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Oligodendrocyte progenitor cells (OPCs) represent a subtype of glia, giving rise to oligodendrocytes, the myelin-forming cells in the central nervous system (CNS). While OPCs are highly proliferative during development, they become relatively quiescent during adulthood, when their fate is strictly influenced by the extracellular context. In traumatic injuries and chronic neurodegenerative conditions, including those of autoimmune origin, oligodendrocytes undergo apoptosis, and demyelination starts. Adult OPCs become immediately activated; they migrate at the lesion site and proliferate to replenish the damaged area, but their efficiency is hampered by the presence of a glial scar-a barrier mainly formed by reactive astrocytes, microglia and the deposition of inhibitory extracellular matrix components. If, on the one hand, a glial scar limits the lesion spreading, it also blocks tissue regeneration. Therapeutic strategies aimed at reducing astrocyte or microglia activation and shifting them toward a neuroprotective phenotype have been proposed, whereas the role of OPCs has been largely overlooked. In this review, we have considered the glial scar from the perspective of OPCs, analysing their behaviour when lesions originate and exploring the potential therapies aimed at sustaining OPCs to efficiently differentiate and promote remyelination.

Gliomas are the most common and deadly types of brain tumors, known for their extensive genetic and epigenetic variability, which poses considerable challenges for pharmacological treatment. Glioma heterogeneity is also related to their intricate and dynamic tumor microenvironment (TME), which comprises a diverse array of cell types, including immune cells, vascular cells, glial cells, and neural precursors, collectively influencing tumor behavior and progression. A pivotal aspect of this intercellular communication relies on the exchange of extracellular vesicles (EVs), which contain and transfer complex molecular cargoes typical of their cells of origin, such as proteins, lipids, carbohydrates, metabolites, and non-coding RNAs (ncRNAs), that encompass microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Glioma cells actively release EVs loaded with specific ncRNAs that can target genes and other ncRNAs in recipient cells residing within the TME. Among these recipient cells, prominent players include tumor-associated macrophages and microglia (TAMs), non-neoplastic astrocytes and endothelial cells. The intricate interplay between EVs derived from glioma cells and these recipient cells significantly contributes to the establishment of a tumor-permissive microenvironment, promoting tumor cell proliferation, migration, angiogenesis, and invasion, by targeting various downstream pathways. This review critically examines the current understanding of the intricate interplay between glioma, exosomal ncRNAs, and various components of the glioma TME. By shedding light on the roles of ncRNAs in mediating intercellular communication, this review underscores their significance in orchestrating TME transformation and highlights their potential as novel therapeutic targets for effectively tackling glioma progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Marangon and Lecca.)

G protein-coupled receptor 17 (GPR17) and the WNT pathway are critical players of oligodendrocyte (OL) differentiation acting as essential timers in developing brain to achieve fully-myelinating cells. However, whether and how these two systems are related to each other is still unknown. Of interest, both factors are dysregulated in developing and adult brain diseases, including white matter injury and cancer, making the understanding of their reciprocal interactions of potential importance for identifying new targets and strategies for myelin repair. Here, by a combined pharmacological and biotechnological approach, we examined regulatory mechanisms linking WNT signaling to GPR17 expression in OLs. We first analyzed the relative expression of mRNAs encoding for GPR17 and the T cell factor/Lymphoid enhancer-binding factor-1 (TCF/LEF) transcription factors of the canonical WNT/β-CATENIN pathway, in PDGFRα + and O4 + OLs during mouse post-natal development. In O4 + cells, Gpr17 mRNA level peaked at post-natal day 14 and then decreased concomitantly to the physiological uprise of WNT tone, as shown by increased Lef1 mRNA level. The link between WNT signaling and GPR17 expression was further reinforced in vitro in primary PDGFRα + cells and in Oli-neu cells. High WNT tone impaired OL differentiation and drastically reduced GPR17 mRNA and protein levels. In Oli-neu cells, WNT/β-CATENIN activation repressed Gpr17 promoter activity through both putative WNT response elements (WRE) and upregulation of the inhibitor of DNA-binding protein 2 (Id2). We conclude that the WNT pathway influences OL maturation by repressing GPR17, which could have implications in pathologies characterized by dysregulations of the OL lineage including multiple sclerosis and oligodendroglioma., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Endocrine disruptors (EDCs) are emerging contaminants that are harmful to health. Human exposure occurs mainly through ingestion or dermal contact, but inhalation could be an additional exposure route; therefore, this study was conducted to evaluate the oestrogenic activity of airborne particulate matter (PM). Outdoor PM was collected for a year in five Italian sites and extracted with organic solvents (four seasonal extracts/site). The oestrogenic activity was assessed using a gene reporter assay (MELN), and the risk to human health through inhalation was quantified using the results. Moreover, extracts were analysed to assess cytotoxicity (WST-1 and LDH assays) on human bronchial cells (BEAS-2B). The extracts induced a significant cytotoxicity and oestrogenic activity. Oestrogenic activity showed a seasonal trend and was correlated with concentrations of benzo(a)pyrene and toxic equivalency factor. Although a low inhalation cancer risk was found, this study confirmed that oestrogenic activity in air could contribute to overall health risks due to EDC exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

