Nonlinear Evolution of Cosmological Structures in Warm Dark Matter Models

The dark energy dominated warm dark matter (WDM) model is a promising alternative cosmological scenario. We explore large-scale structure formation in this paradigm. We do this in two different ways: with the halo model approach and with the help of an ensemble of high resolution N-body simulations. Combining these quasi-independent approaches, leads to a physical understanding of the important processes which shape the formation of structures. We take a detailed look at the halo mass function, the concentrations and the linear halo bias of WDM. In all cases we find interesting deviations with respect to CDM. In particular, the concentration-mass relation displays a turnover for group scale dark matter haloes, for the case of WDM particles with masses of the order ~0.25 keV. This may be interpreted as a hint for top-down structure formation on small scales. We implement our results into the halo model and find much better agreement with simulations. On small scales the WDM halo model now performs as well as its CDM counterpart.Comment: accepted for publication in MNRA

The Maestro (Mro) Gene Is Dispensable for Normal Sexual Development and Fertility in Mice

The mammalian gonad arises as a bipotential primordium from which a testis or ovary develops depending on the chromosomal sex of the individual. We have previously used DNA microarrays to screen for novel genes controlling the developmental fate of the indifferent embryonic mouse gonad. Maestro (Mro), which encodes a HEAT-repeat protein, was originally identified as a gene exhibiting sexually dimorphic expression during mouse gonad development. Wholemount in situ hybridisation analysis revealed Mro to be expressed in the embryonic male gonad from approximately 11.5 days post coitum, prior to overt sexual differentiation. No significant expression was detected in female gonads at the same developmental stage. In order to address its physiological function, we have generated mice lacking Maestro using gene targeting. Male and female mice homozygous for a Mro null allele are viable and fertile. We examined gonad development in homozygous male embryos in detail and observed no differences when compared to wild-type controls. Immunohistochemical analysis of homozygous mutant testes of adult mice revealed no overt abnormalities. Expression profiling using DNA microarrays also indicated no significant differences between homozygote embryonic male gonads and controls. We conclude that Maestro is dispensable for normal male sexual development and fertility in laboratory mice; however, the Mro locus itself does have utility as a site for insertion of transgenes for future studies in the fields of sexual development and Sertoli cell function

Caspase-8 binding to cardiolipin in giant unilamellar vesicles provides a functional docking platform for bid

Caspase-8 is involved in death receptor-mediated apoptosis in type II cells, the proapoptotic programme of which is triggered by truncated Bid. Indeed, caspase-8 and Bid are the known intermediates of this signalling pathway. Cardiolipin has been shown to provide an anchor and an essential activating platform for caspase-8 at the mitochondrial membrane surface. Destabilisation of this platform alters receptor-mediated apoptosis in diseases such as Barth Syndrome, which is characterised by the presence of immature cardiolipin which does not allow caspase-8 binding. We used a simplified in vitro system that mimics contact sites and/or cardiolipin-enriched microdomains at the outer mitochondrial surface in which the platform consisting of caspase-8, Bid and cardiolipin was reconstituted in giant unilamellar vesicles. We analysed these vesicles by flow cytometry and confirm previous results that demonstrate the requirement for intact mature cardiolipin for caspase-8 activation and Bid binding and cleavage. We also used confocal microscopy to visualise the rupture of the vesicles and their revesiculation at smaller sizes due to alteration of the curvature following caspase-8 and Bid binding. Biophysical approaches, including Laurdan fluorescence and rupture/tension measurements, were used to determine the ability of these three components (cardiolipin, caspase-8 and Bid) to fulfil the minimal requirements for the formation and function of the platform at the mitochondrial membrane. Our results shed light on the active functional role of cardiolipin, bridging the gap between death receptors and mitochondria

Cuspy No More: How Outflows Affect the Central Dark Matter and Baryon Distribution in Lambda CDM Galaxies

We examine the evolution of the inner dark matter (DM) and baryonic density profile of a new sample of simulated field galaxies using fully cosmological, Lambda CDM, high resolution SPH + N-Body simulations. These simulations include explicit H2 and metal cooling, star formation (SF) and supernovae (SNe) driven gas outflows. Starting at high redshift, rapid, repeated gas outflows following bursty SF transfer energy to the DM component and significantly flatten the originally `cuspy' central DM mass profile of galaxies with present day stellar masses in the 10^4.5 -- 10^9.8 Msolar range. At z=0, the central slope of the DM density profile of our galaxies (measured between 0.3 and 0.7 kpc from their centre) is well fitted by rhoDM propto r^alpha with alpha \simeq -0.5 + 0.35 log_10(Mstar/10^8Msolar) where Mstar is the stellar mass of the galaxy and 4 < log_10 Mstar < 9.4. These values imply DM profiles flatter than those obtained in DM--only simulations and in close agreement with those inferred in galaxies from the THINGS and LITTLE THINGS survey. Only in very small halos, where by z=0 star formation has converted less than ~ 0.03% of the original baryon abundance into stars, outflows do not flatten the original cuspy DM profile out to radii resolved by our simulations. The mass (DM and baryonic) measured within the inner 500 pc of each simulated galaxy remains nearly constant over four orders of magnitudes in stellar mass for Mstar 10^9 Msolar. This finding is consistent with estimates for faint Local Group dwarfs and field galaxies. These results address one of the outstanding problems faced by the CDM model, namely the strong discrepancy between the original predictions of cuspy DM profiles and the shallower central DM distribution observed in galaxies.Comment: MNRAS in press. Accepted version, a few references added. 12 pages. Animation at http://youtu.be/FbcgEovabDI?hd=

