A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade

Quantum Computing

Quantum mechanics---the theory describing the fundamental workings of nature---is famously counterintuitive: it predicts that a particle can be in two places at the same time, and that two remote particles can be inextricably and instantaneously linked. These predictions have been the topic of intense metaphysical debate ever since the theory's inception early last century. However, supreme predictive power combined with direct experimental observation of some of these unusual phenomena leave little doubt as to its fundamental correctness. In fact, without quantum mechanics we could not explain the workings of a laser, nor indeed how a fridge magnet operates. Over the last several decades quantum information science has emerged to seek answers to the question: can we gain some advantage by storing, transmitting and processing information encoded in systems that exhibit these unique quantum properties? Today it is understood that the answer is yes. Many research groups around the world are working towards one of the most ambitious goals humankind has ever embarked upon: a quantum computer that promises to exponentially improve computational power for particular tasks. A number of physical systems, spanning much of modern physics, are being developed for this task---ranging from single particles of light to superconducting circuits---and it is not yet clear which, if any, will ultimately prove successful. Here we describe the latest developments for each of the leading approaches and explain what the major challenges are for the future.Comment: 26 pages, 7 figures, 291 references. Early draft of Nature 464, 45-53 (4 March 2010). Published version is more up-to-date and has several corrections, but is half the length with far fewer reference

Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

The Effects of Dietary Carotenoid Supplementation and Retinal Carotenoid Accumulation on Vision-Mediated Foraging in the House Finch

BACKGROUND: For many bird species, vision is the primary sensory modality used to locate and assess food items. The health and spectral sensitivities of the avian visual system are influenced by diet-derived carotenoid pigments that accumulate in the retina. Among wild House Finches (Carpodacus mexicanus), we have found that retinal carotenoid accumulation varies significantly among individuals and is related to dietary carotenoid intake. If diet-induced changes in retinal carotenoid accumulation alter spectral sensitivity, then they have the potential to affect visually mediated foraging performance. METHODOLOGY/PRINCIPAL FINDINGS: In two experiments, we measured foraging performance of house finches with dietarily manipulated retinal carotenoid levels. We tested each bird's ability to extract visually contrasting food items from a matrix of inedible distracters under high-contrast (full) and dimmer low-contrast (red-filtered) lighting conditions. In experiment one, zeaxanthin-supplemented birds had significantly increased retinal carotenoid levels, but declined in foraging performance in the high-contrast condition relative to astaxanthin-supplemented birds that showed no change in retinal carotenoid accumulation. In experiments one and two combined, we found that retinal carotenoid concentrations predicted relative foraging performance in the low- vs. high-contrast light conditions in a curvilinear pattern. Performance was positively correlated with retinal carotenoid accumulation among birds with low to medium levels of accumulation (∼0.5-1.5 µg/retina), but declined among birds with very high levels (>2.0 µg/retina). CONCLUSION/SIGNIFICANCE: Our results suggest that carotenoid-mediated spectral filtering enhances color discrimination, but that this improvement is traded off against a reduction in sensitivity that can compromise visual discrimination. Thus, retinal carotenoid levels may be optimized to meet the visual demands of specific behavioral tasks and light environments

Potential efficacy of mitochondrial genes for animal DNA barcoding: a case study using eutherian mammals

<p>Abstract</p> <p>Background</p> <p>A well-informed choice of genetic locus is central to the efficacy of DNA barcoding. Current DNA barcoding in animals involves the use of the 5' half of the mitochondrial cytochrome oxidase 1 gene (<it>CO1</it>) to diagnose and delimit species. However, there is no compelling <it>a priori </it>reason for the exclusive focus on this region, and it has been shown that it performs poorly for certain animal groups. To explore alternative mitochondrial barcoding regions, we compared the efficacy of the universal <it>CO1 </it>barcoding region with the other mitochondrial protein-coding genes in eutherian mammals. Four criteria were used for this comparison: the number of recovered species, sequence variability within and between species, resolution to taxonomic levels above that of species, and the degree of mutational saturation.</p> <p>Results</p> <p>Based on 1,179 mitochondrial genomes of eutherians, we found that the universal <it>CO1 </it>barcoding region is a good representative of mitochondrial genes as a whole because the high species-recovery rate (> 90%) was similar to that of other mitochondrial genes, and there were no significant differences in intra- or interspecific variability among genes. However, an overlap between intra- and interspecific variability was still problematic for all mitochondrial genes. Our results also demonstrated that any choice of mitochondrial gene for DNA barcoding failed to offer significant resolution at higher taxonomic levels.</p> <p>Conclusions</p> <p>We suggest that the <it>CO1 </it>barcoding region, the universal DNA barcode, is preferred among the mitochondrial protein-coding genes as a molecular diagnostic at least for eutherian species identification. Nevertheless, DNA barcoding with this marker may still be problematic for certain eutherian taxa and our approach can be used to test potential barcoding loci for such groups.</p

