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L’Insonnia fatale familiare lascia tracce periferiche: nuovi biomarcatori in sangue e urine
No full textLa Fatal Familial Insomnia (FFI) è una rara malattia prionica genetica caratterizzata da disturbi progressivi del sonno e declino neurologico. La diagnosi precoce rimane una sfida, in particolare per forme presintomatiche o atipiche. Recentemente, i Seed Amplification Assays (SAA) hanno permesso la rilevazione altamente sensibile di prioni mal ripiegati in matrici periferiche, come sangue e urine, aprendo nuove prospettive per approcci diagnostici non invasivi. La presentazione illustra i progressi nell’applicazione dei SAA alla FFI ottenuti nel laboratorio di biochimica specialistica delle proteinopatie neurologiche e BSL3, con focus sulla sensibilità e specificità nella rilevazione dei prioni in campioni biologici periferici
INTEGRATED CHARACTERIZATION OF DUAL SPECIFICITY PHOSPHATASE 12 (DUSP12): FROM PUTATIVE REGULATION OF EIF6 TO MEDIATION OF CELLULAR ADAPTATION TO STRESS
No full textPrecise regulation of protein synthesis and ribosome biogenesis is fundamental for cellular homeostasis, growth, and adaptation. These energy-intensive processes are tightly controlled by signaling networks in which reversible phosphorylation plays a central role. A key node is eukaryotic initiation factor 6 (eIF6), a conserved anti-association factor that binds the 60S ribosomal subunit to prevent premature joining with the 40S subunit. Its release, required for 80S ribosome formation, is regulated by post-translational modifications, with phosphorylation of Ser235 emerging as a critical switch. Using non-phosphorylatable (S235A) and phosphomimetic (S235E) mutants, we showed that Ser235 phosphorylation is required for efficient eIF6 release and optimal translational output in vivo.
However, unbiased biochemical approaches failed to identify stable upstream regulators of this modification, suggesting that eIF6 phosphorylation is controlled by transient or context-dependent interactions. Guided by proximity-labeling datasets, we focused on the atypical dual-specificity phosphatase DUSP12, a high-confidence proximity interactor of eIF6 previously implicated in ribosome biogenesis.
Functional analyses revealed that DUSP12 overexpression enhances global protein synthesis, as measured by puromycin incorporation, without inducing major alterations in polysome profiles.
Quantitative phosphoproteomics identified a broad set of DUSP12-dependent phosphorylation changes affecting nuclear proteins, ribosome biogenesis factors, and components of protein quality control, including the ER chaperone Calnexin and the nucleolar protein NOLC1. Comparative analyses further demonstrated that the C-terminal Zinc-Binding Domain (ZBD) of DUSP12 plays a critical role in shaping the downstream phosphoproteomic and proteomic landscape,
Beyond its impact on translation-related pathways, DUSP12 overexpression was associated with a ZBD-dependent remodeling of the mitochondrial proteome, characterized by increased abundance of proteins involved in oxidative metabolism. This proteomic signature occurred in the absence of detectable changes in mitochondrial mass and was accompanied by functional metabolic alterations, including increased ATP levels and reduced lactate production. Integration with transcriptomic data revealed that these mitochondrial changes are largely uncoupled from corresponding transcriptional regulation, indicating a dominant contribution of post-transcriptional mechanisms. RNA sequencing instead revealed a limited and selective transcriptional response centered on stress-adaptive and signaling-related genes.
Overall, this work indicates that DUSP12 influences cellular physiology through multilayered regulatory mechanisms operating predominantly downstream of transcription. Rather than functioning as a global transcriptional regulator, DUSP12 is positioned at the intersection of translational output, proteostasis, and mitochondrial metabolism in a domain-dependent manner, thereby contributing to cellular adaptation to biosynthetic and metabolic demands. These findings place DUSP12 as a regulatory node linking ribosome-associated processes to metabolic and stress-response pathways, with broader implications for understanding cellular adaptation in both physiological and pathological contexts
Proteinopatie: cosa ci dicono i test di aggregazione e quali sono i limiti per ottenere risultati attendibili
No full textI Seed Amplification Assays (SAA) rappresentano metodiche altamente sensibili in grado di rilevare biomarcatori proteici patologici in numerosi tessuti periferici facilmente accessibili, ampliando in modo significativo le possibilità diagnostiche nelle malattie neurodegenerative. In questa presentazione sintetizzo lo stato dell’arte dell’applicazione clinica e di ricerca delle SAA nelle malattie da prioni, nella malattia di Alzheimer, nelle proteinopatie da TDP‐43, nelle alfa‐sinucleinopatie e nelle tauopatie, evidenziandone prestazioni, limiti e potenzialità. Concludo mostrando come queste tecniche stiano emergendo come strumenti di grande impatto per la diagnosi precoce, la stratificazione biologica e l’identificazione di co‐patologie, pur richiedendo una rigorosa contestualizzazione clinica e un’adeguata armonizzazione dei protocolli analitici
EXPLORING BRAIN COMPLEXITY AND ITS MECHANISMS: FROM THEORY TO PRACTICE AND BACK
No full textThis thesis explores brain complexity and its structural and functional substrates, linking theoretical principles, empirical TMS–EEG recordings, and multi-scale computational modeling. The central question it addresses is how brain networks sustain complex dynamics and how these dynamics break down in pathology. Across five interconnected studies, it standardizes experimental TMS–EEG data analysis and whole-brain computational pipelines to investigate how structural connectivity, network topology, and dynamical regimes jointly shape brain complexity.
