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2.
Biol Sport ; 41(1): 135-144, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38188122

RESUMO

Estimated ages at take-off (TO) and at peak height velocity (PHV) based on two models and maturity status based upon age at PHV and skeletal age (SA) were compared in a longitudinal sample of male soccer players. In addition, estimated ages at PHV in 13 longitudinal samples of soccer players were compared. The longitudinal height records of 58 players of European ancestry, measured annually on four or five occasions between 11 and 16 years, were modeled with Superimposition by Translation and Rotation (SITAR) and Functional Principal Component Analysis (FPCA) to estimate ages at TO and PHV. SAs were assessed with the Fels method. Ages at PHV in 13 longitudinal samples of soccer players (Europe 7, Japan 6) were evaluated with meta-analysis. Estimated ages at TO, 11.2 ± 0.8 (SITAR) and 11.0 ± 0.8 (FCPA) years, and at PHV, 13.6 ± 0.9 (SITAR) and 13.7 ± 0.0 (FCPA) years, were similar. An earlier age at PHV was associated with advanced skeletal maturity status (rho = -0.77 at ~14 years). Ages at PHV among European players indicated a north (later) - south (earlier) gradient, and were later than ages at PHV among Japanese players. In summary, ages at TO and PHV were similar with SITAR and FPCA, and ages at PHV were most strongly correlated with SA at ~14 years. Mean ages at PHV showed a north-south gradient among European samples, and were later compared to Japanese samples.

3.
Prev Vet Med ; 223: 106082, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38176150

RESUMO

Few practical methods are available to monitor the PRRSV status of the sows. Common sampling methods for sows like serum sampling, and tonsil scraping involve restraining individual sows and are labor-intensive, time-consuming, relatively invasive, and therefore, have limited use in large-scale production settings. Thus, a practical and rapid method of sampling large numbers of sows is needed. This study aimed to develop a new sampling method, named tonsil-oral scraping (TOSc) and compare TOSc to serum and tonsil scraping in terms of PRRSV qPCR detection rate and Ct values in thirty matched sows, thirty days after PRRSV outbreak. TOSc recovered a mixture of oral fluids and tonsil exudates from the sow oral cavity within seconds without restraining the animals. Results showed that, numerically, the TOSc samples had higher PRRSV qPCR detection rate (100 %) compared to serum (16.8 %) and tonsil scraping (73.1 %). Moreover, TOSc samples had lower average Ct values (29.7) than tonsil scraping (30.7) and serum (35.2). There was no significant difference in the detection rate between TOSc and tonsil scraping (Tukey test, p = 0.992), while there was a significant difference between serum and tonsil scraping (Tukey test, p < 0.001), as well as between serum and TOSc (Tukey test, p < 0.001). In terms of Ct values, there was no statistically significant difference between TOSc and tonsil scrapings (Dunn Test, p > 0.05), while there was a significant difference between tonsil scraping with serum (Dunn Test, p < 0.01), and TOSc with serum (Dunn Test, p < 0.01). Our results suggest great potential of the TOSc as a novel, practical, and rapid tool for PRRSV RNA detection in sows to assess sow herd status.


Assuntos
Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Doenças dos Suínos , Suínos , Animais , Feminino , Síndrome Respiratória e Reprodutiva Suína/diagnóstico , Tonsila Palatina , Soro , Boca
4.
Int J Pediatr Otorhinolaryngol ; 176: 111830, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38141550

RESUMO

OBJETIVE: Parental stress is defined as a subjective perception that parenting demands are higher than their resources and is reportedly higher in parents who have children with both chronic and acute illnesses. Ear-nose-throat (ENT) disorders, such as recurrent infections and obstruction sleep disorders, are one of the most prevalent comorbidities in pediatric age. Worldwide, tonsillectomy stands as the surgical treatment for these conditions, associated with a significant burden on both the children and their parents. The purpose of this study is to determine parental stress levels before and after tonsillectomy and to ascertain whether these levels improve after the children's surgery. METHODS: This is a prospective cohort study enrolling 48 parents accompanying their children aged 3-10 for outpatient tonsillectomy surgery in a tertiary portuguese hospital. Consent for participation in this study was obtained and parental stress was determined using the portuguese version of Parental Stress Scale (PSS). All parents completed PSS before surgery and at the 6-month follow-up evaluation. RESULTS: Of the 48 surveys obtained, 38 were mothers aged from 24 to 45 years. The median age of children was 3 (3-9) years and half were girls. Surgery was performed due to obstruction sleep disorders in about 71 % of children. The overall average stress level was 29,19 (standard deviation 7,5), with higher scores being associated with male children. At the 6-month reevaluation PSS was significantly lower (26,98), with a prominent reduction in the parental stress subscale in mothers comparing to fathers. CONCLUSIONS: These results highlight the importance of prompt diagnosis and treatment of children requiring tonsillectomy, as this condition may affect not only their physical health, but also parental relations, reflecting on their upbringing.


