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GPR6 is an orphan G protein–coupled receptor with high constitutive activity found in D2-type dopamine receptor–expressing medium spiny neurons of the striatopallidal pathway, which is aberrantly hyperactivated in Parkinson's disease. Here, we solved crystal structures of GPR6 without the addition of a ligand (a pseudo-apo state) and in complex with two inverse agonists, including CVN424, which improved motor symptoms in patients with Parkinson's disease in clinical trials. In addition, we obtained a cryo–electron microscopy structure of the signaling complex between GPR6 and its cognate Gs heterotrimer. The pseudo-apo structure revealed a strong density in the orthosteric pocket of GPR6 corresponding to a lipid-like endogenous ligand. A combination of site-directed mutagenesis, native mass spectrometry, and computer modeling suggested potential mechanisms for high constitutive activity and inverse agonism in GPR6 and identified a series of lipids and ions bound to the receptor. The structures and results obtained in this study could guide the rational design of drugs that modulate GPR6 signaling. Editor's summary: The rigidity and immobility caused by the progression of Parkinson's disease are caused by loss of dopaminergic neurons in the substantia nigra. Dopamine replacement therapy offers only temporary relief with potentially severe side effects. Barekatain et al. performed structural analysis of GPR6, a G protein–coupled receptor important for the activity of dopaminergic neurons that stop movement. An inverse agonist for GPR6 that is currently in clinical trials ameliorates locomotor deficits related to Parkinson's disease. The authors' data provide the structural basis for the high basal activity of GPR6 and how other inverse agonists targeting GPR6 could be designed to provide a nondopaminergic treatment option for patients with Parkinson's disease. —Wei Wong [ABSTRACT FROM AUTHOR]

Emotional hardcore and other music genres featuring screamed vocals are puzzling for the appreciator. The typical fan attaches appreciative value to musical screams of emotional pain, all the while acknowledging it would be inappropriate to hold similar attitudes towards their sonically similar everyday counterpart: actual human screaming. Call this the screamed vocals problem. To solve the problem, I argue we must attend to the anti-sublimating aims that get expressed in the emotional hardcore vocalist's choice to scream the lyrics. Screamed vocals help us see the value in rejecting (a) restrictive social norms of emotional expressiveness and (b) restrictive artistic norms about how one ought to express or represent pain in art—namely that if one is going to do so, one must ensure the pain has been 'beautified'. In developing this second point, I argue that emotional hardcore is well-suited (although not individually so) for putting pressure on longstanding views in the history of aesthetics about the formal relationship between art and human pain. [ABSTRACT FROM AUTHOR]

Smallholder farmers are the mainstay of the agricultural economies of sub-Saharan Africa (SSA), where they produce several crops, predominantly centered on maize. Smallholder productivity remains limited resulting from a range of confounding factors, but a primary cause is loss from pests and diseases, particularly insects. To improve productivity, recommendations for the mitigation of crop loss globally include early-warning and management systems for in-season indigenous pests. There are many early-warning systems in temperate regions; however, such systems are poorly established in Africa. This is in part due to the need for a combination of pest modeling, data handling and dissemination infrastructure, capacity, and resource provision. While each of these components is progressing in Africa, the means to successfully deploy such systems remain limited. To bridge this, the development of the Pest Risk Information Service (PRISE) began in 2017 for farmers in SSA. Implemented in Kenya, Ghana, Malawi, and Zambia, PRISE developed temperature-driven phenology models for major maize, bean, and tomato pests. Using downscaled and processed Earth Observation data to drive the models, PRISE partnered with African national agencies to communicate pre- and in-season pest alerts that forecast the time to act against key insect pests. Alerts were designed to be integrated into country-specific Good Agricultural Practice (GAP) recommendations to provide a complementary package to agricultural stakeholders. End line studies with farmers showed that those who received information about the target crops including PRISE pest forecasts, generally reported better outcomes in terms of reduced losses and increased incomes compared with farmers who did not. [ABSTRACT FROM AUTHOR]

