Myosin-I nomenclature.

We suggest that the vertebrate myosin-I field adopt a common nomenclature system based on the names adopted by the Human Genome Organization (HUGO). At present, the myosin-I nomenclature is very confusing; not only are several systems in use, but several different genes have been given the same name. Despite their faults, we believe that the names adopted by the HUGO nomenclature group for genome annotation are the best compromise, and we recommend universal adoption

Using a whole-body 31P birdcage transmit coil and 16-element receive array for human cardiac metabolic imaging at 7T.

PURPOSE: Cardiac phosphorus magnetic resonance spectroscopy (31P-MRS) provides unique insight into the mechanisms of heart failure. Yet, clinical applications have been hindered by the restricted sensitivity of the surface radiofrequency-coils normally used. These permit the analysis of spectra only from the interventricular septum, or large volumes of myocardium, which may not be meaningful in focal disease. Löring et al. recently presented a prototype whole-body (52 cm diameter) transmit/receive birdcage coil for 31P at 7T. We now present a new, easily-removable, whole-body 31P transmit radiofrequency-coil built into a patient-bed extension combined with a 16-element receive array for cardiac 31P-MRS. MATERIALS AND METHODS: A fully-removable (55 cm diameter) birdcage transmit coil was combined with a 16-element receive array on a Magnetom 7T scanner (Siemens, Germany). Electro-magnetic field simulations and phantom tests of the setup were performed. In vivo maps of B1+, metabolite signals, and saturation-band efficiency were acquired across the torsos of eight volunteers. RESULTS: The combined (volume-transmit, local receive array) setup increased signal-to-noise ratio 2.6-fold 10 cm below the array (depth of the interventricular septum) compared to using the birdcage coil in transceiver mode. The simulated coefficient of variation for B1+ of the whole-body coil across the heart was 46.7% (surface coil 129.0%); and the in vivo measured value was 38.4%. Metabolite images of 2,3-diphosphoglycerate clearly resolved the ventricular blood pools, and muscle tissue was visible in phosphocreatine (PCr) maps. Amplitude-modulated saturation bands achieved 71±4% suppression of phosphocreatine PCr in chest-wall muscles. Subjects reported they were comfortable. CONCLUSION: This easy-to-assemble, volume-transmit, local receive array coil combination significantly improves the homogeneity and field-of-view for metabolic imaging of the human heart at 7T

Ipl1/aurora kinase suppresses S-CDK-driven spindle formation during prophase I to ensure chromosome integrity during meiosis

Cells coordinate spindle formation with DNA repair and morphological modifications to chromosomes prior to their segregation to prevent cell division with damaged chromosomes. Here we uncover a novel and unexpected role for Aurora kinase in preventing the formation of spindles by Clb5-CDK (S-CDK) during meiotic prophase I and when the DDR is active in budding yeast. This is critical since S-CDK is essential for replication during premeiotic S-phase as well as double-strand break induction that facilitates meiotic recombination and, ultimately, chromosome segregation. Furthermore, we find that depletion of Cdc5 polo kinase activity delays spindle formation in DDR-arrested cells and that ectopic expression of Cdc5 in prophase I enhances spindle formation, when Ipl1 is depleted. Our findings establish a new paradigm for Aurora kinase function in both negative and positive regulation of spindle dynamics

Heteropolymeric Triplex-Based Genomic Assay® to Detect Pathogens or Single-Nucleotide Polymorphisms in Human Genomic Samples