Assuntos
Apneia Obstrutiva do Sono , Tonsilectomia , Feminino , Criança , Humanos , Masculino , Pré-Escolar , Tonsilectomia/efeitos adversos , Tonsilectomia/métodos , Adenoidectomia/métodos , Estudos Prospectivos , Apneia Obstrutiva do Sono/cirurgia , Pais , Inquéritos e Questionários
5.
Cell Chem Biol ; 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38056465

RESUMO

Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3.

6.
Arch Virol ; 169(1): 3, 2023 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-38071687

RESUMO

In this study, we examined various brain suspension concentrations and viral loads in Neuro-2a cell cultures using 20 rabies-positive bovine samples. The reproducibility of results varied: 65% showed consistent outcomes across all concentrations, while 35% disagreed in at least one. Viral titers ranged from less than 25 × 101 to 25 × 103.50 TCID50/mL, with 20% below 25 × 101 TCID50/mL. Concentrations between 5% and 20% yielded over 90% agreement in positive results, but at 30%, agreement dropped from 85% to 50%. Cell confluence was successfully maintained at 5%, 10%, and 20%, while concentrations of 30% and above led to confluence loss. Low viral loads also negatively impacted reproducibility. These results suggest that sample concentration has a direct influence on preservation of cell confluence and that low viral loads may influence the reproducibility of the rabies tissue culture infection test (RTCIT).


Assuntos
Vírus da Raiva , Raiva , Bovinos , Animais , Raiva/diagnóstico , Carga Viral , Reprodutibilidade dos Testes , Encéfalo
7.
Genet Mol Biol ; 46(4): e20230088, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37992304

RESUMO

The tribe Serrasalmini is a diverse group with paraphyletic genera and taxonomic uncertainties. Several studies have been carried out in this group of fish in order to understand this problem, including the cytogenetic approach. In this study, three species of a clade of Serrasalmini were characterized cytogenetically - Pristobrycon striolatus, Catoprion absconditus and Pygopristis denticulatus. The three species presented diploid number (2n) equal to 62 chromosomes, of one and two arms, with karyotypic formulas and species-specific fundamental numbers. Heterochromatin is centromeric and terminal (bi-telomeric) in most chromosomes, with a conspicuous interstitial block at pair 1 (m) in all three species. The nucleolar organizer regions were multiple and C-band positive, and their location was confirmed via 18S ribosomal DNA mapping; however, with additional sites. The 5S rDNA was located in interstitial region of long arm of pair 1 (m), in the three species (homeologous). Moreover, we observed synteny between 18S and 5S in the species C. absconditus and P. denticulatus, which, according to fiber-FISH, are interspersed. Thus, the maintenance of 2n (62) evidences the diversification of chromosomal formulas within the clade by non-Robertsonian rearrangements and reflects the paraphyly of the related species.

8.
Nat Commun ; 14(1): 5945, 2023 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-37741832

RESUMO

Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Animais , Feminino , Humanos , Camundongos , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes Reguladores , Fígado , Ensaios Clínicos Fase III como Assunto
9.
PLoS One ; 18(7): e0288382, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37494376