(1) Background: This study evaluates, one year later, the levels of burnout, anxious-depressive, and post-traumatic symptoms and the general health status in the Health Workers (HWs) involved in the SARS-COVID-19 pandemic in the Novara area. (2) Methods: The survey was sent via a link in an email to doctors, nurses, and other operators during the period between June and August 2021. The survey collected socio-demographic data and contained some self-administered questionnaires. (3) Results: A total of 688 HWs completed the survey, 53% were aged 30-49 years, 68% were female, 76% were cohabiting, 55% had children, 86% reported family habit changes, and 20% had non-COVID related health problems. Only a few of the respondents had a follow-up by a specialist (12%), of which there were even less in recent times (6%). It was observed that the respondents had undergone burnout; a poor state of general mental health (62%); depressive symptoms (70%); post-traumatic symptoms (29%); and less frequently, anxious symptoms (16%). The data of this study are in line with other studies in the literature. (4) Conclusions: The data indicate that psychological-based suffering was no longer markedly concentrated in some specific bands of HWs. In conclusion, it would be essential to enhance HW support strategies.

Extracellular vesicles (EVs) have been increasingly recognized as essential players in cell communication in many organs and systems, including the central nervous system (CNS). A proper interaction between neural cells is fundamental in the regulation of neurophysiological processes and its alteration could induce several pathological phenomena, such as neurodegeneration, neuroinflammation, and demyelination. EVs contain and transfer complex molecular cargoes typical of their cells of origin, such as proteins, lipids, carbohydrates, and metabolites to recipient cells. EVs are also enriched in non-coding RNAs (e.g., microRNAs, lncRNAs, and circRNA), which were formerly considered as cell-intrinsic regulators of CNS functions and pathologies, thus representing a new layer of regulation in the cell-to-cell communication. In this review, we summarize the most recent and advanced studies on the role of EV-derived ncRNAs in the CNS. First, we report the potential of neural stem cell-derived ncRNAs as new therapeutic tools for neurorepair. Then, we discuss the role of neuronal ncRNAs in regulating glia activation, and how alteration in glial ncRNAs influences neuronal survival and synaptic functions. We conclude that EV-derived ncRNAs can act as intercellular signals in the CNS to either propagate neuroinflammatory waves or promote reparative functions.

In the mature central nervous system (CNS), oligodendrocytes (OLs) provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, OLs require energy and building blocks for lipids, which implies a great investment of energy fuels and molecular sources of carbon. The oligodendroglial G protein-coupled receptor 17 (GPR17) has emerged as a key player in OL maturation; it reaches maximal expression in pre-OLs, but then it has to be internalized to allow terminal maturation. In this study, we aim at elucidating the role of physiological GPR17 downregulation in OL metabolism by applying transcriptomics, metabolomics and lipidomics on differentiating OLs. After GPR17 silencing, we found a significant increase in mature OL markers and alteration of several genes involved in glucose metabolism and lipid biosynthesis. We also observed an increased release of lactate, which is partially responsible for the maturation boost induced by GPR17 downregulation. Concomitantly, GPR17 depletion also changed the kinetics of specific myelin lipid classes. Globally, this study unveils a functional link between GPR17 expression, lactate release and myelin composition, and suggests that innovative interventions targeting GPR17 may help to foster endogenous myelination in demyelinating diseases.

