Comparative Transcriptomics of Fat Bodies between Symbiotic and Quasi-Aposymbiotic Adult Females of Blattella germanica with Emphasis on the Metabolic Integration with Its Endosymbiont Blattabacterium and Its Immune System.

We explored the metabolic integration of Blattella germanica and its obligate endosymbiont Blattabacterium cuenoti by the transcriptomic analysis of the fat body of quasi-aposymbiotic cockroaches, where the endosymbionts were almost entirely removed with rifampicin. Fat bodies from quasi-aposymbiotic insects displayed large differences in gene expression compared to controls. In quasi-aposymbionts, the metabolism of phenylalanine and tyrosine involved in cuticle sclerotization and pigmentation increased drastically to compensate for the deficiency in the biosynthesis of these amino acids by the endosymbionts. On the other hand, the uricolytic pathway and the biosynthesis of uric acid were severely decreased, probably because the reduced population of endosymbionts was unable to metabolize urea to ammonia. Metabolite transporters that could be involved in the endosymbiosis process were identified. Immune system and antimicrobial peptide (AMP) gene expression was also reduced in quasi-aposymbionts, genes encoding peptidoglycan-recognition proteins, which may provide clues for the maintenance of the symbiotic relationship, as well as three AMP genes whose involvement in the symbiotic relationship will require additional analysis. Finally, a search for AMP-like factors that could be involved in controlling the endosymbiont identified two orphan genes encoding proteins smaller than 200 amino acids underexpressed in quasi-aposymbionts, suggesting a role in the host-endosymbiont relationship.

Sensing Apps and Public Data Sets for Digital Phenotyping of Mental Health: Systematic Review.

BACKGROUND: Mental disorders are normally diagnosed exclusively on the basis of symptoms, which are identified from patients' interviews and self-reported experiences. To make mental health diagnoses and monitoring more objective, different solutions have been proposed such as digital phenotyping of mental health (DPMH), which can expand the ability to identify and monitor health conditions based on the interactions of people with digital technologies. OBJECTIVE: This article aims to identify and characterize the sensing applications and public data sets for DPMH from a technical perspective. METHODS: We performed a systematic review of scientific literature and data sets. We searched 8 digital libraries and 20 data set repositories to find results that met the selection criteria. We conducted a data extraction process from the selected articles and data sets. For this purpose, a form was designed to extract relevant information, thus enabling us to answer the research questions and identify open issues and research trends. RESULTS: A total of 31 sensing apps and 8 data sets were identified and reviewed. Sensing apps explore different context data sources (eg, positioning, inertial, ambient) to support DPMH studies. These apps are designed to analyze and process collected data to classify (n=11) and predict (n=6) mental states/disorders, and also to investigate existing correlations between context data and mental states/disorders (n=6). Moreover, general-purpose sensing apps are developed to focus only on contextual data collection (n=9). The reviewed data sets contain context data that model different aspects of human behavior, such as sociability, mood, physical activity, sleep, with some also being multimodal. CONCLUSIONS: This systematic review provides in-depth analysis regarding solutions for DPMH. Results show growth in proposals for DPMH sensing apps in recent years, as opposed to a scarcity of public data sets. The review shows that there are features that can be measured on smart devices that can act as proxies for mental status and well-being; however, it should be noted that the combined evidence for high-quality features for mental states remains limited. DPMH presents a great perspective for future research, mainly to reach the needed maturity for applications in clinical settings.

Identification of the Gene Repertoire of the IMD Pathway and Expression of Antimicrobial Peptide Genes in Several Tissues and Hemolymph of the Cockroach Blattella germanica.

Antimicrobial peptide (AMP) genes, triggered by Toll and IMD pathways, are essential components of the innate immune system in the German cockroach Blattella germanica. Besides their role in killing pathogenic bacteria, AMPs could be involved in controlling its symbiotic systems (endosymbiont and microbiota). We found that the IMD pathway was active in the adult female transcriptomes of six tissues (salivary glands, foregut, midgut, hindgut, Malpighian tubules and fat body) and hemolymph. Total expression of AMP genes was high in hemolymph and salivary glands and much lower in the other sample types. The expression of specific AMP genes was very heterogeneous among sample types. Two genes, defensin_g10 and drosomycin_g5, displayed relevant expression in the seven sample types, although higher in hemolymph. Other genes only displayed high expression in one tissue. Almost no expression of attacin-like and blattellicin genes was observed in any sample type, although some of them were among the genes with the highest expression in adult female whole bodies. The expression of AMP genes in salivary glands could help control pathogens ingested with food and even determine gut microbiota composition. The low expression levels in midgut and hindgut are probably related to the presence of beneficial microbiota. Furthermore, a reduction in the expression of AMP genes in fat body could be the way to prevent damage to the population of the endosymbiont Blattabacterium cuenoti within bacteriocytes.