First, a standardized analysis framework (TEPpy) is developed to map the temporal and spectral signatures of TMS-evoked potentials, operationalizing local circuit differentiation by characterizing peak-based features and natural frequencies. Second, an integrated whole-brain modeling workflow (TVB–Cobrawap) is introduced to tune connectome-based neural mass models toward biologically realistic regimes that jointly reproduce spontaneous rhythms, features of criticality, and high perturbational complexity in evoked responses, thereby unifying expectations for spontaneous and evoked activity within a single tuned model. Third, local virtual manipulations in a whole-brain computational model show that silencing highly central posterior hubs produces the largest reductions in perturbational complexity, indicating a central role of posterior network hubs in sustaining complex dynamics. Fourth, a multiscale computational model demonstrates that structural disconnection alone is sufficient to generate cortical bistability and slow waves via neuronal disfacilitation, and further shows that their propagation depends on hierarchical topology and the temporal coherence of afferent slow wave activity, providing a mechanistic account of perilesional sleep-like dynamics and large-scale slow wave propagation after focal lesions. Fifth, a computational analysis across rewired networks indicates that perturbational complexity peaks in small-world regimes and remains robust to common-driver confounds, whereas observational measures exhibit systematic biases toward segregation or integration. This clarifies complexity metric sensitivities and provides a principled basis for interpreting complexity markers.
Collectively, these contributions provide standardized empirical and computational tools, establish a mechanistic link between criticality and perturbational complexity, and bridge abstract information-theoretic constructs with the neurobiology of brain structure and dynamics. They further delineate translational avenues for assessing brain complexity and modeling slow wave dynamics following brain injury
Intraligamentary Anesthesia in Pediatric Patients: Is It an Effective Technique? A Systematic Review and Meta-Analysis
No full textBackground: Effective pain control is fundamental in pediatric dentistry. Supraperiosteal infiltration (SPA) and inferior alveolar nerve block (IANB) are the most used local anesthesia (LA) techniques. This review evaluated the available evidence on intraligamentary anesthesia (ILA) to assess its efficacy, safety, and viability as an alternative to conventional techniques. Methods: The review protocol was registered in PROSPERO (CRD420261284494) and conducted in accordance with PRISMA guidelines. Three databases were searched for RCTs published in English after 2000 involving children. Studies that compared ILA, delivered via either traditional or computer-controlled systems (CC-ILA), with other LA techniques were included. Risk of bias was assessed using the Cochrane’s RoB 2.0 tool. Meta-analysis was performed using a random-effects model with Stata/SE 18.0. Results: The database search yielded 347 records; after duplicate removal, 153 articles were screened. Thirty-four papers were assessed, of which thirteen studies were included, and three were retained for the meta-analysis. Significantly lower pain perception and improved physiological parameters were reported with ILA compared with IANB. CC-ILA demonstrated greater efficacy and reduced procedural discomfort than conventional ILA. Patients favored CC-ILA over IANB (68.0% vs. 32.0%). Postoperative lip biting occurred more frequently following IANB and CC-SPA than after ILA. Overall risk of bias was low. Meta-analysis revealed no significant difference in pain perception between ILA and IANB (z = −0.26; p = 0.79). Conclusions: ILA, particularly CC-ILA, appears to be an effective, safe, and well-tolerated technique and may be considered a valid anesthetic option in pediatric dentistry. The review did not receive any funding
Effectiveness of meditation in the management of epilepsy: An updated mini systematic review of recent findings
No full textBackground: Epilepsy is a chronic neurological disorder characterized by altered cortical excitability. The disorder is often associated with psychological distress and reduced quality of life. The purpose of the present review is to critically summarize the evidence on the effectiveness of meditation-based interventions for people with epilepsy.
Methods: A comprehensive search was conducted in PubMed, Scopus, and Web of Science for articles published in English between January 2020 and May 2025. Five studies met the inclusion criteria (two randomized controlled trials, two open-label studies and one case report).