RESUMO

Learning effect occurs when the best performance is not achieved at the earliest trial of a repeated protocol of evaluation. The present study examined, within testing session, the intra-individual variation in an isokinetic strength protocol composed of five reciprocal concentric and eccentric contractions of knee extensors (KE) and knee flexors (KF) among male adolescent swimmers. Additionally, test-retest reliability was determined as intra-individual mean differences between two consecutive testing sessions. The sample included 38 swimmers aged 10.1-13.3 years. A subsample (n = 17) completed a second visit. Isokinetic dynamometry was used to assess concentric and eccentric contractions of KE and KF at an angular velocity of 60°.s-1. The protocol included three preliminary repetitions that were not retained for analysis, a 60-second interval, and five reciprocal maximal concentric contractions (cc). The preceding sequence was repeated for eccentric contractions (ecc) of KE and KF. Multilevel regression confirmed intra-individual and inter-individual levels as significant sources of variance in peak torque (PT) values. Intra-class correlation (ICC) fluctuated between 0.582 and 0.834 and, in general, a substantial percentage of participants need more than three repetitions to attain their best PT: KEcc (36.8%), KEecc (23.7%), KFcc (39.5%), KFecc (18.4%). For the subsample of 17 swimmers who completed a second testing session, intra-individual mean differences of the best PT were trivial or small. In summary, the validity of shorter protocols may be compromised if swimmers do not attain their best peak torque in the first few attempts, and the reliability of a 5-repetition protocol seemed acceptable.


Assuntos
Joelho , Músculo Esquelético , Humanos , Masculino , Adolescente , Reprodutibilidade dos Testes , Articulação do Joelho , Atletas , Torque , Força Muscular
10.
Natal; s.n; 28 jul. 2023. 73 p. ilus, tab, graf.
Tese em Português | LILACS, BBO - Odontologia | ID: biblio-1532152

RESUMO

Introdução: O líquen plano oral é uma doença crônica imunologicamente mediada relativamente comum, que acomete a mucosa oral. Clinicamente, o LPO é classificado em seis padrões bem identificados: placa, reticular, bolhoso, atrófico, papular e erosivo.Sendo os mais comuns oos tipos reticulares e erosivos. A ativação dos linfócitos TCD4+ no LPO, pode induzir os ceratinócitos ao processo de apoptose através da respostaimunológica citotóxica. A proteína Bax desempenha uma função relevante para o processo apoptótico. Deste modo, a presente pesquisa consistiu em um estudo transversal retrospectivo, descritivo, quantitativo e comparativo. Objetivo: Avaliar a expressão imuno-histoquímica das proteínas MMP9 e Bax no LPO. Método: Foram utilizados 43 casos de LPO para análise da imunoexpressão de Bax e MMP-9. Os resultados foram analisados através dos testes estatísticos apropriados e serão considerados significativos, valores onde p<0,05. Resultado: A imunoexpressão de MMP9 foi significativamente maior nos ceratinócitos e quando analisados os subtipos de líquen plano oral, não foram observados diferenças estatísticas entre os tipos reticulares e erosivos para as proteínas analisadas. Conclusões: Com essas observações, infere-se que a alteração na expressão das proteínas estudadas sugere um distúrbio nos mecanismos apoptóticos, os quais estão associados às lesões de LPO, e podemos concluir também que as imunoexpressões dessas proteínas não apresentaram diferença, quando relacionada ao tipo clínico reticular ou erosivo. Com esse resultado pode-se contribuir para um maior entendimento sobre os possíveis mecanismos celulares envolvidos na etiopatogenia dessa lesão (AU).


Background: Oral lichen planus is a relatively common immune-mediated chronic disease that affects the oral mucosa. Clinically, OLP is classified into six well-identified patterns: plaque, reticular, bullous, atrophic, papular, and erosive. The most common being the reticular and erosive types. The activation of TCD4+ lymphocytes in the OLP can induce keratinocytes to the process of apoptosis through the cytotoxic immune response. Thus, the present research consisted of a retrospective, descriptive, quantitative and comparative crosssectional study. Objective: to evaluate the immunohistochemical expression of MMP-9 and Bax proteins in OLP. Methods: We used 20 cases of Inflammatory Fibrous Hyperplasia as control. The results were analyzed through the appropriate statistical tests and will be considered significant, values where p<0.05. Results: The immunoexpression of MMP-9 was significantly higher in keratinocytes and when the subtypes of oral lichen planus were analyzed, no statistical differences were observed between the reticular and erosive types for the proteins analyzed. Conclusions: With these observations, it is inferred that the alteration in the expression of the studied proteins suggests a disturbance in the proliferative and apoptotic mechanisms, which are associated with a pathological behavior of the oral mucosa, and consequently with a repercussion on the lesions of OLP, and we can also conclude that the immunoexpression of these proteins had no difference, when related to the reticular or erosive clinical type. This research aims to contribute to a greater understanding of the possible cellular mechanisms involved in the etiopathogenesis of this lesion, thus enabling the understanding of the clinical aspects of the pathology (AU).


