The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity.

Over recent years, accumulated evidence suggests that autophagy induction is protective in animal models of a number of neurodegenerative diseases. Intense research in the field has elucidated different pathways through which autophagy can be upregulated and it is important to establish how modulation of these pathways impacts upon disease progression in vivo and therefore which, if any, may have further therapeutic relevance. In addition, it is important to understand how alterations in these target pathways may affect normal physiology when constitutively modulated over a long time period, as would be required for treatment of neurodegenerative diseases. Here we evaluate the potential protective effect of downregulation of calpains. We demonstrate, in Drosophila, that calpain knockdown protects against the aggregation and toxicity of proteins, like mutant huntingtin, in an autophagy-dependent fashion. Furthermore, we demonstrate that, overexpression of the calpain inhibitor, calpastatin, increases autophagosome levels and is protective in a mouse model of Huntington's disease, improving motor signs and delaying the onset of tremors. Importantly, long-term inhibition of calpains did not result in any overt deleterious phenotypes in mice. Thus, calpain inhibition, or activation of autophagy pathways downstream of calpains, may be suitable therapeutic targets for diseases like Huntington's disease.This is the published version of the manuscript. It is available online from NPG in Cell Death and Differentiaiton here: http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd2014151a.html

Thresholds of riparian forest use by terrestrial mammals in a fragmented Amazonian deforestation frontier

Species persistence in fragmented landscapes is intimately related to the quality, structure, and context of remaining habitat remnants. Riparian vegetation is legally protected within private landholdings in Brazil, so we quantitatively assessed occupancy patterns of terrestrial mammals in these remnants, examining under which circumstances different species effectively use them. We selected 38 riparian forest patches and five comparable riparian sites within continuous forest, at which we installed four to five camera-traps per site (199 camera-trap stations). Terrestrial mammal assemblages were sampled for 60 days per station during the dry seasons of 2013 and 2014. We modelled species occupancy and detection probabilities within riparian forest remnants, and examined the effects of patch size, habitat quality, and landscape structure on occupancy probabilities. We then scaled-up modelled occupancies to all 1915 riparian patches throughout the study region to identify which remnants retain the greatest potential to work as habitat for terrestrial vertebrates. Of the ten species for which occupancy was modelled, six responded to forest quality (remnant degradation, cattle intrusion, palm aggregations, and understorey density) or structure (remnant width, isolation, length, and area of the patch from which it originates). Patch suitability was lower considering habitat quality than landscape structure, and virtually all riparian remnants were unsuitable to maintain a high occupancy probability for all species that responded to forest patch quality or structure. Beyond safeguarding legal compliance concerning riparian remnant amount, ensuring terrestrial vertebrate persistence in fragmented landscapes will require curbing the drivers of forest degradation within private landholdings

Interactive Effects of Large- and Small-Scale Sources of Feral Honey-Bees for Sunflower in the Argentine Pampas

Pollinators for animal pollinated crops can be provided by natural and semi-natural habitats, ranging from large vegetation remnants to small areas of non-crop land in an otherwise highly modified landscape. It is unknown, however, how different small- and large-scale habitat patches interact as pollinator sources. In the intensively managed Argentine Pampas, we studied the additive and interactive effects of large expanses (up to 2200 ha) of natural habitat, represented by untilled isolated “sierras”, and narrow (3–7 m wide) strips of semi-natural habitat, represented by field margins, as pollinator sources for sunflower (Helianthus annus). We estimated visitation rates by feral honey-bees, Apis mellifera, and native flower visitors (as a group) at 1, 5, 25, 50 and 100 m from a field margin in 17 sunflower fields 0–10 km distant from the nearest sierra. Honey-bees dominated the pollinator assemblage accounting for >90% of all visits to sunflower inflorescences. Honey-bee visitation was strongly affected by proximity to the sierras decreasing by about 70% in the most isolated fields. There was also a decline in honey-bee visitation with distance from the field margin, which was apparent with increasing field isolation, but undetected in fields nearby large expanses of natural habitat. The probability of observing a native visitor decreased with isolation from the sierras, but in other respects visitation by flower visitors other than honey-bees was mostly unaffected by the habitat factors assessed in this study. Overall, we found strong hierarchical and interactive effects between the study large and small-scale pollinator sources. These results emphasize the importance of preserving natural habitats and managing actively field verges in the absence of large remnants of natural habitat for improving pollinator services

Health behaviour modelling for prenatal diagnosis in Australia: a geodemographic framework for health service utilisation and policy development

