A Mild Impairment of Mitochondrial Electron Transport Has Sex-Specific Effects on Lifespan and Aging in Mice

Impairments of various aspects of mitochondrial function have been associated with increased lifespan in various model organisms ranging from Caenorhabditis elegans to mice. For example, disruption of the function of the ‘Rieske’ iron-sulfur protein (RISP) of complex III of the mitochondrial electron transport chain can result in increased lifespan in the nematode worm C. elegans. However, the mechanisms by which impaired mitochondrial function affects aging remain under investigation, including whether or not they require decreased electron transport. We have generated knock-in mice with a loss-of-function Risp mutation that is homozygous lethal. However, heterozygotes (Risp+/P224S) were viable and had decreased levels of RISP protein and complex III enzymatic activity. This decrease was sufficient to impair mitochondrial respiration and to decrease overall metabolic rate in males, but not females. These defects did not appear to exert an overtly deleterious effect on the health of the mutants, since young Risp+/P224S mice are outwardly normal, with unaffected performance and fertility. Furthermore, biomarkers of oxidative stress were unaffected in both young and aged animals. Despite this, the average lifespan of male Risp+/P224S mice was shortened and aged Risp+/P224S males showed signs of more rapidly deteriorating health. In spite of these differences, analysis of Gompertz mortality parameters showed that Risp heterozygosity decreased the rate of increase of mortality with age and increased the intrinsic vulnerability to death in both sexes. However, the intrinsic vulnerability was increased more dramatically in males, which resulted in their shortened lifespan. For females, the slower acceleration of age-dependent mortality results in significantly increased survival of Risp+/P224S mice in the second half of lifespan. These results demonstrate that even relatively small perturbations of the mitochondrial electron transport chain can have significant physiological effects in mammals, and that the severity of those effects can be sex-dependent

Mclk1+/- mice are not resistant to the development of atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Mice with a single copy of <it>Mclk1 </it>(a.k.a. <it>Coq7</it>), a gene that encodes a mitochondrial enzyme required for the biosynthesis of ubiquinone and other functions, live longer than wild-type mice. The prolonged survival implies a decreased mortality from age-dependent lethal pathologies. Atherosclerosis is one of the main age-dependent pathologies in humans and can be modeled in mice that lack Apolipoprotein E (<it>ApoE</it>^-/-) or mice that lack the Low Density Lipoprotein Receptor (<it>LDLr</it>^-/-) in addition to being fed an atherosclerosis-inducing diet. We sought to determine if <it>Mclk1 </it>heterozygosity protects against atherosclerosis and dyslipidemia in these models.</p> <p>Results</p> <p>We found that <it>Mclk1 </it>heterozygosity did not protect against dyslipidemia, oxidative stress, or atherosclerosis in young (6 or 10 months) or older (18 months) mice. Furthermore, the absence of <it>ApoE </it>suppressed the lifespan-promoting effects of <it>Mclk1 </it>heterozygosity.</p> <p>Conclusion</p> <p>These findings indicate that although <it>Mclk1 </it>heterozygosity can extend lifespan of mice, it does not necessarily protect against atherosclerosis. Moreover, in the presence of hyperlipidemia and chronic inflammation, <it>Mclk1 </it>heterozygosity is incapable of extending lifespan.</p

Primary care consultations and costs among HIV-positive individulas in UK primary care 1995-2005: a cohort study

Objectives: To investigate the role of primary care in the management of HIV and estimate primary care-associated costs at a time of rising prevalence. Methods: Retrospective cohort study between 1995 and 2005, using data from general practices contributing data to the UK General Practice Research Database. Patterns of consultation and morbidity and associated consultation costs were analysed among all practice-registered patients for whom HIV-positive status was recorded in the general practice record. Results: 348 practices yielded 5504 person-years (py) of follow-up for known HIV-positive patients, who consult in general practice frequently (4.2 consultations/py by men, 5.2 consultations/py by women, in 2005) for a range of conditions. Consultation rates declined in the late 1990s from 5.0 and 7.3 consultations/py in 1995 in men and women, respectively, converging to rates similar to the wider population. Costs of consultation (general practitioner and nurse, combined) reflect these changes, at £100.27 for male patients and £117.08 for female patients in 2005. Approximately one in six medications prescribed in primary care for HIV-positive individuals has the potential for major interaction with antiretroviral medications. Conclusion: HIV-positive individuals known in general practice now consult on a similar scale to the wider population. Further research should be undertaken to explore how primary care can best contribute to improving the health outcomes of this group with chronic illness. Their substantial use of primary care suggests there may be potential to develop effective integrated care pathways

UniFHy v0.1.1: a community modelling framework for the terrestrial water cycle in Python