Assuntos
Líquen Plano Bucal/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteína X Associada a bcl-2/metabolismo , Registros Médicos , Epidemiologia Descritiva , Estudos Transversais/métodos , Estudos Retrospectivos , Análise de Variância , Interpretação Estatística de Dados , Estatísticas não Paramétricas , Diagnóstico Diferencial , Mucosa Bucal/lesões
11.
J Bras Pneumol ; 49(3): e20230056, 2023.
Artigo em Inglês, Português | MEDLINE | ID: mdl-37283402

RESUMO

OBJECTIVE: COVID-19 has been associated with a significant burden to those who survive the acute phase. We aimed to describe the quality of life and symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD) at 90 days after hospital discharge of COVID-19 patients. METHODS: Patients with COVID-19 admitted to a private hospital in the city of São Paulo, Brazil, between April of 2020 and April of 2021 were interviewed by telephone at 30 and 90 days after discharge to assess the quality of life and symptoms of depression, anxiety, and PTSD. RESULTS: A total of 2,138 patients were included. The mean age was 58.6 ± 15.8 years, and the median length of hospital stay was 9.0 (5.0-15.8) days. Between the two time points, depression increased from 3.1% to 7.2% (p < 0.001), anxiety increased from 3.2% to 6.2% (p < 0.001), and PTSD increased from 2.3% to 5.0% (p < 0.001). At least one physical symptom related to COVID-19 diagnosis persisted in 32% of patients at day 90. CONCLUSIONS: Persistence of physical symptoms was high even at 90 days after discharge. Although the prevalence of symptoms of anxiety, depression, and PTSD was low, these symptoms persisted for three months, with a significant increase between the time points. This finding indicates the need to identify at-risk patients so that they can be given an appropriate referral at discharge.


Assuntos
COVID-19 , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Estudos de Coortes , COVID-19/epidemiologia , Qualidade de Vida , Brasil/epidemiologia , Teste para COVID-19 , Ansiedade/epidemiologia , Ansiedade/etiologia , Depressão/epidemiologia
12.
Rev. neurol. (Ed. impr.) ; 76(5): 153-158, Ene-Jun. 2023. tab
Artigo em Espanhol | IBECS | ID: ibc-216665

RESUMO

Introducción: La epilepsia de la infancia con puntas centrotemporales (EIPCT) es la epilepsia focal autolimitada más frecuente. Este estudio tenía como objetivo evaluar los aspectos cognitivos, conductuales y otros aspectos neuropsicológicos de niños con EIPCT, y compararlos con un grupo de control. Sujetos y métodos: Se realizó un estudio de casos y controles entre enero y mayo de 2022. Se seleccionó para su inclusión en el estudio a pacientes con EIPCT, con edades comprendidas entre 6 y 18 años, en seguimiento en nuestro hospital. Por cada caso, se reclutó, de forma aleatoria, a dos controles de la misma edad. Todos los participantes realizaron la prueba EpiTrack Junior®, y sus padres rellenaron la lista de verificación del comportamiento infantil (CBCL). Resultados: Se incluyó a 18 pacientes (edad media: 8,7 ± 1,7 años). En el momento del diagnóstico de EIPCT, el 83% de los casos presentaba un desarrollo psicomotor adecuado, y el 17%, un trastorno del neurodesarrollo. Las puntuaciones del EpiTrack-Junior® y de la escala total de problemas de la CBCL no se vieron influidas por la lateralidad del foco epiléptico ni por el número de crisis. El 61% de los casos mostró un trastorno leve o significativo en la prueba EpiTrack-Junior® frente al 44% de los controles (p = 0,712), y el 39% de los casos frente al 14% de los controles tuvieron puntuaciones ‘clínicamente significativas’ en la escala total de problemas de la CBCL. Conclusiones: Aunque este estudio no encontró diferencias estadísticamente significativas entre casos y controles, cabe señalar que la mayor parte de los pacientes con EIPCT presentaba un deterioro leve o significativo en las funciones ejecutivas. Un porcentaje considerable de casos se encontraba en el rango patológico en cuanto a problemas emocionales/conductuales. Este estudio destaca la importancia de examinar los problemas cognitivos, conductuales y emocionales de los pacientes con EIPCT.(AU)


