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A simple and sustainable propylphosphonic anhydride (T3P)-assisted methodology for the synthesis of N-acyl tryptamines, an interesting class of gut microbiota-derived endocannabinoid-like lipid mediators, was proposed. This protocol is characterized by great operational simplicity, and all products were obtained at room temperature, without the use of an inert atmosphere and by using limited amounts of non-halogenated solvents. Finally, the possibility to realize the reaction under mechanochemical conditions was explored with interesting results. [ABSTRACT FROM AUTHOR]

The synthesis of some N-(3-acyloxyacyl)glycines, an interesting class of bioactive gut microbiota metabolites, is described. This procedure involves seven reaction steps using the commercially available Meldrum's acid to obtain highly pure products, in normal or deuterated form. The key point of the synthetic strategy was the use of commendamide t-butyl ester as a synthetic intermediate, a choice that allowed the removal of the protecting group at the end of the synthetic procedure without degrading of the other ester bond present in the molecule. The developed synthetic sequence is particularly simple, uses readily available reagents and involves a limited number of purifications by chromatographic column, with a reduction in the volume of solvent and energy used. [ABSTRACT FROM AUTHOR]

Organisations heavily dependent on paper documents still spend a significant amount of time managing a large volume of documents. An intelligent document management system (DMS) is presented to automate the processing of tax and administrative documents. The proposed system fills a gap in the landscape of practical tools in the field of DMS and advances the state of the art. This system represents a complex process of integrated AI-powered technologies that creates an ontology, extracts information from documents, defines profiles, maps the extracted data in RDF format, and applies inference through a reasoning engine. The DMS was designed to help all those companies that manage their clients' tax and administrative documents daily. Automation speeds up the management process so that companies can focus more on value-added services. The system was tested in a case study that focused on the preparation of tax returns. The results demonstrated the efficacy of the system in providing document management service. [ABSTRACT FROM AUTHOR]

Smart grids play an important role for energy management by directly supporting the socio-ecological transition of neighbourhoods. This research provides the design of a coordination model to enable the management and exchange of electrical energy between producers and consumers at a micro-grid level. This model, which derives from the SAPERE coordination model, allows the intelligent digital twins to interact and generate services on the fly to meet different needs in real time. We have designed producer and consumer digital twins, which autonomously generate supply contracts in the form of a transaction, and supervisor digital twins, which regulate energy at the node level, managing threshold violations and proactively avoiding future threshold violations by using predictions. This coordination model allows energy exchanges in a single node and in a micro-grid structure that contains several neighbouring nodes. We have implemented and tested the platform with realistic data, based on the consumption statistics of a real household, and with real data, collected in the living-lab of "Les Vergers" located near Geneva. The results show that the combination of a coordination model and intelligent digital twins actually supports self-adaptive energy management in a smart grid. Such approaches are fundamental to develop efficient and reliable smart grids. [ABSTRACT FROM AUTHOR]

The vascular endothelium is key target for immune and thrombotic responses that has to be controlled in successful xenotransplantation. Several genes were identified that, if induced or overexpressed, help to regulate the inflammatory response and preserve the transplanted organ function and metabolism. However, few studies addressed combined expression of such genes. The aim of this work was to evaluate in vivo the effects of the simultaneous expression of three human genes in a mouse generated using the multi-cistronic F2A technology. Male 3-month-old mice that express human heme oxygenase 1 (hHO-1), ecto-5′-nucleotidase (hE5NT), and ecto-nucleoside triphosphate diphosphohydrolase 1 (hENTPD1) (Transgenic) were compared to wild-type FVB mice (Control). Background analysis include extracellular nucleotide catabolism enzymes profile on the aortic surface, blood nucleotide concentration, and serum L-arginine metabolites. Furthermore, inflammatory stress induced by LPS in transgenic and control mice was used to characterize interleukin 6 (IL-6) and adhesion molecules endothelium permeability responses. Transgenic mice had significantly higher rates of extracellular adenosine triphosphate and adenosine monophosphate hydrolysis on the aortic surface in comparison to control. Increased levels of blood AMP and adenosine were also noticed in transgenics. Moreover, transgenic animals demonstrated the decrease in serum monomethyl-L-arginine level and a higher L-arginine/monomethyl-L-arginine ratio. Importantly, significantly decreased serum IL-6, and adhesion molecule levels were observed in transgenic mice in comparison to control after LPS treatment. Furthermore, reduced endothelial permeability in the LPS-treated transgenic mice was noted as compared to LPS-treated control. The human enzymes (hHO-1, hE5NT, hENTPD1) simultaneously encoded in transgenic mice demonstrated benefits in several biochemical and functional aspects of endothelium. This is consistent in use of this approach in the context of xenotransplantation. [ABSTRACT FROM AUTHOR]

Smallholder farmers produce about 70% of the world's food and employ more than one billion people. They therefore have an important role to play in eradicating food insecurity and poverty among the world's growing population. Although there are different digital services for smallholder farmers, the existing services lack sustainability in the agriculture context and hardly meet their needs. Data management and sharing among different agriculture stakeholders has the potential to make agriculture sustainable, but there is a need to enable access to digital services in an entire farming cycle under one roof. This paper aims to propose the design of a comprehensive data management digital framework to solve common challenges of smallholder farmers in Tanzania and other countries' agricultural systems. We follow the design science research (DSR) method to develop an artifact that interacts with the problem context. To illustrate the framework's applicability, we use different case studies in Tanzania. [ABSTRACT FROM AUTHOR]

