Cardiac myosin activation: a potential therapeutic approach for systolic heart failure

Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.     

Phenotypic and molecular characterization of the resistance to azoxystrobin and pyraclostrobin in Fusarium graminearum populations from Brazil

Wheat farmers rely on fungicides to protect fields against several foliar and flowering diseases, including Fusarium head blight (FHB). A range of active ingredients is used in isolation or in dual premixes that include a dimethylation inhibitor (DMI) or a quinone outside inhibitor (QoI) fungicide. Comprehensive information about fungicide resistance in F. graminearum is available for DMIs, while for QoIs the data are scarce. We characterized 225 strains obtained from two states in southern Brazil, Rio Grande do Sul (RS) and Paraná (PR), in relation to their response to two QoIs. The median EC₅₀ (effective concentration leading to 50% inhibition of conidial germination) value for azoxystrobin (n = 25 isolates) was 2.20 μg/ml in the PR population and 4.04 μg/ml in the RS population. For pyraclostrobin (n = 50), the median EC₅₀ was 0.28 μg/ml in the PR population and 0.24 μg/ml in the RS population. Evidence of cross-resistance could not be detected. Screening using a discriminatory dose (DD) for azoxystrobin in a larger number of isolates from PR (n = 75) and RS (n = 100) states allowed the detection of 50% and 28% sensitive strains, respectively. Using the DD for pyraclostrobin, 33% and 18.8% were classified as less sensitive in the PR and RS isolates, respectively. In RS, the frequency of less-sensitive isolates increased over time (2007–2011). No point mutation at any of the target spots (F129L, G137R, G143A) was detected. Our results represent an important step towards the establishment of a sensitivity profile for two of the most commonly used QoIs in commercial premixes targeting FHB control.     

Survival of submerged larvae of cranberry girdler, Chrysoteuchia topiaria, in the laboratory

Flooding for several days in late summer or early fall is reported to control larvae of the cranberry girdler, Chrysoteuchia topiaria (Zeller) (Lepidoptera: Pyralidae), which feed on roots of cranberry, Vaccinium macrocarpon Aiton (Ericales: Ericaceae). During flooding, larvae float to the surface or remain submerged. Floating larvae are vulnerable to bird predation, but the fate of submerged larvae has not been studied. The factorially designed laboratory experiments reported here examined survival of submerged cranberry girdler larvae at water temperatures of 10, 15 or 20 °C, and flood durations of 24, 48 or 72 h. These conditions are characteristic of floods applied to western Canadian cranberry farms. In the first year of the study, more submerged larvae survived at 10 °C than at 15 or 20 °C, and more survived 24-h submersion than 48- or 72-h submersion; there was no difference between survival at 15 and 20 °C or 48- and 72-h submersion. In the second year of the study, when there were no 10 °C treatments, more submerged larvae survived at 15 than at 20 °C, and more survived 24-h submersion than 72-h submersion; survival after 48 h was not significantly different from survival after 24 or 72 h. In both years, there was no interaction effect of water temperature and duration of submersion: survival of submerged larvae decreased with longer flood durations and higher temperatures. Dissolved oxygen concentrations before submersion ranged from 5.8±0.1 to 6.3±0.2 ppm in the first year, and 5.5±0.1 to 5.7±0.1 ppm in the second. After submersion, dissolved oxygen concentrations in cups with larvae were approximately 0.5 ppm lower than in cups without larvae, suggesting that larvae continued to respire and use oxygen for some time after submersion. Results of the experiments are used to improve guidelines for flooding to control cranberry girdler larvae.     

The Advisory Council on the Welfare Issues of Dog Breeding

This paper summarises the factors that led to the formation of the Advisory Council on the Welfare Issues of Dog Breeding and sets out some of the challenges facing the Council. Common to all types of dog is the irresponsible way in which they can be produced, purchased and owned, and the considerable welfare problems that may arise as a direct consequence of these actions. In pedigree and purebred dogs, specific welfare problems may also be the result of the manner in which some of them are bred, as well as a variety of breed-related and inherited disorders and a number of other complex issues. These include the breeding strategies adopted, including cross-breeding for so-called 'designer dog' hybrids, and the influence of showing and judging on the production of over-exaggerated conformational features. The Advisory Council's science-based collaborative approach is key to tackling these issues.     

