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1.
Hist Philos Life Sci ; 45(3): 27, 2023 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-37347428

RESUMO

We performed a critical review of the historiographical studies on biogeography. We began with the pioneering works of Augustin and Alphonse de Candolle. Then, we analyzed the historical accounts of biogeography developed by (1) Martin Fichman and his history on the extensionism-permanentism debate; (2) Gareth Nelson and his critique of the Neo-Darwinian historiography of biogeography; (3) Ernst Mayr, with his dispersalist viewpoint; (4) Alan Richardson, who wrote a microhistory on the biogeographic model constructed by Darwin; (5) Michael Paul Kinch and the ideas discussed in the 19th century about the geographical distribution of living beings; (6) Janet Browne, who highlighted the importance of the pre-Darwinian naturalists; (7) Peter Bowler, who focused mainly on the influence of paleontology on biogeography; (8) James Larson, who looked into the practices of the naturalists of Northern Europe in the late 18th century; and (9) Malte Ebach, who like Larson, was more interested in analysing the practices rather than the ideas of naturalists who studied the geographical distribution of organisms. Finally, these works are compared with each other. There has not been a dominant paradigm in the construction of historical narratives of biogeography; however, they provide a useful context for understanding problems of biogeography that continue to be debated to this day.


Assuntos
Historiografia , História do Século XX , História do Século XIX , Europa (Continente) , Paleontologia
2.
Neurointervention ; 18(1): 23-29, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36809874

RESUMO

PURPOSE: Internal carotid artery (ICA) aneurysm treatment with a flow diverter (FD) has shown an adequate efficacy and safety profile, presenting high complete occlusion or near occlusion rates with low complications during follow-up. The purpose of this study was to evaluate the efficacy and safety of FD treatment in non-ruptured internal carotid aneurysms. MATERIALS AND METHODS: This is a retrospective, single-center, observational study evaluating patients diagnosed with unruptured ICA aneurysms treated with an FD between January 1, 2014, and January 1, 2020. We analyzed an anonymized database. The primary effectiveness endpoint was complete occlusion (O'Kelly-Marotta D, OKM-D) of the target aneurysm through 1-year follow-up. The safety endpoint was the evaluation of modified Rankin Scale (mRS) 90 days after treatment, considering a favorable outcome an mRS 0-2. RESULTS: A total of 106 patients were treated with an FD, 91.5% were women; the mean follow- up was 427.2±144.8 days. Technical success was achieved in 105 cases (99.1%). All patients included had 1-year follow-up digital subtraction angiography control; 78 patients (73.6%) completed the primary efficacy endpoint by achieving total occlusion (OKM-D). Giant aneurysms had a higher risk of not achieving complete occlusion (risk ratio, 3.07; 95% confidence interval, 1.70 - 5.54]). The safety endpoint of mRS 0-2 at 90 days was accomplished in 103 patients (97.2%). CONCLUSION: Treatment of unruptured ICA aneurysms with an FD showed high 1-year total occlusion results, with very low morbidity and mortality complications.

3.
Dynamis (Granada) ; 43(2): 399-427, 2023. ilus
Artigo em Espanhol | IBECS | ID: ibc-229573

RESUMO

Estudios recientes sobre la historia de la ciencia han enfatizado el enfoque transnacional que problematiza las narrativas eurocéntricas clásicas, las interpretaciones de difusión cultural y la oposición rígida de las categorías de «centro» y «periferia», para explicar la dinámica de los circuitos transnacionales y la circulación de conocimientos, personas, artefactos y prácticas científicas. El presente escrito intenta abonar en esta dirección al mostrar que el trabajo realizado por los genetistas mexicanos en los mil novecientos sesenta y setenta, en especial los trabajos de citogenética, no pueden caracterizarse como periféricos, pues al formar parte de redes de colaboración internacional, el conocimiento generado localmente en instituciones mexicanas y extranjeras logró circular y formar parte de la consolidación de la citogenética a escala global. En este artículo se abordarán las trayectorias de la bióloga y genetista mexicana María Cristina Cortinas, y en menor medida la de la médica y genetista mexicana de origen argentino Susana Kofman. Ellas compartieron agenda médica y de investigación además de tiempo y lugar, participaron en el diagnóstico temprano de enfermedades genéticas y revelaron la correlación entre las observaciones clínicas y el cariotipo. Este manuscrito se centrará, por un lado, en los cromosomas como objetos científicos híbridos que circularon entre la clínica y el laboratorio; por el otro, se abordarán los contextos locales, las culturas materialesy las prácticas específicas que permitieron a estas mujeres genetistas mexicanas ser parte de la producción y transmisión de conocimiento en los años mil novecientos sesenta y setenta, gracias a su pertenencia a redes científicas de colaboración nacionales e internacionales. (AU)


