High-Resolution Transcriptomic Landscape of the Human Submandibular Gland.

Saliva-secreting and transporting cells are part of the complex cellular milieu of the human salivary gland, where they play important roles in normal glandular physiology and diseased states. However, comprehensive molecular characterization, particularly at single-cell resolution, is still incomplete, in part due to difficulty in procuring normal human tissues. Here, we perform an in-depth analysis of male and female adult human submandibular gland (SMG) samples by bulk RNA sequencing (RNA-seq) and examine the molecular underpinnings of the heterogeneous cell populations by single-cell (sc) RNA-seq. Our results from scRNA-seq highlight the remarkable diversity of clusters of epithelial and nonepithelial cells that reside in the SMG that is also faithfully recapitulated by deconvolution of the bulk-RNA data sets. Our analyses reveal complex transcriptomic heterogeneity within both the ductal and acinar subpopulations and identify atypical SMG cell types, such as mucoacinar cells that are unique to humans and ionocytes that have been recently described in the mouse. We use CellChat to explore ligand-receptor interactome predictions that likely mediate crucial cell-cell communications between the various cell clusters. Finally, we apply a trajectory inference method to investigate specific cellular branching points and topology that offers insights into the dynamic and complex differentiation process of the adult SMG. The data sets and the analyses herein comprise an extensive wealth of high-resolution information and a valuable resource for a deeper mechanistic understanding of human SMG biology and pathophysiology.

Genetic Study of Elf5 and Ehf in the Mouse Salivary Gland.

Salivary gland (SG) development, maturation, and homeostasis require coordinated roles of transcription factors (TFs) that dictate specific cell identities and fate. The ETS family of proteins are important transcriptional drivers of diverse cell lineages, tissue development, and differentiation programs and hence are also likely to play an important role in the SG. Here we have leveraged genomic and epigenomic data of the SG to examine the expression profile of ETS genes and identified 2 closely related paralogs, Elf5 and Ehf, that are highly expressed in distinct epithelial subpopulations. By using a well-defined mouse knockout model of Elf5, we show that Elf5, despite its enriched expression in the acinar cells, is functionally dispensable for maintaining the homeostatic state of the adult SG epithelium. The lack of a discernible phenotype of the Elf5-null SG might be due to possible functional redundancy with Ehf or other ETS factors. To probe this possibility and to examine the specific consequences of Ehf loss in the SG, we used CRISPR-Cas9 to generate mice in which the DNA-binding ETS domain of Ehf is disrupted due to an insertion mutation. We demonstrate that the Ehf mutant (EhfMut) mice exhibit a distinct cellular phenotype with decreased granular convoluted tubules that are accompanied by an increased accumulation of the intercalated Sox9-positive ductal cell population. Interestingly, the ductal phenotype of the EhfMut animals is highly pronounced in males, reaffirming the established sexual dimorphism of the SG that exists in rodents. Our results show that unlike Elf5, Ehf plays a nonredundant role in directing ductal cell differentiation of the SG and highlights the phenotypic subtlety in mutant mice of closely related TFs and the importance of careful consideration of cell type-specific studies.

Electrical coupling of individual electrocatalytic oscillators.

The catalytic electro-oxidation of some small organic molecules is known to display kinetic instabilities, which reflect on potential and/or current oscillations. Under oscillatory conditions, those systems can be considered electrocatalytic oscillators and, therefore, can be described by their amplitude, frequency, and waveform. Just like mechanical oscillators, the electrocatalytic ones can be coupled and their dynamics can be changed by setting different coupling parameters. In the present work, we study the unidirectional coupling of electrocatalytic oscillators, namely, those comprehending the catalytic electro-oxidation of methanol and formic acid on polycrystalline platinum in acidic media under potentiostatic control. Herein, we explore two different scenarios (the coupling of compositionally identical and non-identical oscillators) and investigate the effects of the master's identity and of the coupling constant on the slave's dynamics. For the master (methanol)-slave (methanol) coupling, the oscillators exhibited phase lag synchronization and complete phase synchronization. On the other hand, for the master (formic acid)-slave (methanol) coupling, the oscillators exhibited complete phase synchronization with phase-locking with a 2:3 ratio, complete phase synchronization with phase-locking with a 1:2 ratio, phase lag synchronization, and complete phase synchronization. The obtained results suggest that both the master's identity and the coupling constant (sign and magnitude) are parameters that play an important role on the coupled systems, in such a way that even for completely different systems, synchronization could emerge by setting a suitable coupling constant. To the best of our knowledge, this is the first report concerning the electrical coupling of hidden N-shaped-negative differential resistance type systems.

