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Computational understanding of non-coding RNA pairwise interactions
No full textNon-coding RNAs (ncRNAs) govern a vast network of regulatory interactions within the cells, yet their pairwise relationships remain largely uncharted due to the complexity of RNA structure and the limits of current experimental methods. We present CUPID (Computational Understanding of Pairwise Interactions in ncRNA Data), a deep learning framework that predicts ncRNA-ncRNA interactions directly from primary sequence information. CUPID uses embeddings from a pre-trained RNA language model combined with a feed-forward classifier to identify patterns linked to molecular pairing. This approach avoids reliance on thermodynamic models or manual feature design and, unlike previously proposed models, is able to generalize across different types of ncRNAs, including long non-coding, circular, micro-, and small nuclear RNAs. By learning the hidden rules that govern RNA recognition, CUPID provides a scalable tool for exploring ncRNA interaction networks and advancing our understanding of RNA-based regulation
Unmasking the Apex: Multimodality Imaging for the Evaluation of Left Ventricular Apical Obliteration
No full textLeft ventricular (LV) apical obliteration represents a convergent imaging phenotype arising from diverse cardiac conditions, including thrombotic, hypertrophic, infiltrative, congenital, and neoplastic diseases. These conditions, despite sharing overlapping morphological features, require profoundly different management strategies. In this context, an accurate characterization of the LV apex is a cornerstone point, and can be performed through various techniques. Advances in multimodality imaging have substantially improved diagnostic precision, allowing clinicians to differentiate true obliteration from mimicking conditions such as hypertrabeculation, apical hypertrophy, or subendocardial fibrosis. This review provides a comprehensive overview of the anatomical variability of the LV apex and its implications for imaging interpretation. We appraise the role of echocardiography, including contrast-enhanced and speckle-tracking studies—alongside cardiac magnetic resonance (CMR), computed tomography (CT), and selective nuclear imaging in the evaluation of apical pathology. For each principal cause of apical obliteration—LV thrombus, apical hypertrophic cardiomyopathy, left ventricular non-compaction, endomyocardial fibrosis, cardiac amyloidosis, and intracardiac tumors—we outline key diagnostic clues, imaging red flags, and distinguishing tissue characteristics. Special emphasis is given to the incremental value of CMR for tissue characterization, thrombus detection, and fibrosis mapping, as well as to the interpretative challenges posed by apical foreshortening, near-field artefacts, and suboptimal acoustic windows. A practical, stepwise imaging framework is proposed to guide clinicians through the differential diagnosis of apical obliteration using an integrated multimodality approach. Future directions include the incorporation of 4D flow, advanced mapping techniques, and artificial intelligence-powered analysis to refine apical phenotyping and identify early disease signatures. Recognizing the full spectrum of apical pathology and its imaging manifestations is essential to prevent misdiagnosis, enable timely therapeutic decisions, and improve risk stratification
IFNAR2 p.F8S Variant Associates with Severe COVID-19 and Adaptive Immune Cell Activation Modulation
No full textSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a wide range of clinical manifestations modulated by genetic factors. The aim of this study was to identify genetic determinants of severe COVID-19 affecting protein sequence to gain insight into disease pathogenesis. Variants prioritized in two patients requiring lung transplant were tested in the Milan FOGS cohort (487/869 cases/controls), highlighting an independent association between the p.F8S low-frequency variant of interferon alpha receptor 2 gene (IFNAR2) and severe disease (OR = 1.73 [1.24–2.42], p = 0.001), replicated in the COVID-19 Host Genetics Initiative cohort (26,167/2,061,934 cases/controls). In the FOGS cohort, the p.F8S variant was linked to higher circulating IL-6 levels. In keeping, bulk transcriptomic analysis in PBMCs at the peak of infection (n = 57) showed that carriers of the p.F8S variant had upregulation of immune signaling and pathogens response (p < 0.05). Functional flow cytometry experiments in healthy donors (n = 12) revealed that membrane IFNAR2 protein expression was reduced in B lymphocytes, but higher in dendritic cells (p < 0.05). Finally, by interrogating a public scRNAseq resource of PBMC of people with COVID-19, we showed that p.F8S carriers had upregulation of immune pathways specifically in dendritic cells (p < 0.05). These results suggest that the p.F8S variant may influence COVID-19 severity by enhancing adaptive immune response, thereby favoring inflammation
Immediate TMS-EEG responses reveal motor cortex excitability
No full textThe combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is typically used
to probe cortical excitability at the network level, as local excitability measures were previously not feasible.