Recent studies on the history of science have emphasized the transnational approach that problematizes classic Eurocentric narratives, interpretations of cultural diffusion, and the rigid opposition of the categories of “center” and “periphery” to explain the dynamics of transnational circuits and the circulation of knowledge, people, artifacts, and scientific practices. This paper attempts to contribute to this direction by showing that the work carried out by Mexican geneticists in the 1960s and 1970s, especially the work on cytogenetics, cannot be characterized as peripheral because knowledge generated locally in Mexican and foreign institutions was able to circulate and become part of the consolidation of cytogenetics on a global scale, participating in international collaborative networks. This article addresses the trajectories of the Mexican biologist and geneticist María Cristina Cortinas, and to a lesser extent those of the Argentineborn Mexican physician and geneticist Susana Kofman. They shared a medical and research agenda and a time and place, participating in the early diagnosis of genetic diseases and revealing the correlation between clinical observations and the karyotype. This manuscript focuses on chromosomes as hybrid scientific objects that circulated between clinic and laboratory and on the local contexts, material cultures and specific practices that allowed these Mexican women geneticists to take part in the production and transmission of knowledge in the 1960s and 1970s, attributed to their participation in national and international scientific collaborative networks. (AU)


Assuntos
Humanos , Feminino , História do Século XX , Citogenética/história , Médicas/história , Comportamento Cooperativo , Redes de Informação de Ciência e Tecnologia , México
4.
Repert. med. cir ; 32(1): 29-37, 2023. ilus, tab
Artigo em Espanhol | LILACS, COLNAL | ID: biblio-1526551

RESUMO

Objetivo: describir los hallazgos ecográficos en las glándulas salivares para el diagnóstico del síndrome de Sjögren primario. Metodología: se realizó una revisión narrativa de la literatura, con búsqueda en bases de datos seleccionando los principales artículos de revisión e investigaciones originales en español e inglés publicados en los últimos 20 años. Resultados: los hallazgos confirman el valor diagnóstico de la ecografía como estudio no invasivo de las glándulas salivares. Conclusión: la ecografía de glándulas salivares es un método útil y confiable para el diagnóstico del síndrome de Sjögren.


Objective: to describe salivary glands ultrasonography findings for the diagnosis of primary Sjögren ́s syndrome. Methodology: a narrative review of the literature by a database search selecting the main original review and research articles published in the last 20 years in Spanish and English. Results: findings confirm ultrasonography diagnostic value as a non-invasive method for salivary glands evaluation. Conclusion: sonographic evaluation of the salivary glands is a useful and reliable method for diagnosing Sjögren ́s syndrome.


Assuntos
Humanos , Diagnóstico
5.
ACS Pharmacol Transl Sci ; 5(11): 1156-1168, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36407952

RESUMO

Bruton's tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK's inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt's lymphoma, causing a 30-40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% "on-target" efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment.

