Immunohistochemical assessment of protein phosphorylation state: the dream and the reality

The development of phosphorylation state-specific antibodies (PSSAs) in the 1980s, and their subsequent proliferation promised to enable in situ analysis of the activation states of complex intracellular signaling networks. The extent to which this promise has been fulfilled is the topic of this review. I review some applications of PSSAs primarily in the assessment of solid tumor signaling pathway activation status. PSSAs have received considerable attention for their potential to reveal cell type-specific activation status, provide added prognostic information, aid in the prediction of response to therapy, and most recently, demonstrate the efficacy of kinase-targeted chemotherapies. However, despite some successes, many studies have failed to demonstrate added value of PSSAs over general antibody immunohistochemistry. Moreover, there is still a large degree of uncertainty about the interpretation of complex and heterogeneous staining patterns in tissue samples and their relationship to the actual phosphorylation states in vivo. The next phase of translational research in applications of PSSAs will entail the hard work of antibody validation, gathering of detailed information about epitope-specific lability, and implementation of methods for standardization

The direct healthcare costs associated with psychological distress and major depression : A population-based cohort study in Ontario, Canada

The objective of our study was to estimate direct healthcare costs incurred by a population-based sample of people with psychological distress or depression. We used the 2002 Canadian Community Health Survey on Mental Health and Well Being and categorized individuals as having psychological distress using the Kessler-6, major depressive disorder (MDD) using DSM-IV criteria and a comparison group of participants without MDD or psychological distress. Costs in 2013 USD were estimated by linking individuals to health administrative databases and following them until March 31, 2013. Our sample consisted of 9,965 individuals, of whom 651 and 409 had psychological distress and MDD, respectively. Although the age-and-sex adjusted per-capita costs were similarly high among the psychologically distressed ($3,364, 95$2,791, $3,937) and those with MDD ($3,210, 95% CI: $2,413,$4,008) compared to the comparison group ($2,629, 95$2,312, $2,945), the population-wide excess costs for psychological distress ($441 million) were more than twice that for MDD ($210 million) as there was a greater number of people with psychological distress than depression. We found substantial healthcare costs associated with psychological distress and depression, suggesting that psychological distress and MDD have a high cost burden and there may be public health intervention opportunities to relieve distress. Further research examining how individuals with these conditions use the healthcare system may provide insight into the allocation of limited healthcare resources while maintaining high quality care

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

On profiling bots in social media

Submit request for dataset at https://larc.smu.edu.sg/twitter-bot-profiling</p

Quality of life returns from basic research

<p>Abstract</p> <p>Background</p> <p>Assessing the consequences of research is an increasingly important task in research and innovation policy. This paper takes a broader view of those consequences than the conventional economic approach, placing researchers and their activities in the centre of the assessment process and examining results for professional practice and general education as well as contributions to knowledge.</p> <p>Methods</p> <p>The paper uses historical and documentary analysis to illustrate the approach, focusing on U.S. biomedicine over the past century. At aggregate level, the analysis attributes portions of the change in aggregate health indicators to research and research-based institutions, through several available types of logic: either through correlations between timing of institutional changes and changes in the indicators or through direct or indirect causal connections.</p> <p>Results</p> <p>The analysis shows that while biomedical research has certainly contributed to improved health in the United States, other factors have also contributed. In some ways the institutional structure of science-based medicine has worked against creating benefits for some groups in U.S. society.</p> <p>Conclusions</p> <p>The paper concludes with a call for more strategic attention to dimensions of impact other than knowledge outcomes and for participatory planning for research.</p

Slab melting as a barrier to deep carbon subduction

Interactions between crustal and mantle reservoirs dominate the surface inventory of volatile elements over geological time, moderating atmospheric composition and maintaining a lifesupporting planet1. While volcanoes expel volatile components into surface reservoirs, subduction of oceanic crust is responsible for replenishment of mantle reservoirs2,3. Many natural, ‘superdeep’ diamonds originating in the deep upper mantle and transition zone host mineral inclusions, indicating an affinity to subducted oceanic crust4–7. Here we show that the majority of slab geotherms will intersect a deep depression along the melting curve of carbonated oceanic crust at depths of approximately 300 to 700 kilometres, creating a barrier to direct carbonate recycling into the deep mantle. Low-degree partial melts are alkaline carbonatites that are highly reactive with reduced ambient mantle, producing diamond. Many inclusions in superdeep diamonds are best explained by carbonate melt–peridotite reaction. A deep carbon barrier may dominate the recycling of carbon in the mantle and contribute to chemical and isotopic heterogeneity of the mantle reservoir

Epidemiology of and prenatal molecular distinction between invasive and colonizing group B streptococci in The Netherlands and Taiwan

The identification of markers for virulent group B streptococci (GBS) could guide prenatal prevention and intervention strategies. We compared the distribution of serotypes and potential pathogenicity islands (PPIs) between invasive and colonizing GBS. Colonizing and invasive strains from The Netherlands and Taiwan were serotyped. We used polymerase chain reaction (PCR) for the amplification of several new PPI markers. Several combinations of PPI-specific markers and serotypes were associated with invasiveness. For Dutch neonatal strains, a receiver operating characteristic (ROC) curve with serotype and five PPI markers showed an area under the curve (AUC) of 0.963 (95% confidence interval [CI] 0.935–0.99). For Taiwanese neonatal strains, serotype and four different PPI markers resulted in an ROC curve with an AUC of 0.894 (95% CI 0.826–0.963). PPI-specific and serological markers can distinguish local neonatal invasive GBS strains from colonizing ones. Apparently, there are clear regional differences in the GBS epidemiology and infection potential of clones

A theoretical entropy score as a single value to express inhibitor selectivity

<p>Abstract</p> <p>Background</p> <p>Designing maximally selective ligands that act on individual targets is the dominant paradigm in drug discovery. Poor selectivity can underlie toxicity and side effects in the clinic, and for this reason compound selectivity is increasingly monitored from very early on in the drug discovery process. To make sense of large amounts of profiling data, and to determine when a compound is sufficiently selective, there is a need for a proper quantitative measure of selectivity.</p> <p>Results</p> <p>Here we propose a new theoretical entropy score that can be calculated from a set of IC₅₀data. In contrast to previous measures such as the 'selectivity score', Gini score, or partition index, the entropy score is non-arbitary, fully exploits IC₅₀data, and is not dependent on a reference enzyme. In addition, the entropy score gives the most robust values with data from different sources, because it is less sensitive to errors. We apply the new score to kinase and nuclear receptor profiling data, and to high-throughput screening data. In addition, through analyzing profiles of clinical compounds, we show quantitatively that a more selective kinase inhibitor is not necessarily more drug-like.</p> <p>Conclusions</p> <p>For quantifying selectivity from panel profiling, a theoretical entropy score is the best method. It is valuable for studying the molecular mechanisms of selectivity, and to steer compound progression in drug discovery programs.</p