However, a recent study revealed immediate TMS-evoked potentials (i-TEPs) following primary motor cortex
(M1) stimulation, yet their physiological origin remains uncertain. Here, we aimed to test whether this imme-
diate activity is replicable, physiological, and related to motor cortex excitability.
Analyses were conducted on data from 28 healthy participants who underwent M1 stimulation using two
opposite biphasic current directions. We run a minimal preprocessing and then, upon visual inspection, we
divided the sample according to the presence/absence of muscle artifacts (Muscle/NoMuscle groups). First, we
successfully replicated i-TEPs for both current directions. Second, source localization revealed that the i-TEPs
signal originated in the precentral gyrus of the stimulated hemisphere. Third, we computed the immediate TMS-
related power (i-TRP) to disentangle the components contributing to the i-TEP signal. Two oscillatory peaks
emerged at 100–200 Hz and 600–800 Hz. Finally, we tested the relationship between i-TRP components and
motor evoked potentials (MEPs) amplitude in NoMuscle groups (n = 8 for both current directions, n = 14 for
anterior-to-posterior and posterior-to-anterior induced current). The analysis showed a robust positive associa-
tion between i-TRP in the 600–800 Hz range and MEP amplitude, suggesting that this component reflects M1
excitability.
Overall, our findings converge in indicating the physiological nature of immediate TMS-EEG responses, sug-
gesting that they reflect the excitability of the stimulated cortex
Dall’ordine post-bellico di Bretton Woods al capitalismo finanziario. Riflessioni sull’Italia e sull’economia globale dal 1945 a oggi
No full textL’evoluzione del capitalismo italiano e internazionale dal 1945 a oggi rappresenta
un laboratorio privilegiato per indagare le tensioni tra stabilità ed
efficienza, tra modelli di sviluppo statalisti e dinamiche di liberalizzazione,
tra economia reale e crescente finanziarizzazione. Nel secondo dopoguerra,
la ricostruzione e l’inserimento dell’Italia nel sistema di Bretton Woods furono
accompagnati da un assetto istituzionale e creditizio che privilegiava la
coesione e la solidità complessive rispetto all’efficienza dei mercati. La centralità
dello Stato, il ruolo delle partecipazioni pubbliche e la funzione di garanzia
esercitata dalla Banca d’Italia costituirono i pilastri di un capitalismo “protetto”, che sostenne la straordinaria stagione di crescita culminata nel
“miracolo economico”.
A partire dagli anni ’70, la fine del regime dei cambi fissi, i ripetuti shock
petroliferi e la stagflazione misero in crisi i paradigmi keynesiani e aprirono
la strada a un progressivo riassetto. Il neoliberismo, affermatosi dapprima
negli Stati Uniti e nel Regno Unito, diffuse l’idea che la riduzione del ruolo
pubblico, la deregolamentazione finanziaria e la privatizzazione delle imprese
statali fossero condizioni necessarie per la modernizzazione. In Italia,
tuttavia, la persistenza di un tessuto produttivo dominato da piccole e medie
imprese, la centralità del credito bancario e l’eredità delle partecipazioni statali
resero questo processo più contraddittorio e diseguale, intrecciando modernizzazione
e fragilità strutturali.
Dagli anni ’90 la globalizzazione, l’integrazione europea e la rivoluzione
tecnologica hanno accelerato la trasformazione del capitalismo, rafforzando
la supremazia della finanza e accentuando le pressioni competitive. La crisi
del 2008, lungi dall’invertire la tendenza, ha consolidato il predominio di
pochi grandi fondi e conglomerati globali, la cui logica estrattiva ha posto
nuove sfide alla sovranità degli Stati e alla coesione sociale. Analizzare tale
parabola consente di comprendere come, nel lungo periodo, l’Italia e le economie
avanzate abbiano privilegiato la salvaguardia della stabilità sistemica
– della moneta, delle istituzioni creditizie, dei mercati finanziari – anche al
prezzo di sacrificare l’efficienza allocativa, la capacità di innovazione e, in
ultima analisi, la sostenibilità sociale dello sviluppo
Detection of Gasping through Transthoracic Impedance: a New Approach to Early Cardiac Arrest Recognition
No full textTimely recognition of cardiac arrest (CA) is often delayed because gasping, a frequent sign of CA, is misinterpreted as normal breathing. In a porcine model of untreated CA with frequent gasps, we tested whether transthoracic impedance (TTI), continuously measured through defibrillator pads, could capture gasping-related thoracic volume changes. Gasping-induced inspiratory efforts produced large, distinctive TTI fluctuations. This observation was then confirmed in a healthy human volunteer simulating gasping under open and closed airway conditions. These translational findings support automated, TTI-based gasping detection via automated external defibrillators as a feasible strategy to improve early CA recognition and accelerate bystander CPR initiation
Evaluation of in vitro antivi0212ral activity against different SARS-CoV-2 variants of a protease PROTAC degrader
No full textTRANSCORONARY COOLING AND DILUTION FOR CARDIOPROTECTION DURING REVASCULARISATION FOR ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION: THE STEMI-COOL PILOT STUDY.