6.
Hist Philos Life Sci ; 44(4): 56, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36326965

RESUMO

The 1968 Olympic Games in Mexico included innovative practices and technological knowledge of human biology. The first time that cytogenetic techniques had been applied to athletes was in the 1966 European Athletics Championship in Budapest and used on Olympic athletes for the first time in Mexico in 1968. The Genetics and Human Biology Program (Programa de Genética y Biología Humanas, PGBH) was created for this purpose in 1966 in close collaboration with the Local Organizing Committee (Comité Organizador, CO), by Mexican geneticists Alfonso León de Garay and Rodolfo Félix Estrada who led the project. The main objective was to study the genetic and anthropological components which determine an Olympic athlete's abilities. This investigation studied 1,265 game participants and included family studies, cytological analyses, research on single genes, and the study of sex determination. In terms of influence beyond Mexico, this Program was significant as a site of transnational collaboration. It mobilized cognitive and financial resources, scientific practices, and material culture to set up a clinical laboratory in the Olympic Village. The Program also hosted three international seminars in Mexico City, two before the games, to calibrate clinical trials and anthropological tests. One in 1969 to analyze the results and proceed to their publication in 1974. This manuscript will focus on the PGBH to show how its work fits in the larger tapestry of post-1945 human biological studies. Also, to explore how the Olympic athlete populations studied can be considered laboratories of knowledge production or sites of cognition conceived as specific entities for scientific inquiry, standardization of medical practices, and the production or application of medicines. Finally, through the narrative of the different trajectories and collaborations of the leaders of the PGBH, this manuscript will show how contact between their scientific practices brought cytogenetics and sports together.


Assuntos
Esportes , Humanos , México , Citogenética , Análise Citogenética
7.
Genet Med ; 24(12): 2475-2486, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36197437

RESUMO

PURPOSE: We aimed to investigate the molecular basis of a novel recognizable neurodevelopmental syndrome with scalp and enamel anomalies caused by truncating variants in the last exon of the gene FOSL2, encoding a subunit of the AP-1 complex. METHODS: Exome sequencing was used to identify genetic variants in all cases, recruited through Matchmaker exchange. Gene expression in blood was analyzed using reverse transcription polymerase chain reaction. In vitro coimmunoprecipitation and proteasome inhibition assays in transfected HEK293 cells were performed to explore protein and AP-1 complex stability. RESULTS: We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder, enamel hypoplasia, and congenital cataracts. Mutant FOSL2 messenger RNAs escaped nonsense-mediated messenger RNA decay. Truncated FOSL2 interacts with c-JUN, thus mutated AP-1 complexes could be formed. CONCLUSION: Truncating variants in the last exon of FOSL2 associate a distinct clinical phenotype by altering the regulatory degradation of the AP-1 complex. These findings reveal a new role for FOSL2 in human pathology.


Assuntos
Transtorno do Espectro Autista , Displasia Ectodérmica , Transtornos do Neurodesenvolvimento , Humanos , Couro Cabeludo/anormalidades , Couro Cabeludo/metabolismo , Transtorno do Espectro Autista/genética , Células HEK293 , Fator de Transcrição AP-1/genética , Éxons/genética , Displasia Ectodérmica/genética , Transtornos do Neurodesenvolvimento/genética , RNA Mensageiro , Antígeno 2 Relacionado a Fos/genética
8.
Am J Hum Genet ; 109(10): 1828-1849, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36084634

RESUMO

Orofaciodigital syndrome (OFD) is a genetically heterogeneous ciliopathy characterized by anomalies of the oral cavity, face, and digits. We describe individuals with OFD from three unrelated families having bi-allelic loss-of-function variants in SCNM1 as the cause of their condition. SCNM1 encodes a protein recently shown to be a component of the human minor spliceosome. However, so far the effect of loss of SCNM1 function on human cells had not been assessed. Using a comparative transcriptome analysis between fibroblasts derived from an OFD-affected individual harboring SCNM1 mutations and control fibroblasts, we identified a set of genes with defective minor intron (U12) processing in the fibroblasts of the affected subject. These results were reproduced in SCNM1 knockout hTERT RPE-1 (RPE-1) cells engineered by CRISPR-Cas9-mediated editing and in SCNM1 siRNA-treated RPE-1 cultures. Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were severely reduced in SCNM1-deficient cells. Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia. Conversely, cilia length and expression of SCNM1-regulated genes were restored in SCNM1-deficient fibroblasts following reintroduction of SCNM1 via retroviral delivery. Additionally, functional analysis in SCNM1-retrotransduced fibroblasts showed that SCNM1 is a positive mediator of Hedgehog (Hh) signaling. Our findings demonstrate that defective U12 intron splicing can lead to a typical ciliopathy such as OFD and reveal that primary cilia length and Hh signaling are regulated by the minor spliceosome through SCNM1 activity.