Background: Mental health-related symptoms can persist over time beyond the most common respiratory clinical features of COVID-19. A recent meta-analysis underlined that mental health sequalae may be relevant for COVID-19 survivors and reported the following prevalence rates: 20% for post-traumatic stress disorder, 22% for anxiety, 36% for psychological distress, and 21% for depression. In the context of a multi-disciplinary follow-up project, we already investigated the mid-term (4 months) psychiatric outcomes in a sample of COVID-19 survivors. Patients were re-assessed after 1-year since hospital discharge., Methods: Follow-up conducted after 1 year involved 196 individuals recovered from COVID-19. Patients were assessed with a multi-disciplinary approach; including both a clinical interview performed by an experienced psychiatrist, trained in the use of the Mini-International Neuropsychiatric Interview (MINI) to assess the presence of anxiety, stress, and depressive symptoms and the following self-administered questionnaires: Beck Anxiety Inventory, Beck Depression Inventory-II, Resilience Scale for Adults, Impact of Event Scale, and COVID-19 Peritraumatic Distress Index (CPDI)., Results: Anxiety ( p < 0.0001) and depressive ( p < 0.0003) symptoms registered at the clinical interview showed a significant improvement from the 4 to 12-months follow-up. Logistic regression model showed that female gender ( p = 0.006), arterial hypertension ( p = 0.01), obesity (0.04), anxiety ( p < 0.0001), and depressive ( p = 0.02) symptoms at 4-months follow-up were associated with persistence of anxiety symptoms at 12 months. At logistic regression analysis female gender ( p = 0.02) and depressive symptoms at 4-months follow-up ( p = 0.01) were associated with depressive symptoms after 12 months., Conclusion: Severity of the disease in the acute phase, in this study, was not a determining factor in identifying subjects at risk of developing clinically relevant anxiety and depression as a consequence of COVID-19 disease. Findings from the logistic regressions suggest that the factors most affecting depression and anxiety in COVID survivors after 12 months were female gender, the presence of anxiety and depression after 4 months and some physical symptoms, not necessarily COVID-related. Impact of infection and consequent hospitalization for COVID-19 did no longer represent a relevant issue for depressive symptoms, compared to other general factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gramaglia, Gattoni, Gambaro, Bellan, Balbo, Baricich, Sainaghi, Pirisi, Binda, Feggi, Jona, Marangon, Prosperini, Zeppegno and the NO-MORE COVID Group.)

One of the most substantial and established environmental risk factors for neurological and psychiatric disorders is stress exposure, whose detrimental consequences hinge on several variables including time. In this regard the gestational period is known to present an intrinsic vulnerability to environmental insults and thus stressful events during pregnancy can lead to severe consequences on the offspring's brain development with long-term repercussions throughout adulthood. On this basis, we investigated the long-lasting impact of prenatal stress exposure on the susceptibility to the experimental autoimmune encephalomyelitis (EAE), a well-established murine model of multiple sclerosis. Although stress is considered a triggering factor for this chronic, progressive, autoimmune disease, little is known about the underlying mechanisms. To this end, EAE was induced by immunization with MOG35-55/CFA and pertussis toxin administration in adult female C57BL/6 mice born from control or stressed dams exposed to restraint stress during the last days of gestation. Our results demonstrate that gestational stress induces a marked increase in the severity of EAE symptoms in adulthood. Further, we highlight an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE mice, as indicated by the higher levels of GPR17, a marker of immature oligodendrocyte precursor cells. These behavioral and molecular alterations are paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination. Since several already marketed drugs are able to modulate BDNF levels, these results pave the way to the possibility of repositioning these drugs in multiple sclerosis., (© 2020. The Author(s).)

