Transformation Pathways of Silica under High Pressure

Concurrent molecular dynamics simulations and ab initio calculations show that densification of silica under pressure follows a ubiquitous two-stage mechanism. First, anions form a close-packed sub-lattice, governed by the strong repulsion between them. Next, cations redistribute onto the interstices. In cristobalite silica, the first stage is manifest by the formation of a metastable phase, which was observed experimentally a decade ago, but never indexed due to ambiguous diffraction patterns. Our simulations conclusively reveal its structure and its role in the densification of silica.Comment: 14 pages, 4 figure

Globotriaosylsphingosine Accumulation and Not Alpha-Galactosidase-A Deficiency Causes Endothelial Dysfunction in Fabry Disease

BACKGROUND: Fabry disease (FD) is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA) resulting in the accumulation of globotriaosylsphingosine (Gb3) in a variety of tissues. While GLA deficiency was always considered as the fulcrum of the disease, recent attention shifted towards studying the mechanisms through which Gb3 accumulation in vascular cells leads to endothelial dysfunction and eventually multiorgan failure. In addition to the well-described macrovascular disease, FD is also characterized by abnormalities of microvascular function, which have been demonstrated by measurements of myocardial blood flow and coronary flow reserve. To date, the relative importance of Gb3 accumulation versus GLA deficiency in causing endothelial dysfunction is not fully understood; furthermore, its differential effects on cardiac micro- and macrovascular endothelial cells are not known. METHODS AND RESULTS: In order to assess the effects of Gb3 accumulation versus GLA deficiency, human macro- and microvascular cardiac endothelial cells (ECs) were incubated with Gb3 or silenced by siRNA to GLA. Gb3 loading caused deregulation of several key endothelial pathways such as eNOS, iNOS, COX-1 and COX-2, while GLA silencing showed no effects. Cardiac microvascular ECs showed a greater susceptibility to Gb3 loading as compared to macrovascular ECs. CONCLUSIONS: Deregulation of key endothelial pathways as observed in FD vasculopathy is likely caused by intracellular Gb3 accumulation rather than deficiency of GLA. Human microvascular ECs, as opposed to macrovascular ECs, seem to be affected earlier and more severely by Gb3 accumulation and this notion may prove fundamental for future progresses in early diagnosis and management of FD patients

Roles of Salivary Components in Streptococcus mutans Colonization in a New Animal Model Using NOD/SCID.e2f1−/− Mice

Streptococcus mutans plays an important role in biofilm formation on the tooth surface and is the primary causative agent of dental caries. The binding of S. mutans to the salivary pellicle is of considerable etiologic significance and is important in biofilm development. Recently, we produced NOD/SCID.e2f1−/− mice that show hyposalivation, lower salivary antibody, and an extended life span compared to the parent strain: NOD.e2f1−/−. In this study we used NOD/SCID.e2f1−/− 4 or 6 mice to determine the roles of several salivary components in S. mutans colonization in vivo. S. mutans colonization in NOD/SCID.e2f1−/− mice was significantly increased when mice were pre-treated with human saliva or commercial salivary components. Interestingly, pre-treatment with secretory IgA (sIgA) at physiological concentrations promoted significant colonization of S. mutans compared with sIgA at higher concentrations, or with human saliva or other components. Our data suggest the principal effects of specific sIgA on S. mutans occur during S. mutans colonization, where the appropriate concentration of specific sIgA may serve as an anti-microbial agent, agglutinin, or an adherence receptor to surface antigens. Further, specific sIgA supported biofilm formation when the mice were supplied 1% sucrose water and a non-sucrose diet. The data suggests that there are multiple effects exerted by sIgA in S. mutans colonization, with synergistic effects evident under the condition of sIgA and limited nutrients on colonization in NOD/SCID.e2f1−/− mice. This is a new animal model that can be used to assess prevention methods for dental biofilm-dependent diseases such as dental caries

Beyond crime statistics: the construction and application of a criminogenity monitor in Amsterdam

Criminologists have devoted a great deal of attention to risk factors - also called criminogenic factors - leading to criminal offending. This paper presents a criminogenity monitor which includes 19 risk factors that underlie crime. These factors do not themselves cause criminal behaviour; rather, they must be seen as signals that crimes may be committed. After discussing how the criminogenity monitor was constructed, we apply the risk factors we examined to the situation in Amsterdam, capital city of the Netherlands. The monitor is intended to function particularly as an instrument to rationalise policy-makers' work in targeting and preventing symptoms of crime at three geographical levels: the entire city, its boroughs and its neighbourhoods. © 2012 The Author(s)