Management of Hypothyroidism in Internal Medicine: Patient Profile and Effects of an Educational Programme in the Cluster-Randomized FADOI TIAMO Study.

Background and aims: There is still limited knowledge regarding the clinical profile and appropriateness of treatment in patients with hypothyroidism hospitalized in Internal Medicine (IM) Departments in Italy. The aim of this study is to evaluate: 1) the characteristics of patients and possible deviations from national and international clinical practice recommendations (CPRs) in evidence-based guidelines (EBGs); 2) the improvement of patient management by means of a standardized educational programme (EP). Methods: A nationwide multicentre study, comprising two replications of a retrospective survey (phases 1 and 3) with an intervening EP (phase 2) in half of the centres and no EP in the other half, was conducted. The EP was based on outreach visits. Centres were assigned to the two arms of the study, labelled the training group (TG) and control group (CG) respectively, by cluster randomization. Four EBGs and 39 CPRs provided the basis on which 22 treatment management indicators were identified (7 referring to the time of hospital admission, 15 to post-admission). Results: The 21 participating centres recruited 587 hospitalized patients with hypothyroidism, 421 of which were females (71.7%, mean age 74.1 + 14.4 yrs): 318 in phase 1 and 269 in phase 3. The cause of hypothyroidism was unknown in 282 patients (48%). Evaluation at the time of admission identified satisfactory adherence to CPRs (>50%) for 63.6% of the indicators. In the phase 3, TG centres showed significant improvement vs CG in 4 of the 15 post-admission indicators, while 1 out of 15 was significantly worse. Conclusions: The EP based on outreach visits significantly improved some indicators in the management of patients with hypothyroidism, with specific reference to appropriateness of TSH dosage and levothyroxine (LT4) treatment modality. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05314790.

In vitro evaluation of the cis-[Ru(phen)2(pPDIp)]2+⁎⁎ complex for antimicrobial photodynamic therapy against Sporothrix brasiliensis and Candida albicans.

BACKGROUND: Photodynamic therapy (PDT) activates a photosensitizer by visible light to generate cytotoxic oxygen species that lead to cell death. With proper illumination, PDT is often used in applications on superficial and sub-surface lesions. Sporotrichosis infection occurs by Sporothrix fungi which causes a skin wound, worsened by Candida albicans infections. This study investigated the photosensitizing efficiency of the Ru(phen)2(pPDIp)(PF6)2 complex, RupPDIp, against S. brasiliensis and C. albicans. MATERIAL AND METHODS: RupPDIp efficiency against these fungi was tested using 450 nm (blue light and 36 J/cm2) and 525 nm (green light, 25.2 J/cm2) at 0.05-20 µM concentrations. To ensure PDT effectiveness, control groups were tested in the absence and in the presence of RupPDIp under light irradiation and in the dark. RESULTS: RupPDIp eliminated both fungi at ≤5.0 µM. Green light showed the best results, eliminating S. brasiliensis and C. albicans colonies at RupPDIp 0.5 µM and 0.05 µM, respectively. CONCLUSION: RupPDIp is a promising photosensitizer in aPDT, eliminating 106 CFU/mL of both fungi at 450 nm and 525 nm, with lower light doses and concentrations when treated with the green light compared to the blue light.

Compositional and Morphological Characterization of 'Sorrento' and 'Chandler' Walnuts.

In Italy, most of the cultivated walnuts belong to the Sorrento ecotype, and they are considered commercially valuable due to their specific organoleptic characteristics. The aim of this study is to evaluate and compare the morphological and compositional characteristics of walnuts sampled from 'Sorrento' trees cultivated in different locations in Campania and trees of both the 'Chandler' and 'Sorrento' varieties derived from the same location. The results demonstrated that 'Sorrento' and 'Chandler' walnuts have different biometric characteristics and a different fat content, with the highest fat content being found in the 'Sorrento' variety. Regarding the fatty acid (FA) composition, the content of monounsaturated and saturated fatty acids (MUFAs and SFAs) was highest in the 'Sorrento' variety (from 13 to 15% for MUFAs and from 11 to 13% for SFAs), while the polyunsaturated fatty acids (PUFAs) content was highest in the 'Chandler' variety (77%). The total phenolics content (TPC) was highest in the 'Sorrento' variety (from 910 to 1230 mg GAE/100 g), while no difference in γ-tocopherol content was found. Furthermore, the influence of walnut area cultivation was shown for fat content, FA composition and TPC. Therefore, both walnut varieties demonstrated good nutritional properties considering the PUFAs and γ-tocopherol content.

