Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner

Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1R) distal C-terminus-associated protein that modulates CB1R signaling via G proteins, and CB1R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB(1)Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1R by a dynamin-and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1R loss was followed by a cycloheximide-sensitive recovery of surface receptors (30120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB(1)Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)mediated increase in cell surface CB(1)Rs, which is postulated to be as a result of rimonabant effects on \u27non-agonist-driven\u27 internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface

The cross-pathway control system regulates production of the secondary metabolite toxin, sirodesmin PL, in the ascomycete, Leptosphaeria maculans

<p>Abstract</p> <p>Background</p> <p>Sirodesmin PL is a secondary metabolite toxin made by the ascomycetous plant pathogen, <it>Leptosphaeria maculans</it>. The sirodesmin biosynthetic genes are clustered in the genome. The key genes are a non-ribosomal peptide synthetase, <it>sirP</it>, and a pathway-specific transcription factor, <it>sirZ</it>. Little is known about regulation of sirodesmin production.</p> <p>Results</p> <p>Genes involved in regulation of sirodesmin PL in <it>L. maculans </it>have been identified. Two hundred random insertional T-DNA mutants were screened with an antibacterial assay for ones producing low levels of sirodesmin PL. Three such mutants were isolated and each transcribed <it>sirZ </it>at very low levels. One of the affected genes had high sequence similarity to <it>Aspergillus fumigatus cpcA</it>, which regulates the cross-pathway control system in response to amino acid availability. This gene was silenced in <it>L. maculans </it>and the resultant mutant characterised. When amino acid starvation was artificially-induced by addition of 3-aminotriazole for 5 h, transcript levels of <it>sirP </it>and <it>sirZ </it>did not change in the wild type. In contrast, levels of <it>sirP </it>and <it>sirZ </it>transcripts increased in the silenced <it>cpcA </it>mutant. After prolonged amino acid starvation the silenced <it>cpcA </it>mutant produced much higher amounts of sirodesmin PL than the wild type.</p> <p>Conclusions</p> <p>Production of sirodesmin PL in <it>L. maculans </it>is regulated by the cross pathway control gene, <it>cpcA</it>, either directly or indirectly via the pathway-specific transcription factor, <it>sirZ</it>.</p

Using legume-based mixtures to enhance the nitrogen use efficiency and economic viability of cropping systems - Final report (LK09106/HGCA3447)

As costs for mineral fertilisers rise, legume-based leys are recognised as a potential alternative nitrogen source for crops. Here we demonstrate that including species-rich legume-based leys in rotations helps to maximise synergies between agricultural productivity and other ecosystem services. By using functionally diverse plant species mixtures, these services can be optimised and fine-tuned to regional and farm-specific needs. Replicated field experiments were conducted over three years at multiple locations, testing the performance of 12 legume species and 4 grass species sown in monocultures, as well as in a mixture of 10 of the legumes and all 4 grasses (called the All Species Mix, ASM). In addition, we compared this complex mixture to farmer-chosen ley mixtures on 34 sites across the UK. The trials showed that there is a large degree of functional complementarity among the legume species. No single species scored high on all evaluation criteria. In particular, the currently most frequently used species, white clover, is outscored by other legume species on a number of parameters such as early development and resistance to decomposition. Further complementarity emerged from the different responses of legume species to environmental variables, with soil pH and grazing or cutting regime being among the more important factors. For example, while large birdsfoot trefoil showed better performance on more acidic soils, the opposite was true for sainfoin, lucerne and black medic. In comparison with the monocultures, the ASM showed increased ground cover, increased above-ground biomass and reduced weed biomass. Benefits of mixing species with regard to productivity increased over time. In addition, the stability of biomass production across sites was greater in the ASM than in the legume monocultures. Within the on-farm trials, we further found that on soils low in organic matter the biomass advantage of the ASM over the Control ley was more marked than on the soils with higher organic matter content. Ecological modelling revealed that the three best multifunctional mixtures all contained black medic, lucerne and red clover. Within the long term New Farming Systems (NFS) rotational study, the use of a clover bi-crop showed improvement to soil characteristics compared to current practice (e.g. bulk density and water infiltration rate). Improvements in wheat yield were also noted with respect to the inclusion of a clover bi-crop in 2010, but there was evidence of a decline in response as the N dose was increased. Cumulatively, over both the wheat crop and the spring oilseed rape crop, the clover bi-crop improved margin over N. The highest average yield response (~9%) was associated with the ASM legume species mix cover cropping approach