First observations of separated atmospheric nu_mu and bar{nu-mu} events in the MINOS detector

The complete 5.4 kton MINOS far detector has been taking data since the beginning of August 2003 at a depth of 2070 meters water-equivalent in the Soudan mine, Minnesota. This paper presents the first MINOS observations of nuµ and [overline nu ]µ charged-current atmospheric neutrino interactions based on an exposure of 418 days. The ratio of upward- to downward-going events in the data is compared to the Monte Carlo expectation in the absence of neutrino oscillations, giving Rup/downdata/Rup/downMC=0.62-0.14+0.19(stat.)±0.02(sys.). An extended maximum likelihood analysis of the observed L/E distributions excludes the null hypothesis of no neutrino oscillations at the 98% confidence level. Using the curvature of the observed muons in the 1.3 T MINOS magnetic field nuµ and [overline nu ]µ interactions are separated. The ratio of [overline nu ]µ to nuµ events in the data is compared to the Monte Carlo expectation assuming neutrinos and antineutrinos oscillate in the same manner, giving R[overline nu ][sub mu]/nu[sub mu]data/R[overline nu ][sub mu]/nu[sub mu]MC=0.96-0.27+0.38(stat.)±0.15(sys.), where the errors are the statistical and systematic uncertainties. Although the statistics are limited, this is the first direct observation of atmospheric neutrino interactions separately for nuµ and [overline nu ]µ

Variation in the Male Pheromones and Mating Success of Wild Caught Drosophila melanogaster

Drosophila melanogaster males express two primary cuticular hydrocarbons (male-predominant hydrocarbons). These act as sex pheromones by influencing female receptivity to mating. The relative quantities of these hydrocarbons vary widely among natural populations and can contribute to variation in mating success. We tested four isofemale lines collected from a wild population to assess the effect of intrapopulation variation in male-predominant hydrocarbons on mating success. The receptivity of laboratory females to males of the four wild-caught lines varied significantly, but not consistently in the direction predicted by variation in male-predominant hydrocarbons. Receptivity of the wild-caught females to laboratory males also varied significantly, but females from lines with male-predominant hydrocarbon profiles closer to a more cosmopolitan one did not show a correspondingly strong mating bias toward a cosmopolitan male. Among wild-caught lines, the male-specific ejaculatory bulb lipid, cis-vaccenyl acetate, varied more than two-fold, but was not associated with variation in male mating success. We observed a strong inverse relationship between the receptivity of wild-caught females and the mating success of males from their own lines, when tested with laboratory flies of the opposite sex

Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice

<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy.</p> <p>Methods</p> <p>Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R) agonist treatment has on diaphragm function, morphology and gene expression.</p> <p>Results</p> <p>We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression.</p> <p>Conclusion</p> <p>Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.</p

Suppression of MMP-2 Attenuates TNF-α Induced NF-κB Activation and Leads to JNK Mediated Cell Death in Glioma

BACKGROUND: Abrogation of apoptosis for prolonged cell survival is essential in cancer progression. In our previous studies, we showed the MMP-2 downregulation induced apoptosis in cancer cell lines. Here, we attempt to investigate the exact molecular mechanism of how MMP-2 depletion leads to apoptosis in glioma xenograft cell lines. METHODOLOGY/PRINCIPAL FINDINGS: MMP-2 transcriptional suppression by MMP-2siRNA (pM) induces apoptosis associated with PARP, caspase-8 and -3 cleavage in human glioma xenograft cells 4910 and 5310. Western blotting and cytokine array showed significant decrease in the cellular and secreted levels of TNF-α with concomitant reduction in TNFR1, TRADD, TRAF2, RIP, IKKβ and pIκBα expression levels resulting in inhibition of p65 phosphorylation and nuclear translocation in pM-treated cells when compared to mock and pSV controls. In addition MMP-2 suppression led to elevated Fas-L, Fas and FADD expression levels along with increased p38 and JNK phosphorylation. The JNK-activity assay showed prolonged JNK activation in pM-transfected cells. Specific inhibition of p38 with SB203580 did not show any effect whereas inhibition of JNK phosphorylation with SP600125 notably reversed pM-induced cleavage of PARP, caspase-8 and -3, demonstrating a significant role of JNK in pM-induced cell death. Supplementation of rhMMP-2 counteracted the effect of pM by remarkably elevating TNF-α, TRADD, IKKβ and pIκBα expression and decreasing FADD, Fas-L, and phospho-JNK levels. The EMSA analysis indicated significant reversal of pM-inhibited NF-κB activity by rhMMP-2 treatment which rescued cells from pM-induced cell death. In vivo studies indicated that pM treatment diminished intracranial tumor growth and the immuno histochemical analysis showed decreased phospho-p65 and enhanced phospho-JNK levels that correlated with increased TUNEL-positive apoptotic cells in pM-treated tumor sections. CONCLUSION/SIGNIFICANCE: In summary, our study implies a role of MMP-2 in the regulation of TNF-α mediated constitutive NF-κB activation and Fas-mediated JNK mediated apoptosis in glioma xenograft cells in vitro and in vivo

