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- The proteasome controls presynaptic differentiation through modulation of an on-site pool of polyubiquitinated conjugatesPublication . Pinto, Maria J.; Alves, Pedro L.; Martins, Luís; Pedro, Joana R.; Ryu, Hyun R.; Jeon, Noo Li; Taylor, Anne M.; Almeida, Ramiro D.Differentiation of the presynaptic terminal is a complex and rapid event that normally occurs in spatially specific axonal regions distant from the soma; thus, it is believed to be dependent on intra-axonal mechanisms. However, the full nature of the local events governing presynaptic assembly remains unknown. Herein, we investigated the involvement of the ubiquitin-proteasome system (UPS), the major degradative pathway, in the local modulation of presynaptic differentiation. We found that proteasome inhibition has a synaptogenic effect on isolated axons. In addition, formation of a stable cluster of synaptic vesicles onto a postsynaptic partner occurs in parallel to an on-site decrease in proteasome degradation. Accumulation of ubiquitinated proteins at nascent sites is a local trigger for presynaptic clustering. Finally, proteasome-related ubiquitin chains (K11 and K48) function as signals for the assembly of presynaptic terminals. Collectively, we propose a new axon-intrinsic mechanism for presynaptic assembly through local UPS inhibition. Subsequent on-site accumulation of proteins in their polyubiquitinated state triggers formation of presynapses.
- Puzzling out presynaptic differentiationPublication . Pinto, Maria J.; Almeida, Ramiro D.Proper brain function in the nervous system relies on the accurate establishment of synaptic contacts during development. Countless synapses populate the adult brain in an orderly fashion. In each synapse, a presynaptic terminal loaded with neurotransmitters-containing synaptic vesicles is perfectly aligned to an array of receptors in the postsynaptic membrane. Presynaptic differentiation, which encompasses the events underlying assembly of new presynaptic units, has seen notable advances in recent years. It is now consensual that as a growing axon encounters the receptive dendrites of its partner, presynaptic assembly will be triggered and specified by multiple postsynaptically-derived factors including soluble molecules and cell adhesion complexes. Presynaptic material that reaches these distant sites by axonal transport in the form of pre-assembled packets will be retained and clustered, ultimately giving rise to a presynaptic bouton. This review focuses on the cellular and molecular aspects of presynaptic differentiation in the central nervous system, with a particular emphasis on the identity of the instructive factors and the intracellular processes used by neuronal cells to assemble functional presynaptic terminals. We provide a detailed description of the mechanisms leading to the formation of new presynaptic terminals. In brief, soma-derived packets of pre-assembled material are trafficked to distant axonal sites. Synaptogenic factors from dendritic or glial provenance activate downstream intra-axonal mediators to trigger clustering of passing material and their correct organization into a new presynaptic bouton. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".
- Visualizing K48 Ubiquitination during Presynaptic Formation By Ubiquitination-Induced Fluorescence Complementation (UiFC)Publication . Pinto, Maria J.; Pedro, Joana R.; Costa, Rui O.; Almeida, Ramiro D.In recent years, signaling through ubiquitin has been shown to be of great importance for normal brain development. Indeed, fluctuations in ubiquitin levels and spontaneous mutations in (de)ubiquitination enzymes greatly perturb synapse formation and neuronal transmission. In the brain, expression of lysine (K) 48-linked ubiquitin chains is higher at a developmental stage coincident with synaptogenesis. Nevertheless, no studies have so far delved into the involvement of this type of polyubiquitin chains in synapse formation. We have recently proposed a role for polyubiquitinated conjugates as triggering signals for presynaptic assembly. Herein, we aimed at characterizing the axonal distribution of K48 polyubiquitin and its dynamics throughout the course of presynaptic formation. To accomplish so, we used an ubiquitination-induced fluorescence complementation (UiFC) strategy for the visualization of K48 polyubiquitin in live hippocampal neurons. We first validated its use in neurons by analyzing changing levels of polyubiquitin. UiFC signal is diffusely distributed with distinct aggregates in somas, dendrites and axons, which perfectly colocalize with staining for a K48-specific antibody. Axonal UiFC aggregates are relatively stable and new aggregates are formed as an axon grows. Approximately 65% of UiFC aggregates colocalize with synaptic vesicle clusters and they preferentially appear in the axonal domains of axo-somatodendritic synapses when compared to isolated axons. We then evaluated axonal accumulation of K48 ubiquitinated signals in bead-induced synapses. We observed rapid accumulation of UiFC signal and endogenous K48 ubiquitin at the sites of newly formed presynapses. Lastly, we show by means of a microfluidic platform, for the isolation of axons, that presynaptic clustering on beads is dependent on E1-mediated ubiquitination at the axonal level. Altogether, these results indicate that enrichment of K48 polyubiquitin at the site of nascent presynaptic terminals is an important axon-intrinsic event for presynaptic differentiation.
