IRCCS San Raffaele Scientific Institute Showcase

Gene-environment correlations (rGE) may drive the clinical heterogeneity of major depressive disorder (MDD) through their effects on brain structure. However, previous literature focused on isolated components of these interplays. Here, we jointly investigate how rGE shape neurobiological profiles in MDD, and whether rGE-driven brain signatures can disentangle depression subtypes. In 5951 MDD patients with genetic, trauma-related and neuroimaging data from the UK Biobank, cross-validated sparse canonical correlation analysis was employed to assess multivariate associations between polygenic scores (PGSs) for mental health conditions and adverse childhood experiences (ACEs). Linear regressions tested the impact of the shared PGSs–ACEs dimensions on gray matter (GM) measures. Consensus clustering was applied to the neuroimaging features significantly associated with PGSs or ACEs to identify latent biotypes of MDD, and the emerged clusters were compared for depressive symptomatology and organic comorbidities. We found a significant canonical correlation between PGSs and ACEs (r = 0.11, p < 0.001). The most contributing PGSs were schizophrenia, attention deficit-hyperactivity disorder, autism (positive weights) and education (negative weight). Canonical variates of PGSs and ACEs associated with reduced GM in frontal, temporal, cingulate, parietal and subcortical regions (b = [-0.041; -0.021], pFDR<0.05). Such rGE-sensitive brain regions underpinned two clusters of patients, with one showing higher genetic/environmental risk, reduced GM integrity, and a worse clinical profile, including atypical symptoms, anhedonia, lethargy, sleep alterations and diabetes comorbidity. These findings indicate that rGE-driven neurobiological signatures contribute to the clinical heterogeneity of depression, supporting biologically informed subtyping in MDD.

Targeted genomic integration of gene-sized cassettes into hematopoietic stem and progenitor cells (HSPCs) for genetic disease treatment is constrained by the low efficiency of homology-directed repair (HDR) and frequent unintended genetic changes at the editing site. To overcome these challenges, we introduce Selection by Means of Artificial Transactivators (SMArT), which transiently implements AND reporter gates to achieve templated integration of a functional cassette at the target site. HDR-edited HSPCs were enriched to very high purity through transient selector expression, whereas cells carrying undesired and potentially genotoxic on-target edits were preferentially depleted. Xenotransplantation of SMArT-enriched HSPCs in immunodeficient mice resulted in fully HDR-edited human grafts with the selector no longer detectable. SMArT strategies were implemented through clinically compliant manufacturing and selectors. They support both safe harbor integration and gene correction, can preserve physiological transcriptional regulation, and are portable across loci also with polyfunctional editors. Overall, SMArT strategies may broaden therapeutic applicability of gene-sized editing while reducing its genotoxic burden.

Objectives: The role of neutrophils in systemic sclerosis (SSc) remains incompletely understood. Methods: To address this, blood samples from 39 SSc patients, 39 healthy controls, and 22 systemic lupus erythematosus (SLE) patients were analyzed. Results: In SSc, neutrophils exhibited substantial activation, evidenced by granule mobilization, elevated plasma levels of Neutrophil Extracellular Trap (NET) byproducts, and upregulated TIE2 expression. In parallel, they underwent metabolic reprogramming, characterized by increased autophagy, likely to support the heightened energy demands of activation. By contrast, neutrophils from SLE patients displayed minimal autophagy, lacked TIE2 expression, and shifted toward low-density granulocytes. Neutrophil reprogramming in SSc correlated with plasma levels of HMGB1+ EVs. Mechanistically, EVs purified from the plasma of patients with SSc adhered to neutrophils when injected in immunodeficient NSG mice, inducing autophagy, TIE2 expression, and promoting lung inflammation and fibrosis. These effects were abrogated by HMGB1 inhibitors and required the HMGB1 receptor, RAGE. Recombinant HMGB1 recapitulated EV-induced effects, while neutrophil targeting by liposome-encapsulated clodronate prevented them. Conclusions: In summary, neutrophils in SSc exhibit a dual phenotype of autophagy and activation driven by HMGB1+ EVs, representing a pathogenic mechanism with therapeutic potential in SSc. This mechanism operates similarly in male and female mice and is sufficient to induce neutrophil-driven lung injury in vivo.