BACKGROUND: Despite the wide availability of prenatal screening and diagnosis, a number of studies have reported no decrease in the rate of babies born with Down syndrome. The objective of this study was to investigate the geodemographic characteristics of women who have prenatal diagnosis in Victoria, Australia, by applying a novel consumer behaviour modelling technique in the analysis of health data. METHODS: A descriptive analysis of data on all prenatal diagnostic tests, births (1998 and 2002) and births of babies with Down syndrome (1998 to 2002) was undertaken using a Geographic Information System and socioeconomic lifestyle segmentation classifications. RESULTS: Most metropolitan women in Victoria have average or above State average levels of uptake of prenatal diagnosis. Inner city women residing in high socioeconomic lifestyle segments who have high rates of prenatal diagnosis spend 20% more on specialist physician's fees when compared to those whose rates are average. Rates of prenatal diagnosis are generally low amongst women in rural Victoria, with the lowest rates observed in farming districts. Reasons for this are likely to be a combination of lack of access to services (remoteness) and individual opportunity (lack of transportation, low levels of support and income). However, there are additional reasons for low uptake rates in farming areas that could not be explained by the behaviour modelling. These may relate to women's attitudes and choices. CONCLUSION: A lack of statewide geodemographic consistency in uptake of prenatal diagnosis implies that there is a need to target health professionals and pregnant women in specific areas to ensure there is increased equity of access to services and that all pregnant women can make informed choices that are best for them. Equally as important is appropriate health service provision for families of children with Down syndrome. Our findings show that these potential interventions are particularly relevant in rural areas. Classifying data to lifestyle segments allowed for practical comparisons of the geodemographic characteristics of women having prenatal diagnosis in Australia at a population level. This methodology may in future be a feasible and cost-effective tool for service planners and policy developers

Evaluation of exercise on individuals with dementia and their carers: a randomised controlled trial

Background Almost all of the 820,000 people in the UK with dementia will experience Behavioural and Psychological Symptoms of Dementia (BPSD). However, research has traditionally focused on treating cognitive symptoms, thus neglecting core clinical symptoms that often have a more profound impact on living with dementia. Recent evidence (Kales et al, 2007; Ballard et al, 2009) indicates that the popular approach to managing BPSD - prescription of anti-psychotic medication - can increase mortality and the risk of stroke in people with dementia as well as impair quality of life and accelerate cognitive decline. Consequently, there is a need to evaluate the impact that non-pharmacological interventions have on BPSD; we believe physical exercise is a particularly promising approach. Methods/Design We will carry out a pragmatic, randomised, single-blind controlled trial to evaluate the effectiveness of exercise (planned walking) on the behavioural and psychological symptoms of individuals with dementia. We aim to recruit 146 people with dementia and their carers to be randomized into two groups; one will be trained in a structured, tailored walking programme, while the other will continue with treatment as usual. The primary outcome (BPSD) will be assessed with the Neuropsychiatric Inventory (NPI) along with relevant secondary outcomes at baseline, 6 and 12 weeks. Discussion Designing this study has been challenging both ethically and methodologically. In particular to design an intervention that is simple, measurable, safe, non-invasive and enjoyable has been testing and has required a lot of thought. Throughout the design, we have attempted to balance methodological rigour with study feasibility. We will discuss the challenges that were faced and overcome in this paper

Loss of expression of TGF-βs and their receptors in chronic skin lesions induced by sulfur mustard as compared with chronic contact dermatitis patients

<p>Abstract</p> <p>Background</p> <p>Sulfur mustard (SM) is a blister-forming agent that has been used as a chemical weapon. Sulfur mustard can cause damage in various organs, especially the skin, respiratory system, and eyes. Generally, the multiple complications of mustard gas result from its alkalizing potency; it reacts with cellular components like DNA, RNA, proteins, and lipid membranes.</p> <p>TGF-β is a multi-functional cytokine with multiple biological effects ranging from cell differentiation and growth inhibition to extracellular matrix stimulation, immunosuppression, and immunomodulation. TGF-β has 3 isoforms (TGF-β 1, 2, 3) and its signaling is mediated by its receptors: R1, R2 and intracellular Smads molecules.</p> <p>TGF-β has been shown to have anti-inflammatory effects. TGF-βs and their receptors also have an important role in modulation of skin inflammation, proliferation of epidermal cells, and wound healing, and they have been implicated in different types of skin inflammatory disorders.</p> <p>Methods</p> <p>Seventeen exposed SM individuals (48.47 ± 9.3 years), 17 chronic dermatitis patients (46.52 ± 14.6 years), and 5 normal controls (44.00 ± 14.6 years) were enrolled in this study.</p> <p>Evaluation of TGF-βs and their receptors expressions was performed by semiquantitative RT-PCR. Only TGF1was analyzed immunohistochemically.</p> <p>Results</p> <p>Our results showed significant decreases in the expression percentages of TGF-β 1, 2 and R1, R2 in chemical victims in comparison with chronic dermatitis and normal subjects and significant decreases in the intensity of R1 and R2 expressions in chemical victims in comparison with chronic dermatitis and normal controls. (P value < 0.05)</p> <p>Conclusions</p> <p>TGF-βs and their receptors appear to have a noticeable role in chronic inflammatory skin lesions caused by sulfur mustard.</p

Design, Validation and Annotation of Transcriptome-Wide Oligonucleotide Probes for the Oligochaete Annelid Eisenia fetida

