Elastin is Localised to the Interfascicular Matrix of Energy Storing Tendons and Becomes Increasingly Disorganised With Ageing

Tendon is composed of fascicles bound together by the interfascicular matrix (IFM). Energy storing tendons are more elastic and extensible than positional tendons; behaviour provided by specialisation of the IFM to enable repeated interfascicular sliding and recoil. With ageing, the IFM becomes stiffer and less fatigue resistant, potentially explaining why older tendons become more injury-prone. Recent data indicates enrichment of elastin within the IFM, but this has yet to be quantified. We hypothesised that elastin is more prevalent in energy storing than positional tendons, and is mainly localised to the IFM. Further, we hypothesised that elastin becomes disorganised and fragmented, and decreases in amount with ageing, especially in energy storing tendons. Biochemical analyses and immunohistochemical techniques were used to determine elastin content and organisation, in young and old equine energy storing and positional tendons. Supporting the hypothesis, elastin localises to the IFM of energy storing tendons, reducing in quantity and becoming more disorganised with ageing. These changes may contribute to the increased injury risk in aged energy storing tendons. Full understanding of the processes leading to loss of elastin and its disorganisation with ageing may aid in the development of treatments to prevent age related tendinopathy

Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing

Aprataxin (APTX) deficiency causes progressive cerebellar degeneration, ataxia and oculomotor apraxia in man. Cell free assays and crystal structure studies demonstrate a role for APTX in resolving 5'-adenylated nucleic acid breaks, however, APTX function in vertebrates remains unclear due to the lack of an appropriate model system. Here, we generated a murine model in which a pathogenic mutant of superoxide dismutase 1 (SOD1(G93A)) is expressed in an Aptx-/- mouse strain. We report a delayed population doubling and accelerated senescence in Aptx-/- primary mouse fibroblasts, which is not due to detectable telomere instability or cell cycle deregulation but is associated with a reduction in transcription recovery following oxidative stress. Expression of SOD1(G93A) uncovers a survival defect ex vivo in cultured cells and in vivo in tissues lacking Aptx. The surviving neurons feature numerous and deep nuclear envelope invaginations, a hallmark of cellular stress. Furthermore, they possess an elevated number of high-density nuclear regions and a concomitant increase in histone H3 K9 trimethylation, hallmarks of silenced chromatin. Finally, the accelerated cellular senescence was also observed at the organismal level as shown by down-regulation of insulin-like growth factor 1 (IGF-1), a hallmark of premature ageing. Together, this study demonstrates a protective role of Aptx in vivo and suggests that its loss results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of premature ageing, systemically

Bonding trends within ternary Isocoordinate chalcogenide glasses GeAsSe

A structural study is presented of ab-initio molecular dynamics simulations of Ge-As-Se calcogenide glasses performed at the same mean coordination number but differing stoichiometry ranging between Se rich and Se poor glasses. Starting configurations are generated via Reverse Monte Carlo (RMC) simulations of Extended X-ray Absorption Fine Structure (EXAFS) measurements of experimental samples. Structural analysis is presented illustrating the bonding trends found with changing stoichiometry.Comment: 26 pages, 9 figures. Submitted to Physical Review

Mean-field equations for stochastic firing-rate neural fields with delays: Derivation and noise-induced transitions

In this manuscript we analyze the collective behavior of mean-field limits of large-scale, spatially extended stochastic neuronal networks with delays. Rigorously, the asymptotic regime of such systems is characterized by a very intricate stochastic delayed integro-differential McKean-Vlasov equation that remain impenetrable, leaving the stochastic collective dynamics of such networks poorly understood. In order to study these macroscopic dynamics, we analyze networks of firing-rate neurons, i.e. with linear intrinsic dynamics and sigmoidal interactions. In that case, we prove that the solution of the mean-field equation is Gaussian, hence characterized by its two first moments, and that these two quantities satisfy a set of coupled delayed integro-differential equations. These equations are similar to usual neural field equations, and incorporate noise levels as a parameter, allowing analysis of noise-induced transitions. We identify through bifurcation analysis several qualitative transitions due to noise in the mean-field limit. In particular, stabilization of spatially homogeneous solutions, synchronized oscillations, bumps, chaotic dynamics, wave or bump splitting are exhibited and arise from static or dynamic Turing-Hopf bifurcations. These surprising phenomena allow further exploring the role of noise in the nervous system.Comment: Updated to the latest version published, and clarified the dependence in space of Brownian motion

The treatment experiences of people living with ileostomies: an interpretative phenomenological analysis