- Untangling self-reported interoceptive attention and accuracy: Evidence from the european portuguese validation of the body perception questionnaire and the interoceptive accuracy scalePublication . Campos, Carlos; Rocha, Nuno; Barbosa, FernandoThis study included an online community-sample (n = 515) and aimed to: (1) explore the factor structure and psychometric properties of the European Portuguese versions of the Interoceptive Accuracy Scale (IAS) and the Body Perception Questionnaire (BPQ) - Body Awareness and Autonomic Reactivity scales; (2) examine the association between self-reported interoceptive attention and accuracy (indexed by the BPQ Body Awareness and IAS, respectively). Parallel-analysis indicated a one-factor solution for the BPQ Body Awareness. For the IAS and BPQ Autonomic Reactivity, bifactor ESEM models were retained. Ancillary measures revealed that both scales were mainly unidimensional and presented reliable total scores. All scales displayed excellent internal consistency, although test-rest reliability was modest. There was a quadratic U-shaped association between the IAS and BPQ Body Awareness. Alexithymia was negatively correlated with the IAS and unassociated with the BPQ Body Awareness. These findings suggest that interoceptive attention and accuracy may be dissociated using self-report questionnaires.
- The perspectives of current health professionals regarding their interaction with specific technologyPublication . Amorim, Manuela; Mota, Sandra; Tavares, DianaTechnological evolution in healthcare has been continuous. To access the advantages and disadvantages of professional-machine interaction from the user's perspective in health professionals we developed an online questionnaire. A total of 107 responses were obtained from 12 health technologies areas, showing some differences between them. The majority are 5 to 10 years of experience (28.0%). Speed, safety and efficiency stands out as benefits and dehumanization of the care provided and the reduction of jobs as risks. The user's perspective contributes in an elementary way to the current and future industry in the health area, and therefore should not be neglected.
- Refining the link between psychopathy, antisocial behavior, and empathy: a meta-analytical approach across different conceptual frameworksPublication . Campos, Carlos; Pasion, Rita; Azeredo, Andreia; Eduarda, Ramião; Mazer, Prune; Machado, Inês; Barbosa, FernandoThe current meta-analysis included 431 records (N= 123,414) to comprehensively explore the complex interaction between psychopathy, antisocial behavior, and empathy. First, empathy domains (cognitive and affective) were used to provide critical insights for distinguishing antisocial behavior from psychopathy. Cognitive empathy was more impaired in antisocial groups (gcognitive= -.40; gaffective= -.11), while high psychopathy samples displayed larger deficits in affective empathy (gaffective= -.44; gcognitive= -.23), although this dissociation was not clear in correlational analyses. Secondly, the specific associations between empathy domains and psychopathy dimensions were evaluated. Psychopathy traits closely related to antisocial behavior were mildly associated with both empathy domains (r= -.07 to -.14). Callous-affective traits were largely associated with affective empathy (r= -.32 to -.35) and moderately correlated to cognitive empathy (r= -.26). Diverging results were found for the interpersonal dimension, as boldness-adaptive manifestations were unrelated to cognitive empathy (r= .05), while non-adaptive interpersonal traits were negatively associated with both empathy domains (rcognitive= -.14; raffective= -.25). Overall, these findings suggest that: (1) psychopathy and antisocial behavior display distinct empathic profiles; (2) psychopathy dimensions are differentially associated with cognitive and affective empathy; (3) the interaction between interpersonal traits and empathic processes is different across the conceptual models of psychopathy.
- The sound of silence: Quantification of typical absence seizures by sonifying EEG signals from a custom‐built wearable devicePublication . Borges, Daniel Filipe; Fernandes, João; Soares, Joana Isabel; Casalta‐Lopes, João; Carvalho, Daniel; Beniczky, Sándor; Leal, AlbertoObjective: To develop and validate a method for long- term (24- h) objective quantification of absence seizures in the EEG of patients with childhood absence epilepsy (CAE) in their real home environment using a wearable device (waEEG), comparing automatic detection methods with auditory recognition after seizure sonification. Methods: The waEEG recording was acquired with two scalp electrodes. Automatic analysis was performed using previously validated software (Persyst® 14) and then fully reviewed by an experienced clinical neurophysiologist. The EEG data were converted into an audio file in waveform format with a 60- fold time compression factor. The sonified EEG was listened to by three inexperienced observers and the number of seizures and the processing time required for each data set were recorded blind to other data. Quantification of seizures from the patient diary was also assessed. Results: Eleven waEEG recordings from seven CAE patients with an average age of 8.18 ± 1.60 years were included. No differences in the number of seizures were found between the recordings using automated methods and expert audio assessment, with significant correlations between methods (ρ > .89, p < .001) and between observers (ρ > .96, p < .001). For the entire data set, the audio assessment yielded a sensitivity of .830 and a precision of .841, resulting in an F1 score of .835. Significance: Auditory waEEG seizure detection by lay medical personnel provided similar accuracy to post- processed automatic detection by an experienced clinical neurophysiologist, but in a less time- consuming procedure and without the need for specialized resources. Sonification of long- term EEG recordings in CAE provides a user- friendly and cost- effective clinical workflow for quantifying seizures in clinical practice, minimizing human and technical constraints.
