Dynamic metabolomic data analysis: a tutorial review

In metabolomics, time-resolved, dynamic or temporal data is more and more collected. The number of methods to analyze such data, however, is very limited and in most cases the dynamic nature of the data is not even taken into account. This paper reviews current methods in use for analyzing dynamic metabolomic data. Moreover, some methods from other fields of science that may be of use to analyze such dynamic metabolomics data are described in some detail. The methods are put in a general framework after providing a formal definition on what constitutes a ‘dynamic’ method. Some of the methods are illustrated with real-life metabolomics examples

RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in the Portuguese population

<p>Abstract</p> <p>Background</p> <p>Several polymorphisms within the renin-angiotensin system cluster of genes have been associated with the advent of coronary artery disease (CAD) or related pathologies. We investigated the distribution of 5 of these polymorphisms in order to find any association with CAD development and distinguish if any of the biochemical and behavioural factors interact with genetic polymorphisms in the advent of the disease.</p> <p>Methods</p> <p><it>ACE </it>I/D (rs4340), <it>ACE </it>A11860G (rs4343), <it>AT1R </it>A1166C (rs5186), <it>AGT </it>T174M (rs4762) and <it>AGT </it>M235T (rs699) gene polymorphisms were PCR-RFLP analysed in 298 CAD patients and 510 controls from Portugal. Several biochemical and behavioural markers were obtained.</p> <p>Results</p> <p><it>ACE </it>I/D DD and <it>ACE</it>11860 GG genotypes are risk factors for CAD in this population. The simultaneous presence of <it>ACE </it>I/D I and <it>ACE</it>11860 A alleles corresponds to a significant trend towards a decrease in CAD incidence. We found several synergistic effects between the studied polymorphisms and classical risk factors such as hypertension, obesity, diabetes and dyslipidaemia: the presence of the DD genotype of <it>ACE </it>I/D (and also <it>ACE</it>11860 GG) increases the odds of developing CAD when associated to each one of these classical risk factors, particularly when considering the male and early onset CAD subgroup analysis; <it>AGT</it>235 TT also increases the CAD risk in the presence of hypertension and dyslipidaemia, and <it>AT1R</it>1166 interacts positively with hypertension, smoking and obesity.</p> <p>Conclusion</p> <p><it>ACE </it>polymorphisms were shown to play a major role in individual susceptibility to develop CAD. There is also a clear interaction between RAS predisposing genes and some biochemical/environmental risk factors in CAD onset, demonstrating a significant enhancement of classical markers particularly by <it>ACE </it>I/D and <it>ACE</it>11860.</p

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner’s syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner’s syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed

Pre- and syn-eruptive degassing and crystallisation processes of the 2010 and 2006 eruptions of Merapi volcano, Indonesia

The 2010 eruption of Merapi (VEI 4) was the volcano’s largest since 1872. In contrast to the prolonged and effusive dome-forming eruptions typical of Merapi’s recent activity, the 2010 eruption began explosively, before a new dome was rapidly emplaced. This new dome was subsequently destroyed by explosions, generating pyroclastic density currents (PDCs), predominantly consisting of dark coloured, dense blocks of basaltic andesite dome lava. A shift towards open-vent conditions in the later stages of the eruption culminated in multiple explosions and the generation of PDCs with conspicuous grey scoria and white pumice clasts resulting from sub-plinian convective column collapse. This paper presents geochemical data for melt inclusions and their clinopyroxene hosts extracted from dense dome lava, grey scoria and white pumice generated during the peak of the 2010 eruption. These are compared with clinopyroxene-hosted melt inclusions from scoriaceous dome fragments from the prolonged dome-forming 2006 eruption, to elucidate any relationship between pre-eruptive degassing and crystallisation processes and eruptive style. Secondary ion mass spectrometry analysis of volatiles (H2O, CO2) and light lithophile elements (Li, B, Be) is augmented by electron microprobe analysis of major elements and volatiles (Cl, S, F) in melt inclusions and groundmass glass. Geobarometric analysis shows that the clinopyroxene phenocrysts crystallised at depths of up to 20 km, with the greatest calculated depths associated with phenocrysts from the white pumice. Based on their volatile contents, melt inclusions have re-equilibrated during shallower storage and/or ascent, at depths of ~0.6–9.7 km, where the Merapi magma system is interpreted to be highly interconnected and not formed of discrete magma reservoirs. Melt inclusions enriched in Li show uniform “buffered” Cl concentrations, indicating the presence of an exsolved brine phase. Boron-enriched inclusions also support the presence of a brine phase, which helped to stabilise B in the melt. Calculations based on S concentrations in melt inclusions and groundmass glass require a degassing melt volume of 0.36 km3 in order to produce the mass of SO2 emitted during the 2010 eruption. This volume is approximately an order of magnitude higher than the erupted magma (DRE) volume. The transition between the contrasting eruptive styles in 2010 and 2006 is linked to changes in magmatic flux and changes in degassing style, with the explosive activity in 2010 driven by an influx of deep magma, which overwhelmed the shallower magma system and ascended rapidly, accompanied by closed-system degassing