Orchard Day, August 18, 1955; Results of Fruit Research

Storing peaches / Donald Comin -- Trends in storages / Donald Comin -- Grape varieties ; Grape soil management and fertilization ; Nitrogen fertilizers for apple trees / J. M. Beattie -- Colorset on Golden Delicious and Grimes ; Planting distance influence on yield of apples ; Harvest dates for apples ; Summer varieties of apples ; Pre-harvest spraying for Baldwin / C. W. Ellenwood -- Peach investigations ; The blueberry planting ; Strawberry studies ; Plum varieties and culture ; Grape weed control studies / R. G. Hill, Jr. -- Semi-dwarf apple trees in Ohio / Freeman S. Howlett and T. E. Fowler -- The Franklin Apple / Freeman S. Howlett and C. W. Ellenwood -- Status of intermediate (trunk-forming) stocks for the apple ; Pruning the newly planted apple tree ; Status of the pear industry in Ohio / Freeman S. Howlett -- Pear variety collection indicates several deserve limited trial / Freeman S. Howlett and C. W. Ellenwoo

Nutrition interventions for healthy ageing across the lifespan:a conference report

Thanks to advances in modern medicine over the past century, the world's population has experienced a marked increase in longevity. However, disparities exist that lead to groups with both shorter lifespan and significantly diminished health, especially in the aged. Unequal access to proper nutrition, healthcare services, and information to make informed health and nutrition decisions all contribute to these concerns. This in turn has hastened the ageing process in some and adversely affected others' ability to age healthfully. Many in developing as well as developed societies are plagued with the dichotomy of simultaneous calorie excess and nutrient inadequacy. This has resulted in mental and physical deterioration, increased non-communicable disease rates, lost productivity and quality of life, and increased medical costs. While adequate nutrition is fundamental to good health, it remains unclear what impact various dietary interventions may have on improving healthspan and quality of life with age. With a rapidly ageing global population, there is an urgent need for innovative approaches to health promotion as individual's age. Successful research, education, and interventions should include the development of both qualitative and quantitative biomarkers and other tools which can measure improvements in physiological integrity throughout life. Data-driven health policy shifts should be aimed at reducing the socio-economic inequalities that lead to premature ageing. A framework for progress has been proposed and published by the World Health Organization in its Global Strategy and Action Plan on Ageing and Health. This symposium focused on the impact of nutrition on this framework, stressing the need to better understand an individual's balance of intrinsic capacity and functional abilities at various life stages, and the impact this balance has on their mental and physical health in the environments they inhabit

A 'large and valuable' Siwalik fossil collection in the archives of the Oxford University Museum of Natural History

This article describes results from a review of South Asian fossils in the Oxford University Museum of Natural History. These materials include two early 19th century collections of fossils from the Siwalik Hills in India. While this assemblage was summarised in 1837 by William Buckland as ‘large and valuable collections of fossil bones’, it has remained largely unstudied and unpublished in any detail since collection. Here, as a precursor to a comprehensive re-evaluation, we establish a chronological and geographical context of one collection event, provide details of its donor, and outline its history after arrival in Oxford. We then describe select taxa in the collection, including a well-preserved maxilla and toothrow of the large extinct giraffid, Sivatherium giganteum, as a basis to justify our current understanding of the biostratigraphic affinity of the assemblage. Conservatively, the collection is a ‘classic’ Upper Siwalik Plio-Pleistocene fauna, possibly the first to be transported to the UK. While further analyses will realise the scientific potential of the fossils, the narrative of their journey from India to Oxford remains incomplete. Further investigation of the hidden history of the collection is warranted

Home administration of lanreotide Autogel® by patients with acromegaly, or their partners, is safe and effective

Summary. Objective The introduction of ready-to-use lanreotide Autogel® has presented the possibility of patients receiving their acromegaly treatment at home. The objective of this study was to assess the ability of patients (or their partners) to administer repeat, unsupervised, injections of lanreotide Autogel without compromising efficacy or safety. Design Multicentre (10 UK regional endocrine centres), open-label, nonrandomised, controlled study. Patients elected either to receive/administer unsupervised home injections after injection technique training (Test group) or continued to receive injections from a healthcare professional (Control group). Patients received monthly injections of lanreotide Autogel® at their established dose. Effects were monitored for up to 40 weeks. Patients Thirty patients (15 per treatment group) with acromegaly treated with a stable dose of lanreotide Autogel® (60, 90 or 120 mg) for ≥ 4 months before screening. Measurements The main outcome measure was the proportion of patients/partners who successfully administered injections throughout the study. Results All Test group patients/partners qualified to administer injections. Fourteen of 15 patients fulfilled all criteria for successful administration of unsupervised injections (95% confidence interval, 70%–99%). Fourteen of 15 Test and 14/15 Control patients maintained growth hormone and IGF-1 control. Local injection tolerability was good for both treatment groups, and safety profiles were similar. All Test group patients continued with unsupervised injections after the study. Conclusions Patients with acromegaly or their partners were able to administer lanreotide Autogel® injections with no detrimental effect on efficacy and safety; therefore, unsupervised home injections are a viable alternative to healthcare professional injections for suitably motivated patients