- The sound of silence: Quantification of typical absence seizures by sonifying EEG signals from a custom‐built wearable devicePublication . Borges, Daniel Filipe; Fernandes, João; Soares, Joana Isabel; Casalta‐Lopes, João; Carvalho, Daniel; Beniczky, Sándor; Leal, AlbertoTo develop and validate a method for long-term (24-h) objective quantification of absence seizures in the EEG of patients with childhood absence epilepsy (CAE) in their real home environment using a wearable device (waEEG), comparing automatic detection methods with auditory recognition after seizure sonification. The waEEG recording was acquired with two scalp electrodes. Automatic analysis was performed using previously validated software (Persyst® 14) and then fully reviewed by an experienced clinical neurophysiologist. The EEG data were converted into an audio file in waveform format with a 60-fold time compression factor. The sonified EEG was listened to by three inexperienced observers and the number of seizures and the processing time required for each data set were recorded blind to other data. Quantification of seizures from the patient diary was also assessed. Eleven waEEG recordings from seven CAE patients with an average age of 8.18 ± 1.60 years were included. No differences in the number of seizures were found between the recordings using automated methods and expert audio assessment, with significant correlations between methods (ρ > .89, p < .001) and between observers (ρ > .96, p < .001). For the entire data set, the audio assessment yielded a sensitivity of .830 and a precision of .841, resulting in an F1 score of .835. Auditory waEEG seizure detection by lay medical personnel provided similar accuracy to post-processed automatic detection by an experienced clinical neurophysiologist, but in a less time-consuming procedure and without the need for specialized resources. Sonification of long-term EEG recordings in CAE provides a user-friendly and cost-effective clinical workflow for quantifying seizures in clinical practice, minimizing human and technical constraints.
- Validity of central pain processing biomarkers for predicting the occurrence of oncological chronic pain: a study protocolPublication . Carrillo‑de‑la‑Peña, M. T.; Fernandes, C.; Castro, Catarina; Medeiros, R.Despite recent improvements in cancer detection and survival rates, managing cancer-related pain remains a significant challenge. Compared to neuropathic and inflammatory pain conditions, cancer pain mechanisms are poorly understood, despite pain being one of the most feared symptoms by cancer patients and significantly impairing their quality of life, daily activities, and social interactions. The objective of this work was to select a panel of biomarkers of central pain processing and modulation and assess their ability to predict chronic pain in patients with cancer using predictive artificial intelligence (AI) algorithms. We will perform a prospective longitudinal cohort, multicentric study involving 450 patients with a recent cancer diagnosis. These patients will undergo an in-person assessment at three different time points: pretreatment, 6 months, and 12 months after the first visit. All patients will be assessed through demographic and clinical questionnaires and self-report measures, quantitative sensory testing (QST), and electroencephalography (EEG) evaluations. We will select the variables that best predict the future occurrence of pain using a comprehensive approach that includes clinical, psychosocial, and neurophysiological variables. This study aimed to provide evidence regarding the links between poor pain modulation mechanisms at precancer treatment in patients who will later develop chronic pain and to clarify the role of treatment modality (modulated by age, sex and type of cancer) on pain. As a final output, we expect to develop a predictive tool based on AI that can contribute to the anticipation of the future occurrence of pain and help in therapeutic decision making.
- The Dianalund experience: A review of the 6th ILAE School on Advanced EEG and EpilepsyPublication . Borges, Daniel Filipe; Primicerio, Giulia; Perjoc, Radu‐Ștefan; Bloch, Lars Ølgaard; Cacic Hribljan, MelitaThe 6th International League Against Epilepsy (ILAE)School on Advanced EEG and Epilepsy (DSSEE6) tookplace between July 20 and 28, 2024. It is a biennial courseheld in Dianalund @ Danish Epilepsy Center—Filadelfia,Denmark, since 2012. This year's event was hosted in ahybrid format and was organized under the auspices ofthe ILAE Academy and the Danish Epilepsy Society.