The serine protease domain of MASP-3: enzymatic properties and crystal structure in complex with ecotin.

International audienceMannan-binding lectin (MBL), ficolins and collectin-11 are known to associate with three homologous modular proteases, the MBL-Associated Serine Proteases (MASPs). The crystal structures of the catalytic domains of MASP-1 and MASP-2 have been solved, but the structure of the corresponding domain of MASP-3 remains unknown. A link between mutations in the MASP1/3 gene and the rare autosomal recessive 3MC (Mingarelli, Malpuech, Michels and Carnevale,) syndrome, characterized by various developmental disorders, was discovered recently, revealing an unexpected important role of MASP-3 in early developmental processes. To gain a first insight into the enzymatic and structural properties of MASP-3, a recombinant form of its serine protease (SP) domain was produced and characterized. The amidolytic activity of this domain on fluorescent peptidyl-aminomethylcoumarin substrates was shown to be considerably lower than that of other members of the C1r/C1s/MASP family. The E. coli protease inhibitor ecotin bound to the SP domains of MASP-3 and MASP-2, whereas no significant interaction was detected with MASP-1, C1r and C1s. A tetrameric complex comprising an ecotin dimer and two MASP-3 SP domains was isolated and its crystal structure was solved and refined to 3.2 Å. Analysis of the ecotin/MASP-3 interfaces allows a better understanding of the differential reactivity of the C1r/C1s/MASP protease family members towards ecotin, and comparison of the MASP-3 SP domain structure with those of other trypsin-like proteases yields novel hypotheses accounting for its zymogen-like properties in vitro

Patient-reported outcome measures of the impact of cancer on patient’s everyday lives: a systematic review

Purpose: Patients with advanced disease are living longer and commonly used patient-reported outcome measures (PROMs) may miss relevant elements of the quality of extended survival. This systematic review examines the measures used to capture aspects of the quality of survival including impact on patients’ everyday lives such as finances, work and family roles. Methods: Searches were conducted in MEDLINE, EMBASE, CINAHL and PsycINFO restricted to English language articles. Information on study characteristics, instruments and outcomes was systematically extracted and synthesised. A predefined set of criteria was used to rate the quality of studies. Results: From 2761 potentially relevant articles, 22 met all inclusion criteria, including 10 concerning financial distress, 3 on roles and responsibilities and 9 on multiple aspects of social well-being. Generally, studies were not of high quality; many lacked bias free participant selection, had confounding factors and had not accounted for all participants. High levels of financial distress were reported and were associated with multiple demographic factors such as age and income. There were few reports concerned with impacts on patients’ roles/responsibilities in everyday life although practical and emotional struggles with parenting were identified. Social difficulties were common and associated with multiple factors including being a caregiver. Many studies were single time-point surveys and used non-validated measures. Exceptions were employment of the COST and Social Difficulties Inventory (SDI), validated measures of financial and social distress respectively. Conclusions: Impact on some important parts of patients’ everyday lives is insufficiently and inconsistently captured. Further PROM development focussing on roles and responsibilities, including work and caring for dependents, is warranted. Implications for Cancer Survivors: Factors such as finances, employment and responsibility for caring for dependents (e.g. children and elderly relatives) can affect the well-being of cancer survivors. There is a need to ensure that any instruments used to assess patients’ social well-being are broad enough to include these areas so that any difficulties arising can be better understood and appropriately supported

Nothing Lasts Forever: Environmental Discourses on the Collapse of Past Societies

The study of the collapse of past societies raises many questions for the theory and practice of archaeology. Interest in collapse extends as well into the natural sciences and environmental and sustainability policy. Despite a range of approaches to collapse, the predominant paradigm is environmental collapse, which I argue obscures recognition of the dynamic role of social processes that lie at the heart of human communities. These environmental discourses, together with confusion over terminology and the concepts of collapse, have created widespread aporia about collapse and resulted in the creation of mixed messages about complex historical and social processes

Management Impacts on Forest Floor and Soil Organic Carbon in Northern Temperate Forests of the US

<p>Abstract</p> <p>Background</p> <p>The role of forests in the global carbon cycle has been the subject of a great deal of research recently, but the impact of management practices on forest soil dynamics at the stand level has received less attention. This study used six forest management experimental sites in five northern states of the US to investigate the effects of silvicultural treatments (light thinning, heavy thinning, and clearcutting) on forest floor and soil carbon pools.</p> <p>Results</p> <p>No overall trend was found between forest floor carbon stocks in stands subjected to partial or complete harvest treatments. A few sites had larger stocks in control plots, although estimates were often highly variable. Forest floor carbon pools did show a trend of increasing values from southern to northern sites. Surface soil (0-5 cm) organic carbon content and concentration were similar between treated and untreated plots. Overall soil carbon (0-20 cm) pool size was not significantly different from control values in sites treated with partial or complete harvests. No geographic trends were evident for any of the soil properties examined.</p> <p>Conclusions</p> <p>Results indicate that it is unlikely that mineral soil carbon stocks are adversely affected by typical management practices as applied in northern hardwood forests in the US; however, the findings suggest that the forest floor carbon pool may be susceptible to loss.</p