AIMS: To explore treatment and healthcare experiences of people living with ileostomies, so nurses can build on best practice whilst caring for these patients. Background Ileostomies, in which the small intestine is re-directed out of a stoma in the abdominal wall so waste is collected using a bag, are used to treat conditions including Inflammatory Bowel Disease. Existing research suggests that although life with a stoma can be challenging, ileostomy patients are largely supported by multi-disciplinary teams. However, more research is needed to understand the nuances of these relationships and experiences of treatment, with a view to improving clinical care. DESIGN: Participants took part in semi-structured interviews consisting of open ended questions about their experiences of life with an ileostomy and their treatments and time in hospital. Points of interest were followed up. Data were collected between July and December of 2014. METHODS: The qualitative method Interpretative Phenomenological Analysis was used to analyse interviews with 21 people living with ileostomies. FINDINGS: We present findings from two clinical themes: Issues around treatment and Relationships with multi-disciplinary teams. Surgical complications were common, and several participants reported concerns about addiction to painkillers. Varying attitudes were found around reversal surgery. Many reported experiencing distressing, dehumanising care, whilst some felt supported by excellent healthcare providers. CONCLUSION: People living with ileostomies have a very mixed experience of multi-disciplinary teams and treatments, and much could be done to support them more fully. For example, more information about ileostomies could be given to patients and more training given to nurses around stomas

The bashful and the boastful : prestigious leaders and social change in Mesolithic Societies

The creation and maintenance of influential leaders and authorities is one of the key themes of archaeological and historical enquiry. However the social dynamics of authorities and leaders in the Mesolithic remains a largely unexplored area of study. The role and influence of authorities can be remarkably different in different situations yet they exist in all societies and in almost all social contexts from playgrounds to parliaments. Here we explore the literature on the dynamics of authority creation, maintenance and contestation in egalitarian societies, and discuss the implications for our interpretation and understanding of the formation of authorities and leaders and changing social relationships within the Mesolithic

Mid-Infrared Frequency Comb Fourier Transform Spectrometer

Optical frequency-comb-based-high-resolution spectrometers offer enormous potential for spectroscopic applications. Although various implementations have been demonstrated, the lack of suitable mid-infrared comb sources has impeded explorations of molecular fingerprinting. Here we present for the first time a frequency-comb Fourier transform spectrometer operating in the 2100-to-3700-cm-1 spectral region that allows fast and simultaneous acquisitions of broadband absorption spectra with up to 0.0056 cm-1 resolution. We demonstrate part-per-billion detection limits in 30 seconds of integration time for various important molecules including methane, ethane, isoprene, and nitrous oxide. Our system enables precise concentration measurements even in gas mixtures that exhibit continuous absorption bands, and it allows detection of molecules at levels below the noise floor via simultaneous analysis of multiple spectral features. This system represents a near real-time, high-resolution, high-bandwidth mid-infrared spectrometer which is ready to replace traditional Fourier transform spectrometers for many applications in trace gas detection, atmospheric science, and medical diagnostics.Comment: 23 pages (double spaced), 5 figures, 1 tabl

Effects on quality of life, anti-cancer responses, breast conserving surgery and survival with neoadjuvant docetaxel: a randomised study of sequential weekly versus three-weekly docetaxel following neoadjuvant doxorubicin and cyclophosphamide in women with primary breast cancer

<p>Abstract</p> <p>Background</p> <p>Weekly docetaxel has occasionally been used in the neoadjuvant to downstage breast cancer to reduce toxicity and possibly enhance quality of life. However, no studies have compared the standard three weekly regimen to the weekly regimen in terms of quality of life. The primary aim of our study was to compare the effects on QoL of weekly versus 3-weekly sequential neoadjuvant docetaxel. Secondary aims were to determine the clinical and pathological responses, incidence of Breast Conserving Surgery (BCS), Disease Free Survival (DFS) and Overall Survival (OS).</p> <p>Methods</p> <p>Eighty-nine patients receiving four cycles of doxorubicin and cyclophosphamide were randomised to receive twelve cycles of weekly docetaxel (33 mg/m²) or four cycles of 3-weekly docetaxel (100 mg/m²). The Functional Assessment of Cancer Therapy-Breast and psychosocial questionnaires were completed.</p> <p>Results</p> <p>At a median follow-up of 71.5 months, there was no difference in the Trial Outcome Index scores between treatment groups. During weekly docetaxel, patients experienced less constipation, nail problems, neuropathy, tiredness, distress, depressed mood, and unhappiness. There were no differences in overall clinical response (93% vs. 90%), pathological complete response (20% vs. 27%), and breast-conserving surgery (BCS) rates (49% vs. 42%). Disease-free survival and overall survival were similar between treatment groups.</p> <p>Conclusions</p> <p>Weekly docetaxel is well-tolerated and has less distressing side-effects, without compromising therapeutic responses, Breast Conserving Surgery (BCS) or survival outcomes in the neoadjuvant setting.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN09184069">ISRCTN09184069</a></p