Abstract Protected areas (PAs) are often seen as a solution to the biodiversity crisis, however, such conservation intervention can drive environmental change and conflict. Despite being presented as neutral and technically informed, PA establishment is highly political, often concealing social, economic, and political factors. Political ecology research examines how dominant narratives shape PA establishment, helping to better understand multi-layered conflicts involving often marginalized communities, conservation actors and wildlife in East Africa. This paper presents a meta-synthesis of PA expansion in the region, revealing the intricate relationship between conservation and conflict. The analysis identifies four key themes: ‘commodification of wilderness’, ‘the war for biodiversity’, ‘community marginalization on the periphery’, and ‘conservation biopolitics’. By novel utilization of meta-synthesis methodology, this paper contributes two-fold: themes provide nuanced regional understandings of the processes driving conservation conflicts while drawing theoretical insights from case study research which reveal the general applicability of findings from political ecology research. [ABSTRACT FROM AUTHOR]

This article reviews various conceptual views behind the digital twins paradigm, highlights software technologies to develop digital twins, analyzes the use of digital twins during the lifecycle of industrial assets, and discusses a generic scenario from the electricity domain. [ABSTRACT FROM AUTHOR]

Simple Summary: B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. Even though the cure rate actually exceeds 85%, the prognosis of relapsed/refractory patients is dismal. Recent literature data indicate that the bone marrow (BM) microenvironment could play a crucial role in the onset, maintenance and progression of the disease. In particular, mesenchymal stromal cells (MSCs), which are key components of the BM niche, actively crosstalk with leukemic cells providing crucial signals for their survival and resistance to therapy. We hereby review the main mechanisms exploited by MSCs to nurture and protect B-ALL cells that could become appealing targets for innovative microenvironment remodeling therapies to be coupled with classical leukemia-directed strategies. Mesenchymal stromal cells (MSCs) are structural components of the bone marrow (BM) niche, where they functionally interact with hematopoietic stem cells and more differentiated progenitors, contributing to hematopoiesis regulation. A growing body of evidence is nowadays pointing to a further crucial contribution of MSCs to malignant hematopoiesis. In the context of B-cell acute lymphoblastic leukemia (B-ALL), MSCs can play a pivotal role in the definition of a leukemia-supportive microenvironment, impacting on disease pathogenesis at different steps including onset, maintenance and progression. B-ALL cells hijack the BM microenvironment, including MSCs residing in the BM niche, which in turn shelter leukemic cells and protect them from chemotherapeutic agents through different mechanisms. Evidence is now arising that altered MSCs can become precious allies to leukemic cells by providing nutrients, cytokines, pro-survivals signals and exchanging organelles, as hereafter reviewed. The study of the mechanisms exploited by MSCs to nurture and protect B-ALL blasts can be instrumental in finding new druggable candidates to target the leukemic BM microenvironment. Some of these microenvironment-targeting strategies are already in preclinical or clinical experimentation, and if coupled with leukemia-directed therapies, could represent a valuable option to improve the prognosis of relapsed/refractory patients, whose management represents an unmet medical need. [ABSTRACT FROM AUTHOR]

The endocannabinoidome (eCBome) is defined as an ensemble of (1) lipid mediators bearing chemical and, to some extent, biochemical and functional similarity with the two endogenous ligands of cannabinoid type-1 and type-2 (CB1 and CB2, respectively) receptors, that is, the endocannabinoids (eCBs) I N i -arachidonoyl-ethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2-AG); (2) the molecular targets for these mediators; and (3) their anabolic and catabolic enzymes.[1] By definition, the eCBome thus includes the eCBs as well as several families of eCB-like molecules, and proteins controlling their levels or mediating their actions. A microbiome-dependent gut-brain pathway regulates motivation for exercise. Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system. [Extracted from the article]

The discovery of the endocannabinoidome (eCBome) is evolving gradually with yet to be elucidated functional lipid mediators and receptors. The diet modulates these bioactive lipids and the gut microbiome, both working in an entwined alliance. Mounting evidence suggests that, in different ways and with a certain specialisation, lipid signalling mediators such as N-acylethanolamines (NAEs), 2-monoacylglycerols (2-MAGs), and N-acyl-amino acids (NAAs), along with endocannabinoids (eCBs), can modulate physiological mechanisms underpinning appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition, and immunity. This knowledge has been primarily utilised in pharmacology and medicine to develop many drugs targeting the fine and specific molecular pathways orchestrating eCB and eCBome activity. Conversely, the contribution of dietary NAEs, 2-MAGs and eCBs to the biological functions of these molecules has been little studied. In this review, we discuss the importance of (Wh) olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N) utrition (WHEN), in the management of obesity and related disorders. [ABSTRACT FROM AUTHOR]

The discovery of the endocannabinoidome (eCBome) is evolving gradually with yet to be elucidated functional lipid mediators and receptors. The diet modulates these bioactive lipids and the gut microbiome, both working in an entwined alliance. Mounting evidence suggests that, in different ways and with a certain specialisation, lipid signalling mediators such as N-acylethanolamines (NAEs), 2-monoacylglycerols (2-MAGs), and N-acyl-amino acids (NAAs), along with endocannabinoids (eCBs), can modulate physiological mechanisms underpinning appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition, and immunity. This knowledge has been primarily utilised in pharmacology and medicine to develop many drugs targeting the fine and specific molecular pathways orchestrating eCB and eCBome activity. Conversely, the contribution of dietary NAEs, 2-MAGs and eCBs to the biological functions of these molecules has been little studied. In this review, we discuss the importance of (Wh) olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N) utrition (WHEN), in the management of obesity and related disorders. [ABSTRACT FROM AUTHOR]

Background: Renal cell carcinoma (RCC) frequently metastasizes to distal organs such as the lungs, abdomen, bones, and brain. Although rare cases of adrenal gland metastasis from RCC have been described, to our knowledge, no cases have reported the use of stereotactic body radiotherapy (SBRT) in contralateral kidney oligometastasis in a nephrectomized patient with RCC. Case Report: We report a rare case of single contralateral renal metastasis from RCC in a 65-year-old female that occurred 1 year after right radical nephrectomy. At diagnosis of relapse, the patient received targeted therapy with sunitinib for 9 consecutive months, resulting in a partial regression of renal metastasis. To preserve the organ and consolidate response, SBRT was administered to the residual mass. Targeted therapy was temporarily discontinued 15 days before and after SBRT. Total SBRT dose was 40 Gy in 5 daily fractions given with volumetric modulated arc and image-guided technique. Three months later, magnetic resonance imaging documented a complete regression of disease, a result that persisted at the last follow-up 19 months after SBRT. Conclusion: The combination of sequential targeted therapy and SBRT provided an excellent outcome in a patient with a solitary kidney who experienced contralateral kidney metastasis from RCC. This treatment approach was well tolerated and controlled the disease. [ABSTRACT FROM AUTHOR]