Overnight variation in tidal expiratory flow limitation in COPD patients and its correction: an observational study.

BACKGROUND: Tidal expiratory flow limitation (EFLT) is common among COPD patients. Whether EFLT changes during sleep and can be abolished during home ventilation is not known. METHODS: COPD patients considered for noninvasive ventilation used a ventilator which measured within-breath reactance change at 5 Hz (∆Xrs) and adjusted EPAP settings to abolish EFLT. Participants flow limited (∆Xrs > 2.8) when supine underwent polysomnography (PSG) and were offered home ventilation for 2 weeks. The EPAP pressure that abolished EFLT was measured and compared to that during supine wakefulness. Ventilator adherence and subjective patient perceptions were obtained after home use. RESULTS: Of 26 patients with supine EFLT, 15 completed overnight PSG and 10 the home study. In single night and 2-week home studies, EFLT within and between participants was highly variable. This was unrelated to sleep stage or body position with only 14.6% of sleep time spent within 1 cmH2O of the awake screening pressure. Over 2 weeks, mean EPAP was almost half the mean maximum EPAP (11.7 vs 6.4 cmH2O respectively). Group mean ∆Xrs was ≤ 2.8 for 77.3% of their home use with a mean time to abolish new EFLT of 5.91 min. Adherence to the ventilator varied between 71 and 100% in prior NIV users and 36-100% for naïve users with most users rating therapy as comfortable. CONCLUSIONS: Tidal expiratory flow limitation varies significant during sleep in COPD patients. This can be controlled by auto-titrating the amount of EPAP delivered. This approach appears to be practical and well tolerated by patients. TRIAL REGISTRATION: The trial was retrospectively registered at CT.gov NCT04725500.

A Global Vista of the Epigenomic State of the Mouse Submandibular Gland.

The parotid, submandibular, and sublingual glands represent a trio of oral secretory glands whose primary function is to produce saliva, facilitate digestion of food, provide protection against microbes, and maintain oral health. While recent studies have begun to shed light on the global gene expression patterns and profiles of salivary glands, particularly those of mice, relatively little is known about the location and identity of transcriptional control elements. Here we have established the epigenomic landscape of the mouse submandibular salivary gland (SMG) by performing chromatin immunoprecipitation sequencing experiments for 4 key histone marks. Our analysis of the comprehensive SMG data sets and comparisons with those from other adult organs have identified critical enhancers and super-enhancers of the mouse SMG. By further integrating these findings with complementary RNA-sequencing based gene expression data, we have unearthed a number of molecular regulators such as members of the Fox family of transcription factors that are enriched and likely to be functionally relevant for SMG biology. Overall, our studies provide a powerful atlas of cis-regulatory elements that can be leveraged for better understanding the transcriptional control mechanisms of the mouse SMG, discovery of novel genetic switches, and modulating tissue-specific gene expression in a targeted fashion.

Understanding the electronic properties of BaTiO3 and Er3+ doped BaTiO3 films through confocal scanning microscopy and XPS: the role of oxygen vacancies.

Photonic and electronic properties exist inherently in ferroelectric barium titanate (BaTiO3); severe luminescence quenching also exists due to the insufficient confinement of excitons. In this sense, high optical emission can only be achieved by its chemical and structural modification. Thin BaTiO3 and Er:BaTiO3 films were grown by the spin coating method on a glass substrate at room temperature. Self-trapping of excitons in the thin BaTiO3 film and its structural modification due to the doping with Er3+ ions (Er:BaTiO3) are verified using scanning confocal fluorescence microscopy (SCFM), where self-trapping excitons never occured in its pure state. By thermal treatment and doping (BaTiO3 and Er:BaTiO3) we obtained localization of the excitons, which would further induce lattice strain around the surface defects, to accommodate the self-trapped excitons. With such a self-trapped state, the structure of BaTiO3 generates broadband emission of several overlapping bands between 1.95 and 2.65 eV at room temperature, while the structure Er:BaTiO3 showed defined emission bands at 2.24 and 2.35 eV, with very weak contributions of the emission due to the self-trapping state. The influence of the variation of the excitation wavelength using 1PE and 2PE on the emission bands of BaTiO3 and Er:BaTiO3 is also investigated. The results of enhanced emission bands suggest a clear dependence of the emission intensity on the excitation energy, where a ∼3 fold enhancement in emission has been demonstrated under Er3+ (1.55 eV) excitation, which can be attributed to effective energy transfer between the Er3+ ions. As a result, it is concluded that the developed BaTiO3 and Er:BaTiO3 can pave the way for future photonic devices.