Electron acceleration in laboratory-produced turbulent collisionless shocks

Astrophysical collisionless shocks are among the most powerful particle accelerators in the Universe. Generated by violent interactions of supersonic plasma flows with the interstellar medium, supernova remnant shocks are observed to amplify magnetic fields and accelerate electrons and protons to highly relativistic speeds. In the well-established model of diffusive shock acceleration, relativistic particles are accelerated by repeated shock crossings. However, this requires a separate mechanism that pre-accelerates particles to enable shock crossing. This is known as the ‘injection problem’, which is particularly relevant for electrons, and remains one of the most important puzzles in shock acceleration. In most astrophysical shocks, the details of the shock structure cannot be directly resolved, making it challenging to identify the injection mechanism. Here we report results from laser-driven plasma flow experiments, and related simulations, that probe the formation of turbulent collisionless shocks in conditions relevant to young supernova remnants. We show that electrons can be effectively accelerated in a first-order Fermi process by small-scale turbulence produced within the shock transition to relativistic non-thermal energies, helping overcome the injection problem. Our observations provide new insight into electron injection at shocks and open the way for controlled laboratory studies of the physics underlying cosmic accelerators

Empirical Models of Transitions between Coral Reef States: Effects of Region, Protection, and Environmental Change

There has been substantial recent change in coral reef communities. To date, most analyses have focussed on static patterns or changes in single variables such as coral cover. However, little is known about how community-level changes occur at large spatial scales. Here, we develop Markov models of annual changes in coral and macroalgal cover in the Caribbean and Great Barrier Reef (GBR) regions

Induced abortion, pregnancy loss and intimate partner violence in Tanzania: a population based study

BACKGROUND: Violence by an intimate partner is increasingly recognized as an important public and reproductive health issue. The aim of this study is to investigate the extent to which physical and/or sexual intimate partner violence is associated with induced abortion and pregnancy loss from other causes and to compare this with other, more commonly recognized explanatory factors. METHODS: This study analyzes the data of the Tanzania section of the WHO Multi-Country Study on Women's Health and Domestic Violence, a large population-based cross-sectional survey of women of reproductive age in Dar es Salaam and Mbeya, Tanzania, conducted from 2001 to 2002. All women who answered positively to at least one of the questions about specific acts of physical or sexual violence committed by a partner towards her at any point in her life were considered to have experienced intimate partner violence. Associations between self reported induced abortion and pregnancy loss with intimate partner violence were analysed using multiple regression models. RESULTS: Lifetime physical and/or sexual intimate partner violence was reported by 41% and 56% of ever partnered, ever pregnant women in Dar es Salaam and Mbeya respectively. Among the ever pregnant, ever partnered women, 23% experienced involuntary pregnancy loss, while 7% reported induced abortion. Even after adjusting for other explanatory factors, women who experienced intimate partner violence were 1.6 (95%CI: 1.06,1.60) times more likely to report an pregnancy loss and 1.9 (95%CI: 1.30,2.89) times more likely to report an induced abortion. Intimate partner violence had a stronger influence on induced abortion and pregnancy loss than women's age, socio-economic status, and number of live born children. CONCLUSIONS: Intimate partner violence is likely to be an important influence on levels of induced abortion and pregnancy loss in Tanzania. Preventing intimate partner violence may therefore be beneficial for maternal health and pregnancy outcomes

Fine-Scale Variation and Genetic Determinants of Alternative Splicing across Individuals

Recently, thanks to the increasing throughput of new technologies, we have begun to explore the full extent of alternative pre–mRNA splicing (AS) in the human transcriptome. This is unveiling a vast layer of complexity in isoform-level expression differences between individuals. We used previously published splicing sensitive microarray data from lymphoblastoid cell lines to conduct an in-depth analysis on splicing efficiency of known and predicted exons. By combining publicly available AS annotation with a novel algorithm designed to search for AS, we show that many real AS events can be detected within the usually unexploited, speculative majority of the array and at significance levels much below standard multiple-testing thresholds, demonstrating that the extent of cis-regulated differential splicing between individuals is potentially far greater than previously reported. Specifically, many genes show subtle but significant genetically controlled differences in splice-site usage. PCR validation shows that 42 out of 58 (72%) candidate gene regions undergo detectable AS, amounting to the largest scale validation of isoform eQTLs to date. Targeted sequencing revealed a likely causative SNP in most validated cases. In all 17 incidences where a SNP affected a splice-site region, in silico splice-site strength modeling correctly predicted the direction of the micro-array and PCR results. In 13 other cases, we identified likely causative SNPs disrupting predicted splicing enhancers. Using Fst and REHH analysis, we uncovered significant evidence that 2 putative causative SNPs have undergone recent positive selection. We verified the effect of five SNPs using in vivo minigene assays. This study shows that splicing differences between individuals, including quantitative differences in isoform ratios, are frequent in human populations and that causative SNPs can be identified using in silico predictions. Several cases affected disease-relevant genes and it is likely some of these differences are involved in phenotypic diversity and susceptibility to complex diseases