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Entrevista com Pablo del Río.

The solution of conflicts, cases of violence and harmful offences through alternatives to the penal system has been encouraged by Brazil’s Conselho Nacional de Justiça/National Justice Council (CNJ) since 2010. However, empirical studies that assess the impact of restorative practices when applied to domestic violence cases are sparse because most of them tend to highlight the retributive model’s insufficiency compared to the restorative model. In attempt to break away from that logic, the article analyses the insertion of practices of restorative justice regarding domestic violence by examining empirical studies carried out at the Rio Grande do Sul’s Justice Court, a pioneer in the employment of restorative justice. The study shows that restorative practices for domestic violence are residual, do not disrupt the traditional model and are not understood as restorative by women. Therefore, a broad and serious discussion about the model being implemented in Brazil is needed.

Extracellular vesicles (EVs) carry bioactive molecules associated with various biological processes, including miRNAs. In both Huntington’s disease (HD) models and human samples, altered expression of miRNAs involved in synapse regulation were reported. Recently, the use of EV cargo to reverse phenotypic alterations in disease models with synaptopathy as the end-result of the pathophysiological cascade has become an interesting possibility. Here, we assessed the contribution of EVs to GABAergic synaptic alterations using a human HD model and studied the miRNA content of isolated EVs. After differentiating HD human induced-pluripotent stem cells into electrophysiologically active striatal-like GABAergic neurons, we found that HD-derived neurons displayed reduced density of inhibitory synapse markers and of GABA receptor-mediated ionotropic signaling. Treatment with EVs secreted by control (CTR) fibroblasts reversed the deficits in GABAergic synaptic transmission and increased the density of inhibitory synapses on HD-neuron cultures, while EVs from HD-derived fibroblasts had the opposite effects on CTR-neurons. Moreover, analysis of miRNAs from purified EVs identified a set of differentially expressed miRNAs between manifest HD, premanifest and CTR lines with predicted synaptic targets. The EVs-mediated reversal of the abnormal GABAergic phenotype in HD-derived neurons reinforces the potential role of EVs-miRNAs on synapse regulation.

O texto apresenta o resultado da entrevista com duas pesquisadoras brasileiras, destacadas precursoras dos postulados da psicologia histórico-cultural no Brasil a partir dos anos 1980. Seus estudos, publicações, conferências e aulas tiveram (e ainda têm) um papel muito relevante na divulgação e aprofundamento das ideias de Vigotski e seus colaboradores, especialmente entre o público da educação. Elas também foram importantes formadoras da primeira geração de pesquisadores nacionais nessa orientação teórica. Além de gozarem de significativo prestígio nacional, são também muito respeitadas no cenário internacional, reconhecidas como grandes conhecedoras dessa escola de pensamento. Por meio de um olhar retrospectivo, as entrevistadas são convidadas a fazer um exercício metateórico, buscando reconstruir a gênese de seus interesses pela perspectiva histórico-cultural, as questões centrais que motivaram seus programas de pesquisa, as redes de contato e interlocuções que foram estabelecendo ao longo do tempo com pesquisadores do Brasil e de diversas partes do mundo. As pesquisadoras fazem, também, reflexões instigantes sobre as origens de algumas de suas publicações, sobretudo aquelas que acabaram se tornando obras clássicas, referências obrigatórias entre estudiosos e profissionais do campo educacional. Além de permitir que os leitores conheçam seus percursos individuais, seus depoimentos oferecem um registro histórico e, ao mesmo tempo, um balanço da disseminação, interpretação e desenvolvimento da psicologia histórico-cultural no Brasil ao longo dos últimos 40 anos em suas interfaces com a educação.