Evaluation of the genotoxic potential of cypermethrin, chlorpyrifos and their subsequent mixture, on cultured bovine lymphocytes.

Cypermethrin (CYP) and chlorpyrifos (CPF) are insecticides/parasiticides used in the production of fruits, vegetables and beef cattle. These substances or their metabolites are frequently reported as residues in food, whose consumption in a diet implies a genotoxic risk. The potential for chronic toxicity of CYP and CPF is unclear, and only a few genotoxicological evaluations based on their mixture have been performed. The aim of this study was to evaluate the genotoxic potential of CYP, CPF and CYP + CPF in five concentrations, from 5.9 to 175 µg/mL, on bovine lymphocytes. By means of the cytokinesis-block micronucleus cytome assay, a decrease in the cell proliferation index was observed (r = -0.89 p = 0.04); and also an increase in the frequencies of binucleated cells (BN) with micronuclei (BNMn) (r = 0.93, p = 0.02) and BN with nuclear buds (BNBud) (r = 0.778 p = 0.04), depending on the concentrations of CPF. An increase in BNMn frequencies was observed as a function of CYP concentrations (r = 0.89, p = 0.04) and also of the CYP + CPF mix (r = 0.99, p = 0.008). CYP caused greater genotoxic damage (BNMn) than CPF and the mixture on bovine lymphocytes. Cells with simultaneous presentation of micronuclei and nuclear buds were detected, as well as cells with irregular nuclei, something never previously reported, whose origin and significance should be investigated. The genotoxic effect of chlorpyrifos, cypermethrin and their mixture on bovine lymphocytes was observed. We recognized the value of the use of primary bovine cultures, animal species adjacent to man in the food chain, for genotoxicity studies.

Hay or silage? How the forage preservation method changes the volatile compounds and sensory properties of Caciocavallo cheese.

The aim of this study was to determine the effect of the forage preservation method (silage vs. hay) on volatile compounds and sensory properties of a traditional Caciocavallo cheese during ripening. A brown-midrib sudangrass hybrid was cultivated on a 7-ha field and at harvesting it was half ensiled in plastic silo bags and half dried to hay. Forty-four lactating cows were equally allotted into 2 groups fed a isonitrogenous and isoenergetic total mixed ration containing as the sole forage either sorghum hay (H group) or sorghum silage (S group). Milk from the 2 groups was used to produce 3 batches/diet of Caciocavallo ripened for 30, 60, and 90 d. Milk yield and composition as well as cheese chemical and fatty acid composition were not markedly affected by the diet treatment and ripening time. By contrast, ripening induced increased levels of the appearance attribute "yellowness," along with the "overall flavor," the odor/flavor attributes "butter" and "hay," the "salty," "bitter," and "umami" tastes, and the texture attribute "oiliness," whereas the appearance attribute "uniformity" and the texture attribute "elasticity" were reduced. The silage-based diet induced higher perceived intensities of several attributes such as "yellowness"; "overall flavor"; "butter"; "grass" and "hay" odor/flavors; "salty," "bitter," and "umami" tastes; and "tenderness" and "oiliness" textures. In S cheese we also observed higher amounts of ketones and fatty acids. Conversely, H cheese showed the terpene α-pinene, which was not detected in S cheese, and a higher intensity of the appearance attribute "uniformity." These differences allowed the trained panel to discriminate the products, determined an increased consumer liking for 90-d ripened cheese, and tended to increase consumer liking for hay cheese.

Transcriptomic and Single-Cell Analysis of the Murine Parotid Gland.