No full textBackground: The effectiveness of primary percutaneous coronary intervention (pPCI) in ST-elevation myocardial infarction (STEMI) is limited by reperfusion injury (RI), for which no therapy has yet proven beneficial. Transcoronary hypothermia has shown good tolerability and safety but with a neutral effect on outcomes in previous clinical trials. Potential reasons include complex protocols that prolong ischaemia and transient reperfusion prior to cardioprotection. Transcoronary haemodilution may also reduce RI by effectively slowing reperfusion. We developed a novel, simple method combining transcoronary cooling and dilution (TCCD) to reduce RI during pPCI.
Methods: STEMI-Cool is a pragmatic, registry-based randomised pilot assessing recruitment, feasibility, and safety of a simplified TCCD strategy for cardioprotection. Sixty STEMI patients (1 drop out) presenting within 12 h of symptom onset, regardless of infarct territory, were randomised 1:1 to standard of care (SOC) pPCI or pPCI with TCCD. Patients in cardiogenic shock or resuscitated after cardiac arrest were also included. Up to 750 mL of room temperature normal saline (NS) was infused through the guiding catheter in the culprit vessel using a pressure bag, starting before crossing the occlusion, with pressure adjusted to reduce proximal coronary temperature by 6-8°C. A pressure/thermistor wire was used as a guidewire or placed proximally for monitoring. Post-procedure index of microvascular resistance (IMR) was measured. A subgroup underwent cardiac magnetic resonance (CMR) at 1-7 days. Clinical follow-up was at 6 weeks (completed) and 1 year (ongoing). Continuous variables were compared using the Student’s t-test or Mann–Whitney U test, as appropriate. Categorical data were analysed using the chi-square test or Fisher’s exact test.
Results: An average of 549±229 mL of room temperature NS was infused at a rate of 61±29 mL/min, achieving a coronary temperature reduction of 6.37±1.22°C. Steady-state recruitment rate was ~5 patients/month at a single centre. Establishing TCCD protection before crossing the occlusion was feasible in 24/30 (80%) cases. The following data are presented as treatment vs SOC arms: there was no periprocedural mortality, while there were 2 vs 4 postprocedural deaths (p=0.37). There was an increase in ventricular fibrillation (VF): 10 vs 2, p=0.01, mainly occurring on reperfusion, however all patients were successfully defibrillated. CMR area at risk was similar: 23.69±11.01% vs 22.70±14.79%, p=0.87, with a trend towards infarct size reduction: 11.73±10.40% vs 17.74±12.39%, p=0.24. Further favourable trends in mechanistic outcomes are summarised in the table. We built a linear regression model linking diastolic blood pressure (DBP) to pressure required in the infusion bag to achieve target temperature (=DBP×4–100 mmHg).
Conclusions: Preliminary results from STEMI-Cool suggest good recruitability and feasibility of the combined cooling and dilution cardioprotective strategy. There was an increased incidence of reperfusion arrhythmia in the intervention arm with no associated difference in clinical outcomes. NS was chosen for its reported safety in other studies, but the high incidence of VF may be related to lack of physiological plasma electrolytes. Harmann’s solution was safe in our previous proof-of-concept study and might be preferred for future investigation. We demonstrated a relationship linking DBP to infusion pressure that may eliminate the need for a thermistor wire facilitating widespread adoption of this therapy if effective. The encouraging trends in mechanistic outcomes suggest the need for a multicentre, efficacy-powered trial to detect infarct size reduction
NEUROBIOLOGIA DEL SUICIDIO NEL DISTURBO DEPRESSIVO MAGGIORE: STUDIO MORFOLOGICO POST-MORTEM PER L¿INDAGINE DEL NETWORK GLIALE E VASCOLARE, CON ANALISI TOSSICOLOGICHE PER LA VALUTAZIONE DELL¿ADERENZA ALLA TERAPIA PSICHIATRICA
No full textSuicide is one of the leading causes of death worldwide, with over 700,000 deaths each year. In recent years, numerous studies have focused on analyzing its epidemiology and predisposing factors. Among the biological factors involved, cerebral glial cells have attracted growing attention due to postmortem evidence linking their pathological alterations to major depressive disorder (MDD) and suicidal behavior. The research project underlying this thesis focused on the postmortem analysis of human brain tissue from individuals diagnosed with MDD who died by suicide, with the aim of investigating alterations in the glial network—astrocytes and microglia—as well as in cerebral vascularization, in brain regions involved in mood regulation and suicide vulnerability. The experimental approach combined morphological, immunohistochemical, and