Introduction: Self-limited epilepsy with centrotemporal spikes (SeLECTS) is the most frequent self-limited focal epilepsy. This study aimed to assess the cognitive, behavioral, and other neuropsychological aspects of children with SeLECTS, and compare them with a control group. Subjects and methods: A case-control study was carried out between January and May 2022. Patients with SeLECTS, aged between 6 and 18 years, and followed-up at our hospital were selected for inclusion in the study. For each case, two age-matched controls were opportunistically recruited. All the participants performed the EpiTrack Junior® test, and their parents filled out the Child Behavior Checklist (CBCL). Results: Eighteen patients were included (mean age: 8.7 ± 1.7 years). At SeLECTS’ diagnosis, 83% of cases had adequate psychomotor development, and 17% had a neurodevelopmental disorder. The EpiTrack-Junior® and the Total Problems CBCL scores were not influenced by the laterality of the epileptic focus nor by the number of seizures. 61% of cases showed mild or significant impairment in the EpiTrack-Junior® test versus 44% of controls (p = 0.712), and 39% of cases vs. 14% of controls had ‘clinically significant’ scores on the Total Problems CBCL scale (p = 0.087). Conclusions: Although this study did not find statistically significant differences between cases and controls, it should be noted that most patients with SeLECTS had a mild or significant disability in executive functions. A considerable percentage of cases were in the pathological range regarding emotional/behavioral problems. This study highlights the importance of screening the cognitive, behavioral, and emotional problems in all patients with SeLECTS.(AU)


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Comorbidade , Epilepsia Rolândica , Epilepsia , Convulsões , Disfunção Cognitiva , Testes Neuropsicológicos , Estudos de Casos e Controles , Neurologia , Doenças do Sistema Nervoso
13.
Genes (Basel) ; 14(5)2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37239330

RESUMO

Robust capuchin monkeys, Sapajus genus, are among the most phenotypically diverse and widespread groups of primates in South America, with one of the most confusing and often shifting taxonomies. We used a ddRADseq approach to generate genome-wide SNP markers for 171 individuals from all putative extant species of Sapajus to access their evolutionary history. Using maximum likelihood, multispecies coalescent phylogenetic inference, and a Bayes Factor method to test for alternative hypotheses of species delimitation, we inferred the phylogenetic history of the Sapajus radiation, evaluating the number of discrete species supported. Our results support the recognition of three species from the Atlantic Forest south of the São Francisco River, with these species being the first splits in the robust capuchin radiation. Our results were congruent in recovering the Pantanal and Amazonian Sapajus as structured into three monophyletic clades, though new morphological assessments are necessary, as the Amazonian clades do not agree with previous morphology-based taxonomic distributions. Phylogenetic reconstructions for Sapajus occurring in the Cerrado, Caatinga, and northeastern Atlantic Forest were less congruent with morphology-based phylogenetic reconstructions, as the bearded capuchin was recovered as a paraphyletic clade, with samples from the Caatinga biome being either a monophyletic clade or nested with the blond capuchin monkey.


Assuntos
Cebus , Sapajus , Animais , Filogenia , Cebus/genética , Teorema de Bayes , Haplorrinos
14.
BMC Pediatr ; 23(1): 196, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-37101252