Assuntos
Ciliopatias , Síndromes Orofaciodigitais , Cílios/genética , Cílios/metabolismo , Ciliopatias/genética , Proteínas Hedgehog/metabolismo , Humanos , Íntrons/genética , Mutação/genética , Síndromes Orofaciodigitais/genética , Splicing de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Interferente Pequeno/metabolismo , Spliceossomos/genética , Spliceossomos/metabolismo
9.
NTM ; 30(2): 245-270, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35536307

RESUMO

After WWII, global concerns about the uses of nuclear energy and radiation sources in agriculture, medicine, and industry brought about calls for radiation protection. At the beginning of the 1960s radiation protection involved the identification and measurement of all sources of radiation to which a population was exposed, and the evaluation and assessment of populations in terms of the biological hazard their exposure posed. Mexico was not an exception to this international trend. This paper goes back to the origins of the first studies on the effects of radiation and on radioprotective compounds in the Genetics and Radiobiology Program of the National Commission of Nuclear Energy founded in 1960, at a time when the effects of radiation on living beings and radiation protection demanded the attention of highly localized groups of scientists and the creation of international as well as national institutions, and its connection to dosimetry and radiation protection until the 1990s. This historical reconstruction examines the circulation of knowledge, scientists, and their material and cognitive resources, to show that radiobiology, with dosimetry and radiation protection as cases in point, not only were carried out with high international standards in parallel with international agencies, but also reflected local material needs, including the standardization of new experimental techniques.


Assuntos
Energia Nuclear , Proteção Radiológica , História do Século XX , Agências Internacionais , México , Radiobiologia
10.
Mult Scler Relat Disord ; 54: 103120, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34243104

RESUMO

BACKGROUND: The COVID-19 pandemic has resulted in uncertain access to medical treatment for people with multiple sclerosis (pwMS) all over the world. However, there is no data regarding its impact on access to health care of pwMS from Latin America. OBJECTIVES: We investigated and described changes in health care delivery for pwMS from Latin America during the COVID-19 pandemic. METHODS: PwMS from 18 patient organizations of the region completed a web-based survey hosted from May to October 2020. RESULTS: A total of 602 pwMS completed the questionnaire. Changes in disease-modifying therapies (DMTs) use: 6.7% of pwMS on continuous DMTs claimed to stopped them; 14.1% of those on infusion therapies declared to postpone their dosing; 68.8% declared delaying the initiation of a DMT. Disruptions in accessing rehabilitation services were reported by 65.7%. Changes in laboratory and MRI monitoring were reported by 30% and 33%, respectively. In a multivariable-adjusted logistic regression model, changes in laboratory monitoring were significantly associated with increased odds of postponing MRI monitoring (OR 4.09 CI95% 2.79-6.00, p < 0.001). CONCLUSIONS: The COVID-19 pandemic has disrupted all aspects of the routine care for pwMS from Latin America. Consequences are yet to be determined.


Assuntos
COVID-19 , Esclerose Múltipla , Atenção à Saúde , Humanos , América Latina/epidemiologia , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/terapia , Pandemias , SARS-CoV-2
11.
Genet Med ; 23(4): 679-688, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33442026

RESUMO

PURPOSE: This study aimed to identify the genetic cause of a new multiple congenital anomalies syndrome observed in three individuals from two unrelated families. METHODS: Clinical assessment was conducted prenatally and at different postnatal stages. Genetic studies included exome sequencing (ES) combined with single-nucleotide polymorphism (SNP) array based homozygosity mapping and trio ES. Dermal fibroblasts were used for functional assays. RESULTS: A clinically recognizable syndrome characterized by severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet was identified. Additional features included eye abnormalities, hearing impairment, and electroencephalogram anomalies. ES detected different homozygous truncating variants in MAPKAPK5 in both families. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization. CONCLUSION: Our data indicate that loss-of-function variants in MAPKAPK5 result in a severe developmental disorder and reveal a major role of this gene in human brain, heart, and limb development.


