Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

Animal disease and the limits of local knowledge: dealing with ticks and tick-borne diseases in South Africa

Some proponents of local knowledge, such as Sillitoe (2010), have expressed second thoughts about its capacity to effect development on the ‘revolutionary’ scale once predicted. Our argument in this article follows a similar route. Recent research into the management of livestock in South Africa makes clear that rural African livestock farmers experience uncertainty in relation to the control of stock diseases. State provision of veterinary services has been significantly reduced over the past decade. Both white and African livestock owners are to a greater extent left to their own devices. In some areas of animal disease management, African livestock owners have recourse to tried-and-tested local remedies, which are largely plant-based. But especially in the critical sphere of tick control, efficacious treatments are less evident, and livestock owners struggle to find adequate solutions to high tickloads. This is particularly important in South Africa in the early twenty-first century because land reform and the freedom to purchase land in the post-apartheid context affords African stockowners opportunities to expand livestock holdings. Our research suggests that the limits of local knowledge in dealing with ticks is one of the central problems faced by African livestock owners. We judge this not only in relation to efficacy but also the perceptions of livestock owners themselves. While confidence and practice varies, and there is increasing resort of chemical acaricides we were struck by the uncertainty of livestock owners over the best strategies.

From farmers’ perspective : pesticide use and pest control

Many studies have shown that farmers in developing countries often overuse pesticides and do not adopt safety practices. Policies and interventions to promote a safer use of pesticides are often based on a limited understanding of the farmers’ own perspective of pesticide use. This often results in ineffective policies and the persistence of significant pesticide-related health and environmental problems, especially in developing countries. This chapter explores potentials and limitations of different approaches to study pesticide use in agriculture from the farmers’ perspective. In contrast to the reductionist and mono-disciplinary approaches often adopted, this chapter calls for integrative methodological approaches to provide a realistic and thorough understanding of the farmers’ perspective on pesticide use and illustrates the added value of such an approach with three case studies of pesticide use in Iran, India, and Colombia.

Plasma free fatty acids do not provide the link between obesity and insulin resistance or β-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study

Aims To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and β-cell function. Methods An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. Results After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: β = −0.357; waist circumference: β = −0.380; body fat mass: β = −0.375) and disposition index (BMI: β = −0.215; waist circumference: β = −0.248; body fat mass: β = −0.221) and positively associated with acute insulin response to glucose [BMI: β = 0.200; waist circumference: β = 0.195; body fat mass β = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (β = −0.133), acute insulin response to glucose (β = −0.148) and disposition index [β = −0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. Conclusions Plasma free fatty acid levels have a modest negative association with insulin sensitivity, β-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or β-cell dysfunction.

Animal infectious disease and climate change: a selected review

It is indisputable that climate is an important factor in many livestock diseases. Nevertheless, our knowledge of the impact of climate change on livestock infectious diseases is much less certain. Therefore, the aim of the article is to conduct a systematic review of the literature on the topic utilizing available retrospective data and information. Across a corpus of 175 formal publications, limited empirical evidence was offered to underpin many of the main arguments. The literature reviewed was highly polarized and often inconsistent regarding what the future may hold. Historical explorations were rare. However, identifying past drivers to livestock disease may not fully capture the extent that new and unknown drivers will influence future change. As such, our current predictive capacity is low. We offer a number of recommendations to strengthen this capacity in the coming years. We conclude that our current approach to research on the topic is limiting and unlikely to yield sufficient, actionable evidence to inform future praxis. Therefore, we argue for the creation of a reflexive, knowledge-based system, underpinned by a collective intelligence framework to support the drawing of inferences across the literature.

Modelling the resistance of Enterprise Architecture adoption: linking strategic level of Enterprise Architecture to organisational changes and change resistance

During the last few years Enterprise Architecture (EA) has received increasing attention among industry and academia. By adopting EA, organisations may gain a number of benefits such as better decision making,increased revenues and cost reduction, and alignment of business and IT. However, EA adoption has been found to be difficult. In this paper a model to explain resistance during EA adoption process (REAP) is introduced and validated. The model reveals relationships between strategic level of EA, resulting organisational changes, and sources of resistance. By utilising REAP model, organisations may anticipate and prepare for the organisational change resistance during EA adoption.