Our objectives were to determine if milk casein as a percentage of true protein (CN%TP) estimated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) is equivalent to CN%TP estimated by Kjeldahl, and to determine the proportion of casein (CN), casein proteolysis products (CNPP), and serum protein (SP) from milk true protein (TP) that goes into the Kjeldahl noncasein nitrogen (NCN) filtrate and the proportion that stays in the NCN precipitate using SDS-PAGE. Raw milk samples were collected from 16 mid-lactation Holstein cows twice a week for 2 wk. These milks were analyzed for Kjeldahl total nitrogen, nonprotein nitrogen, and NCN content in duplicate, and by SDS-PAGE. The CN%TP determined by Kjeldahl was compared with the CN%TP estimated by SDS-PAGE calculated in 2 ways: as a percentage of only intact caseins divided by TP and as a percentage of both intact caseins and CNPP divided by TP. Three milks varying in fat, lactose, TP, CN, and SP content were formulated. These milks were analyzed in duplicate for Kjeldahl total nitrogen, nonprotein nitrogen, and NCN content, and each of the NCN filtrate and NCN precipitate were analyzed in duplicate by SDS-PAGE for relative quantity (%) of CN, CNPP, and SP. We found that the estimate of CN%TP by Kjeldahl was higher than the estimate of CN%TP by SDS-PAGE that was calculated as only intact CN divided by the total of all protein bands. However, no difference was detected in the estimate of CN%TP by Kjeldahl compared with CN%TP by SDS-PAGE when CNPP were included as CN in the calculation of SDS-PAGE results. Based on SDS-PAGE results, we found that a majority (89%) of the CNPP from the milk (approximately 10.13 out of 11.41% TP) were retained in the Kjeldahl NCN precipitate. Thus, CN%TP measured by Kjeldahl underestimates the amount of proteolytic damage that has been done to CN in milk. It is important for the dairy industry to correctly and rapidly measure the extent of proteolytic damage to milk protein to correctly value milk from a product quality and yield point of view. A rapid and quantitative measure of proteolytic damage to milk protein is needed. [ABSTRACT FROM AUTHOR]

This article proposes an automated methodology for the analysis of online political discourse. Drawing from the discourse quality index (DQI) by Steenbergen et al., it applies a machine learning–based quantitative approach to measuring the discourse quality of political discussions online. The DelibAnalysis framework aims to provide an accessible, replicable methodology for the measurement of discourse quality that is both platform and language agnostic. The framework uses a simplified version of the DQI to train a classifier, which can then be used to predict the discourse quality of any non-coded comment in a given political discussion online. The objective of this research is to provide a systematic framework for the automated discourse quality analysis of large datasets and, in applying this framework, to yield insight into the structure and features of political discussions online. [ABSTRACT FROM AUTHOR]

Context-aware, pervasive systems, mobile devices, intelligent virtual assistants activating services or controlling connected devices are pervading our everyday life. These systems rely on centralized services provided by servers in a cloud gathering all requests, performing pre-defined computations and involving pre-defined devices. Large-scale scenarios, involving unanticipated devices, adaptation to dynamically changing conditions, call for alternative solutions favoring edge computing and decentralized behavior. For several years, we have worked on a new type of applications, built and spontaneously composed on-demand. Applications arise from the interactions of multiple sensors and devices, working together as a decentralized collective adaptive system. Our solution relies on a learning-based coordination model providing decentralized communication platforms among agents working on behalf of heterogeneous devices. Each device provides few simple services and data regarding itself (properties and capabilities). In this article, we discuss first the design of complex services, arising from the spontaneous self-composition of simpler services. Second, we present our learning-based coordination model combining coordination and reinforcement learning, and how this approach ensures reliable self-composition of services in terms of functionality and expected quality of services. On the basis of a humanitarian scenario, we show the feasibility of the approach and discuss our current implementation. Preliminary results show convergence toward learning and correct functionality. Spontaneous self-composition and learning provide a self-adaptive solution for creating on-demand complex services evolving in highly dynamic scenarios comprising large numbers of connected devices. [ABSTRACT FROM AUTHOR]

Despite the underwater explosion phenomena (UNDEX) have been studied for decades and several numerical methods have been proposed in literature, the simulation of the whole phenomenon in issue is even nowadays a matter of research. In this paper, a Volume of Fluid (VOF) approach, which allows the simulation of Fluid-Structure Interaction (FSI), including the effects of seawater and vapor of cavitation on structures, is calibrated according to theory and experimental data. As a benchmark, a parallelepiped of fluid is built, verifying the effectiveness of the method with reference to some close-in explosions available in literature. In addition, VOF results are compared with the ones achieved from other researchers using the acoustic approximation. Strengths and limits of VOF coupling method are pointed out. In the end, the modelling strategy proposed and validated can be considered a suitable tool for the design of naval structures subject to underwater explosions. • FSI simulation of underwater explosions is even nowadays a matter of research. • Numerical methods to simulate FSI need preliminary calibration according to tests. • A Volume of Fluid approach is validated to predict UNDEX shock response. • As a benchmark, numerical results are compared with data achieved from literature. • The modelling strategy is a suitable tool for design of ships subject to UNDEX. [ABSTRACT FROM AUTHOR]

Challenging times [ABSTRACT FROM AUTHOR]

