Genetic characterization of Yug Bogdanovac virus

We present pyrosequencing data and phylogenetic analysis for the full genome of Yug Bogdanovac virus (YBV), a member of the Vesicular stomatitis virus serogroup of the Rhabdoviridae isolated from a pool of Phlebotomus perfiliewi sandflies collected in Serbia in 1976. YBV shows very low nucleotide identities to other members of the Vesicular stomatitis virus serogroup and does not contain a reading frame for C′/C proteins

Blood Signature of Pre-Heart Failure: A Microarrays Study

International audienceBACKGROUND: The preclinical stage of systolic heart failure (HF), known as asymptomatic left ventricular dysfunction (ALVD), is diagnosed only by echocardiography, frequent in the general population and leads to a high risk of developing severe HF. Large scale screening for ALVD is a difficult task and represents a major unmet clinical challenge that requires the determination of ALVD biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: 294 individuals were screened by echocardiography. We identified 9 ALVD cases out of 128 subjects with cardiovascular risk factors. White blood cell gene expression profiling was performed using pangenomic microarrays. Data were analyzed using principal component analysis (PCA) and Significant Analysis of Microarrays (SAM). To build an ALVD classifier model, we used the nearest centroid classification method (NCCM) with the ClaNC software package. Classification performance was determined using the leave-one-out cross-validation method. Blood transcriptome analysis provided a specific molecular signature for ALVD which defined a model based on 7 genes capable of discriminating ALVD cases. Analysis of an ALVD patients validation group demonstrated that these genes are accurate diagnostic predictors for ALVD with 87% accuracy and 100% precision. Furthermore, Receiver Operating Characteristic curves of expression levels confirmed that 6 out of 7 genes discriminate for left ventricular dysfunction classification. CONCLUSIONS/SIGNIFICANCE: These targets could serve to enhance the ability to efficiently detect ALVD by general care practitioners to facilitate preemptive initiation of medical treatment preventing the development of HF

Evidence of marine ice-cliff instability in Pine Island Bay from iceberg-keel plough marks.

Marine ice-cliff instability (MICI) processes could accelerate future retreat of the Antarctic Ice Sheet if ice shelves that buttress grounding lines more than 800 metres below sea level are lost. The present-day grounding zones of the Pine Island and Thwaites glaciers in West Antarctica need to retreat only short distances before they reach extensive retrograde slopes. When grounding zones of glaciers retreat onto such slopes, theoretical considerations and modelling results indicate that the retreat becomes unstable (marine ice-sheet instability) and thus accelerates. It is thought that MICI is triggered when this retreat produces ice cliffs above the water line with heights approaching about 90 metres. However, observational evidence confirming the action of MICI has not previously been reported. Here we present observational evidence that rapid deglacial ice-sheet retreat into Pine Island Bay proceeded in a similar manner to that simulated in a recent modelling study, driven by MICI. Iceberg-keel plough marks on the sea-floor provide geological evidence of past and present iceberg morphology, keel depth and drift direction. From the planform shape and cross-sectional morphologies of iceberg-keel plough marks, we find that iceberg calving during the most recent deglaciation was not characterized by small numbers of large, tabular icebergs as is observed today, which would produce wide, flat-based plough marks or toothcomb-like multi-keeled plough marks. Instead, it was characterized by large numbers of smaller icebergs with V-shaped keels. Geological evidence of the form and water-depth distribution of the plough marks indicates calving-margin thicknesses equivalent to the threshold that is predicted to trigger ice-cliff structural collapse as a result of MICI. We infer rapid and sustained ice-sheet retreat driven by MICI, commencing around 12,300 years ago and terminating before about 11,200 years ago, which produced large numbers of icebergs smaller than the typical tabular icebergs produced today. Our findings demonstrate the effective operation of MICI in the past, and highlight its potential contribution to accelerated future retreat of the Antarctic Ice Sheet

Larval Development of Aedes aegypti and Aedes albopictus in Peri-Urban Brackish Water and Its Implications for Transmission of Arboviral Diseases

Aedes aegypti (Linnaeus) and Aedes albopictus Skuse mosquitoes transmit serious human arboviral diseases including yellow fever, dengue and chikungunya in many tropical and sub-tropical countries. Females of the two species have adapted to undergo preimaginal development in natural or artificial collections of freshwater near human habitations and feed on human blood. While there is an effective vaccine against yellow fever, the control of dengue and chikungunya is mainly dependent on reducing freshwater preimaginal development habitats of the two vectors. We show here that Ae. aegypti and Ae. albopictus lay eggs and their larvae survive to emerge as adults in brackish water (water with <0.5 ppt or parts per thousand, 0.5–30 ppt and >30 ppt salt are termed fresh, brackish and saline respectively). Brackish water with salinity of 2 to 15 ppt in discarded plastic and glass containers, abandoned fishing boats and unused wells in coastal peri-urban environment were found to contain Ae. aegypti and Ae. albopictus larvae. Relatively high incidence of dengue in Jaffna city, Sri Lanka was observed in the vicinity of brackish water habitats containing Ae. aegypti larvae. These observations raise the possibility that brackish water-adapted Ae. aegypti and Ae. albopictus may play a hitherto unrecognized role in transmitting dengue, chikungunya and yellow fever in coastal urban areas. National and international health authorities therefore need to take the findings into consideration and extend their vector control efforts, which are presently focused on urban freshwater habitats, to include brackish water larval development habitats

Nuclear localization and cytosolic overexpression of LASP-1 correlates with tumor size and nodal-positivity of human breast carcinoma