Human genomic samples are complex and are considered difficult to assay directly without denaturation or PCR amplification. We report the use of a base-specific heteropolymeric triplex, formed by native duplex genomic target and an oligonucleotide third strand probe, to assay for low copy pathogen genomes present in a sample also containing human genomic duplex DNA, or to assay human genomic duplex DNA for Single Nucleotide Polymorphisms (SNP), without PCR amplification. Wild-type and mutant probes are used to identify triplexes containing FVL G1691A, MTHFR C677T and CFTR mutations. The specific triplex structure forms rapidly at room temperature in solution and may be detected without a separation step. YOYO-1, a fluorescent bis-intercalator, promotes and signals the formation of the specific triplex. Genomic duplexes may be assayed homogeneously with single base pair resolution. The specific triple-stranded structures of the assay may approximate homologous recombination intermediates, which various models suggest may form in either the major or minor groove of the duplex. The bases of the stable duplex target are rendered specifically reactive to the bases of the probe because of the activity of intercalated YOYO-1, which is known to decondense duplex locally 1.3 fold. This may approximate the local decondensation effected by recombination proteins such as RecA in vivo. Our assay, while involving triplex formation, is sui generis, as it is not homopurine sequence-dependent, as are “canonical triplexes”. Rather, the base pair-specific heteropolymeric triplex of the assay is conformation-dependent. The highly sensitive diagnostic assay we present allows for the direct detection of base sequence in genomic duplex samples, including those containing human genomic duplex DNA, thereby bypassing the inherent problems and cost associated with conventional PCR based diagnostic assays

Cardiovascular magnetic resonance of myocardial edema using a short inversion time inversion recovery (STIR) black-blood technique: Diagnostic accuracy of visual and semi-quantitative assessment

<p>Abstract</p> <p>Background</p> <p>The short inversion time inversion recovery (STIR) black-blood technique has been used to visualize myocardial edema, and thus to differentiate acute from chronic myocardial lesions. However, some cardiovascular magnetic resonance (CMR) groups have reported variable image quality, and hence the diagnostic value of STIR in routine clinical practice has been put into question. The aim of our study was to analyze image quality and diagnostic performance of STIR using a set of pulse sequence parameters dedicated to edema detection, and to discuss possible factors that influence image quality. We hypothesized that STIR imaging is an accurate and robust way of detecting myocardial edema in non-selected patients with acute myocardial infarction.</p> <p>Methods</p> <p>Forty-six consecutive patients with acute myocardial infarction underwent CMR (day 4.5, +/- 1.6) including STIR for the assessment of myocardial edema and late gadolinium enhancement (LGE) for quantification of myocardial necrosis. Thirty of these patients underwent a follow-up CMR at approximately six months (195 +/- 39 days). Both STIR and LGE images were evaluated separately on a segmental basis for image quality as well as for presence and extent of myocardial hyper-intensity, with both visual and semi-quantitative (threshold-based) analysis. LGE was used as a reference standard for localization and extent of myocardial necrosis (acute) or scar (chronic).</p> <p>Results</p> <p>Image quality of STIR images was rated as diagnostic in 99.5% of cases. At the acute stage, the sensitivity and specificity of STIR to detect infarcted segments on visual assessment was 95% and 78% respectively, and on semi-quantitative assessment was 99% and 83%, respectively. STIR differentiated acutely from chronically infarcted segments with a sensitivity of 95% by both methods and with a specificity of 99% by visual assessment and 97% by semi-quantitative assessment. The extent of hyper-intense areas on acute STIR images was 85% larger than those on LGE images, with a larger myocardial salvage index in reperfused than in non-reperfused infarcts (p = 0.035).</p> <p>Conclusions</p> <p>STIR with appropriate pulse sequence settings is accurate in detecting acute myocardial infarction (MI) and distinguishing acute from chronic MI with both visual and semi-quantitative analysis. Due to its unique technical characteristics, STIR should be regarded as an edema-weighted rather than a purely T2-weighted technique.</p

Improving the outcome of patients with castration-resistant prostate cancer through rational drug development

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease

Novel Anti-Metastatic Action of Cidofovir Mediated by Inhibition of E6/E7, CXCR4 and Rho/ROCK Signaling in HPV+ Tumor Cells

