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The novel neuropeptide phoenixin is highly co-expressed with nesfatin-1 in the rat hypothalamus, an immunohistochemical study.
No full textThe hypothalamus regulates a number of autonomic functions essential for homeostasis; therefore, investigations concerning hypothalamic neuropeptides and their functions and distribution are of great importance in contemporary neuroscience. Recently, novel regulatory factors expressed in the hypothalamus have been discovered, of which nesfatin-1 and phoenixin (PNX), show intriguing similarities in their brain distributions. There are currently few studies characterizing PNX expression, so it is imperative to accurately trace its localization, with particular attention to the hypothalamic nuclei and nesfatin-1 co-expression. Using fluorescence and classical immunohistochemical stainings on adult rat brain, we visualized the potential co-expression of nesfatin-1 and PNX immunoreactive cells. We have demonstrated a distinct PNX-immunoreactivity in 21-32% of cells in the arcuate nucleus, paraventricular nucleus, ventromedial and lateral hypothalamus. Nesfatin-1 expression reached 45-68% of all neurons in the same sites, while co-expression was strikingly seen in the vast majority (70-86%) of PNX-immunoreactive neurons in the rat hypothalamic nuclei. Our results demonstrate for the first time, a wide distribution of PNX in the hypothalamus which could implicate a potential functional relationship with nesfatin-1, possibly in the regulation of the hypothalamic-pituitary-gonadal axis or other autonomic functions, which require further study
In depth review: Working with asbestos and the possible health risks
No full textBackground The generic term asbestos refers to a group of crystalline mineral silicates that occur naturally in various forms. Because of their properties of strength, heat and electrical resistance and their ability to withstand corrosion by acids and sea water, asbestos was used extensively both in the UK and worldwide.Aims To provide a historical perspective of this ubiquitous occupational hazard, consider the key changes in UK legislation aimed at improving the management of this occupational health risk and describe the evidence from the scientific literature concerning asbestos and disease.Methods Original articles, reviews (including reference textbooks) and scientific literature in PubMed and other principal medical science databases, 1960–2014, were searched. Publications by regulatory agencies and by governmental organizations were also considered and included where relevant.Results Asbestos remains the biggest cause of cancer deaths worldwide. For malignant mesothelioma deaths alone, it is estimated that in the UK, between 2015 and 2020, the number of cases will peak at 2500 cases annually. It is not clear whether there is a safe level of asbestos fibres in air. Evidence for the efficacy of health surveillance is lacking.Conclusions Although the use of asbestos was banned in the UK in 1985 (amosite and crocidolite) and 1999 (chrysotile), it remains a significant occupational risk factor for work-related morbidity and mortality, causing both benign and malignant diseases, often with long latency. Further research is needed regarding exposure levels and health surveillance
Valuing preferences for the process and outcome of Clinical Genetics Services: a pilot study
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Analysis of the impact of controlled release formulation on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model
No full textCatalytic mechanism of cofactor-free dioxygenases and how they circumvent spin-forbidden oxygenation of their substrates.
No full textDioxygenases catalyze a diverse range of biological reactions by incorporating molecular oxygen into organic substrates. Typically, they use transition metals or organic cofactors for catalysis. Bacterial 1-H-3-hydroxy-4-oxoquinaldine-2,4-dioxygenase (HOD) catalyzes the spin-forbidden transfer of dioxygen to its N-heteroaromatic substrate in the absence of any cofactor. We combined kinetics, spectroscopic and computational approaches to establish a novel reaction mechanism. The present work gives insight into the rate limiting steps in the reaction mechanism, the effect of first-coordination sphere amino acids as well as electron-donating/electron-withdrawing substituents on the substrate. We highlight the role of active site residues Ser101/Trp160/His251 and their involvement in the reaction mechanism. The work shows, for the first time, that the reaction is initiated by triplet dioxygen and its binding to deprotonated substrate and only thereafter a spin state crossing to the singlet spin state occurs. As revealed by steady- and transient-state kinetics the oxygen-dependent steps are rate-limiting, whereas Trp160 and His251 are essential residues for catalysis and contribute to substrate positioning and activation, respectively. Computational modeling further confirms the experimental observations and rationalizes the electron transfer pathways, and the effect of substrate and substrate binding pocket residues. Finally, we make a direct comparison with iron-based dioxygenases and explain the mechanistic and electronic differences with cofactor-free dioxygenases. Our multidisciplinary study confirms that the oxygenation reaction can take place in absence of any cofactor by a unique mechanism in which the specially designed fit-for-purpose active-site architecture modulates substrate reactivity toward oxygen
Biphasic decay of the Ca transient results from increased sarcoplasmic reticulum Ca leak.
No full textIn heart failure reduction in Ca transient amplitude and contractile dysfunction can by caused by Ca leak through the sarcoplasmic reticulum (SR) Ca channel (Ryanodine Receptor, RyR) and/or decreased activity of the SR Ca ATPase (SERCA). We have characterized the effects of two forms of Ca leak (Ca-sensitizing and non-sensitizing) on calcium cycling and compared with those of SERCA inhibition. We measured [Ca(2+) ]i with fluo-3 in voltage-clamped rat ventricular myocytes. Increasing SR leak with either caffeine (to sensitize the RyR to Ca activation) or ryanodine (non-sensitizing) had similar effects to SERCA inhibition: decreased systolic [Ca(2+) ]i , increased diastolic [Ca(2+) ]i and slowed decay. However, in the presence of isoproterenol, leak produced a biphasic decay of the Ca transient in the majority of cells while SERCA inhibition produced monophasic decay. Tetracaine reversed the effects of caffeine but not of ryanodine. When caffeine (1 mmol l(-1) ) was added to a cell which displayed Ca waves, the wave frequency initially increased before waves disappeared and biphasic decay developed. Eventually (at higher caffeine concentrations), the biphasic decay was replaced by slow decay. We conclude that, in the presence of adrenergic stimulation, Ca leak can produce biphasic decay; the slow phase results from the leak opposing Ca uptake by SERCA. The degree of leak determines whether Ca waves, biphasic or monophasic decay occur. This article is protected by copyright. All rights reserved