RESUMO

BACKGROUND: Skeletal age (SA) is an estimate of biological maturity status that is commonly used in sport-related medical examinations. This study considered intra-observer reproducibility and inter-observer agreement of SA assessments among male tennis players. METHODS: SA was assessed with the Fels method in 97 male tennis players with chronological ages (CA) spanning 8.7-16.8 years. Radiographs were evaluated by two independent trained observers. Based on the difference between SA and CA, players were classified as late, average or early maturing; if a player was skeletally mature, he was noted as such as an SA is not assigned. RESULTS: The magnitude of intra-individual differences between repeated SA assessments were d = 0.008 year (observer A) and d = 0.001 year (observer B); the respective coefficients of variation were 1.11% and 1.75%. Inter-observer mean differences were negligible (t = 1.252, p = 0.210) and the intra-class correlation coefficient was nearly perfect (ICC = 0.995). Concordance of classifications of players by maturity status between observers was 90%. CONCLUSION: Fels SA assessments were highly reproducible and showed an acceptable level of inter-observer agreement between trained examiners. Classifications of players by skeletal maturity status based on assessments of the two observers were highly concordant, though not 100%. The results highlight the importance of experienced observers in skeletal maturity assessments.


Assuntos
Esportes , Tênis , Humanos , Masculino , Criança , Adolescente , Determinação da Idade pelo Esqueleto/métodos , Variações Dependentes do Observador , Reprodutibilidade dos Testes
15.
Front Mol Neurosci ; 16: 1140719, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37008788

RESUMO

Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/ MJD), is the most frequent polyglutamine (polyQ) neurodegenerative disorder. It is caused by a pathogenic expansion of the polyQ tract, located at the C-terminal region of the protein encoded by the ATXN3 gene. This gene codes for a deubiquitinating enzyme (DUB) that belongs to a gene family, that in humans is composed by three more genes (ATXN3L, JOSD1, and JOSD2), that define two gene lineages (the ATXN3 and the Josephins). These proteins have in common the N-terminal catalytic domain (Josephin domain, JD), that in Josephins is the only domain present. In ATXN3 knock-out mouse and nematode models, the SCA3 neurodegeneration phenotype is not, however, reproduced, suggesting that in the genome of these species there are other genes that are able to compensate for the lack of ATXN3. Moreover, in mutant Drosophila melanogaster, where the only JD protein is coded by a Josephin-like gene, expression of the expanded human ATXN3 gene reproduces multiple aspects of the SCA3 phenotype, in contrast with the results of the expression of the wild type human form. In order to explain these findings, phylogenetic, as well as, protein-protein docking inferences are here performed. Here we show multiple losses of JD containing genes across the animal kingdom, suggesting partial functional redundancy of these genes. Accordingly, we predict that the JD is essential for binding with ataxin-3 and proteins of the Josephin lineages, and that D. melanogaster mutants are a good model of SCA3 despite the absence of a gene from the ATXN3 lineage. The molecular recognition regions of the ataxin-3 binding and those predicted for the Josephins are, however, different. We also report different binding regions between the two ataxin-3 forms (wild-type (wt) and expanded (exp)). The interactors that show an increase in the interaction strength with exp ataxin-3, are enriched in extrinsic components of mitochondrial outer membrane and endoplasmatic reticulum membrane. On the other hand, the group of interactors that show a decrease in the interaction strength with exp ataxin-3 is significantly enriched in extrinsic component of cytoplasm.

16.
ACS Chem Biol ; 18(4): 772-784, 2023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-36893429

RESUMO

Wnt ligands are critical for tissue homeostasis and form a complex with LRP6 and frizzled coreceptors to initiate Wnt/ß-catenin signaling. Yet, how different Wnts achieve various levels of signaling activation through distinct domains on LRP6 remains elusive. Developing tool ligands that target individual LRP6 domains could help elucidate the mechanism of Wnt signaling regulation and uncover pharmacological approaches for pathway modulation. We employed directed evolution of a disulfide constrained peptide (DCP) to identify molecules that bind to the third ß-propeller domain of LRP6. The DCPs antagonize Wnt3a while sparing Wnt1 signaling. Using PEG linkers with different geometries, we converted the Wnt3a antagonist DCPs to multivalent molecules that potentiated Wnt1 signaling by clustering the LRP6 coreceptor. The mechanism of potentiation is unique as it occurred only in the presence of extracellular secreted Wnt1 ligand. While all DCPs recognized a similar binding interface on LRP6, they displayed different spatial orientations that influenced their cellular activities. Moreover, structural analyses revealed that the DCPs exhibited new folds that were distinct from the parent DCP framework they were evolved from. The multivalent ligand design principles highlighted in this study provide a path for developing peptide agonists that modulate different branches of cellular Wnt signaling.


