Altered Oxygen Utilisation in Rat Left Ventricle and Soleus after 14 Days, but Not 2 Days, of Environmental Hypoxia.

The effects of environmental hypoxia on cardiac and skeletal muscle metabolism are dependent on the duration and severity of hypoxic exposure, though factors which dictate the nature of the metabolic response to hypoxia are poorly understood. We therefore set out to investigate the time-dependence of metabolic acclimatisation to hypoxia in rat cardiac and skeletal muscle. Rats were housed under normoxic conditions, or exposed to short-term (2 d) or sustained (14 d) hypoxia (10% O2), after which samples were obtained from the left ventricle of the heart and the soleus for assessment of metabolic regulation and mitochondrial function. Mass-corrected maximal oxidative phosphorylation was 20% lower in the left ventricle following sustained but not short-term hypoxia, though no change was observed in the soleus. After sustained hypoxia, the ratio of octanoyl carnitine- to pyruvate- supported respiration was 11% and 12% lower in the left ventricle and soleus, respectively, whilst hexokinase activity increased by 33% and 2.1-fold in these tissues. mRNA levels of PPARα targets fell after sustained hypoxia in both tissues, but those of PPARα remained unchanged. Despite decreased Ucp3 expression after short-term hypoxia, UCP3 protein levels and mitochondrial coupling remained unchanged. Protein carbonylation was 40% higher after short-term but not sustained hypoxic exposure in the left ventricle, but was unchanged in the soleus at both timepoints. Our findings therefore demonstrate that 14 days, but not 2 days, of hypoxia induces a loss of oxidative capacity in the left ventricle but not the soleus, and a substrate switch away from fatty acid oxidation in both tissues.JAH received a PhD Studentship from the Biotechnology and Biological Sciences Research Council (Grant number: BB/F016581/1, www.bbsrc.ac.uk (http://www.bbsrc.ac.uk/). SLB received no specific funding for this work. HY received a Departmental Summer Studentship Bursary from Imperial College, London (www.imperial.ac.uk (http://www.imperial.ac.uk/)). AJM received an academic fellowship from the Research Councils UK (www.rcuk.ac.uk (http://www.rcuk.ac.uk/)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.013856

Live Fast, Die Young: GMC lifetimes in the FIRE cosmological simulations of Milky Way-mass galaxies

We present the first measurement of the lifetimes of giant molecular clouds (GMCs) in cosmological simulations at z = 0, using the Latte suite of FIRE-2 simulations of Milky Way (MW) mass galaxies. We track GMCs with total gas mass ≳10⁵ M⊙ at high spatial (∼1 pc), mass (7100 M⊙), and temporal (1 Myr) resolution. Our simulated GMCs are consistent with the distribution of masses for massive GMCs in the MW and nearby galaxies. We find GMC lifetimes of 5–7 Myr, or 1–2 freefall times, on average, with less than 2 per cent of clouds living longer than 20 Myr. We find decreasing GMC lifetimes with increasing virial parameter, and weakly increasing GMC lifetimes with galactocentric radius, implying that environment affects the evolutionary cycle of GMCs. However, our GMC lifetimes show no systematic dependence on GMC mass or amount of star formation. These results are broadly consistent with inferences from the literature and provide an initial investigation into ultimately understanding the physical processes that govern GMC lifetimes in a cosmological setting

The potential to improve ascertainment and intervention to reduce smoking in Primary Care: a cross sectional survey

<p>Abstract</p> <p>Background</p> <p>Well established clinical guidelines recommend that systematic ascertainment of smoking status and intervention to promote cessation in all smokers should be a fundamental component of all health care provision. This study aims to establish the completeness and accuracy of smoking status recording in patients' primary care medical records and the level of interest in receiving smoking cessation support amongst primary care patients in an inner city UK population.</p> <p>Methods</p> <p>Postal questionnaires were sent to all patients aged over 18 from 24 general practices in Nottingham UK who were registered as smokers or had no smoking status recorded in their medical notes.</p> <p>Results</p> <p>The proportion of patients with a smoking status recorded varied between practices from 42.4% to 100% (median 90%). Of the recorded smokers who responded to our questionnaire (35.5% of the total), a median of 20.3% reported that they had not smoked cigarettes or tobacco in the last 12 months. Of respondents with no recorded smoking status, 29.8% reported themselves to be current smokers. Of the 6856 responding individuals thus identified as current smokers, 41.4% indicated that they would like to speak to a specialist smoking adviser to help them stop smoking. This proportion increased with socioeconomic disadvantage (measured by the Townsend Index) from 39.1% in the least deprived to 44.6% in the most deprived quintile.</p> <p>Conclusion</p> <p>Whilst in many practices the ascertainment of smoking status is incomplete and/or inaccurate, failure to intervene appropriately on known status still remains the biggest challenge.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN71514078.</p

Structure-based inhibitors of amyloid beta core suggest a common interface with tau.