Mitochondrial deregulation has emerged as one of the earliest pathological events in Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder. Improvement of mitochondrial function in AD has been considered a relevant therapeutic approach. l-carnitine (LC), an amino acid derivative involved in the transport of long-chain fatty acids into mitochondria, was previously demonstrated to improve mitochondrial function, having beneficial effects in neurological disorders; moreover, acetyl-l-carnitine (ALC) is currently under phase 4 clinical trial for AD (ClinicalTrials.gov NCT01320527). Thus, in the present study, we investigated the impact of different forms of carnitines, namely LC, ALC and propionyl-l-carnitine (PLC) on mitochondrial toxicity induced by amyloid-beta peptide 1–42 oligomers (AβO; 1 μM) in mature rat hippocampal neurons. Our results indicate that 5 mM LC, ALC and PLC totally rescued the mitochondrial membrane potential and alleviated both the decrease in oxygen consumption rates and the increase in mitochondrial fragmentation induced by AβO. These could contribute to the prevention of neuronal death by apoptosis. Moreover, only ALC ameliorated AβO-evoked changes in mitochondrial movement by reducing the number of stationary mitochondria and promoting reversal mitochondrial movement. Data suggest that carnitines (LC, ALC and PLC) may act differentially to counteract changes in mitochondrial function and movement in neurons subjected to AβO, thus counteracting AD-related pathological phenotypes.

Neurodegenerative movement disorders, such as Huntington's disease (HD), share a progressive and relentless course with increasing motor disability, linked with neuropsychiatric impairment. These diseases exhibit diverse pathophysiological processes and are a topic of intense experimental and clinical research due to the lack of therapeutic options. Restorative therapies are promising approaches with the potential to restore brain circuits. However, there were less compelling results in the few clinical trials. In this review, we discuss cell replacement therapies applied to animal models and HD patients. We thoroughly describe the initial trials using fetal neural tissue transplantation and recent approaches based on alternative cell sources tested in several animal models. Stem cells were shown to generate the desired neuron phenotype and/or provide growth factors to the degenerating host cells. Besides, genetic approaches such as RNA interference and the CRISPR/Cas9 system have been studied in animal models and human-derived cells. New genetic manipulations have revealed the capability to control or counteract the effect of human gene mutations as described by the use of antisense oligonucleotides in a clinical trial. In HD, innovative strategies are at forefront of human testing and thus other brain genetic diseases may follow similar therapeutic strategies.

O presente artigo tem como objetivo analisar possíveis correspondências aproximativas entre os princípios fundamentais que sustentam a metodologia da Pedagogia da Alternância, com os fundamentos da psicologia histórico-cultural de Lev Semionovich Vigotski, especialmente no que tange à noção de vivência (perejivanie) e de signos culturais como mediadores das internalizações e formação das funções psíquicas superiores. Fomenta-se tal empreitada a escassez de trabalhos nessa direção. Para tanto, fundamenta-se a argumentação por meio da revisão bibliográfica que tratam dos respectivos temas a partir de uma abordagem analítica qualitativa-reflexiva. Com esse propósito, no encadeamento do texto, primeiramente contextualiza-se a Pedagogia da Alternância, assim como apresenta-se algumas das principais características da Psicologia Histórico-Cultural. Em seguida apresenta-se algumas possíveis aproximações, para concluir com a apresentação de aspectos de diferentes teorias educacionais libertárias que também se aproximam das duas perspectivas em análise.

A 36-week premature newborn with trisomy 21, had a fever, runny nose and mild dyspnea at 27 days old. Parents had flu-like symptoms. He was admitted to intensive care unit (ICU), in isolation with support therapy. His reverse transcription-polymerase chain reaction (RT-PCR) test for coronavirus disease 2019 (COVID-19) was positive. He had leukopenia and lymphopenia and increased C-reactive protein (CRP) levels, associated with mixed and interstitial opacities on chest radiography. Antibiotic therapy was performed with ampicillin and gentamicin for 10 days. He had improvement of symptoms, with worsening of CRP levels. On the 11th day of hospitalization antibiotic therapy was replaced by clarithromycin, which was performed for 5 days, with laboratory improvement after introduction. Chest computed tomography (CT) showed bilateral ground-glass lesions. He had a good recovery and was discharged from hospital with 17 days of hospitalization. Int J Clin Pediatr. 2020;9(4):116-119 doi: https://doi.org/10.14740/ijcp396