Non-traditional support workers delivering a brief psychosocial intervention for older people with anxiety and depression: the NOTEPAD feasibility study

ackground: Anxiety and depression often coexist in older people. These disorders are often underdiagnosed and undertreated, and are associated with increased use of health and social care services, and raised mortality. Barriers to diagnosis include the reluctance of older people to present to their general practitioner (GP) with mood symptoms because of the stigma they perceive about mental health problems, and because the treatments offered are not acceptable to them. Objectives: To refine a community-based psychosocial intervention for older people with anxiety and/or depression so that it can be delivered by non-traditional providers such, as support workers (SWs), in the third sector. To determine whether or not SWs can be trained to deliver this intervention to older people with anxiety and/or depression. To test procedures and determine if it is feasible to recruit and randomise patients, and to conduct a process evaluation to provide essential information to inform a randomised trial. Design: Three phases, all informed by a patient and public involvement and engagement group. Qualitative work with older people and third-sector providers, plus a consensus group to refine the intervention, training, SW manuals and patient participant materials (phase 1). Recruitment and training of SWs (phase 2). Feasibility study to test recruitment procedures and assess fidelity of delivery of the intervention; and interviews with study participants, SWs and GPs to assess acceptability of the intervention and impact on routine care (phase 3). Setting: North Staffordshire, in collaboration with Age UK North Staffordshire. © Queen’s Printer and Controller of HMSO 2019. This work was produced by Burroughs et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii ABSTRACT viii Intervention: A psychosocial intervention, comprising one-to-one contact between older people with anxiety and/or depression and a SW employed by Age UK North Staffordshire, based on the principles of behavioural activation (BA), with encouragement to participate in a group activity. Results: Initial qualitative work contributed to refinement of the psychosocial intervention. Recruitment (and retention) of the SWs was possible; the training, support materials and manual were acceptable to them, and they delivered the intervention as intended. Recruitment of practices from which to recruit patients was possible, but the recruitment target (100 patients) was not achieved, with 38 older adults randomised. Retention at 4 months was 86%. The study was not powered to demonstrate differences in outcomes. Older people in the intervention arm found the sessions with SWs acceptable, although signposting to, and attending, groups was not valued by all participants. GPs recognised the need for additional care for older people with anxiety and depression, which they could not provide. Participation in the study did not have an impact on routine care, other than responding to the calls from the study team about risk of self-harm. GPs were not aware of the work done by SWs with patients. Limitations: Target recruitment was not achieved. Conclusions: Support workers recruited from Age UK employees can be recruited and trained to deliver an intervention, based on the principles of BA, to older people with anxiety and/or depression. The training and supervision model used in the study was acceptable to SWs, and the intervention was acceptable to older people. Future work: Further development of recruitment strategies is needed before this intervention can be tested in a fully powered randomised controlled trial. Trial registration: Current Controlled Trials ISRCTN16318986. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 7, No. 25. See the NIHR Journals Library website for further project information

Responsiveness to exercise training in juvenile dermatomyositis: a twin case study

<p>Abstract</p> <p>Background</p> <p>Patients with juvenile dermatomyositis (JDM) often present strong exercise intolerance and muscle weakness. However, the role of exercise training in this disease has not been investigated.</p> <p>Purpose</p> <p>this longitudinal case study reports on the effects of exercise training on a 7-year-old patient with JDM and on her unaffected monozygotic twin sister, who served as a control.</p> <p>Methods</p> <p>Both the patient who was diagnosed with JDM as well as her healthy twin underwent a 16-week exercise training program comprising aerobic and strengthening exercises. We assessed one repetition-maximum (1-RM) leg-press and bench-press strength, balance, mobility and muscle function, blood markers of inflammation and muscle enzymes, aerobic conditioning, and disease activity scores. As a result, the healthy child had an overall greater absolute strength, muscle function and aerobic conditioning compared to her JDM twin pair at baseline and after the trial. However, the twins presented comparable relative improvements in 1-RM bench press, 1-RM leg press, VO_2peak, and time-to-exhaustion. The healthy child had greater relative increments in low-back strength and handgrip, whereas the child with JDM presented a higher relative increase in ventilatory anaerobic threshold parameters and functional tests. Quality of life, inflammation, muscle damage and disease activity scores remained unchanged.</p> <p>Results and Conclusion</p> <p>this was the first report to describe the training response of a patient with non-active JDM following an exercise training regimen. The child with JDM exhibited improved strength, muscle function and aerobic conditioning without presenting an exacerbation of the disease.</p