This paper examines the roles that self-knowledge and reflection play in Schopenhauer’s view of agency. Focusing in particular on the discussion of the acquired character, his cognitive theory of motivation, and the idea of intellectual freedom, I argue that we find two conceptions of rational agency in Schopenhauer. The ‘minimal’ conception sees rational agency primarily as a kind of reflective motivation, whereas the ‘maximal’ or ‘robust’ conception sees rational agency as involving a kind of reflective self-organization. Furthermore, I argue that rational self-organization and acquired character go hand-in-hand: it is only in virtue of achieving the latter that one achieves the former. Although some worry that the discussion of acquired character does not sit well with Schopenhauer’s broader determinist theory of action, the reading offered here aims to demonstrate that the two are reconcilable. [ABSTRACT FROM AUTHOR]

Crop pests (weeds, insect pests and pathogens) are recognised worldwide as a serious challenge to agricultural production and threat to food security. Potential losses due to weeds, animal pests and pathogens have been reported at 34%, 18% and 16%, respectively. In monetary terms losses can be high, for example, annual smallholder losses due to just five invasive species in six African countries have been estimated at US$0.9–1.1 billion. Here, smallholder mixed maize farmers' perceptions of the key constraints to their farming practices are considered. Semi-structured interviews with smallholder households, in addition to key informant interviews, reveal that farmers report insect pests, pathogens and weeds (collectively "pests") as the main constraints to farm production. Farmers report yield losses experienced due to pests, together with control expenditure significantly affect net income whilst undermining other livelihood assets. Farmers in Mwea West are highly vulnerable to a range of pests including a number of invasive alien species. Importantly, the farmer perceptions in this study agree with major research studies and confirm the serious impacts of pests on smallholder livelihoods. In order to achieve positive livelihood outcomes there is an urgent need for support to improve smallholder food security; this is especially important for countries with low gross domestic product. [ABSTRACT FROM AUTHOR]

Fall armyworm, Spodoptera frugiperda, is a crop pest native to the Americas, which has invaded and spread throughout sub-Saharan Africa within two years. Recent estimates of 20-50% maize yield loss in Africa suggest severe impact on livelihoods. Fall armyworm is still infilling its potential range in Africa and could spread to other continents. In order to understand fall armyworm's year-round, global, potential distribution, we used evidence of the effects of temperature and precipitation on fall armyworm life-history, combined with data on native and African distributions to construct Species Distribution Models (SDMs). We also investigated the strength of trade and transportation pathways that could carry fall armyworm beyond Africa. Up till now, fall armyworm has only invaded areas that have a climate similar to the native distribution, validating the use of climatic SDMs. The strongest climatic limits on fall armyworm's yearround distribution are the coldest annual temperature and the amount of rain in the wet season. Much of sub-Saharan Africa can host year-round fall armyworm populations, but the likelihoods of colonising North Africa and seasonal migrations into Europe are hard to predict. South and Southeast Asia and Australia have climate conditions that would permit fall armyworm to invade. Current trade and transportation routes reveal Australia, China, India, Indonesia, Malaysia, Philippines and Thailand face high threat of fall armyworm invasions originating from Africa. [ABSTRACT FROM AUTHOR]

Prolyl hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues that trigger the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. The present study provides a detail kinetic analysis for some of these inhibitors. The data generated in the present study suggest that these compounds are reversible and compete directly with the co-substrate, 2-oxoglutarate (2-OG) for binding at the enzyme active site. Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI)mechanism due to an extremely slow dissociation rate constant, koff, and a long residence time. [ABSTRACT FROM AUTHOR]

Liriomyza huidobrensis (Blanchard) is native to South America but has expanded its range and invaded many regions of the world, primarily on flowers and to a lesser extent on horticultural product shipments. As a result of initial invasion into an area, damage caused is usually significant but not necessarily sustained. Currently, it is an economic pest in selected native and invaded regions of the world. Adults cause damage by puncturing abaxial and adaxial leaf surfaces for feeding and egg laying sites. Larvae mine the leaf parenchyma tissues which can lead to leaves drying and wilting. We have recorded 365 host plant species from 49 families and more than 106 parasitoid species. In a subset of the Argentinian data, we found that parasitoid community composition attacking L. huidobrensis differs significantly in cultivated and uncultivated plants. No such effect was found at the world level, probably due to differences in collection methods in the different references. We review the existing knowledge as a means of setting the context for new and unpublished data. The main objective is to provide an update of widely dispersed and until now unpublished data, evaluate dispersion of the leafminer and management strategies in different regions of the world, and highlight the need to consider the possible effects of climate change on further regional invasions or expansions. [ABSTRACT FROM AUTHOR]

