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Abstract Senescent cells exert their effects through the release of various factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The SASP can induce senescence in healthy cells (secondary senescence), modulate immune system function, reshape the extracellular matrix, and facilitate cancer progression. Among SASP components, certain factors act as key regulators in the induction of secondary senescence. In this study, we evaluated the role of IGFBP7, a crucial SASP component. Our results demonstrated that ROS-prostaglandin signaling is involved in the release of IGFBP7. Furthermore, neutralizing antibodies targeting IGFBP7 attenuated the SASP’s pro-senescence activity. Cells incubated with IGFBP7 also entered a state of senescence. The senescence induced by IGFBP7 appears to be mediated through three primary pathways. First, IGFBP7 can bind to insulin, thereby inhibiting its anti-senescence and pro-growth effects. In addition to this inhibitory effect on the insulin pathway, IGFBP7 may enhance IGFII pro-senescence signaling by promoting its interaction with IGF2R while blocking IGF1R. These activities are dependent on ERK and AKT signaling pathways. Finally, IGFBP7 and Activin A, both of which can induce cellular senescence, appear to regulate and inhibit each other, suggesting a compensatory mechanism to prevent excessive senescence. Notably, our preliminary data indicate that IGFBP7, in addition to blocking Activin A, may interact with its receptors and induce senescence via SMAD pathways. Our findings highlight that IGFBP7, along with other members of the IGFBP family, plays a pivotal role in senescence-related signaling pathways. Therefore, IGFBP7 may serve as a potential target for anti-aging strategies aimed at reducing the burden of senescence on tissues and organs.

Abstract Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current

Abstract The Positive and Negative Syndrome Scale (PANSS) is the most widely used rating scale to assess psychotic symptoms in patients with schizophrenia and other primary psychoses. However, a definitive consensus regarding its dimensional structure remains elusive. The present work aims to determine the number of dimensions of the scale through a network analysis approach in a sample of individuals experiencing first-episode schizophrenia spectrum disorder (FE-SSD) with minimal or no prior exposure to antipsychotic treatment. Baseline data of 446 participants (age 25.96 ± 5.99 years, 70% males) enrolled in the OPTiMiSE trial were analysed. Exploratory Graph Analysis (EGA) was conducted to evaluate the dimensionality of the PANSS, and a bootstrap approach (bootEGA) was employed to assess model stability. The analysis was replicated, excluding unstable items with stability values below 0.75, until a stable model was achieved. The analysis of the 30 items of the PANSS revealed inadequate structural consistency, resulting in the exclusion of 9 unstable items. The final model comprised 21 symptoms distributed across four communities (Positive, Cognitive/Disorganised, Excited/Aggressive and Negative) but lacked a depressive domain. In conclusion, we propose a concise version of the PANSS, incorporating 21 items, to better assess the core symptoms of the first episode of SSD. This revised version provides clinicians with a robust psychometric tool with reduced administration time, but the complementary administration of a dedicated instrument for evaluating affective symptoms is advisable.

IntroductionIn recent years, the increasing presence of refugees and asylum seekers displaced from their country of origin, determined significant social, economic, humanitarian and public health implications in host countries, including Italy. These populations are exposed to several potential stressful experiences which make them vulnerable to psychological distress. In fact, the majority of studies addressing the topic found a higher prevalence of mental disorders, especially post-traumatic stress disorder and major depressive disorder, in refugees and asylum seekers with respect to the general population. However, heterogeneous prevalence rates have been reported among studies, due to methodological factor as well as to the impact of a variety of risk factors related to stressful experiences lived in the country of origin, during the migration journey and in the host country.ObjectivesThe aim of the present study was to assess the prevalence of the main psychiatric diagnoses in a large group of adult refugees and asylum seekers (N=303) in the reception centers of two provinces of the Campania region, as well as to investigate the impact of potential risk factors on the occurrence of psychiatric disorders.MethodsThe diagnosis of psychiatric disorders and the identification of subjects at high risk to develop psychosis were carried out by means of structured diagnostic interviews. The following variables were explored as potential risk/protective factors to the occurrence of psychiatric disorders: socio-demographic variables, migration status (refugees/asylum seekers) and characteristics of the reception center,assessed by means of an ad hoc questionnaire; cognitive indices assessed by using standardized neuropsychological tests; traumatic experiences and level of political terror in the country of origin, assessed by means of reliable and valid self-report questionnaires.ResultsAt least one mental disorder was found in 29.7% of the sample. Most prevalent diagnoses were depressive disorders, anxiety disorders and PTSD. Women showed, with respect to men, a higher prevalence of anxiety disorders, higher trauma levels, and came from more at-risk countries. Higher trauma levels, better cognitive abilities and unemployment and refugee status were associated to the presence of a current psychiatric disorder in the whole sample.ConclusionsOur findings showed a higher prevalence of depressive disorders and PTSD in the sample of refugees and asylum seekers with respect to the general population and highlighted the role of potential risk factors whose identification may guide the implementation of preventive strategies and early treatments in these people.