The COVID-19 pandemic has tested the performance of hospitals and intensive care units around the world. Health care workers (HCWs) have been used to developmental symptoms, but this was especially true during the COVID-19 pandemic when HCWs have been faced with many other sources of stress and anxiety that can usually be avoided. Moreover, long-term shifts and unprecedented population restrictions have weakened people's ability to cope with stress. The research aims to observe the dynamic interplay between burnout, depression, distress, and anxiety in HCWs working in various settings, with specific a focus on emotional exhaustion, depersonalization, and a diminished sense of personal achievement in mediating a worse mental health status during the first wave of the COVID-19 pandemic in Italy. We performed a mediation analysis, which resulted in a strong correlation among depression, psychological distress, health perception and anxiety, and the impact of job burnout on anxiety, depression, and distress. Gender seemed to have a strong correlation with burnout, anxiety, and distress; the impact of the COVID-19 pandemic on Quality of Life seemed to affect anxiety and depression; the possible changes in job tasks and duties (intended as a change in work area or location and role change)influenced depression and job burnout. Encouraging supportive and educational strategies would be recommended to policymakers.

Myelin is the lipidic insulating structure enwrapping axons and allowing fast saltatory nerve conduction. In the central nervous system, myelin sheath is the result of the complex packaging of multilamellar extensions of oligodendrocyte (OL) membranes. Before reaching myelinating capabilities, OLs undergo a very precise program of differentiation and maturation that starts from OL precursor cells (OPCs). In the last 20 years, the biology of OPCs and their behavior under pathological conditions have been studied through several experimental models. When co-cultured with neurons, OPCs undergo terminal maturation and produce myelin tracts around axons, allowing to investigate myelination in response to exogenous stimuli in a very simple in vitro system. On the other hand, in vivo models more closely reproducing some of the features of human pathophysiology enabled to assess the consequences of demyelination and the molecular mechanisms of remyelination, and they are often used to validate the effect of pharmacological agents. However, they are very complex, and not suitable for large scale drug discovery screening. Recent advances in cell reprogramming, biophysics and bioengineering have allowed impressive improvements in the methodological approaches to study brain physiology and myelination. Rat and mouse OPCs can be replaced by human OPCs obtained by induced pluripotent stem cells (iPSCs) derived from healthy or diseased individuals, thus offering unprecedented possibilities for personalized disease modeling and treatment. OPCs and neural cells can be also artificially assembled, using 3D-printed culture chambers and biomaterial scaffolds, which allow modeling cell-to-cell interactions in a highly controlled manner. Interestingly, scaffold stiffness can be adopted to reproduce the mechanosensory properties assumed by tissues in physiological or pathological conditions. Moreover, the recent development of iPSC-derived 3D brain cultures, called organoids, has made it possible to study key aspects of embryonic brain development, such as neuronal differentiation, maturation and network formation in temporal dynamics that are inaccessible to traditional in vitro cultures. Despite the huge potential of organoids, their application to myelination studies is still in its infancy. In this review, we shall summarize the novel most relevant experimental approaches and their implications for the identification of remyelinating agents for human diseases such as multiple sclerosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marangon, Caporale, Boccazzi, Abbracchio, Testa and Lecca.)

Wildland fires, increasing in recent decades in the Mediterranean region due to climate change, can contribute to PM levels and composition. This study aimed to investigate biological effects of PM 2.5 (Ø < 2.5 µm) and PM 10 (Ø < 10 µm) collected near a fire occurred in the North-West of Italy in 2017 and in three other areas (urban and rural areas). Organic extracts were assessed for mutagenicity using Ames test (TA98 and TA100 strains), cell viability (WST-1 and LDH assays) and genotoxicity (Comet assay) with human bronchial cells (BEAS-2B) and estrogenic activity using a gene reporter assay (MELN cells). In all sites, high levels of PM 10 and PM 2.5 were measured during the fire suggesting that near and distant sites were influenced by fire pollutants. The PM 10 and PM 2.5 extracts induced a significant mutagenicity in all sites and the mutagenic effect was increased with respect to historical data. All extracts induced a slight increase of the estrogenic activity but a possible antagonistic activity of PM samples collected near fire was observed. No cytotoxicity or DNA damage was detected. Results confirm that fires could be relevant for human health, since they can worsen the air quality increasing PM concentrations, mutagenic and estrogenic effects.