Using the quasi-experimental setting of the Michael Vick dogfighting case, the researchers employed rich interview content to explore the question, "When a critical event occurs in the animal advocacy field, what motivates advocacy groups to respond?" The investigation reveals that what was thought to be one critical event was in actuality three unique yet interrelated critical events--(1) the revelation of the transgressions; (2) the punishment of the perpetrator; and (3) the decision about whether to ally with the perpetrator in advocacy. The study shows that legitimacy concerns, occasionally paired with reflections on organizational identity, influenced the decision-making of advocacy organizations across all three critical events, as each held the potential either to legitimize or to delegitimize the advocacy organizations and/or the perpetrator (i.e., Vick). [ABSTRACT FROM AUTHOR]

As part of a census of the Indian rhinoceros Rhinoceros unicornis a survey was conducted to measure the extent of invasion by the neotropical plant mikania Mikania micrantha across major habitats of Chitwan National Park important for the conservation of the rhinoceros. Previous work has demonstrated that this fire-adapted plant can smother and kill native flora such as grasses and sapling trees, several of which are important fodder plants of the rhinoceros. Here, additional studies were conducted on the risks of anthropogenic factors (natural resource collection and grassland burning) contributing to the spread and growth of the plant. Mikania is currently found across 44% of habitats sampled and almost 15% of these have a high infestation (> 50% coverage). Highest densities were recorded from riverine forest, tall grass and wetland habitats and this is where the highest numbers of rhinoceroses were recorded in the habitats surveyed during the census. Local community dependence on natural resources in the core area of the Park is high. The range and volume of resources (e.g. fodder) collected and the distances travelled all pose a high risk of the spread of mikania. Of greater significance is the annual burning of the grasslands in the Park by local communities, estimated at 25–50% of the total area. It is imperative, therefore, that core elements of a management plan for mikania incorporate actions to control burning, reduce spread and raise awareness about best practice for local resource management by local communities. [ABSTRACT FROM AUTHOR]

Vegetation community composition and the above- and below-ground invertebrate communities are linked intrinsically, though few studies have assessed the impact of non-native plants on both these parts of the community together. We evaluated the differences in the above- (foliage- and ground-dwelling) and below-ground invertebrate communities in nine uninvaded plots and nine plots invaded by the annual invasive species Impatiens glandulifera, in the UK during 2007 and 2008. Over 139,000 invertebrates were identified into distinct taxa and categorised into functional feeding groups. The impact of I. glandulifera on the vegetation and invertebrate community composition was evaluated using multivariate statistics including principal response curves (PRC) and redundancy analysis (RDA). In the foliage-dwelling community, all functional feeding groups were less abundant in the invaded plots, and the species richness of Coleoptera and Heteroptera was significantly reduced. In the ground-dwelling community, herbivores, detritivores, and predators were all significantly less abundant in the invaded plots. In contrast, these functional groups in the below-ground community appeared to be largely unaffected, and even positively associated with the presence of I. glandulifera. Although the cover of I. glandulifera decreased in the invaded plots in the second year of the study, only the below-ground invertebrate community showed a significant response. These results indicate that the above- and below-ground invertebrate communities respond differently to the presence of I. glandulifera, and these community shifts can potentially lead to a habitat less biologically diverse than surrounding native communities; which could have negative impacts on higher trophic levels and ecosystem functioning. [ABSTRACT FROM AUTHOR]

Binding of IGF to IGF-IR activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology (PH) domain, including AKT and PDK1. PDK1 is highly expressed in breast tumor samples and breast cancer cell lines. Here we demonstrate that targeting PDK1 with the potent and selective PDK1 inhibitor PF-5177624 in the IGF-PI3K pathway blocks breast cancer cell proliferation and transformation. Breast cancer cell lines MCF7 and T47D, representing the luminal ER positive subtype and harboring PIK3CA mutations, were most responsive to IGF-I induction resulting in upregulated AKT and p70S6K phosphorylation via PDK1 activation. PF-5177624 downregulated AKT and p70S6K phosphorylation, blocked cell cycle progression, and decreased cell proliferation and transformation to block IGFR-I induced activation in breast cancer cells. These results may provide insight into clinical strategies for developing an IGFR-I inhibitor and/or a PDK1 inhibitor in luminal breast cancer patients. [ABSTRACT FROM AUTHOR]