The salivary complex of mammals consists of 3 major pairs of glands: the parotid, submandibular, and sublingual glands. While the 3 glands share similar functional properties, such as saliva secretion, their differences are largely based on the types of secretions they produce. While recent studies have begun to shed light on the underlying molecular differences among the glands, few have examined the global transcriptional repertoire over various stages of gland maturation. To better elucidate the molecular nature of the parotid gland, we have performed RNA sequencing to generate comprehensive and global gene expression profiles of this gland at different stages of maturation. Our transcriptomic characterization and hierarchical clustering analysis with adult organ RNA sequencing data sets has identified a number of molecular players and pathways that are relevant for parotid gland biology. Moreover, our detailed analysis has revealed a unique parotid gland-specific gene signature that may represent important players that could impart parotid gland-specific biological properties. To complement our transcriptomic studies, we have performed single-cell RNA sequencing to map the transcriptomes of parotid epithelial cells. Interrogation of the single-cell transcriptomes revealed the degree of molecular and cellular heterogeneity of the various epithelial cell types within the parotid gland. Moreover, we uncovered a mixed-lineage population of cells that may reflect molecular priming of differentiation potentials. Overall our comprehensive studies provide a powerful tool for the discovery of novel molecular players important in parotid gland biology.

Innovative Approaches to Active and Healthy Ageing: Campania Experience to Improve the Adoption of Innovative Good Practices.

The demographic projections on the European population predict that people aged over 60 will increase by about two million/year in the next decades. Since 2012, the Campania Reference Site of the European Innovation Partnership on Active and Healthy Ageing supports the innovation of the Regional Health System, to face up demographic changes and sustainability. Campania Reference Site provides the opportunity to connect loco-regional stakeholders in social and health care services (universities, healthcare providers, social services, local communities and municipalities), with international organizations, in order to adopt and scale up innovative solutions and approaches. This paper describes the building process of Campania Reference Site and the main results achieved, that have been allowing it to become a hub for open innovation in the field of active and healthy aging at regional, national and international level.

Prevalence of Autism Spectrum Disorder in a large Italian catchment area: a school-based population study within the ASDEU project.

AIMS: This study aims to estimate Autism Spectrum Disorders (ASD) prevalence in school-aged children in the province of Pisa (Italy) using the strategy of the ASD in the European Union (ASDEU) project. METHODS: A multistage approach was used to identify cases in a community sample (N = 10 138) of 7-9-year-old children attending elementary schools in Pisa - Italy. First, the number of children with a disability certificate was collected from the Local Health Authority and an ASD diagnosis was verified by the ASDEU team. Second, a Teacher Nomination form (TN) to identify children at risk for ASD was filled in by teachers who joined the study and the Social Communication Questionnaire (SCQ) was filled in by the parents of children identified as positive by the TN; a comprehensive assessment, which included the Autism Diagnostic Observation Schedule-Second Edition, was performed for children with positive TN and SCQ⩾9. RESULTS: A total of 81 children who had a disability certificate also had ASD (prevalence: 0.79%, i.e. 1/126). Specifically, 66 children (57 males and nine females; 62% with intellectual disability -ID-) were certified with ASD, whereas another 15 (11 males and four females; 80% with ID) were recognised as having ASD among those certified with another neurodevelopmental disorder. Considering the population of 4417 (children belonging to schools which agreed to participate in the TN/SCQ procedure) and using only the number of children certified with ASD, the prevalence (38 in 4417) was 0.86%, i.e. one in 116. As far as this population is concerned, the prevalence rises to 1% if we consider the eight new cases (six males and two females; no subject had ID) identified among children with no pre-existing diagnoses and to 1.15%, i.e., one in 87, if probabilistic estimation is used. CONCLUSIONS: This is the first population-based ASD prevalence study conducted in Italy so far and its results indicate a prevalence of ASD in children aged 7-9 years of about one in 87. This finding may help regional, national and international health planners to improve ASD policies for ASD children and their families in the public healthcare system.

The hypothalamic-pituitary-testicular axis and the testicular function are modulated after silver nanoparticle exposure.

Silver nanoparticles (AgNPs) are widely used in industrial and medical applications and humans may be exposed through different routes, increasing the risk of toxicity. We investigated the transcript expression of genes involved in the regulation of the hypothalamic-pituitary-testicular (HPT) axis and the parameters associated with sperm functionality after prepubertal exposure. AgNPs modulated the transcript expression of genes involved in the control of the HPT axis and spermatogenesis in the groups treated with lower doses, while the functional parameters related to sperm and puberty were affected in the groups administered higher doses. These results suggest that the HPT axis is disrupted by AgNPs during the prepubertal and pubertal periods, which are highly susceptible windows for the endocrine-disrupting chemical activity.

The inclusion of fresh forage in the lactating buffalo diet affects fatty acid and sensory profile of mozzarella cheese.