Time-lapse geophysical investigations over known archaeological features using electrical resistivity imaging and earth resistance

Electrical methods of geophysical survey are known to produce results that are hard to predict at different times of the year, and under differing weather conditions. This is a problem which can lead to misinterpretation of archaeological features under investigation. The dynamic relationship between a ‘natural’ soil matrix and an archaeological feature is a complex one, which greatly affects the success of the feature’s detection when using active electrical methods of geophysical survey. This study has monitored the gradual variation of measured resistivity over a selection of study areas. By targeting difficult to find, and often ‘missing’ electrical anomalies of known archaeological features, this study has increased the understanding of both the detection and interpretation capabilities of such geophysical surveys. A 16 month time-lapse study over 4 archaeological features has taken place to investigate the aforementioned detection problem across different soils and environments. In addition to the commonly used Twin-Probe earth resistance survey, electrical resistivity imaging (ERI) and quadrature electro-magnetic induction (EMI) were also utilised to explore the problem. Statistical analyses have provided a novel interpretation, which has yielded new insights into how the detection of archaeological features is influenced by the relationship between the target feature and the surrounding ‘natural’ soils. The study has highlighted both the complexity and previous misconceptions around the predictability of the electrical methods. The analysis has confirmed that each site provides an individual and nuanced situation, the variation clearly relating to the composition of the soils (particularly pore size) and the local weather history. The wide range of reasons behind survey success at each specific study site has been revealed. The outcomes have shown that a simplistic model of seasonality is not universally applicable to the electrical detection of archaeological features. This has led to the development of a method for quantifying survey success, enabling a deeper understanding of the unique way in which each site is affected by the interaction of local environmental and geological conditions.

Effects of rain shelter or simulated rain during grain filling and maturation on subsequent wheat grain quality in the UK

The effects of simulated additional rain (ear wetting, 25 mm) or of rain shelter imposed at different periods after anthesis on grain quality at maturity and the dynamics of grain filling and desiccation were investigated in UK field-grown crops of wheat (Triticum aestivum L., cvar Tybalt) in 2011 and in 2012 when June–August rainfall was 255.0 and 214.6 mm, respectively, and above the decadal mean (157.4 mm). Grain filling and desiccation were quantified well by broken-stick regressions and Gompertz curves, respectively. Rain shelter for 56 (2011) or 70 d (2012) after anthesis, and to a lesser extent during late maturation only, resulted in more rapid desiccation and hence progress to harvest maturity whereas ear wetting had negligible effects, even when applied four times. Grain-filling duration was also affected as above in 2011, but with no significant effect in 2012. In both years, there were strong positive associations between final grain dry weight and duration of filling. The treatments affected all grain quality traits in 2011: nitrogen (N) and sulphur (S) concentrations, N:S ratio, sodium dodecyl sulphate (SDS) sedimentation volume, Hagberg Falling Number (HFN), and the incidence of blackpoint. Only N concentration and blackpoint were affected significantly by treatments in 2012. Rain shelter throughout grain filling reduced N concentration, whereas rain shelter reduced the incidence of blackpoint and ear wetting increased it. In 2011, rain shelter throughout reduced S concentration, increased N:S ratio and reduced SDS. Treatment effects on HFN were not consistent within or between years. Nevertheless, a comparison between the extreme treatment means in 2012 indicated damage from late rain combined with ear wetting resulted in a reduction of c. 0.7 s in HFN/mm August rainfall, whilst that between samples taken immediately after ear wetting at harvest maturity or 7 d later suggested recovery from damage to HFN upon re-drying in planta. Hence, the incidence of blackpoint was the only grain quality trait affected consistently by the diverse treatments. The remaining aspects of grain quality were comparatively resilient to rain incident upon developing and maturing ears of cvar Tybalt. No consistent temporal patterns of sensitivity to shelter or ear wetting were detected for any aspect of grain quality.