Assuntos
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Proteínas Wnt , Ligantes , Proteínas Wnt/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , beta Catenina/metabolismo , Ligação Proteica , Via de Sinalização Wnt , Peptídeos/farmacologia , Peptídeos/metabolismo
17.
Rev Neurol ; 76(5): 153-158, 2023 03 01.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-36843175

RESUMO

INTRODUCTION: Self-limited epilepsy with centrotemporal spikes (SeLECTS) is the most frequent self-limited focal epilepsy. This study aimed to assess the cognitive, behavioral, and other neuropsychological aspects of children with SeLECTS, and compare them with a control group. SUBJECTS AND METHODS: A case-control study was carried out between January and May 2022. Patients with SeLECTS, aged between 6 and 18 years, and followed-up at our hospital were selected for inclusion in the study. For each case, two age-matched controls were opportunistically recruited. All the participants performed the EpiTrack Junior® test, and their parents filled out the Child Behavior Checklist (CBCL). RESULTS: Eighteen patients were included (mean age: 8.7 ± 1.7 years). At SeLECTS' diagnosis, 83% of cases had adequate psychomotor development, and 17% had a neurodevelopmental disorder. The EpiTrack-Junior® and the Total Problems CBCL scores were not influenced by the laterality of the epileptic focus nor by the number of seizures. 61% of cases showed mild or significant impairment in the EpiTrack-Junior® test versus 44% of controls (p = 0.712), and 39% of cases vs. 14% of controls had 'clinically significant' scores on the Total Problems CBCL scale (p = 0.087). CONCLUSIONS: Although this study did not find statistically significant differences between cases and controls, it should be noted that most patients with SeLECTS had a mild or significant disability in executive functions. A considerable percentage of cases were in the pathological range regarding emotional/behavioral problems. This study highlights the importance of screening the cognitive, behavioral, and emotional problems in all patients with SeLECTS.


TITLE: Comorbilidades neurocognitivas y psicológicas en pacientes con epilepsia de la infancia con puntas centrotemporales. Un estudio de casos y controles.Introducción. La epilepsia de la infancia con puntas centrotemporales (EIPCT) es la epilepsia focal autolimitada más frecuente. Este estudio tenía como objetivo evaluar los aspectos cognitivos, conductuales y otros aspectos neuropsicológicos de niños con EIPCT, y compararlos con un grupo de control. Sujetos y métodos. Se realizó un estudio de casos y controles entre enero y mayo de 2022. Se seleccionó para su inclusión en el estudio a pacientes con EIPCT, con edades comprendidas entre 6 y 18 años, en seguimiento en nuestro hospital. Por cada caso, se reclutó, de forma aleatoria, a dos controles de la misma edad. Todos los participantes realizaron la prueba EpiTrack Junior®, y sus padres rellenaron la lista de verificación del comportamiento infantil (CBCL). Resultados. Se incluyó a 18 pacientes (edad media: 8,7 ± 1,7 años). En el momento del diagnóstico de EIPCT, el 83% de los casos presentaba un desarrollo psicomotor adecuado, y el 17%, un trastorno del neurodesarrollo. Las puntuaciones del EpiTrack-Junior® y de la escala total de problemas de la CBCL no se vieron influidas por la lateralidad del foco epiléptico ni por el número de crisis. El 61% de los casos mostró un trastorno leve o significativo en la prueba EpiTrack-Junior® frente al 44% de los controles (p = 0,712), y el 39% de los casos frente al 14% de los controles tuvieron puntuaciones 'clínicamente significativas' en la escala total de problemas de la CBCL. Conclusiones. Aunque este estudio no encontró diferencias estadísticamente significativas entre casos y controles, cabe señalar que la mayor parte de los pacientes con EIPCT presentaba un deterioro leve o significativo en las funciones ejecutivas. Un porcentaje considerable de casos se encontraba en el rango patológico en cuanto a problemas emocionales/conductuales. Este estudio destaca la importancia de examinar los problemas cognitivos, conductuales y emocionales de los pacientes con EIPCT.


