Transthyretin mutagenesis: impact on amyloidogenesis and disease

Funding This work was supported by COMPETE and CENTRO-202010. 13039/501100011929 and by Fundação para a Ciência e a Tecnologia (FCT) through grants UIDB/00313/2020 and UIDP/00313/2020 (to Coimbra Chemistry Center, University of Coimbra) and doctoral fellowship SFRH/BD/137991/2018 (to Z.L.A.).Transthyretin (TTR), a homotetrameric protein found in plasma, cerebrospinal fluid, and the eye, plays a pivotal role in the onset of several amyloid diseases with high morbidity and mortality. Protein aggregation and fibril formation by wild-type TTR and its natural more amyloidogenic variants are hallmarks of ATTRwt and ATTRv amyloidosis, respectively. The formation of soluble amyloid aggregates and the accumulation of insoluble amyloid fibrils and deposits in multiple tissues can lead to organ dysfunction and cell death. The most frequent manifestations of ATTR are polyneuropathies and cardiomyopathies. However, clinical manifestations such as carpal tunnel syndrome, leptomeningeal, and ocular amyloidosis, among several others may also occur. This review provides an up-to-date listing of all single amino-acid mutations in TTR known to date. Of approximately 220 single-point mutations, 93% are considered pathogenic. Aspartic acid is the residue mutated with the highest frequency, whereas tryptophan is highly conserved. “Hot spot” mutation regions are mainly assigned to β-strands B, C, and D. This manuscript also reviews the protein aggregation models that have been proposed for TTR amyloid fibril formation and the transient conformational states that convert native TTR into aggregation-prone molecular species. Finally, it compiles the various in vitro TTR aggregation protocols currently in use for research and drug development purposes. In short, this article reviews and discusses TTR mutagenesis and amyloidogenesis, and their implications in disease onset.info:eu-repo/semantics/publishedVersio

The In Vivo Granulopoietic Response to Dexamethasone Injection Is Abolished in Perforin-Deficient Mutant Mice and Corrected by Lymphocyte Transfer from Nonsensitized Wild-Type Donors

Exogenously administered glucocorticoids enhance eosinophil and neutrophil granulocyte production from murine bone-marrow. A hematological response dependent on endogenous glucocorticoids underlies bone-marrow eosinophilia induced by trauma or allergic sensitization/challenge. We detected a defect in granulopoiesis in nonsensitized, perforin-deficient mice. In steady-state conditions, perforin- (Pfp-) deficient mice showed significantly decreased bone-marrow and blood eosinophil and neutrophil counts, and colony formation in response to GM-CSF, relative to wild-type controls of comparable age and/or weight. By contrast, peripheral blood or spleen total cell and lymphocyte numbers were not affected by perforin deficiency. Dexamethasone enhanced colony formation by GM-CSF-stimulated progenitors from wild-type controls, but not Pfp mice. Dexamethasone injection increased bone-marrow eosinophil and neutrophil counts in wild-type controls, but not Pfp mice. Because perforin is expressed in effector lymphocytes, we examined whether this defect would be corrected by transferring wild-type lymphocytes into perforin-deficient recipients. Short-term reconstitution of the response to dexamethasone was separately achieved for eosinophils and neutrophils by transfer of distinct populations of splenic lymphocytes from nonsensitized wild-type donors. Transfer of the same amount of splenic lymphocytes from perforin-deficient donors was ineffective. This demonstrates that the perforin-dependent, granulopoietic response to dexamethasone can be restored by transfer of innate lymphocyte subpopulations

OS DESAFIOS QUE OS PSICÓLOGOS HOSPITALARES ENCONTRAM AO LONGO DE SUA ATUAÇÃO

O presente estudo teve por objetivo de compreender os desafios de atuação do psicólogo no âmbito hospitalar em distintos hospitais da cidade de Salvador – Ba. Para tanto, foi realizada uma pesquisa qualitativa, por meio de entrevista semiestruturada com quatro psicólogas hospitalares. Os resultados da pesquisa indicaram que há barreiras na inserção profissional no ambiente hospitalar, onde o principal entrave é a dificuldade de comunicação com o restante da equipe. Com efeito, as entrevistadas consideram de suma importância a sua atuação no processo de saúde/doença, com vistas a proporcionar o apoio psicológico ao paciente e à família. De acordo com os relatos das entrevistadas, aponta-se para a necessidade de mudanças da cultura hospitalar que permitam uma relação mais horizontalizada e uma atuação da equipe efetivamente multidisciplinar, permitindo assim um tratamento esperado no cuidado com os pacientes