Evidence that Proteasome-Dependent Degradation of the Retinoblastoma Protein in Cells Lacking A-Type Lamins Occurs Independently of Gankyrin and MDM2

A-type lamins, predominantly lamins A and C, are nuclear intermediate filaments believed to act as scaffolds for assembly of transcription factors. Lamin A/C is necessary for the retinoblastoma protein (pRB) stabilization through unknown mechanism(s). Two oncoproteins, gankyrin and MDM2, are known to promote pRB degradation in other contexts. Consequently, we tested the hypothesis that gankyrin and/or MDM2 are required for enhanced pRB degradation in Lmna-/- fibroblasts. Principal Findings. To determine if gankyrin promotes pRB destabilization in the absence of lamin A/C, we first analyzed its protein levels in Lmna-/- fibroblasts. Both gankyrin mRNA levels and protein levels are increased in these cells, leading us to further investigate its role in pRB degradation. Consistent with prior reports, overexpression of gankyrin in Lmna+/+ cells destabilizes pRB. This decrease is functionally significant, since gankyrin overexpressing cells are resistant to p16(ink4a)-mediated cell cycle arrest. These findings suggest that lamin A-mediated degradation of pRB would be gankyrin-dependent. However, effective RNAi-enforced reduction of gankyrin expression in Lmna-/- cells was insufficient to restore pRB stability. To test the importance of MDM2, we disrupted the MDM2-pRB interaction by transfecting Lmna-/- cells with p14(arf). p14(arf) expression was also insufficient to stabilize pRB or confer cell cycle arrest, suggesting that MDM2 also does not mediate pRB degradation in Lmna-/- cells.Our findings suggest that pRB degradation in Lmna-/- cells occurs by gankyrin and MDM2-independent mechanisms, leading us to propose the existence of a third proteasome-dependent pathway for pRB degradation. Two findings from this study also increase the likelihood that lamin A/C functions as a tumor suppressor. First, protein levels of the oncoprotein gankyrin are elevated in Lmna-/- fibroblasts. Second, Lmna-/- cells are refractory to p14(arf)-mediated cell cycle arrest, as was previously shown with p16(ink4a). Potential roles of lamin A/C in the suppression of tumorigenesis are discussed

Understanding How University Students Use Perceptions of Consent, Wantedness, and Pleasure in Labeling Rape.

While the lack of consent is the only determining factor in considering whether a situation is rape or not, there is sufficient evidence that participants conflate wantedness with consent and pleasurableness with wantedness. Understanding how people appraise sexual scenarios may form the basis to develop appropriate educational packages. We conducted two large-scale qualitative studies in two UK universities in which participants read vignettes describing sexual encounters that were consensual or not, wanted or unwanted and pleasurable or not pleasurable. Participants provided free-text responses as to whether they perceived the scenarios to be rape or not and why they made these judgments. The second study replicated the results of the first and included a condition where participants imagined themselves as either the subject or initiator of the sexual encounter. The results indicate that a significant portion of our participants held attitudes reflecting rape myths and tended to blame the victim. Participants used distancing language when imagining themselves in the initiator condition. Participants indicated that they felt there were degrees of how much a scenario reflected rape rather than it simply being a dichotomy (rape or not). Such results indicate a lack of understanding of consent and rape and highlight avenues of potential educational materials for schools, universities or jurors

Studying the Conditions for Learning Dynamic Bayesian Networks to Discover Genetic Regulatory Networks

On behalf of