Assuntos
Deficiências do Desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Serina-Treonina Quinases/genética , Sindactilia , Criança , Deficiências do Desenvolvimento/genética , Humanos , Fenótipo , Sindactilia/genética
12.
Rev. colomb. reumatol ; 27(supl.2): 31-42, oct.-dic. 2020. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1341337

RESUMO

RESUMEN Introducción: El síndrome de Sjögren (SS) es una enfermedad autoinmune que afecta a las glándulas exocrinas condicionando síndrome seco. Los criterios diagnósticos se basan en pruebas serológicas, oftalmológicas, histopatológicas y flujo salival. Se ha propuesto el uso de la ecografía glandular salival como prueba diagnóstica. Escasos estudios se han realizado en Latinoamérica. Objetivo: Describir las alteraciones ecográficas en las glándulas salivales en una población colombiana que asiste al servicio de reumatología con síntomas secos. Materiales y métodos: Estudio de corte transversal; análisis preliminar de 50 pacientes que asisten por consulta externa (agosto de 2019 a enero de 2020). Evaluación sociodemográfica y clínica a través de cuestionario estructurado, pruebas paraclínicas y oftalmológicas, biopsia de glándula salival menor y valoración ecográfica de las glándulas salivales mayores (puntuación 0-6 basada en De Vita). Análisis univariado y bivariado (Chi-cuadrado y prueba de Fischer). Resultados: El 94% de la población eran mujeres y el 38% tenían SS. El promedio de edad fue de 55,9 ± 9,6 arios. La proporción de pacientes con ecografía positiva para el SS y diagnóstico por criterios del SS es mayor respecto a los pacientes con ecografía negativa (p< 0,0001). Los pacientes con ecografía positiva presentaron mayor proporción de anti-La (p = 0,002), ANA (p = 0,008), anti-Ro (p< 0,0001), linfopenia (p = 0,007), xerostomía objetiva (p = 0,019) y subjetiva (p = 0,041). Conclusiones: La ecografía podría considerarse una herramienta útil en el diagnóstico del SS, dado que los pacientes que presentan alteraciones ecográficas glandulares tienen una mayor proporción de perfil inmunológico positivo (anti-Ro, ANA, anti-La) y su positividad se encuentra asociada al SS por criterios. Se requieren nuevos estudios para evaluar las características operativas de la prueba.


ABSTRACT Introduction: Sjögren's syndrome (SS) is an autoimmune disease affecting the exocrine glands causing dry syndrome. The diagnostic criteria are based on serological, ophthalmological, histopathological, and salivary flow tests. The use of salivary gland ultrasound has been proposed as a diagnostic test. Few studies have been carried out in Latin America. Objective: To describe the ultrasound patterns in the salivary glands in the Colombian population seen in the Rheumatology Department due to dry symptoms. Materials and methods: Cross-sectional study; a preliminary analysis was performed on 50 patients attending the Outpatient Clinic (August-January 2020). A sociodemographic and clinical evaluation was made using a questionnaire. Paraclinical and ophthalmological tests, minor salivary gland biopsy, and ultrasound assessment of the major salivary glands (De Vita score 0-6) were the main items to evaluate. Univariate and bivariate analyses (Chi-squared, Fischer test) were performed. Results: Most (94%) of the population were women, and 38% had SS. The mean age was 55.9±9.6 years old. The proportion of patients with positive ultrasound for SS and a diagnosis using SS criteria was higher compared to patients with negative ultrasound (p<.0001). Patients with positive ultrasound had a higher proportion of anti-La (p=.002), ANAS (p=.008), anti-Ro (p<.0001), lymphopenia (p=.007), and objective and subjective xerostomia (p=.019 and p=.041, respectively). Conclusions: Ultrasound assessment could be considered a useful tool in the diagnosis of SS, since more patients presenting with glandular ultrasound abnormalities have a higher positive immunological profile (anti-Ro, ANAS, anti-La) and their positivity is associated with SS criteria. New studies are required to evaluate the operational characteristics of the test.