Aspectos clínicos do carcinoma epidermóide oral: uma revisão integrativa da literatura

O câncer de boca, tumor maligno que pode se formar em diversas estruturas dentro da cavidade oral, é relativamente comum e pode apresentar uma variedade de perfis histológicos e fatores de risco. O carcinoma epidermóide é o tipo mais comum de câncer de boca e está associado a fatores extrínsecos, como tabagismo, consumo de bebidas alcoólicas e infecção por sífilis, e fatores intrínsecos, como desnutrição geral ou anemia por deficiência de ferro. Os principais sinais e sintomas incluem lesões que não cicatrizam por mais de 15 dias, manchas ou placas na língua, gengivas, palato e mucosa jugal, nódulos no pescoço e rouquidão persistentes. O diagnóstico precoce é fundamental para o tratamento eficaz, que geralmente envolve cirurgia oncológica e/ou radioterapia. O objetivo desta revisão integrativa foi fornecer informações sobre este tipo de lesão, incluindo sua definição, epidemiologia, fatores de risco, características clínicas, sintomas e tratamentos disponíveis. Para tal, foi realizada uma busca de artigos publicados entre os anos de 2013 e 2023 nas bases de dados Biblioteca Virtual de Saúde – BVS, SCIELO e Lilacs. Após aplicação dos critérios de inclusão e exclusão, foram selecionados e incluídos na pesquisa, 15 artigos que respondiam à pergunta de pesquisa. A análise detalhada destes trabalhos revelou que de 2013 a 2018 houve uma mudança na região mais acometida pelo câncer bucal, passando da cavidade oral para a região de orofaringe. O carcinorma epidermóide apresenta superfície rugosa, cor vermelha e crescimento exofítico, sendo mais prevalente entre homens fumantes e etilistas e acima de 65 anos. É consenso na literatura atual que a melhor forma de prevenção é atuar sobre os fatores de risco e através do diagnóstico precoce. Desta forma, é possível inferir a necessidade de políticas públicas que invistam na educação em saúde para a população e na educação para a saúde dos profissionais que prestam atenção à saúde dos usuários, e assim, garantir a melhoria dos indicadores relacionados ao câncer de boca

Postural adjustments and kinematic index finger features in frail older adults under different equilibrium constraints

Background: Anticipatory postural adjustments (APAs) are significantly affected by age and may represent restrictions on functional independence. Previous studies in young adults have already highlighted that changing postural stability (i.e., seated vs. upright posture) affects the motor planning and APAs. In frail older adults (FOAs), the effect of these different conditions of postural stability have not yet been established, and the present study aimed to disentangle this issue. Methods: Participants executed an arm-pointing task to reach a diode immediately after it turned on, under different conditions of stability (seated with and without foot support and in an upright posture). A kinematic profile of the index finger and postural electromyographic data were registered in their dominant-side leg muscles: Tibialis anterior, soleus, rectus femoris, and semitendinosus. Results: The main finding of this study was that the adopted posture and body stabilization in FOAs did not reflect differences in APAs or kinematic features. In addition, they did not present an optimal APA, since postural muscles are recruited simultaneously with the deltoid. Conclusion: Thus, FOAs seem to use a single non-optimal motor plan to assist with task performance and counterbalance perturbation forces in which they present similar APAs and do not modify their kinematics features under different equilibrium constraints