Pep19 Has a Positive Effect on Insulin Sensitivity and Ameliorates Both Hepatic and Adipose Tissue Phenotype of Diet-Induced Obese Mice.

Peptide DIIADDEPLT (Pep19) has been previously suggested to improve metabolic parameters, without adverse central nervous system effects, in a murine model of diet-induced obesity. Here, we aimed to further evaluate whether Pep19 oral administration has anti-obesogenic effects, in a well-established high-fat diet-induced obesity model. Male Swiss mice, fed either a standard diet (SD) or high-fat diet (HFD), were orally administrated for 30 consecutive days, once a day, with saline vehicle or Pep19 (1 mg/kg). Next, several metabolic, morphological, and behavioral parameters were evaluated. Oral administration of Pep19 attenuated HFD body-weight gain, reduced in approximately 40% the absolute mass of the endocrine pancreas, and improved the relationship between circulating insulin and peripheral insulin sensitivity. Pep19 treatment of HFD-fed mice attenuated liver inflammation, hepatic fat distribution and accumulation, and lowered plasma alanine aminotransferase activity. The inguinal fat depot from the SD group treated with Pep19 showed multilocular brown-fat-like cells and increased mRNA expression of uncoupling protein 1 (UCP1), suggesting browning on inguinal white adipose cells. Morphological analysis of brown adipose tissue (BAT) from HFD mice showed the presence of larger white-like unilocular cells, compared to BAT from SD, Pep19-treated SD or HFD mice. Pep19 treatment produced no alterations in mice behavior. Oral administration of Pep19 ameliorates some metabolic traits altered by diet-induced obesity in a Swiss mice model.

(+)-trans-Cannabidiol-2-hydroxy pentyl is a dual CB1R antagonist/CB2R agonist that prevents diabetic nephropathy in mice.

Natural cannabidiol ((-)-CBD) and its derivatives have increased interest for medicinal applications due to their broad biological activity spectrum, including targeting of the cannabinoid receptors type 1 (CB1R) and type 2 (CB2R). Herein, we synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxypentylester ((+)-CBD-HPE) that showed enhanced CB1R and CB2R binding and functional activities compared to their respective (-) enantiomers. (+)-CBD-HPE Ki values for CB1R and CB2R were 3.1 ± 1.1 and 0.8 ± 0.1 nM respectively acting as CB1R antagonist and CB2R agonist. We further tested the capacity of (+)-CBD-HPE to prevent hyperglycemia and its complications in a mouse model. (+)-CBD-HPE significantly reduced streptozotocin (STZ)-induced hyperglycemia and glucose intolerance by preserving pancreatic beta cell mass. (+)-CBD-HPE significantly reduced activation of NF-κB by phosphorylation by 15% compared to STZ-vehicle mice, and CD3+ T cell infiltration into the islets was avoided. Consequently, (+)-CBD-HPE prevented STZ-induced apoptosis in islets. STZ induced inflammation and kidney damage, visualized by a significant increase in plasma proinflammatory cytokines, creatinine, and BUN. Treatment with (+)-CBD-HPE significantly reduced 2.5-fold plasma IFN-γ and increased 3-fold IL-5 levels compared to STZ-treated mice, without altering IL-18. (+)-CBD-HPE also significantly reduced creatinine and BUN levels to those comparable to healthy controls. At the macroscopy level, (+)-CBD-HPE prevented STZ-induced lesions in the kidney and voided renal fibrosis and CD3+ T cell infiltration. Thus, (+)-enantiomers of CBD, particularly (+)-CBD-HPE, have a promising potential due to their pharmacological profile and synthesis, potentially to be used for metabolic and immune-related disorders.

Cutting Forces Assessment in CNC Machining Processes: A Critical Review.

Machining processes remain an unavoidable technique in the production of high-precision parts. Tool behavior is of the utmost importance in machining productivity and costs. Tool performance can be assessed by the roughness left on the machined surfaces, as well as of the forces developed during the process. There are various techniques to determine these cutting forces, such as cutting force prediction or measurement, using dynamometers and other sensor systems. This technique has often been used by numerous researchers in this area. This paper aims to give a review of the different techniques and devices for measuring the forces developed for machining processes, allowing a quick perception of the advantages and limitations of each technique, through the literature research carried out, using recently published works.

Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: a long-term safety and feasibility study.

BACKGROUND: Chronic low back pain due to disc degeneration represents a major social and economic burden worldwide. The current standard of care is limited to symptomatic relief and no current approved therapy promotes disc regeneration. Bone marrow-derived mesenchymal stem cells (MSCs) are easily accessible and well characterized. These MSCs are multipotent and exhibit great tissue regenerative potential including bone, cartilage, and fibrous tissue regeneration. The use of this cell-based biologic for treating protruding disc herniation and/or intervertebral disc degeneration is a promising therapeutic strategy, due to their known regenerative, immuno-modulatory and anti-inflammatory properties. METHODS: Five patients diagnosed with degenerative disc disease received an intra-discal injection of autologous, hypoxic cultured, bone marrow-derived mesenchymal stem cells (15.1-51.6 million cells) as part of a previous study. These patients were re-consented to participate in this study in order to assess long-term safety and feasibility of intra-discal injection of autologous, hypoxic cultured, bone marrow-derived mesenchymal stem cells 4-6 years post mesenchymal stem cell infusion. The follow-up study consisted of a physical examination, a low back MRI, and a quality of life questionnaire. RESULTS: Patients' lower back MRI showed absence of neoplasms or abnormalities surrounding the treated region. Based on the physical examination and the quality of life questionnaire, no adverse events were reported due to the procedure or to the stem cell treatment 4-6 years post autologous, hypoxic cultured mesenchymal stem cell infusion. All patients self-reported overall improvement, as well as improvement in strength, post stem cell treatment, and four out of five patients reported improvement in mobility. CONCLUSION: This early human clinical data suggests the safety and feasibility of the clinical use of hypoxic cultured bone marrow-derived mesenchymal stem cells for the treatment of lower back pain due to degenerative disc disorders and support further studies utilizing hypoxic cultured bone marrow-derived stem cells. The overall improvements reported are encouraging, but a larger double-blind, controlled, randomized clinical study with significant number of patients and implementation of validated endpoint measurements are next steps in order to demonstrate efficacy of this cell-based biologic.

Nature lessons: The whitefly bacterial endosymbiont is a minimal amino acid factory with unusual energetics.

Reductive genome evolution is a universal phenomenon observed in endosymbiotic bacteria in insects. As the genome reduces its size and irreversibly losses coding genes, the functionalities of the cell system, including the energetics processes, are more restricted. Several energetic pathways can also be lost. How do these reduced metabolic networks sustain the energy needs of the system? Among the bacteria with reduced genomes Candidatus Portiera aleyrodidarum, obligate endosymbiont of whiteflies, represents an extreme case since lacks several key mechanisms for ATP generation. Thus, to analyze the cell energetics in this system, a genome-scale metabolic model of this endosymbiont was constructed, and its energy production capabilities dissected using stoichiometric analysis. Our results suggest that energy generation is coupled to the synthesis of essential amino acids and carotenoids, crucial metabolites in the symbiotic association. A deeper insight showed that ATP production via carotenoid synthesis is also connected with amino acid production. This unusual association of energy production with anabolism suggests that, although minimized, endosymbiont metabolic networks maintain a remarkable biosynthetic potential.

Genome reduction and potential metabolic complementation of the dual endosymbionts in the whitefly Bemisia tabaci.

