Insights into the regulation of DMSP synthesis in the diatom Thalassiosira pseudonana through APR activity, proteomics and gene expression analyses on cells acclimating to changes in salinity, light and nitrogen

Despite the importance of dimethylsulphoniopropionate (DMSP) in the global sulphur cycle and climate regulation, the biological pathways underpinning its synthesis in marine phytoplankton remain poorly understood. The intracellular concentration of DMSP increases with increased salinity, increased light intensity and nitrogen starvation in the diatom Thalassiosira pseudonana. We used these conditions to investigate DMSP synthesis at the cellular level via analysis of enzyme activity, gene expression and proteome comparison. The activity of the key sulphur assimilatory enzyme, adenosine 5′- phosphosulphate reductase was not coordinated with increasing intracellular DMSP concentration. Under all three treatments coordination in the expression of sulphur assimilation genes was limited to increases in sulphite reductase transcripts. Similarly, proteomic 2D gel analysis only revealed an increase in phosphoenolpyruvate carboxylase following increases in DMSP concentration. Our findings suggest that increased sulphur assimilation might not be required for increased DMSP synthesis, instead the availability of carbon and nitrogen substrates may be important in the regulation of this pathway. This contrasts with the regulation of sulphur metabolism in higher plants, which generally involves upregulation of several sulphur assimilatory enzymes. In T. pseudonana changes relating to sulphur metabolism were specific to the individual treatments and, given that little coordination was seen in transcript and protein responses across the three growth conditions, different patterns of regulation might be responsible for the increase in DMSP concentration seen under each treatment

Edoxaban: an update on the new oral direct factor Xa inhibitor.

Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. Both edoxaban regimens also provided significant reductions in the risk of hemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to-high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options

Explaining inconsistencies between data on condom use and condom sales

BACKGROUND: Several HIV prevention programs use data on condom sales and survey-based data on condom prevalence to monitor progress. However, such indicators are not always consistent. This paper aims to explain these inconsistencies and to assess whether the number of sex acts and the number of condoms used can be estimated from survey data. This would be useful for program managers, as it would enable estimation of the number of condoms needed for different target groups. METHODS: We use data from six Demographic and Health Surveys to estimate the total annual number of sex acts and number of condoms used. Estimates of the number of sex acts are based on self-reported coital frequency, the proportion reporting intercourse the previous day, and survival methods. Estimates of the number of condoms used are based on self-reported frequency of use, the proportion reporting condom use the previous day and in last intercourse. The estimated number of condoms used is then compared with reported data on condom sales and distribution. RESULTS: Analysis of data on the annual number of condoms sold and distributed to the trade reveals very erratic patterns, which reflect stock-ups at various levels in the distribution chain. Consequently, condom sales data are a very poor indicator of the level of condom use. Estimates of both the number of sexual acts and the number of condoms used vary enormously based on the estimation method used. For several surveys, the highest estimate of the annual number of condoms used is tenfold that of the lowest estimate. CONCLUSIONS: Condom sales to the trade are a poor indicator of levels of condom use, and are therefore insufficient to monitor HIV prevention programs. While survey data on condom prevalence allow more detailed monitoring, converting such data to an estimated number of sex acts and condoms used is not straightforward. The estimation methods yield widely different results, and it is impossible to determine which method is most accurate. Until the reliability of these various estimation methods can be established, estimating the annual number of condoms used from survey data will not be feasible. Collecting survey data on the number of sex acts and the number of condoms used in a fixed time period may enable the calculation of more reliable estimates of the number of sex acts and condoms used

Topographical analysis of the subependymal zone neurogenic niche

The emerging model for the adult subependymal zone (SEZ) cell population indicates that neuronal diversity is not generated from a uniform pool of stem cells but rather from diverse and spatially confined stem cell populations. Hence, when analysing SEZ proliferation, the topography along the anterior-posterior and dorsal-ventral axes must be taken into account. However, to date, no studies have assessed SEZ proliferation according to topographical specificities and, additionally, SEZ studies in animal models of neurological/psychiatric disorders often fail to clearly specify the SEZ coordinates. This may render difficult the comparison between studies and yield contradictory results. More so, by focusing in a single spatial dimension of the SEZ, relevant findings might pass unnoticed. In this study we characterized the neural stem cell/progenitor population and its proliferation rates throughout the rat SEZ anterior-posterior and dorsal-ventral axes. We found that SEZ proliferation decreases along the anterior-posterior axis and that proliferative rates vary considerably according to the position in the dorsal-ventral axis. These were associated with relevant gradients in the neuroblasts and in the neural stem cell populations throughout the dorsal-ventral axis. In addition, we observed spatially dependent differences in BrdU/Ki67 ratios that suggest a high variability in the proliferation rate and cell cycle length throughout the SEZ; in accordance, estimation of the cell cycle length of the neuroblasts revealed shorter cell cycles at the dorsolateral SEZ. These findings highlight the need to establish standardized procedures of SEZ analysis. Herein we propose an anatomical division of the SEZ that should be considered in future studies addressing proliferation in this neural stem cell niche.Fundação para a Ciência e a Tecnologia (FCT