Academic psychiatry is essential for advancing mental health understanding and treatments. However, women encounter more obstacles hindering their progress in academia than men. This Editorial aims to highlight these obstacles and propose strategies to address them, advocating for a more supportive environment for women psychiatrists’ ongoing growth and development. The importance of supportive environments, fair access to opportunities and structural changes, including initiatives for mentorship, funding and flexible work arrangements, are crucial. Collaboration among governments, institutions and organisations is needed to enhance research infrastructure and promote gender equality. Encouraging and recognising women's contributions in research fosters inclusivity and innovation. Prioritising these efforts is vital for the existence, well-being and success of women in academic psychiatry.

The pathophysiology of schizophrenia and bipolar disorder involves a complex interaction between genetic and environmental factors that begins in the early stages of neurodevelopment. Recent advancements in the field of induced pluripotent stem cells (iPSCs) offer a promising tool for understanding the neurobiological alterations involved in these disorders and, potentially, for developing new treatment options. In this review, we summarize the results of iPSC-based research on schizophrenia and bipolar disorder, showing disturbances in neurodevelopmental processes, imbalance in glutamatergic-GABAergic transmission and neuromorphological alterations. The limitations of the reviewed literature are also highlighted, particularly the methodological heterogeneity of the studies, the limited number of studies developing iPSC models of both diseases simultaneously, and the lack of in-depth clinical characterization of the included samples. Further studies are needed to advance knowledge on the common and disease-specific pathophysiological features of schizophrenia and bipolar disorder and to promote the development of new treatment options., Introduction Schizophrenia and bipolar disorder are complex and challenging mental disorders, whose etiopathogenesis can be traced back to a complex interaction between genetic and environmental factors that begins at the [...]

Abstract Osteosarcoma (OS) is the most prevalent and fatal type of bone tumor. It is characterized by great heterogeneity of genomic aberrations, mutated genes, and cell types contribution, making therapy and patients management particularly challenging. A unifying picture of molecular mechanisms underlying the disease could help to transform those challenges into opportunities. This review deeply explores the occurrence in OS of large-scale RNA regulatory networks, denominated “competing endogenous RNA network” (ceRNET), wherein different RNA biotypes, such as long non-coding RNAs, circular RNAs and mRNAs can functionally interact each other by competitively binding to shared microRNAs. Here, we discuss how the unbalancing of any network component can derail the entire circuit, driving OS onset and progression by impacting on cell proliferation, migration, invasion, tumor growth and metastasis, and even chemotherapeutic resistance, as distilled from many studies. Intriguingly, the aberrant expression of the networks components in OS cells can be triggered also by the surroundings, through cytokines and vesicles, with their bioactive cargo of proteins and non-coding RNAs, highlighting the relevance of tumor microenvironment. A comprehensive picture of RNA regulatory networks underlying OS could pave the way for the development of innovative RNA-targeted and RNA-based therapies and new diagnostic tools, also in the perspective of precision oncology.

Abstract The concept of “stemness” incorporates the molecular mechanisms that regulate the unlimited self-regenerative potential typical of undifferentiated primitive cells. These cells possess the unique ability to navigate the cell cycle, transitioning in and out of the quiescent G0 phase, and hold the capacity to generate diverse cell phenotypes. Stem cells, as undifferentiated precursors endow with extraordinary regenerative capabilities, exhibit a heterogeneous and tissue-specific distribution throughout the human body. The identification and characterization of distinct stem cell populations across various tissues have revolutionized our understanding of tissue homeostasis and regeneration. From the hematopoietic to the nervous and musculoskeletal systems, the presence of tissue-specific stem cells underlines the complex adaptability of multicellular organisms. Recent investigations have revealed a diverse cohort of non-hematopoietic stem cells (non-HSC), primarily within bone marrow and other stromal tissue, alongside established hematopoietic stem cells (HSC). Among these non-HSC, a rare subset exhibits pluripotent characteristics. In vitro and in vivo studies have demonstrated the remarkable differentiation potential of these putative stem cells, known by various names including multipotent adult progenitor cells (MAPC), marrow-isolated adult multilineage inducible cells (MIAMI), small blood stem cells (SBSC), very small embryonic-like stem cells (VSELs), and multilineage differentiating stress enduring cells (MUSE). The diverse nomenclatures assigned to these primitive stem cell populations may arise from different origins or varied experimental methodologies. This review aims to present a comprehensive comparison of various subpopulations of multipotent/pluripotent stem cells derived from stromal tissues. By analysing isolation techniques and surface marker expression associated with these populations, we aim to delineate the similarities and distinctions among stromal tissue-derived stem cells. Understanding the nuances of these tissue-specific stem cells is critical for unlocking their therapeutic potential and advancing regenerative medicine. The future of stem cells research should prioritize the standardization of methodologies and collaborative investigations in shared laboratory environments. This approach could mitigate variability in research outcomes and foster scientific partnerships to fully exploit the therapeutic potential of pluripotent stem cells.