BACKGROUND: The whitefly Bemisia tabaci is an important agricultural pest with global distribution. This phloem-sap feeder harbors a primary symbiont, "Candidatus Portiera aleyrodidarum", which compensates for the deficient nutritional composition of its food sources, and a variety of secondary symbionts. Interestingly, all of these secondary symbionts are found in co-localization with the primary symbiont within the same bacteriocytes, which should favor the evolution of strong interactions between symbionts. RESULTS: In this paper, we analyzed the genome sequences of the primary symbiont Portiera and of the secondary symbiont Hamiltonella in the B. tabaci Mediterranean (MED) species in order to gain insight into the metabolic role of each symbiont in the biology of their host. The genome sequences of the uncultured symbionts Portiera and Hamiltonella were obtained from one single bacteriocyte of MED B. tabaci. As already reported, the genome of Portiera is highly reduced (357 kb), but has kept a number of genes encoding most essential amino-acids and carotenoids. On the other hand, Portiera lacks almost all the genes involved in the synthesis of vitamins and cofactors. Moreover, some pathways are incomplete, notably those involved in the synthesis of some essential amino-acids. Interestingly, the genome of Hamiltonella revealed that this secondary symbiont can not only provide vitamins and cofactors, but also complete the missing steps of some of the pathways of Portiera. In addition, some critical amino-acid biosynthetic genes are missing in the two symbiotic genomes, but analysis of whitefly transcriptome suggests that the missing steps may be performed by the whitefly itself or its microbiota. CONCLUSIONS: These data suggest that Portiera and Hamiltonella are not only complementary but could also be mutually dependent to provide a full complement of nutrients to their host. Altogether, these results illustrate how functional redundancies can lead to gene losses in the genomes of the different symbiotic partners, reinforcing their inter-dependency.

Metabolically active human brown adipose tissue derived stem cells.

Brown adipose tissue (BAT) plays a key role in the evolutionarily conserved mechanisms underlying energy homeostasis in mammals. It is characterized by fat vacuoles 5-10 µm in diameter and expression of uncoupling protein one, central to the regulation of thermogenesis. In the human newborn, BAT depots are typically grouped around the vasculature and solid organs. These depots maintain body temperature during cold exposure by warming the blood before its distribution to the periphery. They also ensure an optimal temperature for biochemical reactions within solid organs. BAT had been thought to involute throughout childhood and adolescence. Recent studies, however, have confirmed the presence of active BAT in adult humans with depots residing in cervical, supraclavicular, mediastinal, paravertebral, and suprarenal regions. While human pluripotent stem cells have been differentiated into functional brown adipocytes in vitro and brown adipocyte progenitor cells have been identified in murine skeletal muscle and white adipose tissue, multipotent metabolically active BAT-derived stem cells from a single depot have not been identified in adult humans to date. Here, we demonstrate a clonogenic population of metabolically active BAT stem cells residing in adult humans that can: (a) be expanded in vitro; (b) exhibit multilineage differentiation potential; and (c) functionally differentiate into metabolically active brown adipocytes. Our study defines a new target stem cell population that can be activated to restore energy homeostasis in vivo for the treatment of obesity and related metabolic disorders.

Task-specific modulation of adult humans' tool preferences: number of choices and size of the problem.

In two experiments, we examined the effect of modifications to the features of a stick-and-tube problem on the stick lengths that adult humans used to solve the problem. In Experiment 1, we examined whether people's tool preferences for retrieving an out-of-reach object in a tube might more closely resemble those reported with laboratory crows if people could modify a single stick to an ideal length to solve the problem. Contrary to when adult humans have selected a tool from a set of ten sticks, asking people to modify a single stick to retrieve an object did not generally result in a stick whose length was related to the object's distance. Consistent with the prior research, though, the working length of the stick was related to the object's distance. In Experiment 2, we examined the effect of increasing the scale of the stick-and-tube problem on people's tool preferences. Increasing the scale of the task influenced people to select relatively shorter tools than had selected in previous studies. Although the causal structures of the tasks used in the two experiments were identical, their results were not. This underscores the necessity of studying physical cognition in relation to a particular causal structure by using a variety of tasks and methods.

Adult humans' understanding of support relations: an up-linkage replication.

In an up-linkage replication, three experiments examined adult humans' folk physics, i.e., their naturally occurring and spontaneous understanding of the physical world, using a violation of expectation (VOE) task and stimuli similar to those used to study chimpanzees', monkeys', and rooks' folk physics. Unlike what has been reported with nonhuman primates, adult humans did not look longer at physically impossible than possible events, though they did rate the physically impossible events as more interesting and novel than the possible events. These results underscore that behavior during a VOE experiment has many possible causes, only one of which may be a subject's folk physics.

Mechanical Strength and Surface Analysis of a Composite Made from Recycled Carbon Fibre Obtained via the Pyrolysis Process for Reuse in the Manufacture of New Composites.