This dataset refers to a study where 558 patients with multiple sclerosis (MS) and 214 healthy controls (HC) underwent neurological assessment and 3T MRI acquisition, including resting-state functional MRI (RS fMRI). In addition, 491 MS patients completed a comprehensive neuropsychological evaluation for cognitive status assessment. RS functional connectivity (FC) abnormalities were quantified using degree centrality analysis to characterize large-scale brain network reorganization associated with MS. Spatial patterns of functional abnormalities were then compared between HC and different MS phenotypes, including relapsing-remitting and progressive MS, as well as between cognitively preserved and cognitively impaired patients. To investigate the biological basis of RS FC, spatial correlations were performed between regional degree centrality abnormalities and the expression of 3634 MS-related genes derived from the Allen Human Brain Atlas (AHBA). Genes significantly associated with imaging-derived network alterations underwent pathway enrichment analysis. Compared to HC, MS patients showed increased degree centrality mainly in the default-mode network (DMN), associated with genes involved in inflammation resolution and immune regulation, and reduced centrality in salience network and cerebellar regions linked to cytokine-response genes. Progressive MS patients exhibited higher centrality in DMN and cerebellar areas than HC and relapsing-remitting MS patients, correlating with genes related to epigenetic and mitochondrial functions. Among MS patients, 144 (29.3%) were cognitively impaired and showed increased centrality in DMN and mesial temporal regions compared to cognitively preserved patients and HC. These abnormalities negatively correlated with DNASE1 and CP gene expression, implicated in DNA degradation, iron homeostasis, and neurodegeneration. Regional gene expression spatially correlated with MS-related functional network abnormalities.

Spatial regulation of mRNA polyadenylation is a key emerging mechanism shaping cellular function. The TENT5/FAM46 family comprises four non-canonical poly(A) polymerases that stabilize transcripts encoding ER-targeted proteins, with mutations linked to diseases of professional secretory cells. Using transcriptomic profiling coupled with systematic mutagenesis, we uncover how paralog-specific evolutionary divergence dictates distinct subcellular localization, interaction, and functional outcomes. TENT5D, the most ER-associated member, triggers widespread proteome remodeling, boosting the concerted expression of ER, ERGIC, Golgi, and lysosomal proteins. In contrast, TENT5B lacks ER targeting and regulates proteins involved in cell division. Mechanistically, a member-specific C-terminal region that binds ER-transmembrane FNDC3 proteins is necessary and sufficient for ER localization. Altogether, our findings reveal a domain-encoded mechanism linking TENT5 localization to transcript selectivity and secretory output. The TENT5–FNDC3 axis thus emerges as a key orchestrator of the cellular translatome and organelle identity. OMICS Data: proteomics, RNA-seq and TAIL-Seq Proteomics data folder contains raw data. RNA-seq folder contains BAM files while Fastq are available at GSE326742 (related link below) TAIL-seq folder contains polyA tail lenght results for each samples while Fastq files are available at GSE326755 (related link below)

The EVASION study was a prospective, observational, proof-of-concept study designed to quantify and characterize the HIV reservoir in people living with HIV (PLWH) on suppressive antiretroviral therapy with active oncogenic viral co-infections (HCV, EBV, HPV) and/or virus-driven malignancies, compared to co-infection-free PLWH. In the published work, the EVASION participants with active viral co-infections serve as the control group. The table and figures presented here refer to the entire EVASION cohort and are therefore not restricted to the control group included in the publication.

This dataset was generated to investigate whether integrating demographic, clinical, and magnetic resonance imaging (MRI) features can improve the classification of multiple sclerosis (MS) patients, distinguish disease phenotypes, and predict disability severity. The underlying research hypothesis is that machine learning (ML) models trained on multimodal data can improve disease characterization more accurately than traditional statistical approaches. The dataset includes data from 1554 patients with MS and 520 healthy controls (HC), collected within the the Italian Neuroimaging Network Initiative. For each participant, demographic information (e.g., age, sex), clinical assessments, and brain MRI scans were acquired. Clinical disability was quantified using the Expanded Disability Status Scale (EDSS) score. MRI acquisition included T2-weighted and 3D T1-weighted sequences, from which quantitative imaging features were derived. These features included total and regional T2 lesion volumes (LV), as well as normalized volumetric measures of cortical and subcortical grey matter (GM), white matter, cerebellum, and brainstem. All imaging-derived variables were preprocessed and harmonized across sites. ML models applied to these data (including support vector machines, multi-layer perceptron networks, Random Forest, and Gradient Boosting) demonstrated high performance in disease and phenotype classification, as well as in EDSS prediction. Specifically, classification accuracy for MS vs HC ranged from 89% to 96%, while phenotype classification reached approximately 92% accuracy. Disability prediction achieved strong agreement with observed EDSS scores (intra-class correlation coefficients between 0.7456 and 0.76). Feature importance analyses (using SHAP values) indicated that T2 LV and regional GM volumes (particularly in the brainstem, cerebellum, thalamus, and cortex) were among the most influential variables for classification and prediction tasks. Demographic variables such as age and sex, along with clinical disability scores, also contribute significantly to model performances. This dataset provides a robust, multimodal resource for advancing ML approaches to MS classification and prognosis.