Calcium intake and its relationship with adiposity and insulin resistance in post-pubertal adolescents

Background Dietary calcium intake has been described as being a negative contributor to adiposity. In adolescents, this relationship is not well established. The objectives of the present study were to compare the calcium intake of normal-weight and obese adolescents and to evaluate its relationship with adiposity and insulin resistance. Methods A cross-sectional analysis of 96 post-pubertal adolescents; 47 normal weight and 49 obese, mean age 16.6 (SD +/- 1.3) years. Body composition was assessed by dual-energy X-ray absorptiometry. Dietary intake was evaluated using a 3-day dietary record. The biochemical evaluation comprised the measurements of serum lipids, lipoproteins, glucose and insulin. Insulin resistance was calculated using the Homeostasis Model Assessment of Insulin resistance (HOMA-IR). Results The mean calcium intake, adjusted for energy, was lower in obese adolescents, 585.2 (+/- 249.9) mg, than in normal weight adolescents, 692.1 (+/- 199.5) mg. Only 4% of adolescents had an adequate intake of calcium. Calcium intake was inversely associated with body trunk fat, insulin and HOMA-IR in the obese group. The quartile analysis of calcium intake provided evidence that girls in the highest quartile had decreased adiposity and insulin resistance. Conclusions This study showed a negative relationship between calcium intake and body fat and insulin resistance, mainly in obese girls, and demonstrates the importance of an increased dietary calcium intake.

Grain size and heavy minerals of the Late Quaternary eolian sediments from the Imbituba-Jaguaruna coast, Southern Brazil: Depositional controls linked to relative sea-level changes

The stratigraphic subdivision and correlation of dune deposits is difficult, especially when age datings are not available. A better understanding of the controls on texture and composition of eolian sands is necessary to interpret ancient eolian sediments. The Imbituba-Jaguaruna coastal zone (Southern Brazil, 28 degrees-29 degrees S) stands out due to its four well-preserved Late Pleistocene (eolian generation 1) to Holocene eolian units (eolian generations 2, 3, and 4). In this study, we evaluate the grain-size and heavy-mineral characteristics of the Imbituba-Jaguartma eolian units through statistical analysis of hundreds of sediment samples. Grain-size parameters and heavy-mineral content allow us to distinguish the Pleistocene from the Holocene units. The grain size displays a pattern of fining and better sorting from generation 1 (older) to 4 (younger), whereas the content of mechanically stable (dense and hard) heavy minerals decreases from eolian generation 1 to 4. The variation in grain size and heavy-mineral content records shifts in the origin and balance (input versus output) of eolian sediment supply attributable mainly to relative sea-level changes. Dunefields submitted to relative sea-level lowstand conditions (eolian generation 1) are characterized by lower accumulation rates and intense post-depositional dissection by fluvial incision. Low accumulation rates favor deflation in the eolian system, which promotes concentration of denser and stable heavy minerals (increase of ZTR index) as well as coarsening of eolian sands. Dissection involves the selective removal of finer sediments and less dense heavy minerals to the coastal source area. Under a high rate of relative sea-level rise and transgression (eolian generation 2), coastal erosion prevents deflation through high input of sediments to the coastal eolian source. This condition favors dunefield growth. Coastal erosion feeds sand from local sources to the eolian system. including sands from previous dunefields (eolian generation 1) and from drowned incised valleys. Therefore, dunefields corresponding to transgressive phases inherit the grain-size and heavy-mineral characteristics of previous dunefields, leading to selective enrichment of finer sands and lighter minerals. Eolian generations 3 and 4 developed during a regressive-progradational phase (Holocene relative sea level highstand). The high rate of sediment supply during the highstand phase prevents deflation. The lack of coastal erosion favors sediment supply from distal sources (fluvial sediments rich in unstable heavy minerals). Thus, dunefields of transgressive and highstand systems tracts may be distinguished from dunefields of the lowstand systems tract through high rates of accumulation (low deflation) in the former. The sediment source of the transgressive dunefields (high input of previously deposited coastal sands) differs from that of the highstand dunefields (high input of fluvial distal sands). Based on this case study, we propose a general framework for the relation between relative sea level, sediment supply and the texture and mineralogy of eolian sediments deposited in siliciclastic wet coastal zones similar to the Imbituba-Jaguaruna coast (C) 2009 Elsevier B.V. All rights reserved.