Results: Most studies reported significant improvements in depression, anxiety, concentration and quality of life following meditation interventions. Neurophysiological investigations demonstrated modulation of gamma power, beta burst duration, and interictal epileptiform discharges, suggesting a potential stabilizing effect on neural networks. However, evidence regarding seizure frequency reduction was inconsistent and generally not statistically significant.
Conclusion: Meditation appears to be a promising adjunctive therapy for improving psychological well-being and potentially modulating cortical excitability in epilepsy. Future well-powered randomized controlled trials with standardized protocols and longer follow-up are warranted to confirm these findings and explore effects on seizure control
A finite approach to representable multicategories and related structures
No full textIt is known that monoidal categories have a finite definition, whereas multicategories have an infinite (albeit finitary) definition. Since monoidal categories correspond to representable multicategories, it goes without saying that representable multicategories should also admit a finite description. With this in mind, we give a new finite definition of a structure called a short multicategory, which only has multimaps of dimension at most four, and show that under certain representability conditions short multicategories correspond to various flavours of representable multicategories. This is done in both the classical and skew settings
Longitudinal Monitoring of Measurable Residual Disease in Chronic Lymphocytic Leukemia Patients Treated With Venetoclax: Results of a Prospective Multicenter Real-Life Study
No full textMeasurable residual disease (MRD) status in chronic lymphocytic leukemia (CLL) patients treated with venetoclax is a predictive factor of outcome in clinical trials. This multicenter prospective study was aimed to show the feasibility of MRD assessment in the real-life setting and to confirm the results of clinical trials. Forty-four patients were enrolled: 43% had 17p deleted and/or TP53 mutated (del17p/TP53mut), 62% had complex karyotype, and 65% of patients were previously treated with B-cell receptor inhibitor (BCRi). MRD was evaluated by 8-color flow cytometry (FC) on peripheral blood (PB) every 3 months from therapy start and samples with 10−4 CLL cells were considered as undetectable (uMRD). PB-uMRD patients were evaluated on bone marrow (BM). In 23 patients venetoclax was combined with Rituximab (VR). Median follow-up was 39.47 months (range 31.02–43.32). Median number of PB samples for each patients was 5 (IQR 4–7). Undetectable MRD on PB at any timepoint was obtained in 34/40 patients (85%): 82% in venetoclax monotherapy (Vmono) and 86.9% in VR group. Concordance of PB/BM samples was 92% at 24 months. No significant difference in uMRD rates was detected based on del17p/TP53mut and number of previous therapies. Three-year progression-free survival (PFS) for Vmono and VR was 53.5% and 55%. Median PFS in del17pl/TP53mut was 29.8 and 34 months in Vmono and VR respectively. Landmark analysis based on 9-month MRD showed a trend towards a better PFS in uMRD patients. Median PFS was 21.7 and 13.04 months in 24-month uMRD and detectable MRD patients after VR, respectively (log rank p = 0.0309). In conclusion, in these high-risk relapsed/refractory CLL patients who were MRD-monitored in the context of a real-life study the results were similar compared to published data in more selected patients
Retrieval-augmented generative AI enhances clinical reasoning in odontogenic sinusitis versus maxillary sinus mucositis
No full textPurpose
This exploratory pilot study evaluated whether combining structured clinical information, medical imaging, and literature-derived knowledge could enhance the diagnostic reasoning and output quality of a large language model in distinguishing odontogenic sinusitis from maxillary sinus mucositis.
Methods
Six complex clinical cases were constructed with nasal endoscopy, computed tomography findings, and clinical vignettes. ChatGPT-4.0 was prompted using four strategies: (1) clinical text only, (2) text with medical imaging, (3) text with structured literature excerpts, and (4) text with both imaging and literature input. Seven blinded expert reviewers rated 168 responses across diagnostic accuracy, clinical reasoning, safety, and overall usefulness using a five-point scale. Statistical comparisons and inter-rater reliability were assessed.
Results
All prompting strategies produced clinically safe outputs with minimal hallucinations or unsafe recommendations. Combining structured literature and imaging with clinical text significantly improved clinical reasoning scores (F(3,123) = 4.32, p = 0.0058), ranking first or second in six of seven evaluation domains. No significant differences were observed in diagnostic accuracy or safety across strategies. Inter-rater reliability was substantial (kappa = 0.7).
Conclusion
Providing structured evidence and imaging appeared to enhance the clinical reasoning quality of large language models in this small, simulated dataset, without compromising diagnostic accuracy or safety. These preliminary findings suggest that structured multimodal prompting may help improve the interpretability and reliability of artificial intelligence tools for supporting diagnostic reasoning in sinus-related diseases, though larger prospective validation studies are needed before clinical implementation