This work aims to obtain recycled carbon fibre and develop an application for this new material. The carbon fibres were obtained by recycling aerospace prepreg waste via the pyrolysis process. The recycled fibres were combined with an Araldite LH5052/Aradur LY5053 epoxy resin/hardener system using manual lay-up and vacuum bagging processes. For comparison, the same resin/hardener system was used to produce a composite using commercial carbon fibre. The recycled and commercial composites were subjected to flexural, tensile and Mode I testing. Fracture aspects were analysed via scanning electron microscopy (SEM). The pyrolysis process did not affect the fibre surface as no degradation was observed. The fracture aspect showed a mixture of failure in the recycled composite laminate and interlaminar/translaminar failure near the surface of the commercial composite caused by flexural stress. Flexural and tensile tests showed a loss of mechanical strength due to the recycling process, but the tensile values were twice as high. The sand ladder platform was the project chosen for the development of a product made with recycled carbon fibres. The product was manufactured using the same manufacturing process as the specimens and tested with a 1243 kg car. The method chosen to design, manufacture and test the prototype sand ladder platform made of recycled carbon fibre was appropriate and gave satisfactory results in terms of high mechanical strength to bending and ease of use.

An In-Depth Exploration of Unconventional Machining Techniques for INCONEL® Alloys.

Build-up-edge (BUE), high-temperature machining and tool wear (TW) are some of the problems associated with difficult-to-machine materials for high-temperature applications, contributing significantly to high-cost manufacturing and poor tool life (TL) management. A detailed review of non-traditional machining processes that ease the machinability of INCONEL®, decrease manufacturing costs and suppress assembly complications is thus of paramount significance. Progress taken within the field of INCONEL® non-conventional processes from 2016 to 2023, the most recent solutions found in the industry, and the prospects from researchers have been analysed and presented. In ensuing research, it was quickly noticeable that some techniques are yet to be intensely exploited. Non-conventional INCONEL® machining processes have characteristics that can effectively increase the mechanical properties of the produced components without tool-workpiece contact, posing significant advantages over traditional manufacturing.

Investigations on the Surface Integrity and Wear Mechanisms of TiAlYN-Coated Tools in Inconel 718 Milling Operations.

Inconel 718 is a Ni superalloy with superior mechanical properties, even at high temperatures. However, due to its high hardness and low thermal conductivity, it is considered a difficult-to-machine material. This material is widely used in applications that require good dimensional stability, making the milling process the most used in machining this alloy. The wear resulting from this process and the quality of the machined surface are still challenging factors when it comes to Inconel 718. TiAlN-based coating has been used on cutting tools with Yttrium as a doping element to improve the process performance. Based on this, this work evaluated the machined surface integrity and wear resistance of cutting tools coated using Physical Vapor Deposition (PVD) HiPIMS with TiAlYN in the end milling of Inconel 718, varying the process parameters such as cutting speed (vc), feed per tooth (fz), and cutting length (Lcut). It was verified that the Lcut is the parameter that exerts the most significant influence since, even at small distances, Inconel 718 already generates high tool wear (TW). Furthermore, the main wear mechanisms were abrasive and adhesive wear, with the development of a built-up edge (BUE) under a125 m/min feed rate (f) and a Lcut = 15 m. Chipping, cracking, and delamination of the coating were also observed, indicating a lack of adhesion between the coating and the substrate, suggesting the need for a good interlayer or the adjustment of the PVD parameters.

Diet-dependent modulation of hippocampal expression of endocannabinoid signaling-related proteins in cannabinoid antagonist-treated obese rats.

Diet-induced obesity produces changes in endocannabinoid signaling (ECS), influencing the regulation of energy homeostasis. Recently, we demonstrated that, in high-fat-diet-fed rats, blockade of CB1 receptor by AM251 not only reduced body weight but also increased adult neurogenesis in the hippocampus, suggesting an influence of diet on hippocampal cannabinoid function. To further explore the role of hippocampal ECS in high-fat-diet-induced obesity, we investigated whether the immunohistochemical expression of the enzymes that produce (diacylglycerol lipase alpha and N-acyl phosphatidylethanolamine phospholipase D) and degrade (monoacylglycerol lipase and fatty acid amino hydrolase) endocannabinoids may be altered in the hippocampus of AM251 (3 mg/kg)-treated rats fed three different diets: standard diet (normal chow), high-carbohydrate diet (70% carbohydrate) and high-fat diet (60% fat). Results indicated that AM251 reduced caloric intake and body weight gain, and induced a modulation of the expression of ECS-related proteins in the hippocampus of animals exposed to hypercaloric diets. These effects were differentially restricted to either the 2-arachinodoyl glycerol or anandamide signaling pathways, in a diet-dependent manner. AM251-treated rats fed the high-carbohydrate diet showed a reduction of the diacylglycerol lipase alpha : monoacylglycerol lipase ratio, whereas AM251-treated rats fed the high-fat diet showed a decrease of the N-acyl phosphatidylethanolamine phospholipase D : fatty acid amino hydrolase ratio. These results are consistent with the reduced levels of hippocampal endocannabinoids found after food restriction. Regarding the CB1 expression, AM251 induced specific changes focused in the CA1 stratum pyramidale of high-fat-diet-fed rats. These findings indicated that the cannabinoid antagonist AM251 modulates ECS-related proteins in the rat hippocampus in a diet-specific manner. Overall, these results suggest that the hippocampal ECS participates in the physiological adaptations to different caloric diets.