Extinction risk assessment of the world’s seagrass species

Seagrasses, a functional group of marine flowering plants rooted in the world’s coastal oceans, support marine food webs and provide essential habitat for many coastal species, playing a critical role in the equilibrium of coastal ecosystems and human livelihoods. For the first time, the probability of extinction is determined for the world’s seagrass species under the Categories and Criteria of the International Union for the Conservation of Nature (IUCN) Red List of Threatened Species. Several studies have indicated that seagrass habitat is declining worldwide. Our focus is to determine the risk of extinction for individual seagrass species, a 4-year process involving seagrass experts internationally, compilation of data on species’ status, populations, and distribution, and review of the biology and ecology of each of the world’s seagrass species. Ten seagrass species are at elevated risk of extinction (14% of all seagrass species), with three species qualifying as Endangered. Seagrass species loss and degradation of seagrass biodiversity will have serious repercussions for marine biodiversity and the human populations that depend upon the resources and ecosystem services that seagrasses provide.     

Science, technology, and the limits of judicial competence

Federal courts are increasingly being called upon to adjudicate disputes involving controversial new biomedical technologies or government efforts to control environmental and health risks. The authors cite some examples and examine various proposals that have been made to better equip the courts to deal with these complex disputes. They conclude that the proposals fall seriously short by focusing on questions of technical competence without addressing the basic moral and public policy implications of modern science and technology.     

A -defensin mutation causes black coat color in domestic dogs

Genetic analysis of mammalian color variation has provided fundamental insight into human biology and disease. In most vertebrates, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligand-receptor system that controls pigment type-switching, but in domestic dogs, a third gene is implicated, the K locus, whose genetic characteristics predict a previously unrecognized component of the melanocortin pathway. We identify the K locus as beta-defensin 103 (CBD103) and show that its protein product binds with high affinity to the Mc1r and has a simple and strong effect on pigment type-switching in domestic dogs and transgenic mice. These results expand the functional role of beta-defensins, a protein family previously implicated in innate immunity, and identify an additional class of ligands for signaling through melanocortin receptors.     

Marine mammal stranding response in Mexico: Lessons learned

1. Marine mammals are indicators of ecosystem health, and thus stranding records are an invaluable information source. The response to marine mammal stranding (RMMS) must be comprehensive, taking into account three components: (i) operations, (ii) research, and (iii) information dissemination. Although RMMS had previously been practised in several coastal locations in Mexico, the recent enforcement of a new regulation for RMMS has posed a challenge to actors as they adapt to it.
2. To understand the functioning of RMMS in Mexico, Bahía Todos Santos and Bahía de La Paz, two localities with over 20 years of experience in RMMS, were selected. To achieve this goal, a document review to identify the actors involved and their functions was undertaken together with a social network analysis to identify relevant actors in each locality and semi-structured interviews to identify key topics for RMMS.
3. The composition of the involved actors was similar at both locations. Some actors were found to have mandatory functions (i.e. governmental actors), while others (i.e. civil society organizations) performed functions beyond those established in official documents. Governmental agencies, the academic sector, and civil society organizations were the most connected actors and could help disseminate information, facilitate communication within the network, and influence decision-making.
4. The main topics identified were, in order of relevance: (i) economic constraints; (ii) actors' involvement; (iii) stranding response logistics; and (iv) recognition among actors.
5. In conclusion, several limitations to the RMMS exist at both localities, mainly related to the lack of economic resources, but actors involved in RMMS actions are motivated by their own interests. This study proposes the integration of actors into local networks that take into consideration the biological, physical, and social characteristics of each place.