The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching

Significance: a mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow - 'hypoxic vasodilation' - occur in an attempt to restore oxygen supply. Nitric oxide is a major signalling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent advances: this review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of nitric oxide, and mechanisms underlying the involvement of nitric oxide in hypoxic vasodilation. Recent insights into nitric oxide metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite reductases, and release of nitric oxide from storage pools. The processes through which nitric oxide levels are elevated during hypoxia are presented, namely (i) increased synthesis from nitric oxide synthases, increased reduction of nitrite to nitric oxide by heme- or pterin-based enzymes and increased release from nitric oxide stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical issues: several reviews covered modulation of energetic metabolism by nitric oxide, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression Future directions: we identify a key position for nitric oxide in the body's adaptation to an acute energy supply-demand mismatc

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD

The Wasteland of Random Supergravities

We show that in a general \cal{N} = 1 supergravity with N \gg 1 scalar fields, an exponentially small fraction of the de Sitter critical points are metastable vacua. Taking the superpotential and Kahler potential to be random functions, we construct a random matrix model for the Hessian matrix, which is well-approximated by the sum of a Wigner matrix and two Wishart matrices. We compute the eigenvalue spectrum analytically from the free convolution of the constituent spectra and find that in typical configurations, a significant fraction of the eigenvalues are negative. Building on the Tracy-Widom law governing fluctuations of extreme eigenvalues, we determine the probability P of a large fluctuation in which all the eigenvalues become positive. Strong eigenvalue repulsion makes this extremely unlikely: we find P \propto exp(-c N^p), with c, p being constants. For generic critical points we find p \approx 1.5, while for approximately-supersymmetric critical points, p \approx 1.3. Our results have significant implications for the counting of de Sitter vacua in string theory, but the number of vacua remains vast.Comment: 39 pages, 9 figures; v2: fixed typos, added refs and clarification

The CMB and the measure of the multiverse

In the context of eternal inflation, cosmological predictions depend on the choice of measure to regulate the diverging spacetime volume. The spectrum of inflationary perturbations is no exception, as we demonstrate by comparing the predictions of the fat geodesic and causal patch measures. To highlight the effect of the measure---as opposed to any effects related to a possible landscape of vacua---we take the cosmological model, including the model of inflation, to be fixed. We also condition on the average CMB temperature accompanying the measurement. Both measures predict a 1-point expectation value for the gauge-invariant Newtonian potential, which takes the form of a (scale-dependent) monopole, in addition to a related contribution to the 3-point correlation function, with the detailed form of these quantities differing between the measures. However, for both measures both effects are well within cosmic variance. Our results make clear the theoretical relevance of the measure, and at the same time validate the standard inflationary predictions in the context of eternal inflation.Comment: 28 pages; v2: reference added, some clarification

Is Our Universe Natural?

It goes without saying that we are stuck with the universe we have. Nevertheless, we would like to go beyond simply describing our observed universe, and try to understand why it is that way rather than some other way. Physicists and cosmologists have been exploring increasingly ambitious ideas that attempt to explain why certain features of our universe aren't as surprising as they might first appear.Comment: Invited review for Nature, 11 page

Illness perceptions and explanatory models of viral hepatitis B & C among immigrants and refugees: a narrative systematic review.

© 2015 Owiti et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Hepatitis B and C (HBV, HCV) infections are associated with high morbidity and mortality. Many countries with traditionally low prevalence (such as UK) are now planning interventions (screening, vaccination, and treatment) of high-risk immigrants from countries with high prevalence. This review aimed to synthesise the evidence on immigrants' knowledge of HBV and HCV that might influence the uptake of clinical interventions. The review was also used to inform the design and successful delivery of a randomised controlled trial of targeted screening and treatment. METHODS: Five databases (PubMed, CINHAL, SOCIOFILE, PsycINFO & Web of Science) were systematically searched, supplemented by reference tracking, searches of selected journals, and of relevant websites. We aimed to identify qualitative and quantitative studies that investigated knowledge of HBV and HCV among immigrants from high endemic areas to low endemic areas. Evidence, extracted according to a conceptual framework of Kleinman's explanatory model, was subjected to narrative synthesis. We adapted the PEN-3 model to categorise and analyse themes, and recommend strategies for interventions to influence help-seeking behaviour. RESULTS: We identified 51 publications including quantitative (n = 39), qualitative (n = 11), and mixed methods (n = 1) designs. Most of the quantitative studies included small samples and had heterogeneous methods and outcomes. The studies mainly concentrated on hepatitis B and ethnic groups of South East Asian immigrants residing in USA, Canada, and Australia. Many immigrants lacked adequate knowledge of aetiology, symptoms, transmission risk factors, prevention strategies, and treatment, of hepatitis HBV and HCV. Ethnicity, gender, better education, higher income, and English proficiency influenced variations in levels and forms of knowledge. CONCLUSION: Immigrants are vulnerable to HBV and HCV, and risk life-threatening complications from these infections because of poor knowledge and help-seeking behaviour. Primary studies in this area are extremely diverse and of variable quality precluding meta-analysis. Further research is needed outside North America and Australia

Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma development

<p>Abstract</p> <p>Background</p> <p>Most human cancers show inactivation of both pRB- and p53-pathways. While retinoblastomas are initiated by loss of the <it>RB1 </it>tumor suppressor gene, <it>TP53 </it>mutations have not been found. High expression of the p53-antagonist MDM2 in human retinoblastomas may compromise p53 tumor surveillance so that <it>TP53 </it>mutations are not selected for in retinoblastoma tumorigenesis. We previously showed that p14^ARFprotein, which activates p53 by inhibiting MDM2, is low in retinoblastomas despite high mRNA expression.</p> <p>Methods</p> <p>In human fetal retinas, adult retinas, and retinoblastoma cells, we determined endogenous <it>p14^ARF</it>mRNA, ARF protein, and miR-24 expression, while integrity of p53 signalling in WERI-Rb1 cells was tested using an adenovirus vector expressing p14^ARF. To study p14^ARFbiogenesis, retinoblastoma cells were treated with the proteasome inhibitor, MG132, and siRNA against miR-24.</p> <p>Results</p> <p>In human retinoblastoma cell lines, <it>p14^ARF</it>mRNA was disproportionally high relative to the level of p14^ARFprotein expression, suggesting a perturbation of p14^ARFregulation. When p14^ARFwas over-expressed by an adenovirus vector, expression of p53 and downstream targets increased and cell growth was inhibited indicating an intact p14^ARF-p53 axis. To investigate the discrepancy between <it>p14^ARF</it>mRNA and protein in retinoblastoma, we examined p14^ARFbiogenesis. The proteasome inhibitor, MG132, did not cause p14^ARFaccumulation, although p14^ARFnormally is degraded by proteasomes. miR-24, a microRNA that represses p14^ARFexpression, is expressed in retinoblastoma cell lines and correlates with lower protein expression when compared to other cell lines with high <it>p14^ARF</it>mRNA. Transient over-expression of siRNA against miR-24 led to elevated p14^ARFprotein in retinoblastoma cells.</p> <p>Conclusions</p> <p>In retinoblastoma cells where high levels of <it>p14^ARF</it>mRNA are not accompanied by high p14^ARFprotein, we found a correlation between miR-24 expression and low p14^ARFprotein. p14^ARFprotein levels were restored without change in mRNA abundance upon miR-24 inhibition suggesting that miR-24 could functionally repress expression, effectively blocking p53 tumor surveillance. During retinal tumorigenesis, miR-24 may intrinsically compromise the p53 response to <it>RB1 </it>loss.</p

Assigning Backbone NMR Resonances for Full Length Tau Isoforms: Efficient Compromise between Manual Assignments and Reduced Dimensionality

Tau protein is the longest disordered protein for which nearly complete backbone NMR resonance assignments have been reported. Full-length tau protein was initially assigned using a laborious combination of bootstrapping assignments from shorter tau fragments and conventional triple resonance NMR experiments. Subsequently it was reported that assignments of comparable quality could be obtained in a fully automated fashion from data obtained using reduced dimensionality NMR (RDNMR) experiments employing a large number of indirect dimensions. Although the latter strategy offers many advantages, it presents some difficulties if manual intervention, confirmation, or correction of the assignments is desirable, as may often be the case for long disordered and degenerate polypeptide sequences. Here we demonstrate that nearly complete backbone resonance assignments for full-length tau isoforms can be obtained without resorting either to bootstrapping from smaller fragments or to very high dimensionality experiments and automation. Instead, a set of RDNMR triple resonance experiments of modest dimensionality lend themselves readily to efficient and unambiguous manual assignments. An analysis of the backbone chemical shifts obtained in this fashion indicates several regions in full length tau with a notable propensity for helical or strand-like structure that are in good agreement with previous observations

Root hydrotropism is controlled via a cortex-specific growth mechanism

Plants can acclimate by using tropisms to link the direction of growth to environmental conditions. Hydrotropism allows roots to forage for water, a process known to depend on abscisic acid (ABA) but whose molecular and cellular basis remains unclear. Here, we show that hydrotropism still occurs in roots after laser ablation removed the meristem and root cap. Additionally, targeted expression studies reveal that hydrotropism depends on the ABA signalling kinase, SnRK2.2, and the hydrotropism-specific MIZ1, both acting specifically in elongation zone cortical cells. Conversely, hydrotropism, but not gravitropism, is inhibited by preventing differential cell-length increases in the cortex, but not in other cell types. We conclude that root tropic responses to gravity and water are driven by distinct tissue-based mechanisms. In addition, unlike its role in root gravitropism, the elongation zone performs a dual function during a hydrotropic response, both sensing a water potential gradient and subsequently undergoing differential growth