Genome-wide survey and analysis of microsatellites in nematodes, with a focus on the plant-parasitic species Meloidogyne incognita

<p>Abstract</p> <p>Background</p> <p>Microsatellites are the most popular source of molecular markers for studying population genetic variation in eukaryotes. However, few data are currently available about their genomic distribution and abundance across the phylum Nematoda. The recent completion of the genomes of several nematode species, including <it>Meloidogyne incognita</it>, a major agricultural pest worldwide, now opens the way for a comparative survey and analysis of microsatellites in these organisms.</p> <p>Results</p> <p>Using MsatFinder, the total numbers of 1-6 bp perfect microsatellites detected in the complete genomes of five nematode species (<it>Brugia malayi</it>, <it>Caenorhabditis elegans</it>, <it>M. hapla</it>, <it>M. incognita</it>, <it>Pristionchus pacificus</it>) ranged from 2,842 to 61,547, and covered from 0.09 to 1.20% of the nematode genomes. Under our search criteria, the most common repeat motifs for each length class varied according to the different nematode species considered, with no obvious relation to the AT-richness of their genomes. Overall, (AT)_<it>n</it>, (AG)_{<it>n </it>}and (CT)_{<it>n </it>}were the three most frequent dinucleotide microsatellite motifs found in the five genomes considered. Except for two motifs in <it>P. pacificus</it>, all the most frequent trinucleotide motifs were AT-rich, with (AAT)_{<it>n </it>}and (ATT)_{<it>n </it>}being the only common to the five nematode species. A particular attention was paid to the microsatellite content of the plant-parasitic species <it>M. incognita</it>. In this species, a repertoire of 4,880 microsatellite loci was identified, from which 2,183 appeared suitable to design markers for population genetic studies. Interestingly, 1,094 microsatellites were identified in 801 predicted protein-coding regions, 99% of them being trinucleotides. When compared against the InterPro domain database, 497 of these CDS were successfully annotated, and further assigned to Gene Ontology terms.</p> <p>Conclusions</p> <p>Contrasted patterns of microsatellite abundance and diversity were characterized in five nematode genomes, even in the case of two closely related <it>Meloidogyne </it>species. 2,245 di- to hexanucleotide loci were identified in the genome of <it>M. incognita</it>, providing adequate material for the future development of a wide range of microsatellite markers in this major plant parasite.</p

The Evolution of Mammalian Gene Families

Gene families are groups of homologous genes that are likely to have highly similar functions. Differences in family size due to lineage-specific gene duplication and gene loss may provide clues to the evolutionary forces that have shaped mammalian genomes. Here we analyze the gene families contained within the whole genomes of human, chimpanzee, mouse, rat, and dog. In total we find that more than half of the 9,990 families present in the mammalian common ancestor have either expanded or contracted along at least one lineage. Additionally, we find that a large number of families are completely lost from one or more mammalian genomes, and a similar number of gene families have arisen subsequent to the mammalian common ancestor. Along the lineage leading to modern humans we infer the gain of 689 genes and the loss of 86 genes since the split from chimpanzees, including changes likely driven by adaptive natural selection. Our results imply that humans and chimpanzees differ by at least 6% (1,418 of 22,000 genes) in their complement of genes, which stands in stark contrast to the oft-cited 1.5% difference between orthologous nucleotide sequences. This genomic “revolving door” of gene gain and loss represents a large number of genetic differences separating humans from our closest relatives