Novel O-palmitolylated beta-E1 subunit of pyruvate dehydrogenase is phosphorylated during ischemia/reperfusion injury

<p>Abstract</p> <p>Background</p> <p>During and following myocardial ischemia, glucose oxidation rates are low and fatty acids dominate as a source of oxidative metabolism. This metabolic phenotype is associated with contractile dysfunction during reperfusion. To determine the mechanism of this reliance on fatty acid oxidation as a source of ATP generation, a functional proteomics approach was utilized.</p> <p>Results</p> <p>2-D gel electrophoresis of mitochondria from working rat hearts subjected to 25 minutes of global no flow ischemia followed by 40 minutes of aerobic reperfusion identified 32 changes in protein abundance compared to aerobic controls. Of the five proteins with the greatest change in abundance, two were increased (long chain acyl-coenzyme A dehydrogenase (48 ± 1 versus 39 ± 3 arbitrary units, n = 3, P < 0.05) and α subunit of ATP synthase (189 ± 15 versus 113 ± 23 arbitrary units, n = 3, P < 0.05)), while two were decreased (24 kDa subunit of NADH-ubiquinone oxidoreductase (94 ± 7 versus 127 ± 9 arbitrary units, n = 3, P < 0.05) and D subunit of ATP synthase (230 ± 11 versus 368 ± 47 arbitrary units, n = 3, P < 05)). Two forms of pyruvate dehydrogenase βE1 subunit, the rate-limiting enzyme for glucose oxidation, were also identified. The protein level of the more acidic form of pyruvate dehydrogenase was reduced during reperfusion (37 ± 4 versus 56 ± 7 arbitrary units, n = 3, P < 05), while the more basic form remained unchanged. The more acidic isoform was found to be O-palmitoylated, while both isoforms exhibited ischemia/reperfusion-induced phosphorylation. <it>In silico </it>analysis identified the putative kinases as the insulin receptor kinase for the more basic form and protein kinase Cζ or protein kinase A for the more acidic form. These modifications of pyruvate dehydrogenase are associated with a 35% decrease in glucose oxidation during reperfusion.</p> <p>Conclusions</p> <p>Cardiac ischemia/reperfusion induces significant changes to a number of metabolic proteins of the mitochondrial proteome. In particular, ischemia/reperfusion induced the post-translational modification of pyruvate dehydrogenase, the rate-limiting step of glucose oxidation, which is associated with a 35% decrease in glucose oxidation during reperfusion. Therefore these post-translational modifications may have important implications in the regulation of myocardial energy metabolism.</p

Metric for Measuring the Effectiveness of Clustering of DNA Microarray Expression

BACKGROUND: The recent advancement of microarray technology with lower noise and better affordability makes it possible to determine expression of several thousand genes simultaneously. The differentially expressed genes are filtered first and then clustered based on the expression profiles of the genes. A large number of clustering algorithms and distance measuring matrices are proposed in the literature. The popular ones among them include hierarchal clustering and k-means clustering. These algorithms have often used the Euclidian distance or Pearson correlation distance. The biologists or the practitioners are often confused as to which algorithm to use since there is no clear winner among algorithms or among distance measuring metrics. Several validation indices have been proposed in the literature and these are based directly or indirectly on distances; hence a method that uses any of these indices does not relate to any biological features such as biological processes or molecular functions. RESULTS: In this paper we have proposed a metric to measure the effectiveness of clustering algorithms of genes by computing inter-cluster cohesiveness and as well as the intra-cluster separation with respect to biological features such as biological processes or molecular functions. We have applied this metric to the clusters on the data set that we have created as part of a larger study to determine the cancer suppressive mechanism of a class of chemicals called retinoids. We have considered hierarchal and k-means clustering with Euclidian and Pearson correlation distances. Our results show that genes of similar expression profiles are more likely to be closely related to biological processes than they are to molecular functions. The findings have been supported by many works in the area of gene clustering. CONCLUSION: The best clustering algorithm of genes must achieve cohesiveness within a cluster with respect to some biological features, and as well as maximum separation between clusters in terms of the distribution of genes of a behavioral group across clusters. We claim that our proposed metric is novel in this respect and that it provides a measure of both inter and intra cluster cohesiveness. Best of all, computation of the proposed metric is easy and it provides a single quantitative value, which makes comparison of different algorithms easier. The maximum cluster cohesiveness and the maximum intra-cluster separation are indicated by the metric when its value is 0. We have demonstrated the metric by applying it to a data set with gene behavioral groupings such as biological process and molecular functions. The metric can be easily extended to other features of a gene such as DNA binding sites and protein-protein interactions of the gene product, special features of the intron-exon structure, promoter characteristics, etc. The metric can also be used in other domains that use two different parametric spaces; one for clustering and the other one for measuring the effectiveness