immunofluorescence techniques with tissue clearing and 3D reconstruction using the X CLARITYTM system. Additionally, a toxicological analysis was carried out to assess adherence to psychiatric pharmacological therapy in individuals with mood disorders undergoing treatment at the time of death. The analysis of astrocytic markers (GFAP – Glial Fibrillary Acidic Protein – , S100β – calcium binding protein S100β –, AQP4 – Aquaporin-4 –, ALDH1L1 – Aldehyde Dehydrogenase 1 Family Member L1) showed a trend toward increased cell number and marker expression in suicide cases, particularly in the dorsolateral prefrontal cortex (dlPFC) and white matter. GFAP/S100β colocalization patterns varied by sex and brain region, with higher expression and overlap in male suicide cases. Conversely, densitometric analysis revealed higher expression levels in females, with significant regional differences. No significant changes were observed in AQP4 expression, while pilot testing with ALDH1L1 validated the experimental staining protocol. Regarding microglia, the analysis of IBA1 (Ionized calcium-binding adapter molecule 1) and LEA (Lycopersicon esculentum Agglutinin) markers revealed reduced LEA/IBA1 colocalization in male suicide cases compared 11 to controls in the cortical areas examined. In contrast, increased colocalization was observed in the dlPFC of female suicide cases. Although these differences were not statistically significant, densitometric analysis indicated a trend toward reduced microglial activity in males and increased activity in females. The use of the X-CLARITYTM technique enabled high-resolution 3D reconstruction of glial and vascular architecture. Three-dimensional analysis revealed a statistically significant reduction in cerebral vascularization in suicide cases compared to controls, with a 52.8% decrease, suggesting a potential role of vascular network dysfunction in the pathophysiology of suicide. Finally, the toxicological investigation highlighted poor adherence to psychiatric therapy in individuals with mood disorders who died by suicide: in 70% of the cases analyzed, pharmacological levels were either absent or only partially consistent with prescribed therapy. Overall, the neuromorphological findings suggest the presence of complex and interconnected alterations in the glial and vascular networks in individuals with mood disorders who died by suicide, with notable differences based on sex and brain region. These findings contribute to a deeper understanding of the neurobiological mechanisms underlying suicidal behavior and open new avenues for research in neuropathological, clinical, and forensic contexts. Given that treatment adherence is a key factor in suicide prevention, prospective monitoring of postmortem drug levels, along with synergistic collaboration between clinicians and forensic pathologists, could improve the effectiveness of therapeutic interventions and support the development of more targeted suicide prevention strategies
In vitro characterization of hemoglobin oxygen dissociation curves and electrolyte shifts in human blood under varying PCO2
No full textBackground: Efficient oxygen transport depends on hemoglobin (Hb) affinity for O2, which is modulated by factors like PCO2, as described by the Bohr effect. This in vitro study explored how varying PO2 and PCO2 influence hemoglobin oxygen saturation (HbO2) and plasma electrolyte concentrations in whole human blood. Methods: Blood from six healthy volunteers was equilibrated at 37°C with gas mixtures spanning PO2 and PCO2 ranges. A total of 346 samples were analyzed for blood gases, HbO2, and electrolytes. The HbO2 dissociation curve was modeled using a Gompertz function within a non-linear mixed-effects framework, while electrolyte dynamics were assessed via polynomial models. Results: HbO2 saturation ranged from 1.4 to 99.6%. Increasing PCO2 shifted the dissociation curve rightward, steepening its slope and raising the inflection point—hallmarks of the Bohr effect—without affecting maximal HbO2. Electrolyte analysis revealed that chloride decreased with PCO2 and increased with HbO2, consistent with the erythrocyte chloride shift. Sodium increased with PCO2, and a significant interaction between HbO2 and PCO2 was observed. Strong ion difference (SID) decreased linearly with HbO2 and increased quadratically with PCO2, suggesting a compensatory role in CO2-induced acid-base changes. Conclusion: These findings, validated against external datasets, underscore the tight coupling between respiratory gas exchange and electrolyte homeostasis. The study provides novel insights into how CO2 modulates both oxygen delivery and plasma ionic composition, with implications for understanding acid-base physiology and its regulation in health and disease