The present includes the raw data from the article "The Impact of Aging and Sex on Corneal Nerve Density and Function" (doi:https://doi.org/10.1167/iovs.67.3.3). In this work, we described the role of sex in modulating mouse corneal nerve morphology and function during aging.

Rationale: to evaluate Fibroblast Growth Factor 21 (FGF21) as a possible biomarkers for depressive symtopms in elderly. FGF21 is a stress-induced hepatokine involved in inflammation and neuroendocrine regulation, processes implicated in depression. Methods: We investigated the association between FGF21 and depressive symptoms in community-dwelling older adults. Data were obtained from 52 older individuals (median age 70; 61.5% women) within the FRASNET cohort who underwent longitudinal assessments (2017 for baseline –2024 for follow up). Depressive symptoms were evaluated using the 15-item Geriatric Depression Scale (GDS). Regression models adjusted for age, sex, and body mass index were used to assess associations between FGF21 and depressive symptoms. Results: Circulating FGF21 levels declined significantly over time (p = 0.03) but remained higher in individuals with depressive symptoms at both baseline and follow-up. Elevated baseline FGF21 predicted higher GDS scores at follow-up (adjusted B = 0.003, 95% CI 0.000–0.006, p = 0.049). Discriminatory performance for elevated depressive symptoms was modest (AUC = 0.66). Conclusions: Higher baseline FGF21 levels were associated with greater depressive symptom burden at follow-up. These findings should be considered preliminary and hypothesis-generating. Further studies using diagnostic outcomes and larger samples are warranted.

Rationale: To identify circulating biomarkers of fraily. Participants were eligible if they were ≥65 years old, able to walk >500 m without assistance, and had a life expectancy >6 months. Exclusion criteria included severe cognitive impairment (Mini-Mental State Examination [MMSE] <18), inability to provide informed consent, or severe health conditions such as uncontrolled hypertension, recent fractures of the upper or lower extremities, or myocardial infarction within the previous year. For this analysis, individuals recruited in nursing homes and those with missing data required to compute frailty or body composition were excluded. Data were collected at baseline (2017) and follow-up (2024). Frailty was assessed using three instruments: the Frailty Index (FI), the modified Frailty Phenotype (FP), and the Clinical Frailty Scale (CFS). Nutritional status was evaluated with the Mini Nutritional Assessment–Short Form (MNA-SF) and categorized as malnourished (≤7), at risk (8–11), or well-nourished (12–14). Sarcopenia was screened using the SARC-F questionnaire and confirmed according to EWGSOP2 criteria. Muscle strength was assessed using the SPPB chair-stand test (>15 s indicating reduced strength). Muscle mass was measured by bioelectrical impedance analysis (BIA), with cut-offs <32.9 % in men and <23.9 % in women. Sarcopenic obesity was defined according to ESPEN/EASO criteria as the coexistence of reduced muscle strength, low muscle mass, and excess fat mass (≥30 % in men and ≥42 % in women). Physical activity was assessed with the Physical Activity Scale for the Elderly (PASE; <76 indicating low activity). Cognitive function was measured using the MMSE (≤24 indicating impairment), and depressive symptoms using the Geriatric Depression Scale (GDS-15). Functional status was evaluated through Activities of Daily Living (ADL) and Instrumental ADL (IADL), and fall risk using the Tinetti scale. Biomarker analyses were performed in plasma samples from 52 of 228 participants due to assay costs and sample availability. Participants were randomly selected among those reassessed at follow-up and were representative of the overall cohort. Blood samples were collected in EDTA tubes from non-fasting subjects, processed within 24 h, aliquoted, and stored at −80 °C. Biomarker concentrations were measured using the ELLA™ automated immunoassay system (Bio-Techne, USA). Continuous variables were reported as mean ± SD or median (IQR), and categorical variables as frequencies (%). Baseline and follow-up comparisons used paired t-tests or Wilcoxon tests. Associations between biomarkers and clinical outcomes were examined using regression models adjusted for age and sex. GDF-15 and FGF-21 concentrations were log-transformed. ROC analyses evaluated the ability of baseline biomarkers to discriminate adverse outcomes at follow-up. Optimal thresholds were determined using the Youden index. Analyses were performed using IBM SPSS Statistics version 25.