A considerable proportion of patients with schizophrenia perform below population norms on standardized neuropsychological tests, and the performance of those performing within normal range is lower than predicted based on parental education. Cognitive impairment predates the onset of psychosis, is observed during symptom remission and in non-affected first-degree relatives of patients. At the present time, cognitive deficits are regarded as key features of schizophrenia, important determinants of poor psychosocial outcome and targets for both pharmacological and non-pharmacological treatment strategies. A group of eight key opinion leaders reviewed and discussed latest advances in scientific research and current good clinical practices on assessment, management, and treatment of CIAS. In the present paper they summarize the current evidence, identify main gaps between current knowledge and mental health services clinical practice, and provide practical recommendations to reduce the gap.

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) (N = 135), Clinical High Risk (CHR) (N = 233), and First Episode Psychosis (FEP) (N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52–0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18–0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82–0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design.

BackgroundThe development of neuroimaging biomarkers in patients with schizophrenia (SCZ) requires a refined clinical characterization. A limitation of the neuroimaging literature is the partial uptake of progress in characterizing disease-related features, particularly negative symptoms (NS) and cognitive impairment (CI). In the present study, we assessed NS and CI using up-to-date instruments and investigated the associations of abnormalities in brain resting-state (rs)-activity with disease-related features.MethodsSixty-two community-dwelling SCZ subjects participated in the study. Multiple regression analyses were performed with the rs-activity of nine regions of interest as dependent variables and disease-related features as explanatory variables.ResultsAttention/vigilance deficits were negatively associated with dorsal anterior cingulate rs-activity and, together with depression, were positively associated with right dorsolateral prefrontal cortex rs-activity. These deficits and impairment of Reasoning/problem-solving, together with conceptual disorganization, were associated with right inferior parietal lobule and temporal parietal junction rs-activity. Independent of other features, the NS Expressive Deficit domain was associated with the left ventral caudate, while the Motivational Deficit was associated with the dorsal caudate rs-activity.ConclusionNeurocognitive deficits and the two negative symptom domains are associated with different neural markers. Replications of these findings could foster the identification of clinically actionable biomarkers of poor functional outcomes.

Abstract Cells that are exposed to harmful genetic damage, either from internal or external sources, may undergo senescence if they are unable to repair their DNA. Senescence, characterized by a state of irreversible growth arrest, can spread to neighboring cells through a process known as the senescence-associated secretory phenotype (SASP). This phenomenon contributes to both aging and the development of cancer. The SASP comprises a variety of factors that regulate numerous functions, including the induction of secondary senescence, modulation of immune system activity, remodeling of the extracellular matrix, alteration of tissue structure, and promotion of cancer progression. Identifying key factors within the SASP is crucial for understanding the underlying mechanisms of senescence and developing effective strategies to counteract cellular senescence. Our research has specifically focused on investigating the role of IGFBP5, a component of the SASP observed in various experimental models and conditions. Through our studies, we have demonstrated that IGFBP5 actively contributes to promoting senescence and can induce senescence in neighboring cells. We have gained valuable insights into the mechanisms through which IGFBP5 exerts its pro-senescence effects. These mechanisms include its release following genotoxic stress, involvement in signaling pathways mediated by reactive oxygen species and prostaglandins, internalization via specialized structures called caveolae, and interaction with a specific protein known as RARα. By uncovering these mechanisms, we have advanced our understanding of the intricate role of IGFBP5 in the senescence process. The significance of IGFBP5 as a pro-aging factor stems from an in vivo study we conducted on patients undergoing Computer Tomography analysis. In these patients, we observed an elevation in circulating IGFBP5 levels in response to radiation-induced organismal stress. Globally, our findings highlight the potential of IGFBP5 as a promising therapeutic target for age-related diseases and cancer.