Introduction: Compared to old people who live at home, depressive symptoms are more prevalent in those who live in long-term care facilities (LTCFs). Different kinds of non-pharmacological treatment approaches in LTCFs have been studied, including behavioral and cognitive-behavioral therapy, cognitive bibliotherapy, problem-solving therapy, brief psychodynamic therapy and life review/reminiscence. The aim of the current review was to systematically review non-pharmacological treatments used to treat depressed older adults with no or mild cognitive impairment (as described by a Mini Mental State Examination score > 20) living in LTCFs. Methods: A research was performed on PubMed and Scopus databases. Following the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) flowchart, studies selection was made. The quality of each Randomized Controlled Trial was scored using the Jadad scale, Quasi-Experimental Design studies and Non-Experimental studies were scored based on the Newcastle-Ottawa Scale (NOS) Results: The review included 56 full text articles; according to the type of intervention, studies were grouped in the following areas: horticulture/gardening ( n = 3), pet therapy ( n = 4), physical exercise ( n = 9), psychoeducation/rehabilitation ( n = 15), psychotherapy ( n = 3), reminiscence and story sharing ( n = 14), miscellaneous ( n = 8). Discussion and Conclusion: Despite mixed or negative findings in some cases, most studies included in this systematic review reported that the non-pharmacological interventions assessed were effective in the management of depressed elderly in the LTCFs context. Regrettably, the limitations and heterogeneity of the studies described above hinder the possibility to generalize and replicate results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gramaglia, Gattoni, Marangon, Concina, Grossini, Rinaldi, Panella and Zeppegno.)

Background: Although the usual primary clinical manifestation of Coronavirus disease (COVID-19) is respiratory, several non-respiratory symptoms have been described, including neuropsychiatric ones. The aim of this study was to investigate the mid-term mental health outcomes in patients recovered from COVID-19, 3-4 months after discharge from the University Hospital Maggiore della Carità, Novara, Italy. Furthermore, we investigated the possible association of the mid-term mental health consequences of the COVID-19 infection with patients' clinical current status, persistent physical impairment and severity of acute phase of the disease. Methods: Prospective study involving 238 individuals recovered from COVID-19. In the context of a multi-disciplinary approach, patients' assessment included both a clinical interview performed by an experienced psychiatrist, trained in the use of the Mini-International Neuropsychiatric Interview to assess the presence of anxiety and depressive symptoms and self-administered questionnaires: Beck Anxiety Inventory (BAI), Beck Depression Inventory-II (BDI-II), Resilience Scale for Adults (RSA), Impact of Event Scale (IES). Results: At the psychiatric assessment 32.9 and 29.5% of participants showed anxiety and depressive symptoms, respectively. Changes in appetite and sleep patterns emerged for 15.6 and 31.2% of patients. According to the self-administered questionnaires, 7.1% of participants had moderate-severe anxiety levels (BAI), while 10.5% had mild to severe depression (BDI-II). Twenty-six (11%) participants were referred to further psychiatric consultation. Psychiatric symptoms showed no correlation with acute COVID-19 severity; in our sample patients with depressive symptoms at the clinical interview, as well as those with mild to severe levels of depression according to BDI-II scores, had lower forced expiratory volume in the 1st second (FEV1) values than those without and greater odds for persistent, poor tolerance for physical efforts. Conclusions: As could be expected, an approach including both a psychiatric interview and the use of self-administered questionnaires is likely to capture the psychiatric outcome of patients recovered from COVID-19 better than questionnaires alone. Anxiety and depressive symptoms at follow-up had no correlation with the severity of COVID acute manifestations, but rather with ongoing and persistent physical symptoms. Further studies and longer follow-up duration will allow a better understanding of the complex relationship between residual physical symptoms, quality of life and psychological health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gramaglia, Gambaro, Bellan, Balbo, Baricich, Sainaghi, Pirisi, Baldon, Battistini, Binda, Feggi, Gai, Gattoni, Jona, Lorenzini, Marangon, Martelli, Prosperini, Zeppegno and the NO-MORE COVID Group.)