Mitochondrial and autophagy dysfunction are mechanisms proposed to be involved in the pathogenesis of several neurodegenerative diseases. Huntington’s disease (HD) is a progressive neurodegenerative disorder associated with mutant Huntingtin-induced abnormalities in neuronal mitochondrial dynamics and quality control. Former studies suggest that the removal of defective mitochondria may be compromised in HD. The mitochondrial quality control is a complex, well-orchestrated pathway that can be compromised through mitophagy dysregulation or impairment in the mitochondrial-lysosomal axis. Another mitochondrial stress response is the generation of mitochondrial-derived vesicles that fuse with the endolysosomal system and form multivesicular bodies that are extruded from cells as extracellular vesicles (EVs).In this study, we comprehensively characterized the mitochondrial and autophagy alterations in premanifest and manifest HD patients and performed a proteomic and genomic EVs profile. We observed that manifest HD patients exhibit mitochondrial and autophagy impairment associated with enhanced EVs release. Further, we detected mitochondrial components in EVs released by HD cells and in neuron-derived EVs. The EV-associated mtDNA copies were elevated in manifest HD patients suggesting to be an alternative pathway for secretion of reactive mitochondrial components. This study provides a novel framework connecting EVs enhanced release of mitochondrial components to mitochondrial and lysosomal dysfunction in HD.

Research on the constitution of subjectivity continues to be a relevant topic for Psychology. This study aimed to analyze the relevance of exploring autobiographical narratives as a methodological resource for understanding this process. Anchored in the premises of historical-cultural psychology in dialogue with other theoretical perspectives, the defended thesis is that, through this theoretical-methodological alternative, it is possible to investigate the different interrelated domains in the processes of constitution of subjectivities, such as the works of memory, language and the dynamic character that they establish with historical and cultural circumstances. The text comprises four parts: the first explores the challenges involved in researching subjectivity; the second, the contributions of Vygotskian psychology to the understanding of the phenomenon; the third, the fecundity of narratives as methodological resources for the study of subjectivation processes. In the last topic, considerations are made about some results of research carried out from school memories. Resumo A pesquisa sobre a constituição da subjetividade continua sendo um tema relevante para a Psicologia. Este estudo objetivou analisar a pertinência da exploração das narrativas autobiográficas como recurso metodológico para a compreeensão de tal processo. A tese defendida, ancorada nas premissas da psicologia histórico-cultural em diálogo com outras perspectivas teóricas, é que, por meio dessa alternativa teórico-metodológica, é possível investigar os diferentes domínios inter-relacionados nos processos de constituição das subjetividades, como os trabalhos da memória, da linguagem e o caráter dinâmico que estabelecem com as circunstâncias históricas e culturais. Quatro partes compõem o texto: a primeira explora os desafios envolvidos na pesquisa sobre a subjetividade; a segunda, as contribuições da psicologia vygotskiana para a compreensão do fenômeno; a terceira, a fecundidade das narrativas como recursos metodológicos para o estudo dos processos de subjetivação; no último tópico, são feitas considerações sobre alguns resultados de pesquisas realizadas a partir das memórias escolares. Resumen La investigación sobre la constitución de la subjetividad continúa siendo un tema relevante para la Psicología. Este estudio tuvo como objetivo analizar la pertinencia de explorar las narrativas autobiográficas como recurso metodológico para la comprensión de este proceso. La tesis defendida, anclada en los presupuestos de la psicología histórico-cultural en diálogo con otras perspectivas teóricas, es que, a través de esta alternativa teórico-metodológica, es posible investigar los diferentes dominios interrelacionados en los procesos de constitución de las subjetividades, como el obras de memoria, lenguaje y el carácter dinámico que establecen con las circunstancias históricas y culturales. Cuatro partes componen el texto: la primera explora los desafíos que implica investigar la subjetividad; el segundo, los aportes de la psicología vygotskiana a la comprensión del fenómeno; el tercero, la fecundidad de las narrativas como recursos metodológicos para el estudio de los procesos de subjetivación; en el último tema, se hacen consideraciones sobre algunos resultados de investigaciones realizadas a partir de las memorias escolares.

