The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

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Modern Applied Statistics With S

Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.

Hypoxia — a key regulatory factor in tumour growth

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

ACC
: American College of Cardiology
ACE
: angiotensin-converting enzyme
ACS
: acute coronary syndrome
AF
: atrial fibrillation
AGNES
: Arrhythmia Genetics in the Netherlands
AHA
: American Heart Association
AMIOVIRT
: AMIOdarone Versus Implantable cardioverter-defibrillator:

/pdf/2015-esc-guidelines-for-the-management-of-patients-with-3hzn8vw0c4.pdf

2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)

The letter by Papapetropoulos and colleagues presents an additional study correlating -synuclein expression levels and sporadic PD. Previously we and others published studies of mRNA levels of SNCA in PD brains that have been performed using different methods. Some are in agreement with our results, while others contradict our findings. Recognizing the contradictory findings in the field, our paper explained that there were technical issues that arose in the course of these kinds of studies and emphasized the need to carefully control these assays. Thus the conclusion from Papapetropoulos et al. study to be cautious when analyzing gene expression align perfectly with our previous recommendation to be cautious when designing assays for quantifying mRNA levels since results can also reflect other factors (i.e., cell type, tissue status, studied group, assay used). In this light we believe that increased reproducibility of results can best be achieved by independent analysis of replicate samples to improve the interpretation of results and recommend that others working in this field follow our recommendations. Moreover, the internal controls for these studies have to be carefully chosen, keeping in mind the cell type heterogeneity (neurons, glia) of the tissue and the specific neuronal loss in the PD samples. This is why we chose a neuronal mRNA as an internal control for our studies. The results presented by Papapetropoulos et al. may reflect the use of a ubiquitously expressed gene, 18S rRNA, as an internal control in a heterogenous tissue that undergoes neuron-specific degeneration. The decrease in SNCA-mRNA expression might result from the neuronal loss in the substantia nigra and amygdala of PD brains. Finally, we would like to emphasize that we showed an increase in SNCA-mRNA in the majority, but not in all, sporadic PD mid-brain samples we analyzed. Thus, elevation in SNCA-mRNA levels might contribute to disease pathogenesis in many but, perhaps, not all cases of sporadic PD. Our observation is consistent with the hypothesis that an increase in SNCA expression may be a contributory factor, among other factors, to the development of at least some cases of sporadic PD.

Nanette H. Bishopric

Papers

Expression of α-synuclein mRNA in Parkinson's disease. Authors' reply