Queering identity : becoming queer in the work of Cassils

This chapter explores the work of genderqueer artist Cassils in order to address the question of what it is to be human from a queer perspective. The challenges from queer and postmodern scholarship to the “identity politics” so central to earlier activist and academic agendas have been well documented. Yet, notwithstanding these valid critiques, identity remains a powerful organizing concept in contemporary experience. These contradictory stances on identity serve as a prompt for thinking about what queer brings to our understandings of being human now and in the near future

The effects of migrant remittances on population–environment dynamics in migrant origin areas: international migration, fertility, and consumption in highland Guatemala

International migration impacts origin regions in many ways. As examples, remittances from distant migrants may alter consumption patterns within sending communities, while exposure to different cultural norms may alter other behaviors. This paper combines these insights to offer a unique lens on migration’s environmental impact. From an environmental perspective, we ask the following question: is the likely rise in consumption brought about by remittances counterbalanced by a reduction in fertility in migrant households following exposure to lower fertility cultures? Based on ethnographic case studies in two western highland Guatemalan communities, we argue that the near-term rise in consumption due to remittances is not counterbalanced by rapid decline in migrant household fertility. However, over time, the environmental cost of consumption may be mitigated at the community level through diffusion of contraception and family planning norms yielding lower family size

Drawing to Remember: External Support of Older Adults’ Eyewitness Performance

Although healthy aging is accompanied by a general decline in memory functioning, environmental support at retrieval can improve older adults’ (+65 years) episodic remembering. Despite those over the age of 65years representing a growing proportion of the population, few environmental retrieval support methods have been empirically evaluated for use with older witnesses and victims of crime. Here, the efficacy of a novel retrieval technique, the Sketch Mental Reinstatement of Context, is compared with a standard Mental Reinstatement of Context and a no support control (Control). Fifty-one participants witnessed an unexpected live event, and 48 hours later were interviewed using one of three aforementioned techniques. In line with predictions emanating from cognitive theories of aging and the environmental support hypothesis, participants in the Sketch Mental Reinstatement of Context condition recalled significantly more correct information and fewer inaccurate items. The Sketch Mental Reinstatement of Context technique appears to scaffold memory retrieval in an age-appropriate manner during a post-event interview, possibly by encouraging more effortful retrieval and reducing dual-task load. As such, this procedure offers an effective alternative to current approaches, adding to the toolbox of techniques available to forensic and other interviewers

Estimating Receptive Fields from Responses to Natural Stimuli with Asymmetric Intensity Distributions

The reasons for using natural stimuli to study sensory function are quickly mounting, as recent studies have revealed important differences in neural responses to natural and artificial stimuli. However, natural stimuli typically contain strong correlations and are spherically asymmetric (i.e. stimulus intensities are not symmetrically distributed around the mean), and these statistical complexities can bias receptive field (RF) estimates when standard techniques such as spike-triggered averaging or reverse correlation are used. While a number of approaches have been developed to explicitly correct the bias due to stimulus correlations, there is no complementary technique to correct the bias due to stimulus asymmetries. Here, we develop a method for RF estimation that corrects reverse correlation RF estimates for the spherical asymmetries present in natural stimuli. Using simulated neural responses, we demonstrate how stimulus asymmetries can bias reverse-correlation RF estimates (even for uncorrelated stimuli) and illustrate how this bias can be removed by explicit correction. We demonstrate the utility of the asymmetry correction method under experimental conditions by estimating RFs from the responses of retinal ganglion cells to natural stimuli and using these RFs to predict responses to novel stimuli

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page