of p94(fer). Moreover, the ectopically expressed N-terminal tail of p94(fer) could act as a dominant negative mutant and associated with the endogenous p94(fer) protein in CHO cells. This increased significantly the percentage of cells residing in the G0/G1 phase, thus suggesting a role for p94(fer) in the regulation of G1 progression. Unlike p94(fer), overexpressed p51(ferT) was not autophosphorylated in COS1 cells. However, removal of the unique N-terminal 43 aa of p51(ferT) or the replacement of this region by a parallel segment from p94(fer) endowed the modified p51(ferT) with the ability to autophosphorylate. The unique N-terminal sequences of p51(ferT) thus interfere with its ability to autophosphorylate in vivo. These experiments indicate that the N-terminal sequences of the FER tyrosine kinases direct their different cellular autophosphorylation states, thereby dictating their different cellular functions.     

Phenotypic variation and stress resistance in core and peripheral populations of Hordeum spontaneum

The phenotypic variation and response of plants to water stress were studied in a field trial in populations of wild barley, Hordeum spontaneum Koch. from Israel and Turkmenistan. Populations from the species distributional core and periphery were compared and contrasted for phenotypic variation in 16 phenological and morphological traits. The peripheral populations (six) were found to be phenotypically more variable and more resistant to water stress than core populations (12). The association of water-stress resistance with high phenotypic variability gives support to the hypothesis that populations that are genetically more variable are better adapted or pre-adapted to environmental changes and are thus valuable for conservation.     

CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity

DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.     

Geographic distribution and migration pathways of Pistacia – present,past and future

The global distribution of Pistacia is correlated to its adaptability to environmental conditions and mechanisms that had driven the genus to the current unique narrow latitudinal belt in between 10° North and 45° North. The current geostatisitcal distribution maps of the genus are shown and the derived probability maps over a period between 121 Kyr before present and the year 2100 were calculated. The tolerance of Pistacia trees to harsh climate conditions was related to leaf phenology, evergreeness vs deciduousness, which has led to geographic classification of the genus in two corresponding sections that corroborate recent molecular genetic studies. The deciduous trees are more tolerant to extreme climate conditions (?26°C to 46°C) than the evergreen species (?8°C to 41°C), except Pistacia lentiscus, which occurs at a max. temperature of 45°C. The close spatial distribution of the later species and the deciduous ones may have been conducive in further evolution of the genus. Based on the long evolution of Pistacia (approx. 84 Ma), we suggested that the genus may have originated in the boreal forest and its migration pathways might have been evoked in relation to climate change, shifting the species distribution to evolving suitable environmental conditions. The fact that most of the genera in the family of Anacardiaceae and the whole genus Pistacia are dioecious raised questions about plausible relationships between the geographic distribution, environmental conditions and evolution of dioecy. The genus Pistacia was shown to be a good candidate for research about the relationships between environmental conditions, adaptation traits and geographic distribution.     

N-Arylalkylpiperidine urea derivatives as CC chemokine receptor-3 (CCR3) antagonists

The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils.     

Analytical precision,biological variation,and mathematical normalization in high data density metabolomics

Metabolic serotypes sensitive to caloric intake may enable sera metabolomic profiles to validate epidemiological parameters and predict disease risk in humans. This long-range goal is complicated by the lack of known state markers and the requirement for simultaneous monitoring of multiple small changes. Therefore, analytical precision for appropriate high data density studies using HPLC separations coupled with coulometric array detectors was evaluated over a two month period in pooled rat sera samples (previously collected and stored at –80 °C), and in authentic biochemical standards. In sera, mean coefficients of variation (CV) of retention time and ratio accuracy within the established metabolic serotype varied within ±1% and ±3%, respectively. In sets of purified standards, the same parameters fluctuated, correspondently, in ranges of ±0.1% and ±1%. Median CV of the metabolite concentrations were ~13% in standards and ~11–19% in sera, and varied non-monotonically with the analytical system status and experimental design. These parameters were shown to be sufficiently controlled so as not to dominate intra-group biological variability in serum metabolomics studies. Continuation of experimental runs across an analytical breakpoint (column replacement) was associated with disproportionate changes in metabolite concentrations, independent of maintained analytical precision. These changes were sufficient to shift overall profile localization in megavariate projection analyses. We developed a mathematical approach to normalize this break and use partial least squares projection to latent structure discriminant analysis to confirm validity of this normalization approach. This generally applicable mathematical correction helps enable longer term high data density studies by removing a critical source of systemic variation.     

A nonlinear dynamic model of DNA with a sequence-dependent stacking term

No simple model exists that accurately describes the melting behavior and breathing dynamics of double-stranded DNA as a function of nucleotide sequence. This is especially true for homogenous and periodic DNA sequences, which exhibit large deviations in melting temperature from predictions made by additive thermodynamic contributions. Currently, no method exists for analysis of the DNA breathing dynamics of repeats and of highly G/C- or A/T-rich regions, even though such sequences are widespread in vertebrate genomes. Here, we extend the nonlinear Peyrard–Bishop–Dauxois (PBD) model of DNA to include a sequence-dependent stacking term, resulting in a model that can accurately describe the melting behavior of homogenous and periodic sequences. We collect melting data for several DNA oligos, and apply Monte Carlo simulations to establish force constants for the 10 dinucleotide steps (CG, CA, GC, AT, AG, AA, AC, TA, GG, TC). The experiments and numerical simulations confirm that the GG/CC dinucleotide stacking is remarkably unstable, compared with the stacking in GC/CG and CG/GC dinucleotide steps. The extended PBD model will facilitate thermodynamic and dynamic simulations of important genomic regions such as CpG islands and disease-related repeats.