Open labware: 3-D printing your own lab equipment

The introduction of affordable, consumer-oriented 3-D printers is a milestone in the current “maker movement,” which has been heralded as the next industrial revolution. Combined with free and open sharing of detailed design blueprints and accessible development tools, rapid prototypes of complex products can now be assembled in one’s own garage—a game-changer reminiscent of the early days of personal computing. At the same time, 3-D printing has also allowed the scientific and engineering community to build the “little things” that help a lab get up and running much faster and easier than ever before

In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis

Methodology: We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-Angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-Angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis

Colour in urban places: A case study of Leicester City Football Club blue

By communicating an integrated story, the Leicester City Football Club blue inherits and persists the history and legacy of the football club, which further provides a stable and consistent meaning for the local sports culture. Colour as a medium and agency creates an intimacy and loyalty between the different ethnic and social groups across local, regional, and global contexts. The case study demonstrated that colour could give place identity through branding practice, identity mediation, and visual culture formation. The process reflected that economic and cultural force had a large impact on place‐making, and could be the decisive influence upon colour symbolism

Effectiveness, safety and acceptability of ‘see and treat' with cryotherapy by nurses in a cervical screening study in India

We evaluated a ‘see and treat' procedure involving screening, colposcopy, biopsy and cryotherapy by trained nurses in one-visit in field clinics in a cervical screening study in South India for its acceptability, safety and effectiveness in curing cervical intraepithelial neoplasia (CIN). Women positive on visual inspection with acetic acid (VIA) were advised colposcopy, directed biopsies and cryotherapy if they had colposcopic impression of CIN in one visit by nurses in field clinics supervised by a doctor. Side effects and complications were assessed and cure rates were evaluated with VIA, colposcopy and biopsy if colposcopic abnormalities were suspected. Cure was defined as no clinical or histological evidence of CIN at ⩾6 months from treatment. Of the 2513 women offered ‘see and treat' procedure, 1879 (74.8%) accepted. Of the 1397 women with histologically proved CIN treated with cryotherapy, 1026 reported for follow-up evaluation. Cure rates were 81.4% (752 out of 924) for women with CIN 1; 71.4% (55 out of 77) for CIN 2 and 68.0% (17 out of 25) for CIN 3. Minor side effects and complications were documented in less than 3% of women. ‘See and treat' with cryotherapy by nurses under medical supervision is acceptable, safe and effective for cervical cancer prevention in low-resource settings

Transmission Shifts Underlie Variability in Population Responses to Yersinia pestis Infection

Host populations for the plague bacterium, Yersinia pestis, are highly variable in their response to plague ranging from near deterministic extinction (i.e., epizootic dynamics) to a low probability of extinction despite persistent infection (i.e., enzootic dynamics). Much of the work to understand this variability has focused on specific host characteristics, such as population size and resistance, and their role in determining plague dynamics. Here, however, we advance the idea that the relative importance of alternative transmission routes may vary causing shifts from epizootic to enzootic dynamics. We present a model that incorporates host and flea ecology with multiple transmission hypotheses to study how transmission shifts determine population responses to plague. Our results suggest enzootic persistence relies on infection of an off-host flea reservoir and epizootics rely on transiently maintained flea infection loads through repeated infectious feeds by fleas. In either case, early-phase transmission by fleas (i.e., transmission immediately following an infected blood meal) has been observed in laboratory studies, and we show that it is capable of driving plague dynamics at the population level. Sensitivity analysis of model parameters revealed that host characteristics (e.g., population size and resistance) vary in importance depending on transmission dynamics, suggesting that host ecology may scale differently through different transmission routes enabling prediction of population responses in a more robust way than using either host characteristics or transmission shifts alone

Therapeutic Dosing of Acenocoumarol: Proposal of a Population Specific Pharmacogenetic Dosing Algorithm and Its Validation in North Indians

Objectives: To develop a population specific pharmacogenetic acenocoumarol dosing algorithm for north Indian patients and show its efficiency in dosage prediction. Methods: Multiple and linear stepwise regression analyses were used to include age, sex, height, weight, body surface area, smoking status, VKORC1-1639 G.A, CYP4F2 1347 G.A, CYP2C9*2,*3 and GGCX 12970 C.G polymorphisms as variables to generate dosing algorithms. The new dosing models were compared with already reported algorithms and also with the clinical data for various performance measures. Odds ratios for association of genotypes with drug sensitive and resistant groups were calculated. Results: The pharmacogenetic dosing algorithm generated by multiple regression analysis explains 41.4 % (p-value,0.001) of dosage variation. Validation of the new algorithm showed its predictive ability to be better than the already established algorithms based on similar variables. Its validity in our population is reflected by increased sensitivity, specificity, accuracy and decreased rates of over- and under- estimation in comparison to clinical data. The VKORC1-1639 G.A polymorphism was found to be strongly associated with acenocoumarol sensitivity according to recessive model. Conclusions: We have proposed an efficient north India specific pharmacogenetic acenocoumarol dosing algorithm whic