The 2019-nCOVID pandemic as a public health emergency has faced healthcare systems with unprecedented challenges. Our study aimed to focus on the mental health impact of the 2019-nCOVID pandemic on healthcare workers (HCWs) from North-Eastern Piedmont, Italy. For this purpose, we performed an online survey which was e-mailed to HCWs at the end of the first peak of the pandemic. We involved both frontline and not-frontline HCWs, employed in the hospital or in healthcare services outside the hospital. The primary outcome of our research was the assessment of burnout, while secondary outcomes included the investigation of anxiety, depression, and post-traumatic stress symptoms. We observed higher levels of burnout (especially in the Depersonalization and Personal Accomplishment dimensions), in females, in HCWs aged <30 years, in those exposed to changes in their daily and family habits, in those who had to change their duties at work and in residents in training. In our HCWs sample we found lower levels of anxiety and depression than those reported in the literature. The problematic levels of burnout and adverse psychological outcomes observed during the pandemic cannot be underestimated. Given the recurrence in autumn 2020 of a new pandemic peak, which has once again put a strain on the health system and HCWs, it is supported the importance of a careful assessment of HCWs' mental health, and of the possible risk and protective factors both in the work environment and in the extra-work one., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gramaglia, Marangon, Azzolina, Guerriero, Lorenzini, Probo, Rudoni, Gambaro and Zeppegno.)

In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches.

The finest fraction of Particulate Matter (PM2.5) carries a large number of pollutants, some of which are assessed as genotoxic, such as some Polycyclic Aromatic Hydrocarbons (PAHs). In many countries, PM2.5 in combination with some PAHs are monitored to assess the concentrations of pollutants, while the air quality is rarely assessed by means of biological assays. Epidemiological studies have demonstrated a significant correlation between these two pollutants and human adverse effects, in particular on the respiratory system. Nevertheless, other air pollutants can induce a biological effect and the cumulative effect of the PM2.5 complex mixture may not be easily deduced by PM2.5 and PAH levels. This study aimed to combine the legislative monitoring of PM2.5 with the study of its mutagenicity. During a full year, daily air samples were collected in nine sites of the North-western Italy air quality monitoring network (Piedmont Region) and PM2.5 and PAH concentrations were assessed. Monthly pooled organic extracts were tested with the Salmonella assay using TA98 and TA100 strains, with and without metabolic activation (±S9), and using TA98NR and YG1021 strains. In all sites, a positive response was observed for TA98 and TA100 especially without S9. A significant mutagenic seasonal variation was detected, with higher mutagenicity in winter and lower responses in summer (average total mutagenicity ratio 27:1). The response of TA98NR and YG1021 compared with TA98 suggested a significant contribution of nitro-compounds to the mutagenicity. No significant differences were found between urban background and rural sites denoting the spread of pollution. A mutagenicity increase, 1.28 Total Mutagenicity Factor/20 m 3 , was observed for each PM2.5 μg increment. PAH levels and corresponding Toxic Equivalent Factors were highly correlated to mutagenicity results. This work confirms that complex environmental mixtures can be appropriately assessed through the implementation of physical-chemical analyzes with bioassays able to evaluate synergistic and antagonistic effects, especially for highest and lowest pollution settings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

MicroRNAs are small post-transcriptional regulators that modulate gene expression by directly interacting with their target transcripts. Since the interaction between miRNAs and target mRNAs does not require a perfect match, one single miRNA can influence the expression of several genes and lead to a very broad array of functional consequences. Recently, we identified miR-125a-3p as a new regulator of oligodendrocyte development, showing that its over-expression is associated to impaired oligodendrocyte maturation. However, whether and how miR-125a-3p over-expression is causally related to oligodendrocyte maturation is still obscure, as well as the pathways responsible for this effect. To shed light on this issue and to identify the underlying molecular mechanisms, we determined the transcriptomic profile of miR-125a-3p over-expressing oligodendrocytes and, by means of two complementary bioinformatic approaches, we have identified pathways and biological processes consistently modulated by miR-125a-3p alteration. This analysis showed that miR-125a-3p is involved in the regulation of cell-cell interactions and Wnt signaling. By means of pathway-focused PCR arrays, we confirmed that miR-125a-3p induces changes in the expression of several genes encoding for adhesion molecules and gap junctions, which play key roles in oligodendrocytes after exposure to pathological demyelinating stimuli. Moreover, the expression changes of different Wnt targets suggest an over-activation of this pathway. Globally, our studies show that miR-125a-3p over-expression can alter signaling pathways and biological processes essential for myelin formation in oligodendrocytes, suggesting that alteration of miR-125a-3p levels may contribute to impairing oligodendrocyte maturation in demyelinating diseases.