Pectus Excavatum and Pectus Carinatum in dogs

Background: Deformities of the anterior thoracic wall are called pectus: pectus excavatum and pectus carinatum. Pectus excavatum is characterised by dorsal deviation of the caudal region of the sternum while pectus carinatum consists of protrusion of the sternum and/or adjacent cartilage. Both defects may remain symptom-free, but respiratory and cardiac abnormalities have been reported. Another deformity observed in dogs is the swimming dog syndrome, which consists of the lateral opening of the thoracic and pelvic limbs, associated with the pedalling movement. These disorders are frequently reported in medical practice, are considered rare among canines. This report aims to describe a case of pectus excavatum associated with the swimming dog syndrome (Case 1) and another case of pectus carinatum (Case 2).Case: In Case 1, an approximately 45-day-old male American Pitbull canine had difficulty standing. Physical examination revealed hyperextension of the thoracic and pelvic limb joints and flattening of the thorax. After radiographic examination, pectus excavatum and the swimming dog syndrome were confirmed. The conservative treatment with splinting and hydrotherapy was chosen. At the 3-month follow-up, slight improvement in the limbs and irregular and unsatisfactory growth of the thorax leading to episodes of dyspnoea were observed. In Case 2, a female Pug, approximately 2 months old, had a thorax deformity. Physical examination revealed thorax protrusion, confirmed on radiography as pectus carinatum. Conservative therapy was provided using compressive bandage. One month later, the tutor reported improvement in the condition and absence of respiratory changes.Discussion: Pectus deformities has low incidence, and cases to pectus carinatum, there is a sexual predisposition, that is, males are more predisposed, differing from Case 2, a female dog. In the cases of pectus excavatum, no genetic alteration was directly related to its occurrence, although familial occurrence is reported in humans, as in Case 1, in which the patient was the only one of this litter to present this deformity. Though the possibility is lower, the acquired aetiology has been described in other cases. In pectus carinatum, there is the possibility of an acquired aetiology, which corroborates Case 2, considering that the canine had no history of inbreeding, nor family history. However, it is important consider racial predisposition, where there is an increasing number of cases of pectus carinatum in brachycephalic canines. Respiratory symptoms are frequently reported in cases of pectus excavatum, which the evolution of the condition occurred in Case 1, that can be explained by the displacement of organs or the restriction to ventilation. Humans have shown that pectus excavatum reduces static lung function. Case 2 showed no clinical signs, despite this presented dextrocardia, which in the future may confer cardiac dysfunctions. The diagnosis for pectus is considered simple. Performed only by radiography, it can be complemented by echocardiography. In both cases, conservative treatment was the choice. However, in Case 1 there was no success due to the degree of patient involvement, unlike Case 2, which had a better development of the thoracic wall, ensuring better quality of life for the patient. Thus, it is possible to conclude that some differences were found in these two reported cases when compared to others described in the literature.  The radiographic diagnosis is confirmatory, and the therapy must be adequate to the degree of thoracic wall deformity. In addition, the prognosis is more reserved for pectus excavatum than pectus carinatum

Percepção socioambiental e turística na área de proteção ambiental da Foz do Rio São Francisco em Alagoas / Social environmental and touristic perception in the environmental protection area of Foz Rio San Francisco in Alagoas

Piaçabuçu é um município alagoano que fica situado às margens do rio São Francisco, essa região faz parte de uma APA. Nesse trabalho de pesquisa buscou-se analisar de que forma se dá a percepção turística na Área de Proteção Ambiental na Foz do rio São Francisco em Piaçabuçu-AL. Foi realizado um estudo transversal descrito com abordagem quali-quantitativa aprovado pelo Comitê de Ética em Pesquisa do Centro Universitário CESMAC, sob CAAE: 60278216.6.0000.0039. A aplicação dos questionários se deu na Foz do rio São Francisco, totalizando 160 voluntários que foram divididos em dois grupos: G1 (visitantes excursionistas) e G2 (trabalhadores do turismo). Constatou-se que a percepção varia dependendo da origem, faixa etária, gênero, profissão, escolaridade, e renda familiar. Do ponto de vista da responsabilidade ambiental, a maioria dos indivíduos abordados levou um saco plástico para o depósito do lixo gerado durante o passeio na Foz, sobretudo, verificou-se que 98,13% disseram ter simpatia pelas causas ambientais. Ainda, 35,51% concordam que a preservação do atrativo natural da Foz está ótima e 55,14% boa. Cada indivíduo possui diferentes percepções sobre determinados temas, desse modo, os visitantes excursionistas e os trabalhadores do turismo da Foz, enxergam nesse atrativo turístico natural uma oportunidade de progresso econômico mais rápido e maiores benefícios na qualidade de vida da população local.

Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hallmarks of Niemann-Pick type C disease but is not sufficient to halt neurodegeneration