High density oligonucleotide probe arrays have increasingly become an important tool in genomics studies. In organisms with incomplete genome sequence, one strategy for oligo probe design is to reduce the number of unique probes that target every non-redundant transcript through bioinformatic analysis and experimental testing. Here we adopted this strategy in making oligo probes for the earthworm Eisenia fetida, a species for which we have sequenced transcriptome-scale expressed sequence tags (ESTs). Our objectives were to identify unique transcripts as targets, to select an optimal and non-redundant oligo probe for each of these target ESTs, and to annotate the selected target sequences. We developed a streamlined and easy-to-follow approach to the design, validation and annotation of species-specific array probes. Four 244K-formatted oligo arrays were designed using eArray and were hybridized to a pooled E. fetida cRNA sample. We identified 63,541 probes with unsaturated signal intensities consistently above the background level. Target transcripts of these probes were annotated using several sequence alignment algorithms. Significant hits were obtained for 37,439 (59%) probed targets. We validated and made publicly available 63.5K oligo probes so the earthworm research community can use them to pursue ecological, toxicological, and other functional genomics questions. Our approach is efficient, cost-effective and robust because it (1) does not require a major genomics core facility; (2) allows new probes to be easily added and old probes modified or eliminated when new sequence information becomes available, (3) is not bioinformatics-intensive upfront but does provide opportunities for more in-depth annotation of biological functions for target genes; and (4) if desired, EST orthologs to the UniGene clusters of a reference genome can be identified and selected in order to improve the target gene specificity of designed probes. This approach is particularly applicable to organisms with a wealth of EST sequences but unfinished genome

The History and Prehistory of Natural-Language Semantics

Contemporary natural-language semantics began with the assumption that the meaning of a sentence could be modeled by a single truth condition, or by an entity with a truth-condition. But with the recent explosion of dynamic semantics and pragmatics and of work on non- truth-conditional dimensions of linguistic meaning, we are now in the midst of a shift away from a truth-condition-centric view and toward the idea that a sentence’s meaning must be spelled out in terms of its various roles in conversation. This communicative turn in semantics raises historical questions: Why was truth-conditional semantics dominant in the first place, and why were the phenomena now driving the communicative turn initially ignored or misunderstood by truth-conditional semanticists? I offer a historical answer to both questions. The history of natural-language semantics—springing from the work of Donald Davidson and Richard Montague—began with a methodological toolkit that Frege, Tarski, Carnap, and others had created to better understand artificial languages. For them, the study of linguistic meaning was subservient to other explanatory goals in logic, philosophy, and the foundations of mathematics, and this subservience was reflected in the fact that they idealized away from all aspects of meaning that get in the way of a one-to-one correspondence between sentences and truth-conditions. The truth-conditional beginnings of natural- language semantics are best explained by the fact that, upon turning their attention to the empirical study of natural language, Davidson and Montague adopted the methodological toolkit assembled by Frege, Tarski, and Carnap and, along with it, their idealization away from non-truth-conditional semantic phenomena. But this pivot in explana- tory priorities toward natural language itself rendered the adoption of the truth-conditional idealization inappropriate. Lifting the truth-conditional idealization has forced semanticists to upend the conception of linguistic meaning that was originally embodied in their methodology

Bats in the anthropogenic matrix: Challenges and opportunities for the conservation of chiroptera and their ecosystem services in agricultural landscapes

Intensification in land-use and farming practices has had largely negative effects on bats, leading to population declines and concomitant losses of ecosystem services. Current trends in land-use change suggest that agricultural areas will further expand, while production systems may either experience further intensification (particularly in developing nations) or become more environmentally friendly (especially in Europe). In this chapter, we review the existing literature on how agricultural management affects the bat assemblages and the behavior of individual bat species, as well as the literature on provision of ecosystem services by bats (pest insect suppression and pollination) in agricultural systems. Bats show highly variable responses to habitat conversion, with no significant change in species richness or measures of activity or abundance. In contrast, intensification within agricultural systems (i.e., increased agrochemical inputs, reduction of natural structuring elements such as hedges, woods, and marshes) had more consistently negative effects on abundance and species richness. Agroforestry systems appear to mitigate negative consequences of habitat conversion and intensification, often having higher abundances and activity levels than natural areas. Across biomes, bats play key roles in limiting populations of arthropods by consuming various agricultural pests. In tropical areas, bats are key pollinators of several commercial fruit species. However, these substantial benefits may go unrecognized by farmers, who sometimes associate bats with ecosystem disservices such as crop raiding. Given the importance of bats for global food production, future agricultural management should focus on “wildlife-friendly” farming practices that allow more bats to exploit and persist in the anthropogenic matrix so as to enhance provision of ecosystem services. Pressing research topics include (1) a better understanding of how local-level versus landscape-level management practices interact to structure bat assemblages, (2) the effects of new pesticide classes and GM crops on bat populations, and (3) how increased documentation and valuation of the ecosystem services provided by bats could improve attitudes of producers toward their conservation