In many countries, biogas plants are mainly fed by livestock slurry and dedicated crops, including maize, which still represents one of the main energy crops utilized. Many concerns are now arising on environmental impact due to the high water consumption, chemical fertilizer and pesticide requirements and on adverse effect of maize as energy crop on the price of food and feed commodities. For these reasons two perennial crops, in particular miscanthus (Miscanthus x giganteus) and giant reed (Arundo donax L.), were cultivated at very low input and evaluated for their bio-methane yield at different harvest times and ensilage suitability, in a north-eastern area of Italy. Moreover, considering the agronomic use of the obtained digestate as fertilizer, this has been characterized by the content of heavy metals. Both multi-annual crops have proved highly productive in biomass especially with a harvest time in autumn, at which a satisfactory completion of the silage process without additives was observed. Conversely, bio-methane yield per hectare were not satisfactory with respect to the reference crops such as maize. The low BMP attained showed the main bottleneck of the methanisation of ensiled giant-reed and miscanthus, which is represented by fiber composition with high degree of lignification. The simulation use of digestate obtained as fertilizer in vulnerable areas, could lead to slightly exceed the levels allowed by the legislation of some European countries with regard of heavy metals as Cu, Zn and Cd. [ABSTRACT FROM AUTHOR]

The study investigates the soundness of a popular uncoupled design strategy for diffuser-augmented wind turbines (DAWTs), namely the use of an annular wing to enclose an existing open-rotor. To this aim, the paper presents a numerical analysis of the NREL-Phase-VI rotor enclosed into a shroud whose cross-section consists of the Selig-S1223 airfoil. Particular attention is devoted to the analysis of the blade pressure fields, velocity triangles, blade forces, tip-vortex and wake development. The data show that the duct induces a gain in the rotor inlet axial velocity and, therefore, in the local flow-angle. Consequently, the blade forces, the extracted work, and the risk of flow separation considerably rise. Thanks to the simultaneous increase in the ingested mass flow rate and extracted work, the DAWT experiences a higher power coefficient (C P , e x i t) which, however, would be further improved if a coupled design-procedure was used. Indeed, in the present case, the maximum C P , e x i t is obtained for the wind-speed value corresponding to the duct optimal flow behaviour. However, in this condition, the rotor operates at off-design with an extensive flow-separation on the blade suction-side. Finally, while the inefficiencies magnitude is specific of the analysed case, the conceptual relevance of the achievements remains valid in general. • Can efficient DWTs be designed ducting an existing open rotor? • Blade-resolved analysis of the NREL PhaseVI rotor enclosed in a Selig S1223 airfoil. • Ducting the rotor, the blade forces, the work, and the risk of flow separation rise. • The DWT has a higher C P , ex (0.48, gain: 21.66%) which is, however, lower than 0.59. • The study reveals the uncoupled design flaws yielding not-optimal flow conditions. [ABSTRACT FROM AUTHOR]

Palmitoylethanolamide (PEA) has emerged as a potential nutraceutical, because this compound is naturally produced in many plant and animal food sources, as well as in cells and tissues of mammals, and endowed with important neuroprotective, anti-inflammatory and analgesic actions. Several efforts have been made to identify the molecular mechanism of action of PEA and explain its multiple effects both in the central and the peripheral nervous system. Here, we provide an overview of the pharmacology, efficacy and safety of PEA in neurodegenerative disorders, pain perception and inflammatory diseases. The current knowledge of new formulations of PEA with smaller particle size (i.e. micronized and ultra-micronized) when given alone or in combination with antioxidant flavonoids (i.e. luteolin) and stilbenes (i.e. polydatin) is also reviewed.Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. [ABSTRACT FROM AUTHOR]

Traffic congestion is one of the main issues in the study of transportation planning and management. It creates different problems including environmental pollution and health problem and incurs a cost which is increasing through years. One-third of this congestion is created by cars searching for parking places. Drivers may be aware that parking places are fully occupied but will drive around hoping that a parking place may become vacant. Opportunistic services, involving learning, predicting, and exploiting Internet of Things scenarios, are able to adapt to dynamic unforeseen situations and have the potential to ease parking search issues. Hence, in this paper, a cooperative dynamic prediction mechanism between multiple agents for parking space availability in the neighborhood, integrating foreseen and unforeseen events and adapting for long-term changes, is proposed. An agent in each parking place will use a dynamic and time varying Markov chain to predict the parking availability and these agents will communicate to produce the parking availability prediction in the whole neighborhood. Furthermore, a learning approach is proposed where the system can adapt to different changes in the parking demand including long-term changes. Simulation results, using synthesized data based on an actual parking lot data from a shopping mall in Geneva, show that the proposed model is promising based on the learning accuracy with service adaptation and performance in different cases. [ABSTRACT FROM AUTHOR]

Our objective was to determine the effect of midinfrared (MIR) homogenizer efficiency on accuracy and repeatability of Fourier transform MIR predicted fat, true protein, and anhydrous lactose determination given by traditional filter and partial least squares (PLS) prediction models. Five homogenizers with different homogenization performance based on laser light-scattering particle size analysis were used. Repeatability and accuracy were determined by conducting 17 sequential readings on milk homogenized externally to the instrument (i.e., control) and unhomogenized milk. Milk component predictions on externally homogenized milks were affected by variation in homogenizer performance, but the magnitude of effect were small (i.e., <0.025%) when milks were pumped through both efficient and inefficient homogenizers within a MIR milk analyzer. Variation in the in-line MIR homogenizer performance on unhomogenized milks had a much larger effect on accuracy of component testing than on repeatability. The increase of particle size distribution [d(0.9)] from 1.35 to 3.03 μm (i.e., fat globule diameter above which 10% of the volume of fat is contained) due to poor homogenization affected fat tests the most; traditional filter based fat B (carbon hydrogen stretch; -0.165%), traditional filter-based fat A (carbonyl stretch; -0.074%), and fat PLS (-0.078%) at a d(0.9) of 3.03 μm. Variation in homogenization efficiency also affected traditional filter-based true protein test (+0.012%), true protein PLS prediction (-0.107%), and traditional filter-based anhydrous lactose test (+0.027%) at a d(0.9) of 3.03 μm. Effects of variation in homogenization on anhydrous lactose PLS predictions were small. The accuracy of both traditional filter models and PLS models were influenced by poor homogenization. The value of 1.7 μm for a d(0.9) used by the USDA Federal Milk Market laboratories as a criterion to make the decision to replace the homogenizer in a MIR milk analyzer appears to be a reasonable limit, given the magnitude of effect on the accuracy of fat tests. In the future, as new PLS models are developed to measure other components in milk, the sensitivity of the accuracy of the predictions of these models to factors such as variation of homogenizer performance should be determined as part of the ruggedness testing during PLS model development. [ABSTRACT FROM AUTHOR]