Circuit design requires fast and scalable models which are compatible to modern electronic design automation tools. For this task typically analytical compact models are preferred. However, for emerging device concepts with altered conduction mechanisms like reconfigurable FETs, tunnel FETs or feedback FETs compact models are often not yet ready for circuit simulation environments. Table models help to bridge this gap, as they only require biasing values in form of current- and capacitance tables, which are then interpolated during circuit simulation. However, the conventional approach of generating the data set through DC ramps in physical simulation typically results in a large number of TCAD simulations and many redundant data points. To simplify model building, cut turnaround time and omit redundant data, this work proposes to restrict to a single transient TCAD simulation, where all required bias points for a fully functional predictive table model are provided by nesting harmonic functions. The mathematical reasoning for the selection of appropriate parameters such as frequencies and sampling rate are presented and their influence on the quality of the obtained table model is exposed. This work further presents implementation of the modeling method including validation and post-processing of the transient simulation result. The target device is an emerging reconfigurable FET (RFET) with planar structure. Finally, the performance of the obtained predictive table model of the RFET is demonstrated with circuit simulation of logic cells.

Abstract There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness (n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants (n = 149, mean age = 26, SD = 6.7) and patient data (n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/– 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification.

Abstract DNA damage resulting from genotoxic injury can initiate cellular senescence, a state characterized by alterations in cellular metabolism, lysosomal activity, and the secretion of factors collectively known as the senescence-associated secretory phenotype (SASP). Senescence can have beneficial effects on our bodies, such as anti-cancer properties, wound healing, and tissue development, which are attributed to the SASP produced by senescent cells in their intermediate stages. However, senescence can also promote cancer and aging, primarily due to the pro-inflammatory activity of SASP. Studying senescence is complex due to various factors involved. Genotoxic stimuli cause random damage to cellular macromolecules, leading to variations in the senescent phenotype from cell to cell, despite a shared program. Furthermore, senescence is a dynamic process that cannot be analyzed as a static endpoint, adding further complexity. Investigating SASP is particularly intriguing as it reveals how a senescence process triggered in a few cells can spread to many others, resulting in either positive or negative consequences for health. In our study, we conducted a meta-analysis of the protein content of SASP obtained from different research groups, including our own. We categorized the collected omic data based on: i) cell type, ii) harmful agent, and iii) senescence stage (early and late senescence). By employing Gene Ontology and Network analysis on the omic data, we identified common and specific features of different senescent phenotypes. This research has the potential to pave the way for the development of new senotherapeutic drugs aimed at combating the negative consequences associated with the senescence process. Video Abstract

Abstract Background Cognitive impairment (CI) is one of the most prevalent and burdensome consequences of COVID-19 infection, which can persist up to months or even years after remission of the infection. Current guidelines on post-COVID CI are based on available knowledge on treatments used for improving CI in other conditions. The current review aims to provide an updated overview of the existing evidence on the efficacy of treatments for post-COVID CI. Methods A systematic literature search was conducted for studies published up to December 2023 using three databases (PubMed–Scopus–ProQuest). Controlled and noncontrolled trials, cohort studies, case series, and reports testing interventions on subjects with CI following COVID-19 infection were included. Results After screening 7790 articles, 29 studies were included. Multidisciplinary approaches, particularly those combining cognitive remediation interventions, physical exercise, and dietary and sleep support, may improve CI and address the different needs of individuals with post-COVID-19 condition. Cognitive remediation interventions can provide a safe, cost-effective option and may be tailored to deficits in specific cognitive domains. Noninvasive brain stimulation techniques and hyperbaric oxygen therapy showed mixed and preliminary results. Evidence for other interventions, including pharmacological ones, remains sparse. Challenges in interpreting existing evidence include heterogeneity in study designs, assessment tools, and recruitment criteria; lack of long-term follow-up; and under-characterization of samples in relation to confounding factors. Conclusions Further research, grounded on shared definitions of the post-COVID condition and on the accurate assessment of COVID-related CI, in well-defined study samples and with longer follow-ups, is crucial to address this significant unmet need.

Background Stakeholders worldwide increasingly acknowledge the need to address coercive practices in mental healthcare. Options have been described and evaluated in several countries, as noted recently in major policy documents from the World Health Organization (WHO) and World Psychiatric Association (WPA). The WHO's QualityRights initiative promotes human rights and quality of care for persons with mental health conditions and psychosocial disabilities. A position statement from the WPA calls for implementation of alternatives to coercion in mental healthcare. Aims We describe the engagement of both the WHO and WPA in this work. We discuss their mutual aim to support countries in improving human rights and quality of care, as well as the differences between these two organisations in their stated goals related to coercion in mental healthcare: the WHO's approach to eliminate coercion and the WPA's goal to implement alternatives to coercion. Method We outline and critically analyse the common ground between the two organisations, which endorse a similar range of rights-based approaches to promoting non-coercive practices in service provision, including early intervention in prevention and care and other policy and practice changes. Results Advocacy and action based on an agreed need to find practical solutions and advances in this area have the power to build consensus and unify key actors. Conclusions We conclude that persons with lived experience, families, mental health professionals and policy makers are now coming together in several parts of the world to work toward the common goals of improving quality, promoting human rights and addressing coercion in mental health services.