APOE ε4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer’s disease (AD), expressed in 40–65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked to cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, the exact mechanism underlying ApoE4 impact on AD progression is unclear, while no effective therapies are available for this highly debilitating neurodegenerative disorder. This review describes the current knowledge of ApoE4 interaction with mitochondria, causing mitochondrial dysfunction and neurotoxicity, associated with increased mitochondrial Ca2+ and reactive oxygen species (ROS) levels, and it effects on mitochondrial dynamics, namely fusion and fission, and mitophagy. Moreover, ApoE4 translocates to the nucleus, regulating the expression of genes involved in aging, Aβ production, inflammation and apoptosis, potentially linked to AD pathogenesis. Thus, novel therapeutical targets can be envisaged to counteract the effects induced by ApoE4 in AD brain.

Optic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.

Macroautophagy, a quality control mechanism, is an evolutionarily conserved pathway of lysosomal degradation of protein aggregates, pathogens, and damaged organelles. As part of its vital homeostatic role, macroautophagy deregulation is associated with various human disorders, including neurodegenerative diseases. There are several lines of evidence that associate protein misfolding and mitochondrial dysfunction in the etiology of Alzheimer’s, Parkinson’s, and Huntington’s diseases. Macroautophagy has been implicated in the degradation of different protein aggregates such as Aβ, tau, alpha-synuclein (α-syn), and mutant huntingtin (mHtt) and in the clearance of dysfunctional mitochondria. Taking these into consideration, targeting autophagy might represent an effective therapeutic strategy to eliminate protein aggregates and to improve mitochondrial function in these disorders. The present review describes our current understanding on the role of macroautophagy in neurodegenerative disorders and focuses on possible strategies for its therapeutic modulation.

Background Huntington’s disease (HD) is a brain disorder characterized by motor and cognitive impairment and early psychiatric disturbances, including obsessive-compulsive disorder (OCD). HD is caused by expansion of CAG repeats at the HTT gene, resulting in expression of mutant huntingtin (mHTT), largely affecting cortico-striatal synapses that are enriched in N-methyl-D-aspartate (NMDA) receptors. Former studies demonstrated that the postsynaptic scaffold protein SAPAP3, mainly located in striatum, is an important player in OCD. Unpublished data indicate that SAPAP3 interacts with several mitochondrial proteins. Hence, striatal dysfunction linked to early mitochondrial deregulation may involve changes in SAPAP3, potentially contributing to early HD symptomatology. Aims Investigate whether altered SAPAP3 protein levels affect striatal function in HD models by focusing on mitochondrial dysfunction as a hallmark of the disease. Methods Determine SAPAP3 protein levels in mitochondria isolated from pre-symptomatic (3 m.o.) and symptomatic (6, 10-12 m.o.) YAC128 transgenic vs WT mice, primary striatal/cortical cultures from YAC128 vs WT mice and STHdhQ111/Q111 vs STHdhQ7/Q7 cells. Study the influence of modulating SAPAP3 levels on mitochondrial function and dynamics in HD cells. Results We showed reduced SAPAP3 total/mitochondrial levels in symptomatic YAC128 mice, mature primary neurons from YAC128 mice and STHdhQ111/Q111 cells, compared to respective controls. In YAC128 striatal and cortical neurons, decreased SAPAP3 levels were pronounced at distal neurites. Colocalization between SAPAP3 and both PSD-95 and GluN2B were affected in YAC128 mouse striatal neurites. Of relevance, silencing SAPAP3 impaired mitochondrial dynamics and function, whereas SAPAP3 overexpression ameliorated these mitochondrial phenotypes in HD cells. Conclusion Our data suggest that SAPAP3 levels impact on mitochondrial function, being a potential neuroprotective target in HD.