Our objective was to develop partial least square models using data from Fourier transform mid-infrared (MIR) spectra to predict the particle size distributions d(0.5) and d(0.9), surface volume mean diameter D[3,2], and volume moment mean diameter D[4,3] of milk fat globules and validate the models. The goal of the study was to produce a method built into the MIR milk analyzer that could be used to warn the instrument operator that the homogenizer is near failure and needs to be replaced to ensure quality of results. Five homogenizers with different homogenization efficiency were used to homogenize pasteurized modified unhomogenized milks and farm raw bulk milks. Homogenized milks were collected from the homogenizer outlet and then run through an MIR milk analyzer without an in-line homogenizer to collect a MIR spectrum. A separate portion of each homogenized milk was analyzed with a laser light-scattering particle size analyzer to obtain reference values. The study was replicated 3 times with 3 independent sets of modified milks and bulk tank farm milks. Validation of the models was done with a set of 34 milks that were not used in the model development. Partial least square regression models were developed and validated for predicting the following milk fat globule particle size distribution parameters from MIR spectra: d(0.5) and d(0.9), surface volume mean diameter D[3,2], and volume moment mean diameter D[4,3]. The basis for the ability to model particle size distribution of milk fat emulsions was hypothesized to be the result of the partial least square modeling detecting absorbance shifts in MIR spectra of milk fat due to the Christiansen effect. The independent sample validation of particle size prediction methods found more variation in d(0.9) and D[4,3] predictions than the d(0.5) and D[3,2] predictions relative to laser light-scattering reference values, and this may be due to variation in particle size among different pump strokes. The accuracy of the d(0.9) prediction for routine quality assurance, to determine if a homogenizer within an MIR milk analyzer was near the failure level [i.e., d(0.9) >1.7 μm] and needed to be replaced, is fit-for-purpose. The daily average particle size performance [i.e., d(0.9)] of a homogenizer based on the mean for the day could be used for monitoring homogenizer performance. [ABSTRACT FROM AUTHOR]

Seed dispersal is an essential trait that enables colonization of new favorable habitats, ensuring species survival. In plants with dehiscent fruits, such as Arabidopsis, seed dispersal depends on two processes: the separation of the fruit valves that protect the seeds (fruit dehiscence) and the detachment of the seeds from the funiculus connecting themto themother plant (seed abscission). The key factors required to establish a proper lignin pattern for fruit dehiscence are SHATTERPROOF 1 and 2 (SHP1 and SHP2). Here, we demonstrate that the SHP-related gene SEEDSTICK (STK) is a key factor required to establish the proper lignin pattern in the seed abscission zone but in an opposite way. We show that STK acts as a repressor of lignin deposition in the seed abscission zone through the direct repression of HECATE3, whereas the SHP proteins promote lignin deposition in the valve margins by activating INDEHISCENT. The interaction of STK with the SEUSS co-repressor determines the difference in theway STK and SHP proteins control the lignification patterns. Despite this difference in the molecular control of lignification during seed abscission and fruit dehiscence, we show that the genetic networks regulating these two developmental pathways are highly conserved. [ABSTRACT FROM AUTHOR]

Our objectives were to develop a method to produce milk somatic cell count (SCC) reference materials for calibration of electronic somatic cell count (ESCC) using gravity separation and to determine the effect of refrigerated storage (4°C) and freeze-thaw stability of the skim and whole milk SCC reference materials. Whole raw milk was high-temperature short-time pasteurized and split into 2 portions. One portion was gravity separated at 4°C for 22 h and the second portion was centrifugally separated to produce skim milk that was also gravity separated with somatic cells rising to the surface. After 22 h, stock solutions (low SCC skim milk, high SCC skim milk, high SCC whole milk) were prepared and preserved (bronopol). Two experiments were conducted, one to compare the shelf-life of skim and whole milk SCC standards at 4°C and one to determine the effect of freezing and thawing on SCC standards. Both experiments were replicated 3 times. Gravity separation was an effective approach to isolate and concentrate somatic cells from bovine milk and redistribute them in a skim or whole milk matrix to create a set of reference materials with a wider and more uniformly distributed range of SCC than current calibration sets. The liquid SCC reference materials stored using the common industry practice at 4°C were stable (i.e., fit for purpose, no large decrease in SCC) for a 2-wk period, whereas frozen and thawed reference materials may have a much longer useful life. A gradual decrease occurred in residual difference in ESCC (SCC × 1,000/mL) versus original assigned reference SCC over duration of refrigerated storage for both skim and whole milk SCC samples, indicating that milk ESCC of the preserved milks was gradually decreasing during 28 d of storage at 4°C by about 15,000 SCC/mL. No difference in the ESCC for skim milk was detected between refrigerated and frozen storage, whereas for whole milk the ESCC for frozen was lower than refrigerated samples. Future work is needed to determine the time and temperature of longer term frozen storage over which the SCC results are stable. [ABSTRACT FROM AUTHOR]

