DNA Sequence Profiles of the Colorectal Cancer Critical Gene Set KRAS-BRAF-PIK3CA-PTEN-TP53 Related to Age at Disease Onset

The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patient age remains mostly unknown. We have examined the mutation status of five known cancer critical genes in relation to age at diagnosis, and compared the genomic complexity of tumors from young patients without known CRC syndromes with those from elderly patients. Among 181 CRC patients, stratified by microsatellite instability status, DNA sequence changes were identified in KRAS (32%), BRAF (16%), PIK3CA (4%), PTEN (14%) and TP53 (51%). In patients younger than 50 years (n = 45), PIK3CA mutations were not observed and TP53 mutations were more frequent than in the older age groups. The total gene mutation index was lowest in tumors from the youngest patients. In contrast, the genome complexity, assessed as copy number aberrations, was highest in tumors from the youngest patients. A comparable number of tumors from young (<50 years) and old patients (>70 years) was quadruple negative for the four predictive gene markers (KRAS-BRAF-PIK3CA-PTEN); however, 16% of young versus only 1% of the old patients had tumor mutations in PTEN/PIK3CA exclusively. This implies that mutation testing for prediction of EGFR treatment response may be restricted to KRAS and BRAF in elderly (>70 years) patients. Distinct genetic differences found in tumors from young and elderly patients, whom are comparable for known clinical and pathological variables, indicate that young patients have a different genetic risk profile for CRC development than older patients

Selective Heterogeneity in Exoprotease Production by <em>Bacillus subtilis</em>

Bacteria have elaborate signalling mechanisms to ensure a behavioural response that is most likely to enhance survival in a changing environment. It is becoming increasingly apparent that as part of this response, bacteria are capable of cell differentiation and can generate multiple, mutually exclusive co-existing cell states. These cell states are often associated with multicellular processes that bring benefit to the community as a whole but which may be, paradoxically, disadvantageous to an individual subpopulation. How this process of cell differentiation is controlled is intriguing and remains a largely open question. In this paper, we consider an important aspect of cell differentiation that is known to occur in the Gram-positive bacterium Bacillus subtilis: we investigate the role of two master regulators DegU and Spo0A in the control of extra-cellular protease production. Recent work in this area focussed the on role of DegU in this process and suggested that transient effects in protein production were the drivers of cell-response heterogeneity. Here, using a combination of mathematical modelling, analysis and stochastic simulations, we provide a complementary analysis of this regulatory system that investigates the roles of both DegU and Spo0A in extra-cellular protease production. In doing so, we present a mechanism for bimodality, or system heterogeneity, without the need for a bistable switch in the underlying regulatory network. Moreover, our analysis leads us to conclude that this heterogeneity is in fact a persistent, stable feature. Our results suggest that system response is divided into three zones: low and high signal levels induce a unimodal or undifferentiated response from the cell population with all cells OFF and ON, respectively for exoprotease production. However, for intermediate levels of signal, a heterogeneous response is predicted with a spread of activity levels, representing typical “bet-hedging” behaviour

Mobilizing cognition for speeded action: try-harder instructions promote motivated readiness in the constant-foreperiod paradigm

We examined the effect of motivational readiness on cognitive performance. An important but still not sufficiently elaborated question is whether individuals can voluntarily increase cognitive efficiency for an impending target event, given sufficient preparation time. Within the framework of the constant-foreperiod design (comparing reaction time performance in blocks of short and long foreperiod intervals, FPs), we examined the effect of an instruction to try harder (instructional cue: standard vs. effort) in a choice-reaction task on performance speed and variability. Proceeding from previous theoretical considerations, we expected the instruction to speed-up processing irrespective of FP length, while error rate should be increased in the short-FP but decreased in the long-FP condition. Overall, the results confirmed this prediction. Importantly, the distributional (ex-Gaussian and delta plot) analysis revealed that the instruction to try harder decreased distributional skewness (i.e., longer percentiles were more affected), indicating that mobilization ensured temporal performance stability (persistence)

The determinants of research performance in European universities. A large scale multilevel analysis

The paper examines the research performance of European universities in a disaggregated way, using a large array of indicators from Scopus publications, including indicators of volume (number of articles; number of citations) and indicators of quality (percentage of publications in top 10% and top 25% SNIP journals; percentage of citations from top 10% and top 25% journals). These indicators are considered dependent variables in a multi-level estimation framework, in which research performance in a scientific area depends on variables at the level of university and at the level of the external regional environment. The area examined is Medicine, for the 2007–2010 period. The paper exploits for the first time the integration of publication data with the census of European universities (ETER). A large number of hypotheses are tested and discussed