Assuntos
Epilepsia Rolândica , Função Executiva , Criança , Humanos , Adolescente , Estudos de Casos e Controles , Convulsões , Comorbidade , Epilepsia Rolândica/psicologia
18.
BIS, Bol. Inst. Saúde (Impr.) ; 24(1): 49-54, 2023.
Artigo em Português | Sec. Est. Saúde SP, CONASS, SESSP-ISPROD, Sec. Est. Saúde SP, SESSP-ISACERVO | ID: biblio-1518905

RESUMO

Utilizando o Rio de Janeiro como cenário de disparidades sociais, e com base em reflexões acerca do direito à cidade e o pressuposto de humanidade, o presente ensaio busca ecoar as vozes de pessoas em situação de rua nas suas vivências como os "outros" da cidade. A partir da análise de cartas elaboradas pela população de rua para os residentes em seu entorno, nas atividades de rodas de conversa do Projeto RUAS em 2019, percebe-se que os processos higienistas e de exclusão camuflam um debate mais pungente, do que (e de quem) é considerado humano em nossa sociedade. E a população em situação de rua está atenta a isso, no momento em que reforça uma série de reivindicações que clamam pela dignidade de um tratamento humano na cidade.


Assuntos
Pessoas Mal Alojadas , Planejamento de Cidades , Participação Social , Mudança Social , Recursos Comunitários
20.
J. bras. pneumol ; 49(3): e20230056, 2023. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1440438

RESUMO

ABSTRACT Objective: COVID-19 has been associated with a significant burden to those who survive the acute phase. We aimed to describe the quality of life and symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD) at 90 days after hospital discharge of COVID-19 patients. Methods: Patients with COVID-19 admitted to a private hospital in the city of São Paulo, Brazil, between April of 2020 and April of 2021 were interviewed by telephone at 30 and 90 days after discharge to assess the quality of life and symptoms of depression, anxiety, and PTSD. Results: A total of 2,138 patients were included. The mean age was 58.6 ± 15.8 years, and the median length of hospital stay was 9.0 (5.0-15.8) days. Between the two time points, depression increased from 3.1% to 7.2% (p < 0.001), anxiety increased from 3.2% to 6.2% (p < 0.001), and PTSD increased from 2.3% to 5.0% (p < 0.001). At least one physical symptom related to COVID-19 diagnosis persisted in 32% of patients at day 90. Conclusions: Persistence of physical symptoms was high even at 90 days after discharge. Although the prevalence of symptoms of anxiety, depression, and PTSD was low, these symptoms persisted for three months, with a significant increase between the time points. This finding indicates the need to identify at-risk patients so that they can be given an appropriate referral at discharge.


RESUMO Objetivo: A COVID-19 tem sido associada a um fardo significativo para aqueles que sobrevivem à fase aguda. Nosso objetivo foi descrever a qualidade de vida e sintomas de ansiedade, depressão e transtorno de estresse pós-traumático (TEPT) 90 dias após a alta hospitalar em pacientes com COVID-19. Métodos: Pacientes com COVID-19 internados em um hospital privado na cidade de São Paulo (SP) entre abril de 2020 e abril de 2021 foram entrevistados por telefone 30 e 90 dias após a alta para avaliar a qualidade de vida e sintomas de depressão, ansiedade e TEPT. Resultados: Foram incluídos 2.138 pacientes. A média de idade foi de 58,6 ± 15,8 anos, e a mediana do tempo de internação hospitalar foi de 9,0 (5,0-15,8) dias. Entre os dois momentos, a depressão aumentou de 3,1% para 7,2% (p < 0,001), a ansiedade, de 3,2% para 6,2% (p < 0,001), e o TEPT, de 2,3% para 5,0% (p < 0,001). Pelo menos um sintoma físico relacionado ao diagnóstico de COVID-19 persistia em 32% dos pacientes no 90º dia. Conclusões: A persistência dos sintomas físicos foi elevada mesmo 90 dias após a alta. Embora a prevalência de sintomas de ansiedade, depressão e TEPT tenha sido baixa, esses sintomas persistiram por três meses, com aumento significativo entre os momentos. Esse achado indica a necessidade de identificar os pacientes de risco para que possam receber o encaminhamento adequado no momento da alta.

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