The endocannabinoid system (ECS) is composed of two G protein-coupled receptors (GPCRs), the cannabinoid CB1 and CB2 receptors, and the two main endogenous lipid ligands of such receptors (also known as the “endocannabinoids”), anandamide and 2-arachidonoyl-glycerol. The ECS is a pleiotropic signalling system involved in all aspects of mammalian physiology and pathology, and for this reason it represents a potential target for the design and development of new therapeutic drugs. However, the endocannabinoids as well as some of their congeners also interact with a much wider range of receptors, including members of the Transient Receptor Potential (TRP) channels, Peroxisome Proliferator-Activated Receptors (PPARs), and other GPCRs. Indeed, following the discovery of the endocannabinoids, endocannabinoid-related lipid mediators, which often share the same metabolic pathways of the endocannabinoids, have also been identified or rediscovered. In this review article, we discuss the role of endocannabinoids and related lipids during physiological functions, as well as their involvement in some of the most common neurological disorders. [ABSTRACT FROM AUTHOR]

A series of 31 arylboronic acids designed on the basis of the pharmacophore model for a variety of TRPV1 antagonists was prepared and tested on FAAH and TRPV1 channel. Four of them, that is, compounds 3c , 4a , 5a , b acted as dual FAAH/TRPV1 blockers with IC 50 values between 0.56 and 8.11 μM whereas ten others (compounds 1c , f – i , 2c – f , 4b ) inhibited FAAH and activated/desensitized TRPV1. [ABSTRACT FROM AUTHOR]

Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex ® ), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the ‘therapeutic handshake’, to predict efficacy/safety of compound combinations of either natural or synthetic origin. [ABSTRACT FROM AUTHOR]

The article discusses cannabinoid medicines. Topics including Tetrahydrocannabinol (THC) and cannabidiol (CBD) are primarily studied, particularly because high-grade Cannabis subspecies can produce over 20 percent yield of either compound; THC action in humans is dependent on the CB1 cannabinoid receptor which is the most abundant G protein–coupled receptor (GPCR) in the brain; and CBD is thought to have anti-inflammatory and tissue-protective effects.

• Underwater explosions can cause large deformations on naval composite structures. • Historically transient effects on fiberglass are predicted by quasi-static methods. • A dedicated shock test campaign is realized to characterize laminates dynamically. • A dynamic finite element model is validated to predict shock response in tests. • Experimental+numerical analyses validate modeling strategies for ships shock design. Non-contact underwater explosions (UNDEX) can cause extremely large deformations on naval composite structures related to heavily nonlinear phenomena. For this reason, for military purposes, used materials must have excellent shock resistance properties. Historically, the underwater shock transient effects on fiberglass laminates are predicted using quasi-static approaches. In this paper, the composite materials are characterized by experimental modal analysis as well as by a comprehensive series of shock tests, whose results are compared with numerical models. Namely, the MIL S 901 D Medium Weight Shock Machine (MWSM) was used to perform dedicated shock tests, in which composite specimens are supported on a special constraining structure designed to create large deflections and providing reproducible results. A dynamic implicit finite element model has been set, validated by modal analysis at first, and then applied to simulate the MWSM test behavior and to predict the structural response of different E-Glass polyester resin laminates. In the end, the complete comparison of numerical results and experimental data is reviewed to validate the modeling strategies for shock design of navy ships. [ABSTRACT FROM AUTHOR]

Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ9-tetrahydrocannabinol and cannabidiol ( THC/ CBD) oromucosal spray in patients with multiple sclerosis ( MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/ CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale ( NRS; ~−20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated. [ABSTRACT FROM AUTHOR]

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls - and is affected by - normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics. [ABSTRACT FROM AUTHOR]

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls--and is affected by--normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics. [ABSTRACT FROM AUTHOR]

Highlights: [•] An integral energy balance was derived for the MANOTEA facility. [•] A second equation was derived which frames transients in terms of inventory alone. [•] Both equations were implemented and showed good agreement with experimental data. [•] The equations capture the physical mechanisms behind MANOTEA transients. [•] Physical understanding is required in order to properly model these transients with TRACE. [Copyright &y& Elsevier]

Simple Summary: Dysbiosis, which is an imbalance of gut microbial composition and function, can be caused by several external as well as internal factors, contributing to the onset of human and animal disorders, not limited to the gastrointestinal tract. Accordingly, the mechanisms leading to disease development involve a crucial interaction between the gut microbiota, their metabolic products, and the host. The expanded endocannabinoid system, also known as the "endocannabinoidome", includes endocannabinoids (e.g., anandamide) and endocannabinoid-like mediators (e.g., palmitoylethanolamide), their receptors and metabolic enzymes. Dysregulation of this newly recognized endogenous system is also involved in several diseases. It is becoming increasingly apparent that a link between the endocannabinoidome and the gut microbiome exists. Here, we review some of the latest discoveries related to the functional link between these two complex systems and the disorders emerging from the malfunctioning of such a mutual interaction: for example, idiopathic inflammation, chronic enteropathies, metabolic disease and certain neuroinflammatory disorders. It is expected that in the near future new nutritional tools will emerge based on the expanding knowledge in this cutting-edge field. There is growing evidence that perturbation of the gut microbiome, known as "dysbiosis", is associated with the pathogenesis of human and veterinary diseases that are not restricted to the gastrointestinal tract. In this regard, recent studies have demonstrated that dysbiosis is linked to the pathogenesis of central neuroinflammatory disorders, supporting the existence of the so-called microbiome-gut-brain axis. The endocannabinoid system is a recently recognized lipid signaling system and termed endocannabinoidome monitoring a variety of body responses. Accumulating evidence demonstrates that a profound link exists between the gut microbiome and the endocannabinoidome, with mutual interactions controlling intestinal homeostasis, energy metabolism and neuroinflammatory responses during physiological conditions. In the present review, we summarize the latest data on the microbiome-endocannabinoidome mutual link in health and disease, focalizing the attention on gut dysbiosis and/or altered endocannabinoidome tone that may distort the bidirectional crosstalk between these two complex systems, thus leading to gastrointestinal and metabolic diseases (e.g., idiopathic inflammation, chronic enteropathies and obesity) as well as neuroinflammatory disorders (e.g., neuropathic pain and depression). We also briefly discuss the novel possible dietary interventions based not only on probiotics and/or prebiotics, but also, and most importantly, on endocannabinoid-like modulators (e.g., palmitoylethanolamide) for intestinal health and beyond. [ABSTRACT FROM AUTHOR]