<p>Abstract</p> <p>Background</p> <p>LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration, which was reported to be overexpressed in 8–12 % of human breast cancers and thought to be exclusively located in cytoplasm.</p> <p>Methods</p> <p>In the present work we analyzed the cellular and histological expression pattern of LASP-1 and its involvement in biological behavior of human breast cancer through correlation with standard clinicopathological parameters and expression of c-erbB2 (HER-2/neu), estrogen- (ER) and progesterone-receptors (PR). For this purpose immunohistochemical staining intensity and percentage of stained cells were semi-quantitatively rated to define a LASP-1 immunoreactive score (LASP-1-IRS). LASP-1-IRS was determined in 83 cases of invasive ductal breast carcinomas, 25 ductal carcinomas in situ (DCIS) and 18 fibroadenomas. Cellular LASP-1 distribution and expression pattern was visualized by immunofluorescence and confocal microscopy and assessed through separate Western blots of nuclear and cytosol preparations of BT-20, MCF-7, MDA-MB231, and ZR-75/1 breast cancer cells.</p> <p>Results</p> <p>Statistical analysis revealed that the resulting LASP-1-IRS was significantly higher in invasive carcinomas compared to fibroadenomas (p = 0.0176). Strong cytoplasmatic expression of LASP-1 was detected in 55.4 % of the invasive carcinomas, which correlated significantly with nuclear LASP-1-positivity (p = 0.0014), increased tumor size (p = 0.0159) and rate of nodal-positivity (p = 0.0066). However, levels of LASP-1 expression did not correlate with average age at time point of diagnosis, histological tumor grading, c-erbB2-, ER- or PR-expression.</p> <p>Increased nuclear localization and cytosolic expression of LASP-1 was found in breast cancer with higher tumor stage as well as in rapidly proliferating epidermal basal cells. Confocal microscopy and separate Western blots of cytosolic and nuclear preparations confirmed nuclear localization of LASP-1.</p> <p>Conclusion</p> <p>The current data provide evidence that LASP-1 is not exclusively a cytosolic protein, but is also detectable within the nucleus. Increased expression of LASP-1 in vivo is present in breast carcinomas with higher tumor stage and therefore may be related with worse prognosis concerning patients' overall survival.</p

ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD

Efficiency of Organelle Capture by Microtubules as a Function of Centrosome Nucleation Capacity: General Theory and the Special Case of Polyspermia

Transport of organelles along microtubules is essential for the cell metabolism and morphogenesis. The presented analysis derives the probability that an organelle of a given size comes in contact with the microtubule aster. The question is asked how this measure of functionality of the microtubule aster is controlled by the centrosome. A quantitative model is developed to address this question. It is shown that for the given set of cellular parameters, such as size and total tubulin content, a centrosome nucleation capacity exists that maximizes the probability of the organelle capture. The developed general model is then applied to the capture of the female pronucleus by microtubules assembled on the sperm centrosome, following physiologically polyspermic fertilization. This application highlights an unintuitive reflection of nonlinearity of the nucleated polymerization of the cellular pool of tubulin. The prediction that the sperm centrosome should lower its nucleation capacity in the face of the competition from the other sperm is a stark illustration of the new optimality principle. Overall, the model calls attention to the capabilities of the centrosomal pathway of regulation of the transport-related functionality of the microtubule cytoskeleton. It establishes a quantitative and conceptual framework that can guide experiment design and interpretation

NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies

NADPH oxidase family enzymes (or NOXs) are the major sources of reactive oxygen species (ROS) that are implicated in the pathophysiology of many cardiovascular diseases. These enzymes appear to be especially important in the modulation of redox-sensitive signalling pathways that underlie key cellular functions such as growth, differentiation, migration and proliferation. Seven distinct members of the family have been identified of which four (namely NOX1, 2, 4 and 5) may have cardiovascular functions. In this article, we review our current understanding of the roles of NOX enzymes in several common cardiovascular disease states, with a focus on data from genetic studies and clinical data where available

Initial Characterization of the FlgE Hook High Molecular Weight Complex of

The spirochete periplasmic flagellum has many unique attributes. One unusual characteristic is the flagellar hook. This structure serves as a universal joint coupling rotation of the membrane-bound motor to the flagellar filament. The hook is comprised of about 120 FlgE monomers, and in most bacteria these structures readily dissociate to monomers (∼ 50 kDa) when treated with heat and detergent. However, in spirochetes the FlgE monomers form a large mass of over 250 kDa [referred to as a high molecular weight complex (HMWC)] that is stable to these and other denaturing conditions. In this communication, we examined specific aspects with respect to the formation and structure of this complex. We found that the Lyme disease spirochete Borrelia burgdorferi synthesized the HMWC throughout the in vitro growth cycle, and also in vivo when implanted in dialysis membrane chambers in rats. The HMWC was stable to formic acid, which supports the concept that the stability of the HMWC is dependent on covalent cross-linking of individual FlgE subunits. Mass spectrometry analysis of the HMWC from both wild type periplasmic flagella and polyhooks from a newly constructed ΔfliK mutant indicated that other proteins besides FlgE were not covalently joined to the complex, and that FlgE was the sole component of the complex. In addition, mass spectrometry analysis also indicated that the HMWC was composed of a polymer of the FlgE protein with both the N- and C-terminal regions remaining intact. These initial studies set the stage for a detailed characterization of the HMWC. Covalent cross-linking of FlgE with the accompanying formation of the HMWC we propose strengthens the hook structure for optimal spirochete motility