Cervical cancer is frequently associated with HPV infection. The expression of E6 and E7 HPV oncoproteins is a key factor in its carcinogenicity and might also influence its virulence, including metastatic conversion. The cellular mechanisms involved in metastatic spread remain elusive, but pro-adhesive receptors and their ligands, such as SDF-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α stimulated the invasion of E6/E7-positive cancer cell lines (HeLa and TC-1) in Matrigel though CXCR4 and subsequent Rho/ROCK activation. In pulmonary metastatic foci generated by TC-1 cells IV injection a high proportion of cells expressed membrane-associated CXCR4. In both cases models (in vitro and in vivo) cell adhesion and invasion was abrogated by CXCR4 immunological blockade supporting a contribution of SDF-1α/CXCR4 to the metastatic process. E6 and E7 silencing using stable knock-down and the approved anti-viral agent, Cidofovir decreased CXCR4 gene expression as well as both, constitutive and SDF-1α-induced cell invasion. In addition, Cidofovir inhibited lung metastasis (both adhesion and invasion) supporting contribution of E6 and E7 oncoproteins to the metastatic process. Finally, potential signals activated downstream SDF-1α/CXCR4 and involved in lung homing of E6/E7-expressing tumor cells were investigated. The contribution of the Rho/ROCK pathway was suggested by the inhibitory effect triggered by Cidofovir and further confirmed using Y-27632 (a small molecule ROCK inhibitor). These data suggest a novel and highly translatable therapeutic approach to cervix cancer, by inhibition of adhesion and invasion of circulating HPV-positive tumor cells, using Cidofovir and/or ROCK inhibition

The Role of Tourism and Recreation in the Spread of Non-Native Species: A Systematic Review and Meta-Analysis

Managing the pathways by which non-native species are introduced and spread is considered the most effective way of preventing species invasions. Tourism and outdoor recreation involve the frequent congregation of people, vehicles and vessels from geographically diverse areas. They are therefore perceived to be major pathways for the movement of non-native species, and ones that will become increasingly important with the continued growth of these sectors. However, a global assessment of the relationship between tourism activities and the introduction of non-native species–particularly in freshwater and marine environments–is lacking. We conducted a systematic review and meta-analysis to determine the impact of tourism and outdoor recreation on non-native species in terrestrial, marine and freshwater environments. Our results provide quantitative evidence that the abundance and richness of non-native species are significantly higher in sites where tourist activities take place than in control sites. The pattern was consistent across terrestrial, freshwater and marine environments; across a variety of vectors (e.g. horses, hikers, yachts); and across a range of taxonomic groups. These results highlight the need for widespread biosecurity interventions to prevent the inadvertent introduction of invasive non-native species (INNS) as the tourism and outdoor recreation sectors grow

A Cysteine Protease Is Critical for Babesia spp. Transmission in Haemaphysalis Ticks

Vector ticks possess a unique system that enables them to digest large amounts of host blood and to transmit various animal and human pathogens, suggesting the existence of evolutionally acquired proteolytic mechanisms. We report here the molecular and reverse genetic characterization of a multifunctional cysteine protease, longipain, from the babesial parasite vector tick Haemaphysalis longicornis. Longipain shares structural similarity with papain-family cysteine proteases obtained from invertebrates and vertebrates. Endogenous longipain was mainly expressed in the midgut epithelium and was specifically localized at lysosomal vacuoles and possibly released into the lumen. Its expression was up-regulated by host blood feeding. Enzymatic functional assays using in vitro and in vivo substrates revealed that longipain hydrolysis occurs over a broad range of pH and temperature. Haemoparasiticidal assays showed that longipain dose-dependently killed tick-borne Babesia parasites, and its babesiacidal effect occurred via specific adherence to the parasite membranes. Disruption of endogenous longipain by RNA interference revealed that longipain is involved in the digestion of the host blood meal. In addition, the knockdown ticks contained an increased number of parasites, suggesting that longipain exerts a killing effect against the midgut-stage Babesia parasites in ticks. Our results suggest that longipain is essential for tick survival, and may have a role in controlling the transmission of tick-transmittable Babesia parasites