Abstract: Apart from the psychotropic compound Δ9-tetrahydrocannabinol (THC), evidence suggests that other non-psychotropic phytocannabinoids are also of potential clinical use. This study aimed at elucidating the effect of major non-THC phytocannabinoids on the fate of adult neural stem progenitor cells (NSPCs), which are an essential component of brain function in health as well as in pathology. We tested three compounds: cannabidiol, cannabigerol, and cannabichromene (CBC), and found that CBC has a positive effect on the viability of mouse NSPCs during differentiation in vitro. The expression of NSPC and astrocyte markers nestin and Glial fibrillary acidic protein (GFAP), respectively, was up- and down-regulated, respectively. CBC stimulated ERK1/2 phosphorylation; however, this effect had a slower onset in comparison to typical MAPK stimulation. A MEK inhibitor, U0126, antagonized the up-regulation of nestin but not the down-regulation of GFAP. Based on a previous report, we studied the potential involvement of the adenosine A1 receptor in the effect of CBC on these cells and found that the selective adenosine A1 receptor antagonist, DPCPX, counteracted both ERK1/2 phosphorylation and up-regulation of nestin by CBC, indicating that also adenosine is involved in these effects of CBC, but possibly not in CBC inhibitory effect on GFAP expression. Next, we measured ATP levels as an equilibrium marker of adenosine and found higher ATP levels during differentiation of NSPCs in the presence of CBC. Taken together, our results suggest that CBC raises the viability of NSPCs while inhibiting their differentiation into astroglia, possibly through up-regulation of ATP and adenosine signalling. [Copyright &y& Elsevier]

Abstract: The exploitation of preparations of Cannabis sativa to combat pain seems to date back to time immemorial, although their psychotropic effects, which are at the bases of their recreational use and limit their therapeutic use, are at least as ancient. Indeed, it has always been different to tease apart the unwanted central effects from the therapeutic benefits of Δ9-tetrahydrocannabinol (THC), the main psychotropic component of cannabis. The discovery of the cannabinoid receptors and of their endogenous ligands, the endocannabinoids, which, unlike THC, play a pro-homeostatic function in a tissue- and time-selective manner, offered the opportunity to develop new analgesics from synthetic inhibitors of endocannabinoid inactivation. The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of “multi-target” versus “magic bullet” compounds as new analgesics. [Copyright &y& Elsevier]

Abstract: The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana''s psychoactive principle ∆9-tetrahydrocannabinol [∆9-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article. [Copyright &y& Elsevier]

The psychoactive component of the cannabis resin and flowers, delta9-tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related 'phytocannabinoid' compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the 'endocannabinoids' and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness. [ABSTRACT FROM AUTHOR]

The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ9-tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis. [ABSTRACT FROM AUTHOR]

Abstract: A simplified, integral, rapid-condensation transient device named the UMD-USNA Near One-dimensional Transient Experimental Apparatus (MANOTEA) was constructed at the United States Naval Academy in order to create a rapid-condensation dataset for comparison to TRACE code output. Integral, rapid condensation transients have historically been a challenge to reactor safety codes like TRACE, primarily due to the presence of multi-dimensional, multi-phase flow. MANOTEA was designed to eliminate these difficulties. A series of condensation-driven transients, for various nozzle geometries and sizes, was performed with the MANTOEA facility and the results are presented and explained. The data reveals that transient duration and amount of liquid transferred is a function of both condensation rate and metal mass effects. An energy partition concept is introduced as a convenient way to capture the interplay between nozzle size and geometry. The fundamental criteria for determining the state of any MANOTEA transient is how much liquid inventory has been transferred up to a given instant in time. This behavior is also observed in reactors during a loss of coolant scenario. The authors intend to publish the results of efforts to model the facility with TRACE in a companion paper. [Copyright &y& Elsevier]

Starting from the well-documented effects of marijuana smoking on heart rate and blood pressure, the cardiovascular effects of Δ9-tetrahydrocannabinol (THC, the main psychotropic ingredient of Cannabis) and endocannabinoids [THC endogenous counterparts that activate cannabinoid receptor type 1 (CB1) and 2 (CB2)] have been thoroughly investigated. These studies were mostly aimed at establishing the molecular bases of the hypotensive actions of THC, endocannabinoids and related molecules, but also evaluated their therapeutic potential in cardiac injury protection, metabolic cardiovascular risk factors and atherosclerotic plaque vulnerability. The results of these investigations, reviewed here, also served to highlight some of the most peculiar aspects of endocannabinoid signaling, such as redundancy in endocannabinoid targets and the often dualistic role of CB1 and CB2 receptors during pathological conditions. [ABSTRACT FROM AUTHOR]

This paper addresses a vision of future manufacturing systems, which are highly agile, user friendly, and increasingly based on autonomous components. Evolvable assembly systems (EASs) provide a solution for agile assembly, including a concept for reconfigurability with modularity at the mechanical as well as at the control level. It takes the multilateral relations among product, processes, and systems into account and allows the systems to evolve together with the requirements. Self-organizing assembly systems (SOASs) are a further development of EAS, allowing them to play an active role in layout design and production. This paper focuses on the self-organization mechanisms for the design of SOAS, as well as the system architecture, including agents and self-knowledge. Agentified modules participate in their own arrangement in the system layout and monitor themselves during production. Policies and metadata for self-management during production are described, and performance metrics for agility scenarios are indicated. [ABSTRACT FROM PUBLISHER]