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Síndromes do Olho Seco , Síndrome de Sjogren , Ultrassonografia , Pacientes , Estudos de Coortes , Colômbia
13.
Am J Hum Genet ; 107(5): 977-988, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33058759

RESUMO

PRKACA and PRKACB code for two catalytic subunits (Cα and Cß) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cß subunits of PKA during human development.


Assuntos
Anormalidades Múltiplas/genética , Disfunção Cognitiva/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Dedos/anormalidades , Mutação em Linhagem Germinativa , Defeitos dos Septos Cardíacos/genética , Polidactilia/genética , Dedos do Pé/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Animais , Sequência de Bases , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , AMP Cíclico/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/química , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/deficiência , Feminino , Dedos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Defeitos dos Septos Cardíacos/diagnóstico , Defeitos dos Septos Cardíacos/patologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Holoenzimas/química , Holoenzimas/deficiência , Holoenzimas/genética , Humanos , Recém-Nascido , Masculino , Camundongos , Modelos Moleculares , Mosaicismo , Células NIH 3T3 , Linhagem , Polidactilia/diagnóstico , Polidactilia/patologia , Estrutura Secundária de Proteína , Dedos do Pé/patologia
15.
Transl Res ; 218: 43-56, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31951825

RESUMO

Cardiac alterations (hypertrophic/dilated cardiomyopathy, and rhythm alterations) are one of the major causes of mortality and morbidity in propionic acidemia (PA), caused by the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC), involved in the catabolism of branched-chain amino acids, cholesterol, and odd-chain fatty acids. Impaired mitochondrial oxidative phosphorylation has been documented in heart biopsies of PA patients, as well as in the hypomorphic Pcca-/-(A138T) mouse model, in the latter correlating with increased oxidative damage and elevated expression of cardiac dysfunction biomarkers atrial and brain natriuretic peptides (ANP and BNP) and beta-myosin heavy chain (ß-MHC). Here we characterize the cardiac phenotype in the PA mouse model by histological and echocardiography studies and identify a series of upregulated cardiac-enriched microRNAs (miRNAs) in the PA mouse heart, some of them also altered as circulating miRNAs in PA patients' plasma samples. In PA mice hearts, we show alterations in signaling pathways regulated by the identified miRNAs, which could be contributing to cardiac remodeling and dysfunction; notably, an activation of the mammalian target of rapamycin (mTOR) pathway and a decrease in autophagy, which are reverted by rapamycin treatment. In vitro studies in HL-1 cardiomyocytes indicate that propionate, the major toxic metabolite accumulating in the disease, triggers the increase in expression levels of miRNAs, BNP, and ß-MHC, concomitant with an increase in reactive oxygen species. Our results highlight miRNAs and signaling alterations in the PCC-deficient heart which may contribute to the development of PA-associated cardiomyopathy and provide a basis to identify new targets for therapeutic intervention.


Assuntos
Cardiomiopatias/genética , MicroRNAs/genética , Acidemia Propiônica/genética , Animais , Cardiomiopatias/complicações , Cardiomiopatias/fisiopatologia , Linhagem Celular , Ecocardiografia , Humanos , Camundongos , Acidemia Propiônica/complicações , Acidemia Propiônica/fisiopatologia , Transdução de Sinais
16.
Orig Life Evol Biosph ; 49(3): 111-145, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31399826