Background: Recently, many studies have investigated the role of migration on mental health. Nonetheless, only few focused on the consequences of childhood trauma, hopelessness, and resilience on migrants' psychopathology, including psychiatric disorders and symptoms., Method: 119 migrants were recruited between May 2017 and April 2018, among those applying for assessment to the Mental Health Operational Unit of the National Institute for Health, Migration and Poverty (NIHMP) in Rome, Italy. Assessment included the following: Zung Self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS), Connor-Davidson Resilience Scale (CD-RISC), Childhood Trauma Questionnaire (CTQ), Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), Beck Hopelessness Scale (BHS), Beck's Suicide Intent Scale (SIS), Brief Aggression Questionnaire (BAQ), Deliberate Self-Harm Inventory (DSHI)., Results: 53.39% of migrants scored above the PCL-5 cut-off score (mean score was 39.45). SDS scores below the cutoff suggested the presence of depression in 42.37%, while According to SAS scores anxiety levels were low in 38.98% of migrants. During childhood, physical abuse and neglect were reported respectively by 56.78 and 69.49% of migrants., Conclusion: We found that Post Traumatic Stress Disorders play the role of mediators for the relation between the childhood traumatic experiences and aggressiveness, anxious and depressive symptomatology, while hopelessness is a mediator between the childhood traumatic experiences and the development of depression in adulthood. Hopelessness seems to influence the strength of the relation between childhood traumatic experiences and the individual's current intensity of suicidal attitudes, plans, and behaviors. Further developments and future perspectives of the research project are to address key gaps in the field of resilience by means of a longitudinal evaluation study in migrants, including a native population control group, acceding to NIHMP.

The GPR17 receptor, expressed on oligodendroglial precursors (OPCs, the myelin producing cells), has emerged as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS). However, the proof-of-concept that selective GPR17 ligands actually exert protective activity in vivo is still missing. Here, we exploited an iterative drug discovery pipeline to prioritize novel and selective GPR17 pro-myelinating agents out of more than 1,000,000 compounds. We first performed an in silico high-throughput screening on GPR17 structural model to identify three chemically-diverse ligand families that were then combinatorially exploded and refined. Top-scoring compounds were sequentially tested on reference pharmacological in vitro assays with increasing complexity, ending with myelinating OPC-neuron co-cultures. Successful ligands were filtered through in silico simulations of metabolism and pharmacokinetics, to select the most promising hits, whose dose and ability to target the central nervous system were then determined in vivo. Finally, we show that, when administered according to a preventive protocol, one of them (named by us as galinex) is able to significantly delay the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. This outcome validates the predictivity of our pipeline to identify novel MS-modifying agents., Competing Interests: All the compounds included in this Manuscript are protected by an international Patent Cooperation Treaty (PCT/EP2012/058500, Gpr17 receptor modulators) deposited on May 09th, 2012 and granted on August 6th, 2014. Inventors: Maria Pia Abbracchio, Mario Alberto Battaglia, Ivano Eberini, Marta Fumagalli, Chiara Parravicini, Cristina Sensi, Paola Zaratin This PCT has generated the following patents and national applications: Italy: granted patent - 102012902048704 (MI2012A000785), released on 2014/10/23; Italy: granted patent - 102012902048705 (MI2012A000786), released on 2014/10/23; Japan: granted patent - 2015-510655, released on 2017/01/27; USA: granted patent - 9879030, released on 2018/01/30; China: granted patent - 104428288B, released on 2018/03/13; Israel: granted patent - 235557, released on 2018/11/29; Europe: granted patent - 2850068 (B1) released on 2019/05/29; Korea: 10-2014-7034470, application discontinuation. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Non-financial competing interests: Prof. Ivano Eberini is a member of the Editorial Board of PLOS ONE. I declare that one of the authors of this manuscript has a commercial affiliation: “Luca Raveglia, Aptuit Srl (Evotech Company), Via Alessandro Fleming 4, 37135 Verona, Italy”. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

: Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC-mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA-approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM), we also discuss the role of different ECM components, and report the last findings on new ECM-modifiers able to foster endogenous remyelination., Competing Interests: The authors declare no conflict of interest.