Transgenic Bt cotton, engineered to continuously produce activated 6-endotoxins of the soil bacteria Bacillus thuringiensis, holds great promise in controlling Helicoverpa armigera and other lepidopteran pests. However, it also may impact the invertebrate community, which needs to be clarified. The effects of Bt cotton on two nontarget in sects, Aphis gossypii and Onus sauteri, were assessed under semifield and laboratory conditions. Mean total duration of nymphal stages of A. gossypii was shorter (5.9 versus 6.3 d), and rm was higher (0.418 versus 0.394) on conventional Simian 3 (the most frequently planted non-Bt cotton in northern China) than on Bt transgenic NuCOTN 33B (the first Bt cotton commercially planted in China). Mean duration of fourth-instar 0. sauteri was significantly longer on transgenic GK-12 (3.7 d) than on NuCOTN 33B (3.2 d), but no different from Simian 3. Mean total mortality was significantly lower on Simian 3 (3.7%) than on GK-12 (14.8%). During the fourth in star, the predator consumed a significantly higher number of prey on Simian 3 (202.3 prey) than on NuCOTN 33B (159.0), whereas the mean total number of A. gossypii prey consumed during the nymphal stage was significantly higher on Simian 3 (336.8 prey) and GK-12 (330.3 prey) than on NuCOTN 33B (275.7). No detrimental effects were detected on development (nymphs, adults, and progeny eggs), fecundity, longevity, and egg viability of O. sauteri on Bt cotton aphids compared with non-Bt cotton aphids. These results suggest that Bt cotton cultivars GK-12 and NuCOTN 33B have no direct effect on nontargets A. gossypii and O. sauteni. Germplasm divergence may account for the negative effects observed on A. gossypii and O. sauteni when reared on NuCOTN 33B or NuCOTN 33B-fed aphids. The biological meanings of the small difference observed between GK-12 and Simian 3 on survival of O. sauteri will require close monitoring over longer time periods. [ABSTRACT FROM AUTHOR]

Abstract: Several novel series of nitrile-containing fluoroquinolones with weakly basic amines are reported which have reduced potential for hERG (human ether-a-go-go gene) channel inhibition as measured by the dofetilide assay. The new fluoroquinolones are potent against both Gram-positive and fastidious Gram-negative strains, including Methicillin resistant Staphylococcus aureus and fluoroquinolone-resistant Streptococcus pneumoniae. Several analogs also showed low potential for human genotoxicity as measured by the clonogenicity test. Compounds 22 and 37 (designated PF-00951966 and PF-02298732, respectively), which had good in vitro activity and in vitro safety profiles, also showed good pharmacokinetic properties in rats. [Copyright &y& Elsevier]

Examines the direct detection of triplet phthalocyanine as an intermediate in the process of singlet-oxygen-sensitized delayed fluorescence using tetra-tert-butylphthalocyanine as the fluorescer and carbon 60 as the sensitizer. Modeling the kinetics of the intermediate; Singlet oxygen dimol as the intermediate.

AbstractGlobally, the coffee berry borer (CBB) Hypothenemus hampei (Ferreri) is the most severe pest of the commercial coffee species arabica coffee (Coffea arabica). Heterogenous landscapes characterize many coffee-growing areas. We studied the phenology of coffee and the abundance, and development of infestation by CBB within the context an altitudinal gradient in the coffee-growing region of Caldas, Colombia. This was between 1200 m and 1800 m (a.s.l.) from September 2019 to July 2020 covering two seasons of coffee flowering. Coffee berry phenology did not differ over the altitudinal gradient studied, but CBB abundance and berry infestation differed in quantity and timings, with lower altitudes having higher abundances and proportions of infestation than higher altitudes. In the context of CBB management, October through to December is vital for coffee farms <1500 m as CBB abundance and infestation both spike, and March to June is key for farms between 1500-1700 m for the same reasons. In conclusion, coffee farmers in highly heterogeneous landscapes will have to adjust their CBB management according to the altitude gradients of their farm. [ABSTRACT FROM AUTHOR]

Investigates the host age choice for oviposition in Pauesia juniperorum. Biological control of Cinara cupressivora; Effects of host age on parasitoid development, size of progeny and sex ratio; Impact of parasitoid attack on host population growth.