Background Pridopidine is a highly selective, potent Sigma-1 receptor (S1R) agonist in clinical development for HD and ALS. The S1R is a protein enriched at the endoplasmic reticulum (ER)-mitochondria interface and vital to multiple cellular mechanisms, including mitochondrial function and the ER stress response. By activating the S1R, pridopidine exerts neuroprotective effects in many models of neurodegenerative diseases, including HD. In HD neurons, abnormal ER and mitochondria function increase susceptibility to oxidative stress, causing cell death. Aims Assess the effects of pridopidine on mitochondrial function and ER stress in HD models. Methods In neurons from YAC128 HD model mice, mitochondria and ER structure were assessed., Mitochondrial function was assessed by measuring respiration, ATP production, membrane potential and reactive oxygen species. Motor and mitochondrial function was assessed in vivo in YAC128 mice. ER stress was assessed by measuring levels of proteins involved in the stress response in HEK293 cells expressing normal or mutant Htt. Results Pridopidine restores mitochondrial and ER structure and connectivity (p Pridopidine reduces levels of phosphorylated protein eIF2α (p Conclusion The protective effects of pridopidine are facilitated by S1R-mediated rescue of mitochondrial function and ER stress pathway, both disrupted in HD. These findings shed new light on pridopidine’s mechanism of action.

Mitochondria have been largely described as the powerhouse of the cell and recent findings demonstrate that this organelle is fundamental for neurogenesis. The mechanisms underlying neural stem cells (NSCs) maintenance and differentiation are highly regulated by both intrinsic and extrinsic factors. Mitochondrial-mediated switch from glycolysis to oxidative phosphorylation, accompanied by mitochondrial remodeling and dynamics are vital to NSCs fate. Deregulation of mitochondrial proteins, mitochondrial DNA, function, fission/fusion and metabolism underly several neurodegenerative diseases; data show that these impairments are already present in early developmental stages and NSC fate decisions. However, little is known about mitochondrial role in neurogenesis. In this Review, we describe the recent evidence covering mitochondrial role in neurogenesis, its impact in selected neurodegenerative diseases, for which aging is the major risk factor, and the recent advances in stem cell-based therapies that may alleviate neurodegenerative disorders-related neuronal deregulation through improvement of mitochondrial function and dynamics.

Aim To investigate the effect of resistance training (RT) on hepatocardiovascular and muscle mitochondrial parameters in rats that were fed a high-calorie diet for 12 weeks. Main methods The animals were divided into four groups: control (C), exercise (E), obese (O), and obese plus exercise (OE). Group E and OE rats performed resistance training by climbing on a vertical ladder with load attached to the end of the tail (1×/day, 3×/week, for 12 weeks). Group O and OE rats were fed a high-calorie diet containing chow and a cafeteria diet for 12 weeks. Under anesthesia, the heart and liver were removed for histopathological analysis, and the gastrocnemius muscle was removed for Western blotting. Key findings Group O rats were heavier, with increased fat mass, elevated fasting glycemia, and total triglycerides, and exhibited a significant number of Kupffer cells and diffuse steatosis in the liver. Group O rats also showed increased thickness of the right ventricle, septum, and pulmonary artery. All of these parameters were attenuated by RT. PGC1-α protein levels were increased in both exercise groups. The protein levels of OXPHOS complexes III, IV, and V were reduced in Group O, while RT prevented this alteration. Significance RT exerts a protective effect against hepato-cardiac alterations and prevents changes in the muscle mitochondrial protein profile induced by a high-calorie diet., Obesity; Resistance training; Mitochondrial biogenesis; Hepato-cardiac alterations.