The land surface, hydrological, and groundwater modelling communities all have expertise in simulating the hydrological processes at play in the terrestrial component of the Earth system. However, these communities, and the wider Earth system modelling community, have largely remained distinct with limited collaboration between disciplines, hindering progress in the representation of hydrological processes in the land component of Earth system models (ESMs). In order to address key societal questions regarding the future availability of water resources and the intensity of extreme events such as floods and droughts in a changing climate, these communities must come together and build on the strengths of one another to produce next-generation land system models that are able to adequately simulate the terrestrial water cycle under change. The development of a common modelling infrastructure can contribute to stimulating cross-fertilisation by structuring and standardising the interactions. This paper presents such an infrastructure, a land system framework, which targets an intermediate level of complexity and constrains interfaces between components (and communities) and, in doing so, aims to facilitate an easier pipeline between the development of (sub-)community models and their integration, both for standalone use and for use in ESMs. This paper first outlines the conceptual design and technical capabilities of the framework; thereafter, its usage and useful characteristics are demonstrated through case studies. The main innovations presented here are (1) the interfacing constraints themselves; (2) the implementation in Python (the Unified Framework for Hydrology, unifhy); and (3) the demonstration of standalone use cases using the framework. The existing framework does not yet meet all our goals, in particular, of directly supporting integration into larger ESMs, so we conclude with the remaining limitations of the current framework and necessary future developments.</p

Patient-level predictors of detection of depressive symptoms, referral, and uptake of depression counseling among chronic care patients in KwaZulu-Natal, South Africa

Background: Integration of depression treatment into primary care could improve patient outcomes in low-resource settings. Losses along the depression care cascade limit integrated service effectiveness. This study identified patient-level factors that predicted detection of depressive symptoms by nurses, referral for depression treatment, and uptake of counseling, as part of integrated care in KwaZulu-Natal, South Africa. Methods: This was an analysis of baseline data from a prospective cohort. Participants were adult patients with at least moderate depressive symptoms at primary care facilities in Amajuba, KwaZulu-Natal, South Africa. Participants were screened for depressive symptoms prior to routine assessment by a nurse. Generalized linear mixed-effects models were used to estimate associations between patient characteristics and service delivery outcomes. Results: Data from 412 participants were analyzed. Nurses successfully detected depressive symptoms in 208 [50.5%, 95% confidence interval (CI) 38.9-62.0] participants; of these, they referred 76 (36.5%, 95% CI 20.3-56.5) for depression treatment; of these, 18 (23.7%, 95% CI 10.7-44.6) attended at least one session of depression counseling. Depressive symptom severity, alcohol use severity, and perceived stress were associated with detection. Similar factors did not drive referral or counseling uptake. Conclusions: Nurses detected patients with depressive symptoms at rates comparable to primary care providers in high-resource settings, though gaps in referral and uptake persist. Nurses were more likely to detect symptoms among patients in more severe mental distress. Implementation strategies for integrated mental health care in low-resource settings should target improved rates of detection, referral, and uptake

The cellular and synaptic architecture of the mechanosensory dorsal horn

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception

Deconvolution of Images from BLAST 2005: Insight into the K3-50 and IC 5146 Star-Forming Regions

We present an implementation of the iterative flux-conserving Lucy-Richardson (L-R) deconvolution method of image restoration for maps produced by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). We have analyzed its performance and convergence extensively through simulations and cross-correlations of the deconvolved images with available highresolution maps. We present new science results from two BLAST surveys, in the Galactic regions K3-50 and IC 5146, further demonstrating the benefits of performing this deconvolution. We have resolved three clumps within a radius of 4.'5 inside the star-forming molecular cloud containing K3-50. Combining the well-resolved dust emission map with available multi-wavelength data, we have constrained the Spectral Energy Distributions (SEDs) of five clumps to obtain masses (M), bolometric luminosities (L), and dust temperatures (T). The L-M diagram has been used as a diagnostic tool to estimate the evolutionary stages of the clumps. There are close relationships between dust continuum emission and both 21-cm radio continuum and 12CO molecular line emission. The restored extended large scale structures in the Northern Streamer of IC 5146 have a strong spatial correlation with both SCUBA and high resolution extinction images. A dust temperature of 12 K has been obtained for the central filament. We report physical properties of ten compact sources, including six associated protostars, by fitting SEDs to multi-wavelength data. All of these compact sources are still quite cold (typical temperature below ~ 16 K) and are above the critical Bonner-Ebert mass. They have associated low-power Young Stellar Objects (YSOs). Further evidence for starless clumps has also been found in the IC 5146 region.Comment: 13 pages, 12 Figures, 3 Table

Manipulating ultracold atoms with a reconfigurable nanomagnetic system of domain walls

The divide between the realms of atomic-scale quantum particles and lithographically-defined nanostructures is rapidly being bridged. Hybrid quantum systems comprising ultracold gas-phase atoms and substrate-bound devices already offer exciting prospects for quantum sensors, quantum information and quantum control. Ideally, such devices should be scalable, versatile and support quantum interactions with long coherence times. Fulfilling these criteria is extremely challenging as it demands a stable and tractable interface between two disparate regimes. Here we demonstrate an architecture for atomic control based on domain walls (DWs) in planar magnetic nanowires that provides a tunable atomic interaction, manifested experimentally as the reflection of ultracold atoms from a nanowire array. We exploit the magnetic reconfigurability of the nanowires to quickly and remotely tune the interaction with high reliability. This proof-of-principle study shows the practicability of more elaborate atom chips based on magnetic nanowires being used to perform atom optics on the nanometre scale.Comment: 4 pages, 4 figure

Pedestrian, Crowd, and Evacuation Dynamics

This contribution describes efforts to model the behavior of individual pedestrians and their interactions in crowds, which generate certain kinds of self-organized patterns of motion. Moreover, this article focusses on the dynamics of crowds in panic or evacuation situations, methods to optimize building designs for egress, and factors potentially causing the breakdown of orderly motion.Comment: This is a review paper. For related work see http://www.soms.ethz.c