Cocaine self-administration differentially modulates the expression of endogenous cannabinoid system-related proteins in the hippocampus of Lewis vs. Fischer 344 rats.

The endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) are modulators of glutamate and γ-aminobutyric acid (GABA), two transmitters involved in cocaine addiction. However, little is known on the effects of cocaine on the enzymes that produce and degrade endocannabinoids. The present work addresses the effects of cocaine self-administration on the immunohistochemical expression of endocannabinoid signalling (ECS)-related proteins in the hippocampus. The study has been performed on two different strains of rats, Lewis (Lew) and Fischer 344 (F344), which are characterized for displaying a differential sensitivity to cocaine, thus making them suitable in the study of vulnerability to drug addiction. Both strains showed differences in the expression of ECS-related proteins in the hippocampus, i.e. Lew rats exhibited lower CB1 expression but higher CB2 expression than F344 rats. After setting similar cocaine self-administration, both strains showed clear differences in the expression of ECS-related proteins, which were differentially restricted to either the 2-AG or anandamide signalling pathways in a self-administration training/drug-dependent manner. The decreases observed in CB1 expression and N-acyl phosphatidylethanolamine phospholipase D:fatty acid amino hydrolase ratio after saline self-administration were enhanced only in cocaine self-administered Lew rats. CB2 expression increase and diacylglycerol lipase α:monoacylglycerol lipase ratio decrease detected after saline self-administration were blocked only in cocaine self-administered F344 rats. These findings indicate that cocaine may regulate hippocampal GABA/glutamate synapses by directly modulating endocannabinoid production/degradation enzymes and that these actions are strain-dependent. This differential response suggests that the endogenous cannabinoid system might contribute to genotype/strain differences on the sensitivity to self-administration training and cocaine addiction.

Oleoylethanolamide dose-dependently attenuates cocaine-induced behaviours through a PPARα receptor-independent mechanism.

Oleoylethanolamide (OEA) is an acylethanolamide that acts as an agonist of nuclear peroxisome proliferator-activated receptor alpha (PPARα) to exert their biological functions, which include the regulation of appetite and metabolism. Increasing evidence also suggests that OEA may participate in the control of reward-related behaviours. However, direct experimental evidence for the role of the OEA-PPARα receptor interaction in drug-mediated behaviours, such as cocaine-induced behavioural phenotypes, is lacking. The present study explored the role of OEA and its receptor PPARα on the psychomotor and rewarding responsiveness to cocaine using behavioural tests indicative of core components of addiction. We found that acute administration of OEA (1, 5 or 20 mg/kg, i.p.) reduced spontaneous locomotor activity and attenuated psychomotor activation induced by cocaine (20 mg/kg) in C57Bl/6 mice. However, PPARα receptor knockout mice showed normal sensitization, although OEA was capable of reducing behavioural sensitization with fewer efficacies. Furthermore, conditioned place preference and reinstatement to cocaine were intact in these mice. Our results indicate that PPARα receptor does not play a critical, if any, role in mediating short- and long-term psychomotor and rewarding responsiveness to cocaine. However, further research is needed for the identification of the targets of OEA for its inhibitory action on cocaine-mediated responses.

Description of a bivalent cannabinoid ligand with hypophagic properties.

A series of bivalent cannabinoid ligands is proposed. The synthesis of double amides based on the rimonabant structure separated by an alkyl chain and the evaluation of their affinities for cannabinoid receptors are reported. The data of 4d confirmed that a bivalent structure is a suitable scaffold for CB1 cannabinoid receptor binding. The compound 4d was selected for in vitro and in vivo pharmacological evaluations. Moreover, intraperitoneal administration of 4d to food-deprived rats resulted in a dose-dependent inhibition of feeding that was maintained up to 240 min.