Background: Electrodermal activity (EDA) and other peripheral autonomic electrical parameters have been used as indicators of emotional states, including depressive states and suicidal state. We aimed to review EDA research systematically, focusing on EDA's usefulness as a biomarker for depression and suicidal behaviour., Methods: We searched MEDLINE, Scopus, Cochrane Library, and Web of Science databases, following PRISMA guidelines. The initial screening of articles was based on titles and abstracts; then the full text was reviewed. A preliminary synthesis of findings was developed using tables, thematic analysis and quality ratings., Results: 1287 articles were screened and 77 relevant studies were identified and included in the systematic review. The studies were fairly consistent in maintaining that hypoactive electrodermal response is an established feature of patients affected by depression. There is also preliminary evidence that monitoring EDA may help to differentiate the phases of mood disorders. A few studies provided evidence that EDA can be used to differentiate acutely suicidal subjects from depressed patients who are not severely suicidal. Although EDA has been shown to be a valid, sensitive marker of suicidal ideation, suicide attempts and violent suicidal behaviour, it also seems to be influenced to some extent by antidepressant treatment., Conclusions: Most of the studies summarised in this review are quite outdated and employed a variety of designs and methods to evaluate EDA. This limits the generalisability of the results and makes it difficult to draw clear conclusions about the role of EDA in real-world settings. Electrodermal hypoactivity seems to be a reliable feature of depression and a valid marker of suicidal risk. Nevertheless, the potential utility of EDA in diagnosis, prevention, and treatment planning for depression and suicidal behaviour, should be thoroughly studied.

In the mature central nervous system (CNS), oligodendrocytes provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, oligodendroglial precursors (OPCs) follow a very precise differentiation program, which is finely orchestrated by transcription factors, epigenetic factors and microRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional regulation. Any alterations in this program can potentially contribute to dysregulated myelination, impaired remyelination and neurodegenerative conditions, as it happens in multiple sclerosis (MS). Here, we identify miR-125a-3p, a developmentally regulated miRNA, as a new actor of oligodendroglial maturation, that, in the mammalian CNS regulates the expression of myelin genes by simultaneously acting on several of its already validated targets. In cultured OPCs, over-expression of miR-125a-3p by mimic treatment impairs while its inhibition with an antago-miR stimulates oligodendroglial maturation. Moreover, we show that miR-125a-3p levels are abnormally high in the cerebrospinal fluid of MS patients bearing active demyelinating lesions, suggesting that its pathological upregulation may contribute to MS development, at least in part by blockade of OPC differentiation leading to impaired repair of demyelinated lesions.

Introduction: Both psychiatrists and psychiatric nurses are involved in the psychiatric management of suicidal inpatients. One-to-one observation by qualified nurses and the accommodation of the patient in a room close to the infirmary are usually recommended. Suicidal risk should be reassessed periodically to check response to treatment., Aim: To compare the severity of depressive symptoms in depressed inpatients admitted after an attempted suicide and those admitted for any other reason and to assess the severity of suicide attempts and the management of suicidal risk in clinical settings., Materials and Methods: We divided the sample into two subgroups: patients with a diagnosis of depression admitted because of a recent suicide attempt and depressed patients with no recent history of attempted suicide. Socio-demographic and clinical data were gathered; assessments included the Montgomery-Asberg Depression Rating Scale and the Nurses' Global Assessment of Suicide Risk (NGASR)., Results: Forty-six patients were recruited over a 1-year period: 20 were admitted to the hospital following a suicide attempt; the other 26 had not attempted suicide and were admitted for other depression-related reasons. Multivariate analysis revealed a correlation between use of antidepressants and recent attempted suicide. Attempting suicide was not related to the severity of depressive symptoms. In the recent suicide attempt subgroup, NGASR suicide risk levels were lower at discharge than at admission. Patients with a recent history of attempted suicide had a higher number of suicide attempts in their clinical history than patients with no recent history of attempted suicide., Conclusion: There were no correlations between psychiatric diagnosis, severity of depressive symptoms, and recent suicide attempt. Antidepressant therapy protected against suicide attempts. History of suicide attempts was one of the best predictors of recent attempted suicide. A more thorough understanding of the complex phenomenon of suicide and the reasons for suicidal behavior is needed.