Understanding why adult participants at the World Senior Games choose a healthy diet

BACKGROUND: Identifying those seniors most likely to adopt a healthy diet, the relative importance they place on certain perceived benefits associated with a healthy diet, and whether these perceived benefits are associated with selected demographic, lifestyle, and health history variables is important for directing effective dietary health promotion programs. METHODS: Analyses are based on a cross-sectional convenience sample of 670 seniors aged 50 years and older at the 2002 World Senior Games in St. George, Utah. Data are assessed using frequencies, bivariate analysis, analysis of variance, and multiple logistic regression analysis. RESULTS: Fruit and vegetable consumption was significantly higher in individuals aged 70–79, in women, in those not overweight or obese, and in those with excellent overall health. Dietary fiber consumption was significantly higher in former or never smokers, current and previous alcohol drinkers, in those not overweight or obese, and in those with excellent health. The strongest motivating factors identified for adopting a healthy diet were to improve the quality of life, to increase longevity, and to prevent disease. Of intermediate importance were the need to feel a sense of control and to satisfy likes or dislikes. Least important were the desire to experience a higher level of spirituality, social reasons, and peer acceptance. CONCLUSION: Seniors who have adopted a healthy diet are more likely to have chosen that behavior because of perceived health benefits than for personal and social benefits. Overweight or obese individuals and those in poor health were less likely to be engaged in healthy eating behavior and require special attention by dieticians and public health professionals

Multiple Chronic Conditions: Prevalence, Health Consequences, and Implications for Quality, Care Management, and Costs

Persons with multiple chronic conditions are a large and growing segment of the US population. However, little is known about how chronic conditions cluster, and the ramifications of having specific combinations of chronic conditions. Clinical guidelines and disease management programs focus on single conditions, and clinical research often excludes persons with multiple chronic conditions. Understanding how conditions in combination impact the burden of disease and the costs and quality of care received is critical to improving care for the 1 in 5 Americans with multiple chronic conditions. This Medline review of publications examining somatic chronic conditions co-occurring with 1 or more additional specific chronic illness between January 2000 and March 2007 summarizes the state of our understanding of the prevalence and health challenges of multiple chronic conditions and the implications for quality, care management, and costs

A Three-Stage Colonization Model for the Peopling of the Americas

Background: We evaluate the process by which the Americas were originally colonized and propose a three-stage model that integrates current genetic, archaeological, geological, and paleoecological data. Specifically, we analyze mitochondrial and nuclear genetic data by using complementary coalescent models of demographic history and incorporating nongenetic data to enhance the anthropological relevance of the analysis. Methodology/Findings: Bayesian skyline plots, which provide dynamic representations of population size changes over time, indicate that Amerinds went through two stages of growth &lt;40,000 and &lt;15,000 years ago separated by a long period of population stability. Isolation-with-migration coalescent analyses, which utilize data from sister populations to estimate a divergence date and founder population sizes, suggest an Amerind population expansion starting &lt;15,000 years ago. Conclusions/Significance: These results support a model for the peopling of the New World in which Amerind ancestors diverged from the Asian gene pool prior to 40,000 years ago and experienced a gradual population expansion as they moved into Beringia. After a long period of little change in population size in greater Beringia, Amerinds rapidly expanded into the Americas &lt;15,000 years ago either through an interior ice-free corridor or along the coast. This rapid colonization of the New World was achieved by a founder group with an effective population size of &lt;1,000–5,400 individuals. Our model presents a detailed scenario for the timing and scale of the initial migration to the Americas, substantially refines th