Funding Information: This work was funded by FEDER and by National Funds through Fundação para a Ciência e a Tecnologia (FCT) under project PTDC/MED-NEU/29455/2017 , Bolsa de Investigação da Sociedade Portuguesa de Doenças Metabólicas (SPDM), and BrainVectis Technologies . Publisher Copyright: © 2023 The AuthorsCholesterol 24-hydroxylase (CYP46A1) is an exclusively neuronal cytochrome P450 enzyme responsible for converting cholesterol into 24S-hydroxycholesterol, which serves as the primary pathway for eliminating cholesterol in the brain. We and others have shown that increased activity of CYP46A1 leads to reduced levels of cholesterol and has a positive effect on cognition. Therefore, we hypothesized that CYP46A1 could be a potential therapeutic target in Niemann-Pick type C (NPC) disease, a rare and fatal neurodegenerative disorder, characterized by cholesterol accumulation in endolysosomal compartments. Herein, we show that CYP46A1 ectopic expression, in cellular models of NPC and in Npc1tm(I1061T) mice by adeno-associated virus-mediated gene therapy improved NPC disease phenotype. Amelioration in functional, biochemical, molecular and neuropathological hallmarks of NPC disease were characterized. In vivo, CYP46A1 expression partially prevented weight loss and hepatomegaly, corrected the expression levels of genes involved in cholesterol homeostasis, and promoted a redistribution of brain cholesterol accumulated in late endosomes/lysosomes. Moreover, concomitant with the amelioration of cholesterol metabolism dysregulation, CYP46A1 attenuated microgliosis and lysosomal dysfunction in mouse cerebellum, favoring a pro-resolving phenotype. In vivo CYP46A1 ectopic expression improves important features of NPC disease and may represent a valid therapeutic approach to be used concomitantly with other drugs. However, promoting cholesterol redistribution does not appear to be enough to prevent Purkinje neuronal death in the cerebellum. This indicates that cholesterol buildup in neurons might not be the main cause of neurodegeneration in this human lipidosis.publishersversionpublishe

Modulation of the Effects of Lung Immune Response on Bone Marrow by Oral Antigen Exposure

Allergic airway inflammation is attenuated by oral tolerization (oral exposure to allergen, followed by conventional sensitization and challenge with homologous antigen), which decreases airway allergen challenge-induced eosinophilic infiltration of the lungs and bone marrow eosinophilia. We examined its effects on bone marrow eosinophil and neutrophil production. Mice of wild type (BP-2, BALB/c, and C57BL/6) and mutant strains (lacking iNOS or CD95L) were given ovalbumin (OVA) or water (vehicle) orally and subsequently sensitized and challenged with OVA (OVA/OVA/OVA and H2O/OVA/OVA groups, resp.). Anti-OVA IgG and IgE, bone marrow eosinophil and neutrophil numbers, and eosinophil and neutrophil production ex vivo were evaluated. T lymphocytes from OVA/OVA/OVA or control H2O/OVA/OVA donors were transferred into naïve syngeneic recipients, which were subsequently sensitized/challenged with OVA. Alternatively, T lymphocytes were cocultured with bone marrow eosinophil precursors from histocompatible sensitized/challenged mice. OVA/OVA/OVA mice of the BP-2 and BALB/c strains showed, relative to H2O/OVA/OVA controls, significantly decreased bone marrow eosinophil counts and ex vivo eosinopoiesis/neutropoiesis. Full effectiveness in vivo required sequential oral/subcutaneous/intranasal exposures to the same allergen. Transfer of splenic T lymphocytes from OVA/OVA/OVA donors to naive recipients prevented bone marrow eosinophilia and eosinopoiesis in response to recipient sensitization/challenge and supressed eosinopoiesis upon coculture with syngeneic bone marrow precursors from sensitized/challenged donors

Avaliação da digestão ruminal, intestinal e total da matéria orgânica, proteína bruta e fibra em detergente neutro de rações com diferentes fontes de proteína utilizadas em bovinos

Utilizou-se três novilhos Holandês Preto & Branco (±300 kg) implantados com cânulas: ruminal e duodenal, distribuídos no delineamento em quadrado latino 3x3, para avaliar fontes de proteína nas rações, sobre a digestão ruminal, intestinal e total da matéria orgânica (MO), proteína bruta (PB) e fibra em detergente neutro (FDN). Os tratamentos consistiram de rações formuladas com três fontes de proteína: uréia (UR), farinha de penas (FPE) e farelo de glúten de milho (FGM). Diariamente os animais eram alimentados às 8h e 16h, e nos mesmos horários introduzia-se via cânula ruminal 5 g de Cr2O3. Os períodos tiveram duração de 14 dias, sendo 11 dias para adaptação às rações e 3 dias para coleta. Foram coletadas digesta duodenal e fezes por um período de 72 horas, a cada 6 horas. As fontes de proteína não influenciaram (P > ,05) na ingestão ou nas digestões parcial ou total da MO. Entre os tratamentos houve diferenças (P 0,05) pelos tratamentos. Dessa forma, as rações com as fontes de proteína utilizadas, mesmo apresentando diferenças no potencial de degradação, as digestibilidades totais da MO, PB e FDN não sofreram efeitos