The aim of this study was to determine the effect of inclusion of fresh forage in diet for lactating buffalo on properties of mozzarella cheese under intensive farming conditions. Thirty-two buffalo cows were equally allotted into 2 groups fed diets with (fresh group, FRS) or without (control group, CTL) fresh sorghum. The study consisted of 2 trials. In the first one, animals from group FRS were fed a diet containing 10 kg of fresh sorghum (10-FRS diet) that was doubled to 20 kg (20-FRS diet) in the second trial. All diets were isonitrogenous and isoenergetic, and fresh forage accounted for 13.4 and 26.5 of dietary dry matter, respectively, for the 10-FRS and 20-FRS diet. In each trial, milk from the 2 groups was used to produce 3 batches/diet of Mozzarella di Bufala Campana Protected Designation of Origin cheese. Milk yield and composition were not influenced by dietary treatment. The use of 10-FRS diet did not affect any properties of mozzarella. As the inclusion rate of fresh sorghum doubled to 20 kg, an increment of unsaturated fatty acid percentages and a lowering of short-chain and saturated fatty acids were observed. Moreover, the sensory characteristics of mozzarella were modified, although no effects were observed on consumer acceptance. We conclude that the use of green fodder can represent a low-cost feeding strategy to improve the healthiness of buffalo mozzarella under intensive farming conditions with no detrimental effect on consumer blind acceptance.

Reference values for acetyl and butyrylcholinesterases in cattle under actual management conditions, hepatic and renal function by application of chlorpyrifos.

Chlorpyrifos is an anticholinesterase organophosphate insecticide widely used in Argentina in the production of food derived from animal, fruit and horticultural origin and is reported as a residue within these products. Local reference values for acetyl and butyrylcholinesterase were determined in Aberdeen Angus bovine and cross bred cattle (n = 25), a requirement to be able to evaluate toxicity of commercial organophosphate and carbamate formulations. The activity of cholinesterase enzymes presented an overall mean of 2,183.00 ± 485.6 IU L-1 for erythrocyte acetylcholinesterase and 203.1 ± 42.06 IU L-1 for plasma butyrylcholinesterase, which are used as reference values for meat steers within a system of intensive production in a semi-arid region. The toxic potential of chlorpyrifos in steers of the same breeds (n = 12) was assessed applying chlorpyrifos 15.00% Tipertox® in a single therapeutic dose of 7.50 mg kg-1 by topical route. Prior to application and then on day 1 and day 21 post-application, both blood cholinesterases, serum chlorpyrifos concentration by ultra-high resolution liquid chromatography with mass detector, analysis of blood counts, total proteins, liver enzymes, urea and creatinine were evaluated. The mean plasma concentration of chlorpyrifos was 27.90 ug L-1 at 24 h. The findings indicate that the therapeutic treatment of castrated male bovines treated with chlorpyrifos, applied by pour-on according to the manufacturer's instructions, does not cause changes in the variables evaluated.

Familial aggregation of MATRICS Consensus Cognitive Battery scores in a large sample of outpatients with schizophrenia and their unaffected relatives.

BACKGROUND: The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative-control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands' scores. METHODS: Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands' MCCB scores predicted REL neurocognitive performance. RESULTS: SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning. CONCLUSIONS: In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors.

Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor.

The endogenous fatty acid amide palmitoylethanolamide (PEA) has been shown to exert anti-inflammatory actions mainly through inhibition of the release of pro-inflammatory molecules from mast cells, monocytes and macrophages. Indirect activation of the endocannabinoid (eCB) system is among the several mechanisms of action that have been proposed to underlie the different effects of PEA in vivo. In this study, we used cultured rat microglia and human macrophages to evaluate whether PEA affects eCB signaling. PEA was found to increase CB2 mRNA and protein expression through peroxisome proliferator-activated receptor-α (PPAR-α) activation. This novel gene regulation mechanism was demonstrated through: (i) pharmacological PPAR-α manipulation, (ii) PPAR-α mRNA silencing, (iii) chromatin immunoprecipitation. Moreover, exposure to PEA induced morphological changes associated with a reactive microglial phenotype, including increased phagocytosis and migratory activity. Our findings suggest indirect regulation of microglial CB2R expression as a new possible mechanism underlying the effects of PEA. PEA can be explored as a useful tool for preventing/treating the symptoms associated with neuroinflammation in CNS disorders.