A feasibility study for NOn-Traditional providers to support the management of Elderly People with Anxiety and Depression: the NOTEPAD study Protocol

BACKGROUND: Anxiety and depression are common among older people, with up to 20% reporting such symptoms, and the prevalence increases with co-morbid chronic physical health problems. Access to treatment for anxiety and depression in this population is poor due to a combination of factors at the level of patient, practitioner and healthcare system. There is evidence to suggest that older people with anxiety and/or depression may benefit both from one-to-one interventions and group social or educational activities, which reduce loneliness, are participatory and offer some activity. Non-traditional providers (support workers) working within third-sector (voluntary) organisations are a valuable source of expertise within the community but are under-utilised by primary care practitioners. Such a resource could increase access to care, and be less stigmatising and more acceptable for older people. METHODS: The study is in three phases and this paper describes the protocol for phase III, which will evaluate the feasibility of recruiting general practices and patients into the study, and determine whether support workers can deliver the intervention to older people with sufficient fidelity and whether this approach is acceptable to patients, general practitioners and the third-sector providers. Phase III of the NOTEPAD study is a randomised controlled trial (RCT) that is individually randomised. It recruited participants from approximately six general practices in the UK. In total, 100 participants aged 65 years and over who score 10 or more on PHQ9 or GAD7 for anxiety or depression will be recruited and randomised to the intervention or usual general practice care. A mixed methods approach will be used and follow-up will be conducted 12 weeks post-randomisation. DISCUSSION: This study will inform the design and methods of a future full-scale RCT. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN16318986 . Registered 10 November 2016. The ISRCTN registration is in line with the World Health Organization Trial Registration Data Set. The present paper represents the original version of the protocol. Any changes to the protocol will be communicated to ISRCTN

Predictors of physical activity and barriers to exercise in nursing and medical students

Aims To investigate physical activity levels of nursing and medicine students; examine predictors of physical activity level; and examine the most influential benefits and barriers to exercise. Background Healthcare professionals have low levels of physical activity, which increases their health risk and may influence their health promotion practices with patients. Design We surveyed 361 nursing (n=193) and medicine (n=168) students studying at a UK medical school. Methods Questionnaire survey, active over 12 months in 2014-2015. Measures included physical activity level, benefits and barriers to exercise, social support, perceived stress and self-efficacy for exercise. Results Many nursing and medicine students did not achieve recommended levels of physical activity (nursing: 48%; medicine: 38%). Perceived benefits of exercise were health-related, with medicine students identifying additional benefits for stress-relief. Most notable barriers to exercise were: lack of time, facilities having inconvenient schedules and exercise not fitting around study or placement schedules. Nursing students were less active than medicine students; they perceived fewer benefits and more barriers to exercise and reported lower social support for exercise. Physical activity of nursing and medicine students was best predicted by self-efficacy and social support, explaining 35% of the variance. Conclusion Physical activity should be promoted in nursing and medicine students. Interventions should aim to build self-efficacy for exercise and increase social support. Interventions should be developed that are targeted specifically to shift-working frontline care staff, to reduce schedule-related barriers to exercise and increase accessibility to workplace health and wellbeing initiatives

New therapeutic targets in Alzheimer's disease: brain deregulation of calcium and zinc

The molecular determinants of Alzheimer's (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca2+) and zinc (Zn2+). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-β dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca2+ and Zn2+ dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca2+ and Zn2+ rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca2+ and Zn2+ dyshomeostasis may offer a great opportunity for disease-modifying strategies

Optimality of Human Contour Integration

For processing and segmenting visual scenes, the brain is required to combine a multitude of features and sensory channels. It is neither known if these complex tasks involve optimal integration of information, nor according to which objectives computations might be performed. Here, we investigate if optimal inference can explain contour integration in human subjects. We performed experiments where observers detected contours of curvilinearly aligned edge configurations embedded into randomly oriented distractors. The key feature of our framework is to use a generative process for creating the contours, for which it is possible to derive a class of ideal detection models. This allowed us to compare human detection for contours with different statistical properties to the corresponding ideal detection models for the same stimuli. We then subjected the detection models to realistic constraints and required them to reproduce human decisions for every stimulus as well as possible. By independently varying the four model parameters, we identify a single detection model which quantitatively captures all correlations of human decision behaviour for more than 2000 stimuli from 42 contour ensembles with greatly varying statistical properties. This model reveals specific interactions between edges closely matching independent findings from physiology and psychophysics. These interactions imply a statistics of contours for which edge stimuli are indeed optimally integrated by the visual system, with the objective of inferring the presence of contours in cluttered scenes. The recurrent algorithm of our model makes testable predictions about the temporal dynamics of neuronal populations engaged in contour integration, and it suggests a strong directionality of the underlying functional anatomy