Stemming from the centuries-old and well known effects of Cannabis on intestinal motility and secretion, research on the role of the endocannabinoid system in gut function and dysfunction has received ever increasing attention since the discovery of the cannabinoid receptors and their endogenous ligands, the endocannabinoids. In this article, some of the most recent developments in this field are discussed, with particular emphasis on new data, most of which are published in Neurogastroenterology & Motility, on the potential tonic endocannabinoid control of intestinal motility, the function of cannabinoid type-1 (CB1) receptors in gastric function, visceral pain, inflammation and sepsis, the emerging role of cannabinoid type-2 (CB2) receptors in the gut, and the pharmacology of endocannabinoid-related molecules and plant cannabinoids not necessarily acting via cannabinoid CB1 and CB2 receptors. These novel data highlight the multi-faceted aspects of endocannabinoid function in the GI tract, support the feasibility of the future therapeutic exploitation of this signaling system for the treatment of GI disorders, and leave space for some intriguing new hypotheses on the role of endocannabinoids in the gut. [ABSTRACT FROM AUTHOR]

Studies of the endocannabinoid system in the CNS have been mostly focused on endocannabinoid receptors and inactivating mechanisms. Until recently, very little was known about the role of biosynthetic enzymes in endocannabinoid signaling. New data from the recent development of pharmacological and genetic tools for the study of these enzymes point to their fundamental role in determining where and when endocannabinoids function, and raise the possibility of new intriguing and previously unsuspected concepts in the general strategy of endocannabinoid signaling. However, even with these new tools, the cross-talk between anandamide and 2-arachidonoylglycerol biosynthesis makes it difficult to dissect one from the other, and data will need to be interpreted with this in mind. [ABSTRACT FROM AUTHOR]

Abstract: Evidence suggests that dietary long chain polyunsaturated fatty acids (LCPUFAs), and particularly those belonging to the n-3 family, may influence the brain fatty acid profile and, thereby, the biosynthesis of endocannabinoids in rodents. However, the doses used are usually quite high and not comparable with human intake. Recently, we have shown that relatively low doses of dietary n-3 LCPUFAs (4 weeks), in the form of either fish or krill oil, balanced for EPA and DHA content, and against a control diet with no EPA and DHA and similar contents of oleic, linoleic and α-linolenic acids, lower the concentrations of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in the visceral adipose tissue, and of AEA in the liver and heart, of obese Zucker rats. This, in turn, is associated with lower levels of arachidonic acid in membrane phospholipids and with amelioration of some metabolic syndrome parameters. We investigated here whether in Zucker rats, under the same conditions, fish and krill oil are also able to influence LCPUFA and endocannabinoid profiles in brain. Only krill oil was able to increase significantly DHA levels in brain phospholipids, with no changes in arachidonic acid. DHA increase was associated with lower levels of 2-AG in the brain, whereas AEA and its congeners, N-palmitoylethanolamine and N-oleoylethanolamine, were unchanged. We conclude that, despite the strong impact of dietary n-3 fatty acid on endocannabinoid levels previously observed in peripheral tissues, in the brain only 2-AG is affected by dietary krill oil, suggesting that the beneficial effect of the latter on the metabolic syndrome is mostly exerted by modifying peripheral endocannabinoids. Nevertheless, possible effects of dietary krill oil in the brain through modification of 2-AG levels deserve further investigation. [Copyright &y& Elsevier]

When compared with other modifiable cardiovascular risk factors, such as hypertension, dyslipidemia and smoking, obesity remains a surprisingly puzzling condition to prevent and treat. The history of the development of anti-obesity drugs has known more defeats than even partial victories. With very few drugs on the market, and bad publicity related to adverse events, obesity remains an almost completely unmet challenge for the pharmaceutical industry. In light of past experience with endocannabinoid-system antagonists, such as rimonabant, we propose that a major paradigm shift in clinical practice might be necessary to justify the use of pharmacotherapy for obesity. Furthermore, we suggest that the criteria currently used by regulatory authorities to evaluate and approve anti-obesity drugs should be rigorously re-examined. Finally, we discuss how pharmacological approaches that aim to counteract overactivity of the endocannabinoid system should be revisited in the future to treat visceral (intra-abdominal) obesity and its metabolic consequences. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Endocannabinoids (ECs) control metabolism via cannabinoid receptors type 1 (CB1). Their plasma levels are elevated in overweight type 2 diabetes (T2D) and in obese patients, and decrease postprandially in normoweight individuals. We investigated in two different cohorts of nonobese or obese volunteers whether oral glucose in glucose tolerance tests (OGTT) or acute insulin infusion during euglycemic hyperinsulinemic clamp affect plasma EC levels. DESIGN AND METHODS: OGTT was performed in ten obese hyperinsulinemic patients (body mass index (BMI)=35.8 kg/m2, fasting insulin=14.83 mU/l), and ten normoweight normoinsulinemic volunteers (BMI=21.9 kg/m2, fasting insulin=7.2 mU/l). Insulin clamp was performed in 19 mostly nonobese men (BMI=25.8 kg/m2) with varying degrees of liver fat and plasma triglycerides (TGs), with (n=7) or without T2D. Plasma levels of ECs (anandamide and 2-arachidonoylglycerol (2-AG)) were measured by liquid chromatography–mass spectrometry, before and 60 and 180 min after OGTT, and before and 240 and 480 min after insulin or saline infusion. RESULTS: Oral glucose load decreased anandamide plasma levels to an extent inversely correlated with BMI, waist circumference, subcutaneous fat, fasting insulin and total glucose, and insulin areas under the curve during the OGTT, and nonsignificantly in obese volunteers. Insulin infusion decreased anandamide levels to an extent that weakly, but significantly, correlated negatively with TGs, liver fat and fasting insulin, and positively with high density lipoprotein cholesterol. OGTT decreased 2-AG levels to a lower extent and in a way weakly inversely correlated with fasting insulin. CONCLUSIONS: We suggest that insulin reduces EC levels in a way inversely related to anthropometric and metabolic predictors of insulin resistance and dyslipidemia. [ABSTRACT FROM AUTHOR]