RESUMO

In this review, we describe some of the central philosophical issues facing origins-of-life research and provide a targeted history of the developments that have led to the multidisciplinary field of origins-of-life studies. We outline these issues and developments to guide researchers and students from all fields. With respect to philosophy, we provide brief summaries of debates with respect to (1) definitions (or theories) of life, what life is and how research should be conducted in the absence of an accepted theory of life, (2) the distinctions between synthetic, historical, and universal projects in origins-of-life studies, issues with strategies for inferring the origins of life, such as (3) the nature of the first living entities (the "bottom up" approach) and (4) how to infer the nature of the last universal common ancestor (the "top down" approach), and (5) the status of origins of life as a science. Each of these debates influences the others. Although there are clusters of researchers that agree on some answers to these issues, each of these debates is still open. With respect to history, we outline several independent paths that have led to some of the approaches now prevalent in origins-of-life studies. These include one path from early views of life through the scientific revolutions brought about by Linnaeus (von Linn.), Wöhler, Miller, and others. In this approach, new theories, tools, and evidence guide new thoughts about the nature of life and its origin. We also describe another family of paths motivated by a" circularity" approach to life, which is guided by such thinkers as Maturana & Varela, Gánti, Rosen, and others. These views echo ideas developed by Kant and Aristotle, though they do so using modern science in ways that produce exciting avenues of investigation. By exploring the history of these ideas, we can see how many of the issues that currently interest us have been guided by the contexts in which the ideas were developed. The disciplinary backgrounds of each of these scholars has influenced the questions they sought to answer, the experiments they envisioned, and the kinds of data they collected. We conclude by encouraging scientists and scholars in the humanities and social sciences to explore ways in which they can interact to provide a deeper understanding of the conceptual assumptions, structure, and history of origins-of-life research. This may be useful to help frame future research agendas and bring awareness to the multifaceted issues facing this challenging scientific question.


Assuntos
Biologia/história , Química/história , Historiografia , Informática/história , Origem da Vida , Paleontologia/história , Filosofia/história , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , Biologia Molecular/história
17.
Hist Cienc Saude Manguinhos ; 26(1): 245-264, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30942313

RESUMO

This paper focuses on geneticists Salvador Armendares's and Rubén Lisker's studies from the 1960s to the 1980s, to explore how their work fits into the post-1945 human biological studies, and also how the populations they studied, child and indigenous, can be considered laboratories of knowledge production. This paper describes how populations were considered for different purposes: scientific inquiry, standardization of medical practices, and production or application of medicines. Through the narrative of the different trajectories and collaborations between Armendares and Lisker, this paper also attempts to show the contact of their scientific practices, which brought cytogenetics and population genetics together at the local and global levels from a transnational perspective.


Assuntos
Genética Populacional/história , Genética Humana/história , Povos Indígenas/história , Erros Inatos do Metabolismo dos Carboidratos/história , Criança , Citogenética/história , Deficiência de Glucosefosfato Desidrogenase/história , História do Século XX , Humanos , Povos Indígenas/genética , Cariotipagem/história , Lactase/deficiência , Lactase/história , México
20.
Hist. ciênc. saúde-Manguinhos ; 26(1): 245-264, Jan.-Mar. 2019.
Artigo em Inglês | LILACS | ID: biblio-989863

RESUMO

Abstract This paper focuses on geneticists Salvador Armendares's and Rubén Lisker's studies from the 1960s to the 1980s, to explore how their work fits into the post-1945 human biological studies, and also how the populations they studied, child and indigenous, can be considered laboratories of knowledge production. This paper describes how populations were considered for different purposes: scientific inquiry, standardization of medical practices, and production or application of medicines. Through the narrative of the different trajectories and collaborations between Armendares and Lisker, this paper also attempts to show the contact of their scientific practices, which brought cytogenetics and population genetics together at the local and global levels from a transnational perspective.


Resumo Aborda o trabalho dos geneticistas Salvador Armendares e Rubén Lisker, entre 1960 e 1980, para analisar como se insere nos estudos biológicos humanos do pós-1945, e demonstra como as populações estudadas por eles, a infantil e a indígena, podem ser consideradas laboratórios de produção de conhecimento. O artigo revela como as populações foram consideradas para diversos propósitos: investigação científica, padronização das práticas médicas e produção ou aplicação de suas medicinas. Por meio da narrativa das diferentes trajetórias e colaborações entre Armendares e Lisker, também procura discutir o contato de suas práticas científicas, que colocaram a citogenética e a genética de populações lado a lado nos níveis local e global a partir de uma perspectiva transnacional.


Assuntos
Humanos , Criança , História do Século XX , Genética Humana/história , Povos Indígenas/história , Genética Populacional/história , Erros Inatos do Metabolismo dos Carboidratos/história , Citogenética/história , Lactase/deficiência , Lactase/história , Povos Indígenas/genética , Deficiência de Glucosefosfato Desidrogenase/história , Cariotipagem/história , México
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