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline

Psychotropic Drug Initiation or Increased Dosage and the Acute Risk of Falls: A Prospective Cohort Study of Nursing Home Residents

Background: Previous studies suggest that psychotropic drug changes may signal an acute period of time whereby a person is highly vulnerable to fall. It is unknown whether certain classes of psychotropic agents are less safe with respect to the acute risk of falls. Our purpose was to compare fall rates in the 7 days following a change of an antidepressant, antipsychotic, or benzodiazepine. We also identified specific times when residents are at high risk for falls with respect to a psychotropic drug change. Methods: Residents in our one-year study included 851 long term care residents from two nursing home facilities in Boston, MA, U.S.A. (May 2010 - May 2011). Drug changes (i.e., new prescriptions or increased dose of a previously used drug) were ascertained using the computerized provider order entry system, whereas falls were ascertained by incident reports. Negative binomial regression was used to compare the rate of falls following a drug change between medication classes. Further, we calculated the rate of falls for each of the 7 days before and 7 days after a psychotropic drug change. Results: Forty-eight percent of residents were prescribed a new prescription or increased dose of a psychotropic drug during the study. The rate of falls was similar in the 7 days following a change to a SSRI versus non-SSRI antidepressant (11.9 versus 14.4 falls/1,000 person years; p = 0.58), a typical versus an atypical antipsychotic (25.4 versus 17.1 falls/1,000 person years; p = 0.10), or a short versus long acting benzodiazepine (15.2 versus 13.9 falls/1,000 person years; p = 0.23). Fall risk was highest on day 4 before the drug change (19.0 falls/1,000 person days), on the day of the drug change through 2 days after the drug change (17.6-20.3 falls/1,000 person days), and 5-6 days after the drug change (17.6-19.0 falls/1,000 person days). Conclusions: In the nursing home, risk of falls was similar following a psychotropic drug change of any class. We observed higher fall risk in the days before, but mostly after the drug change. We recommend that nursing home residents be closely monitored following a psychotropic drug change in an effort to reduce falls

Calculus-enhanced energy-first curriculum for introductory physics improves student performance locally and in downstream courses

Here we demonstrate the benefits of a new curriculum for introductory calculus-based physics that motivates classical mechanics using a modified version of Hamiltonian mechanics. This curriculum shifts the initial focus of instruction away from forces and the associated vector mathematics, which are known to be problematic for students, to the scalar quantity energy, which is more closely aligned with their previously established intuition, and associated differential and integral calculus. We show that implementation of this calculus-enhanced “energy-first” curriculum resulted in higher normalized gains on the Force Concept Inventory exam for all students and improved performance in downstream engineering courses for students with lower ACT math scores. In other words, the downstream benefits were largest for students with lower math abilities who also pose a larger retention risk. This new curriculum thus has the potential to improve student retention by specifically helping the students who need help the most, including traditionally underserved populations who often have weaker mathematics preparation. We propose future work to investigate whether this new curriculum has lowered the math transference barrier to learning in introductory physics, resulting concomitantly in improvements in student learning of classical mechanics and in student fluency with applied mathematics.Northrop Grumman Foundatio

Antisense reductions in the PsbO protein of photosystem II leads to decreased quantum yield but similar maximal photosynthetic rates

Photosystem (PS) II is the multisubunit complex which uses light energy to split water, providing the reducing equivalents needed for photosynthesis. The complex is susceptible to damage from environmental stresses such as excess excitation energy and high temperature. This research investigated the in vivo photosynthetic consequences of impairments to PSII in Arabidopsis thaliana (ecotype Columbia) expressing an antisense construct to the PsbO proteins of PSII. Transgenic lines were obtained with between 25 and 60% of wild-type (WT) total PsbO protein content, with the PsbO1 isoform being more strongly reduced than PsbO2. These changes coincided with a decrease in functional PSII content. Low PsbO (less than 50% WT) plants grew more slowly and had lower chlorophyll content per leaf area. There was no change in content per unit area of cytochrome b6f, ATP synthase, or Rubisco, whereas PSI decreased in proportion to the reduction in chlorophyll content. The irradiance response of photosynthetic oxygen evolution showed that low PsbO plants had a reduced quantum yield, but matched the oxygen evolution rates of WT plants at saturating irradiance. It is suggested that these plants had a smaller pool of PSII centres, which are inefficiently connected to antenna pigments resulting in reduced photochemical efficiency.This work was supported by an Australian Postgraduate Award to SAD, the Australian Research Council Centre of Excellence in Plant Energy Biology (MRB), and grants from the Australian Research Council (WSC)

Diagramming social practice theory:An interdisciplinary experiment exploring practices as networks

Achieving a transition to a low-carbon energy system is now widely recognised as a key challenge facing humanity. To date, the vast majority of research addressing this challenge has been conducted within the disciplines of science, engineering and economics utilising quantitative and modelling techniques. However, there is growing awareness that meeting energy challenges requires fundamentally socio-technical solutions and that the social sciences have an important role to play. This is an interdisciplinary challenge but, to date, there remain very few explorations of, or reflections on, interdisciplinary energy research in practice. This paper seeks to change that by reporting on an interdisciplinary experiment to build new models of energy demand on the basis of cutting-edge social science understandings. The process encouraged the social scientists to communicate their ideas more simply, whilst allowing engineers to think critically about the embedded assumptions in their models in relation to society and social change. To do this, the paper uses a particular set of theoretical approaches to energy use behaviour known collectively as social practice theory (SPT) - and explores the potential of more quantitative forms of network analysis to provide a formal framework by means of which to diagram and visualize practices. The aim of this is to gain insight into the relationships between the elements of a practice, so increasing the ultimate understanding of how practices operate. Graphs of practice networks are populated based on new empirical data drawn from a survey of different types (or variants) of laundry practice. The resulting practice networks are analysed to reveal characteristics of elements and variants of practice, such as which elements could be considered core to the practice, or how elements between variants overlap, or can be shared. This promises insights into energy intensity, flexibility and the rootedness of practices (i.e. how entrenched/ established they are) and so opens up new questions and possibilities for intervention. The novelty of this approach is that it allows practice data to be represented graphically using a quantitative format without being overly reductive. Its usefulness is that it is readily applied to large datasets, provides the capacity to interpret social practices in new ways, and serves to open up potential links with energy modeling. More broadly, a significant dimension of novelty has been the interdisciplinary approach, radically different to that normally seen in energy research. This paper is relevant to a broad audience of social scientists and engineers interested in integrating social practices with energy engineering