Foot protein isoforms are expressed at different times during embryonic chick skeletal muscle development.

We have investigated the time course of expression of the alpha and beta triad junctional foot proteins in embryonic chick pectoral muscle. The level of [3H]ryanodine binding in muscle homogenates is low until day E20 of embryonic development, then increases dramatically at the time of hatching reaching adult levels by day N7 posthatch. The alpha and beta foot protein isoforms increase in abundance concomitantly with [3H]ryanodine binding. Using foot protein isoform-specific antibodies, the alpha foot protein is detected in a majority of fibers in day E10 muscle, while the beta isoform is first observed at low levels in a few fibers in day E15 muscle. A high molecular weight polypeptide, distinct from the alpha and beta proteins, is recognized by antifoot protein antibodies. This polypeptide is observed in day E8 muscle and declines in abundance with continued development. It appears to exist as a monomer and does not bind [3H]ryanodine. In contrast, the alpha isoform present in day E10 muscle and the beta isoform in day E20 muscle are oligomeric and bind [3H]ryanodine suggesting that they may exist as functional calcium channels in differentiating muscle. Comparison of the intracellular distributions of the alpha foot protein, f-actin, the heavy chain of myosin and titin in day E10 muscle indicates that the alpha foot protein is expressed during myofibril assembly and Z line formation. The differential expression of the foot protein isoforms in developing muscle, and their continued expression in mature muscle, is consistent with these proteins making different functional contributions. In addition, the expression of the alpha isoform during the time of organization of a differentiated muscle morphology suggests that foot proteins may participate in events involved in muscle differentiation

Clinical case seminar - Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita

Mutations in the orphan nuclear receptor DAX-1 cause X-linked adrenal hypoplasia congenita. Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development because of hypogonadotropic hypogonadism becomes apparent at the time of puberty. We report adult-onset adrenal hypoplasia congenita in a patient who presented with hypogonadism at 28 yr of age. Although he had no clinical evidence of adrenal dysfunction, compensated primary adrenal failure was diagnosed by biochemical testing. Semen analysis showed azoospermia, and he did not achieve fertility after 8 months of treatment with gonadotropins. A novel Y380D DAX-1 missense mutation, which causes partial loss of function in transient gene expression assays, was found in this patient. This case demonstrates that partial loss-of-function mutations in DAX1 can present with hypogonadotropic hypogonadism and covert adrenal failure in adulthood. Further, an important role for DAX-1 in spermatogenesis in humans is confirmed, supporting findings in the Dax1 (Ahch) knockout mouse

Bayesian system identification of MDOF nonlinear systems using highly informative training data

The aim of this paper is to utilise the concept of “highly informative training data” such that, using Markov chain Monte Carlo (MCMC) methods, one can apply Bayesian system identification to multi-degree-of-freedom nonlinear systems with relatively little computational cost. Specifically, the Shannon entropy is used as a measure of information content such that, by analysing the information content of the posterior parameter distribution, one is able to select and utilise a relatively small but highly informative set of training data (thus reducing the cost of running MCMC)

Snapshot Provisioning of Cloud Application Stacks to Face Traffic Surges

Traffic surges, like the Slashdot effect, occur when a web application is overloaded by a huge number of requests, potentially leading to unavailability. Unfortunately, such traffic variations are generally totally unplanned, of great amplitude, within a very short period, and a variable delay to return to a normal regime. In this report, we introduce PeakForecast as an elastic middleware solution to detect and absorb a traffic surge. In particular, PeakForecast can, from a trace of queries received in the last seconds, minutes or hours, to detect if the underlying system is facing a traffic surge or not, and then estimate the future traffic using a forecast model with an acceptable precision, thereby calculating the number of resources required to absorb the remaining traffic to come. We validate our solution by experimental results demonstrating that it can provide instantaneous elasticity of resources for traffic surges observed on the Japanese version of Wikipedia during the Fukushima Daiichi nuclear disaster in March 2011.Les pics de trafic, tels que l'effet Slashdot, apparaissent lorsqu'une application web doit faire face un nombre important de requêtes qui peut potentiellement entraîner une mise hors service de l'application. Malheureusement, de telles variations de traffic sont en général totalement imprévues et d'une grande amplitude, arrivent pendant une très courte période de temps et le retour à un régime normal prend un délai variable. Dans ce rapport, nous présentons PeakForecast qui est une solution intergicielle élastique pour détecter et absorber les pics de trafic. En particulier, PeakForecast peut, à partir des traces de requêtes reçues dans les dernières secondes, minutes ou heures, détecter si le système sous-jacent fait face ou non à un pic de trafic, estimer le trafic futur en utilisant un modèle de prédiction suffisamment précis, et calculer le nombre de ressources nécessaires à l'absorption du trafic restant à venir. Nous validons notre solution avec des résultats expérimentaux qui démontrent qu'elle fournit une élasticité instantanée des ressources pour des pics de trafic qui ont été observés sur la version japonaise de Wikipedia lors de l'accident nucléaire de Fukushima Daiichi en mars 2011

An extragalactic supernebula confined by gravity

Little is known about the origins of the giant star clusters known as globular clusters. How can hundreds of thousands of stars form simultaneously in a volume only a few light years across the distance of the sun to its nearest neighbor? Radiation pressure and winds from luminous young stars should disperse the star-forming gas and disrupt the formation of the cluster. Globular clusters in our Galaxy cannot provide answers; they are billions of years old. Here we report the measurement of infrared hydrogen recombination lines from a young, forming super star cluster in the dwarf galaxy, NGC 5253. The lines arise in gas heated by a cluster of an estimated million stars, so young that it is still enshrouded in gas and dust, hidden from optical view. We verify that the cluster contains 4000-6000 massive, hot "O" stars. Our discovery that the gases within the cluster are bound by gravity may explain why these windy and luminous O stars have not yet blown away the gases to allow the cluster to emerge from its birth cocoon. Young clusters in "starbursting" galaxies in the local and distant universe may be similarly gravitationally confined and cloaked from view.Comment: Letter to Natur

Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach

The bacterial sliding clamp (SC), also known as the DNA polymerase III β subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein-protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21-43 μg/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity. © 2014 American Chemical Society

The Cost-Effectiveness of Early Access to HIV Services and Starting cART in the UK 1996–2008

To calculate use, cost and cost-effectiveness of people living with HIV (PLHIV) starting routine treatment and care before starting combination antiretroviral therapy (cART) and PLHIV starting first-line 2NRTIs+NNRTI or 2NRTIs+PI(boosted), comparing PLHIV with CD4≤200 cells/mm3 and CD4>200 cells/mm3. Few studies have calculated the use, cost and cost-effectiveness of routine treatment and care before starting cART and starting cART above and below CD4 200 cells/mm3.Use, costs and cost-effectiveness were calculated for PLHIV in routine pre-cART and starting first-line cART, comparing CD4≤200 cells/mm3 with CD4>200 cells/mm3 (2008 UK prices).cART naïve patients CD4≤200 cells/mm3 had an annual cost of £6,407 (95%CI £6,382 to £6,425) PPY compared with £2,758 (95%CI £2,752 to £2,761) PPY for those with CD4>200 cells/mm3; cost per life year gained of pre-cART treatment and care for those with CD4>200 cells/mm3 was £1,776 (cost-saving to £2,752). Annual cost for starting 2NRTIs+NNRTI or 2NRTIs+PI(boosted) with CD4≤200 cells/mm3 was £12,812 (95%CI £12,685-£12,937) compared with £10,478 (95%CI £10,376-£10,581) for PLHIV with CD4>200 cells/mm3. Cost per additional life-year gained on first-line therapy for those with CD4>200 cells/mm3 was £4639 (£3,967 to £2,960).PLHIV starting to use HIV services before CD4≤200 cells/mm3 is cost-effective and enables them to be monitored so they start cART with a CD4>200 cells/mm3, which results in better outcomes and is cost-effective. However, 25% of PLHIV accessing services continue to present with CD4≤200 cells/mm3. This highlights the need to investigate the cost-effectiveness of testing and early treatment programs for key populations in the UK

Initial conditions, Discreteness and non-linear structure formation in cosmology

In this lecture we address three different but related aspects of the initial continuous fluctuation field in standard cosmological models. Firstly we discuss the properties of the so-called Harrison-Zeldovich like spectra. This power spectrum is a fundamental feature of all current standard cosmological models. In a simple classification of all stationary stochastic processes into three categories, we highlight with the name ``super-homogeneous'' the properties of the class to which models like this, with $P(0)=0$, belong. In statistical physics language they are well described as glass-like. Secondly, the initial continuous density field with such small amplitude correlated Gaussian fluctuations must be discretised in order to set up the initial particle distribution used in gravitational N-body simulations. We discuss the main issues related to the effects of discretisation, particularly concerning the effect of particle induced fluctuations on the statistical properties of the initial conditions and on the dynamical evolution of gravitational clustering.Comment: 28 pages, 1 figure, to appear in Proceedings of 9th Course on Astrofundamental Physics, International School D. Chalonge, Kluwer, eds N.G. Sanchez and Y.M. Pariiski, uses crckapb.st pages, 3 figure, ro appear in Proceedings of 9th Course on Astrofundamental Physics, International School D. Chalonge, Kluwer, Eds. N.G. Sanchez and Y.M. Pariiski, uses crckapb.st

A review of the methodological features of systematic reviews in maternal medicine

Background In maternal medicine, research evidence is scattered making it difficult to access information for clinical decision making. Systematic reviews of good methodological quality are essential to provide valid inferences and to produce usable evidence summaries to guide management. This review assesses the methodological features of existing systematic reviews in maternal medicine, comparing Cochrane and non-Cochrane reviews in maternal medicine. Methods Medline, Embase, Database of Reviews of Effectiveness (DARE) and Cochrane Database of Systematic Reviews (CDSR) were searched for relevant reviews published between 2001 and 2006. We selected those reviews in which a minimum of two databases were searched and the primary outcome was related to the maternal condition. The selected reviews were assessed for information on framing of question, literature search and methods of review. Results Out of 2846 citations, 68 reviews were selected. Among these, 39 (57%) were Cochrane reviews. Most of the reviews (50/68, 74%) evaluated therapeutic interventions. Overall, 54/68 (79%) addressed a focussed question. Although 64/68 (94%) reviews had a detailed search description, only 17/68 (25%) searched without language restriction. 32/68 (47%) attempted to include unpublished data and 11/68 (16%) assessed for the risk of missing studies quantitatively. The reviews had deficiencies in the assessment of validity of studies and exploration for heterogeneity. When compared to Cochrane reviews, other reviews were significantly inferior in specifying questions (OR 20.3, 95% CI 1.1–381.3, p = 0.04), framing focussed questions (OR 30.9, 95% CI 3.7- 256.2, p = 0.001), use of unpublished data (OR 5.6, 95% CI 1.9–16.4, p = 0.002), assessment for heterogeneity (OR 38.1, 95%CI 2.1, 688.2, p = 0.01) and use of meta-analyses (OR 3.7, 95% CI 1.3–10.8, p = 0.02). Conclusion This study identifies areas which have a strong influence on maternal morbidity and mortality but lack good quality systematic reviews. Overall quality of the existing systematic reviews was variable. Cochrane reviews were of better quality as compared to other reviews. There is a need for good quality systematic reviews to inform practice in maternal medicine