Salmoninae Commensal Bacteria Show a Positive Correlation Between Antibiotic Resistance and Mercury Resistance Profiles

Bacterial isolates from natural sites with high toxic and heavy metal contamination more frequently contain determinants for resistance to antimicrobials. Natural strains were isolated from the ingesta and external slime of Salmo salar (Linnaeus, 1758) and Salvelinusjontinalis (Mitchell, 1814). Fish specimens were acquired from Casco Bay hatcheries, Casco, ME where there is no history of antibiotic use. Seventy-nine bacterial strains, including many well-documented salmonid commensals (an association from which the fish derives no benefit), were identified using 165 rRNA gene sequencing. Mercury resistant isolates were selected for initially on 25μM HgCI2. Strains were then grown at 20-24°C on Trypticase Soy Agar (TSA) plates containing 0-1000μM HgCl2 or 0-130μM Phenyl Mercuric Acetate (PMA). Mercury in the hatchery feed water due to ubiquitous non-point source deposition has selected for the mercury resistance observed in bacterial strains. Antibiotic resistance determinations, as measured by Minimum Inhibitory Concentration MIC) assays were performed on the 79 bacterial isolates using Sensititrel antimicrobial susceptibility panels. A positive linear correlation between the mercury (pMA and HgCl2) MIC's and antibiotic resistance for all observed strains was demonstrated. Conjugation experiments with Pseudomonas, Aeromonas, and Azomonas donors confirmed phenotypic transfer of penicillin and cephem resistances to Escherichia coli DH5a recipients. Conjugation experiments with Pseudomonas donors showed minimal transfer of tetracycline and minoglycoside resistances to Escherichia coli DH5a recipients. Our study suggests that the accumulation of antimicrobial resistances observed in these natural bacterial populations may be due to the indirect selective pressure exerted by environmental mercury.

Caracterização da mutagênese por inserção do retrotransposon Tos17 em genótipos de arroz

O aumento do potencial produtivo da cultura de arroz via melhoramento genético está principalmente relacionado ao rendimento, a qualidade de grãos e a obtenção de plantas resistentes a doenças e pragas. Neste caso, deve ser explorada a variabilidade genética natural ou induzida através de agentes mutagênicos físicos, químicos ou biológicos. A vantagem do uso de mutagênicos biológicos, como os transposons e os retrotransposons, é que ao serem inseridos podem interrompem um gene causando uma mutação. Esta retrotransposição deixa uma marca que possibilita a identificação molecular do local de inserção. No presente trabalho, foi utilizada a estratégia de mutagênese insercional através de eventos de transposição do retrotransposon Tos17, induzido por cultura in vitro. A análise de diferentes genótipos de arroz é muito importante para avaliar se a transposição ocorre de forma similar em genótipos distintos. Foram avaliados calos embriogênicos de cultivares que têm um histórico de variabilidade genética em homozigose, linhagens obtidas através de cruzamentos com espécies silvestres e ecótipos de arroz vermelho, submetidos a 6 meses de cultura in vitro. O método escolhido para avaliar o número de cópias de Tos17 em calos embriogênicos foi a quantificação relativa por PCR em tempo real. A identificação dos genes mutados pela inserção do retrotransposon foi feita através do isolamento e amplificação das seqüências que flanqueiam os insertos de Tos17. O resultado deste experimento indica um aumento no número de cópias de Tos17 em 8 dos 21 genótipos avaliados. O seqüenciamento dos fragmentos de DNA que flanqueiam os insertos do retrotransposon Tos17, indicaram alta similaridade com seqüências genômicas não codificantes de arroz.

Prevalence and antimicrobial resistance patterns of methicillin-resistant staphylococci (MRS) isolated in a Veterinary Teaching Hospital in Brazil

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