RESUMO
Mitochondrial complex III (CIII) deficiency comprises a group of complex and heterogeneous genetic disorders. TTC19 mutations constitute a rare cause of CIII deficiency and are associated with neurological disorders in childhood and adulthood. Herein, we describe a 27-year-old Japanese man with cerebellar ataxia, spastic paraparesis, loss of deep sensation, mild frontal lobe dysfunction and transient psychiatric symptoms. Brain magnetic resonance imaging showed cerebellar atrophy and bilateral high-intensity signals in the inferior olives and regions adjacent to periaqueductal gray matter, on T2-weighted images. On whole-exome sequencing, we detected a novel homozygous frameshift mutation c.157_158dup [p.Pro54Alafs*48] in TTC19. Mitochondrial enzyme assays confirmed mild impairment of CIII enzymatic activity in lymphoblasts, which was consistent with TTC19-related CIII deficiency. His symptoms and radiological findings demonstrated an early stage or mild form of this disease, and further clarify the characteristics of patients with rare TTC19 mutations.
Assuntos
Povo Asiático/genética , Ataxia Cerebelar/genética , Homozigoto , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Mutação , Paraparesia Espástica/genética , Transtornos da Percepção/genética , Adulto , Encéfalo/patologia , Ataxia Cerebelar/diagnóstico , Análise Mutacional de DNA , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Complexo III da Cadeia de Transporte de Elétrons/genética , Humanos , Japão , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Paraparesia Espástica/diagnóstico , Transtornos da Percepção/diagnósticoRESUMO
BACKGROUND: Stroke volume (SV) in trained athletes continuously increases with progressive exercise intensity. We studied whether physical training affected left ventricle (LV) function response to exercise using 3D echocardiography and tissue Doppler imaging (TDI). METHODS: Eleven male university athletes and 12 male university nonathletes were enrolled in this study. After baseline data were collected, subjects performed a symptom-limited supine bicycle ergometer exercise test. Initial workload was 25 Watts (W) and increased 25 W every 3 minutes. At rest and every exercise stage, LV end-systolic and diastolic volume index (LVEDVI and LVESVI), SV index (SVI), cardiac index (CI), LV ejection fraction (LVEF), and early lateral mitral flow velocity (Ea) were evaluated. Heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) were continuously recorded. RESULTS: Nonathletes showed a slow increase in CI, and SVI reached a plateau value at a HR of 90 beats per minute (bpm). In contrast, CI and SVI increased progressively and continuously in athletes. Both CI and SVI were significantly higher in athletes than in nonathletes at HRs of 100, 110, and 120 bpm. LVEDVI kept increasing in athletes while it plateaued in nonathletes. In contrast, LVESV decreased continuously during exercise in both groups. There was no significant difference in LVEF, Ea, SBP, or DBP at rest and during exercise between the two groups. CONCLUSION: LV responses to exercise in athletes were different from those of in nonathletes; thus, habitual physical training may play an important role in the increase in both SVI and CI in young individuals.
Assuntos
Atletas/estatística & dados numéricos , Ecocardiografia Doppler , Ecocardiografia Tridimensional , Exercício Físico/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Função Ventricular Esquerda/fisiologia , Adulto , Teste de Esforço/estatística & dados numéricos , Frequência Cardíaca/fisiologia , Humanos , Masculino , Consumo de Oxigênio/fisiologia , Volume Sistólico/fisiologia , Adulto JovemRESUMO
Many marine species are distributed across incredibly wide geographical ranges spanning thousands of kilometers often due to movement along prevailing ocean currents. However, data are lacking on genetic connectivity among populations of such widespread species within or among ecoregions, possibly due to the lack of appropriate datasets. In this study, we investigated the genetic structure of populations of the mangrove whelk, Terebralia palustris, using mitochondrial cytochrome oxidase subunit I (COI) sequences. Sequences generated for this study from Okinawa, Japan, were compared to samples from the coast of East Africa analyzed in a previous study. Interestingly, despite considerable distance separating them, the African and Japanese populations share major haplotypes and do not show clear genetic differentiation. At lower latitudes, core African populations exhibited higher genetic diversity than either the more southerly African and Japanese populations. Genetic ß-diversity revealed that the northern edge population in Japan has a greater proportion of ßSNE (the nestedness-resultant component), indicating contemporary migration, whereas the southern edge population in Africa is characterized by a predominant ßSIM (the turnover component), suggesting historical demography. A potential cause of this dissimilarity could be due to the strong Kuroshio Current along the Ryukyu Islands, which may promote larval dispersal. These differing patterns suggest that there may be divergent responses to future climate change at the population level at the periphery of the range of T. palustris.
Assuntos
Variação Genética , Animais , Japão , Complexo IV da Cadeia de Transporte de Elétrons/genética , Genética Populacional , África Oriental , HaplótiposRESUMO
Outbreaks of Bordetella pertussis (BP), the causative agent of whooping cough, continue despite broad vaccination coverage and have been increasing since vaccination switched from whole-BP (wP) to acellular BP (aP) vaccines. wP vaccination has been associated with more durable protective immunity and an induced Th1 polarized memory T cell response. Here, a multi-omics approach was applied to profile the immune response of 30 wP and 31 aP-primed individuals and identify correlates of T cell polarization before and after Tdap booster vaccination. We found that transcriptional changes indicating an interferon response on day 1 post-booster along with elevated plasma concentrations of IFN-γ and interferon-induced chemokines that peaked at day 1-3 post-booster correlated best with the Th1 polarization of the vaccine-induced memory T cell response on day 28. Our studies suggest that wP-primed individuals maintain their Th1 polarization through this early memory interferon response. This suggests that stimulating the interferon pathway during vaccination could be an effective strategy to elicit a predominant Th1 response in aP-primed individuals that protects better against infection.
RESUMO
Systems vaccinology studies have identified factors affecting individual vaccine responses, but comparing these findings is challenging due to varying study designs. To address this lack of reproducibility, we established a community resource for comparing Bordetella pertussis booster responses and to host annual contests for predicting patients' vaccination outcomes. We report here on our experiences with the "dry-run" prediction contest. We found that, among 20+ models adopted from the literature, the most successful model predicting vaccination outcome was based on age alone. This confirms our concerns about the reproducibility of conclusions between different vaccinology studies. Further, we found that, for newly trained models, handling of baseline information on the target variables was crucial. Overall, multiple co-inertia analysis gave the best results of the tested modeling approaches. Our goal is to engage community in these prediction challenges by making data and models available and opening a public contest in August 2024.
Assuntos
Multiômica , Vacinas , Humanos , Vacinologia/métodos , Reprodutibilidade dos Testes , Simulação por ComputadorRESUMO
Computational models that predict an individual's response to a vaccine offer the potential for mechanistic insights and personalized vaccination strategies. These models are increasingly derived from systems vaccinology studies that generate immune profiles from human cohorts pre- and post-vaccination. Most of these studies involve relatively small cohorts and profile the response to a single vaccine. The ability to assess the performance of the resulting models would be improved by comparing their performance on independent datasets, as has been done with great success in other areas of biology such as protein structure predictions. To transfer this approach to system vaccinology studies, we established a prototype platform that focuses on the evaluation of Computational Models of Immunity to Pertussis Booster vaccinations (CMI-PB). A community resource, CMI-PB generates experimental data for the explicit purpose of model evaluation, which is performed through a series of annual data releases and associated contests. We here report on our experience with the first such 'dry run' for a contest where the goal was to predict individual immune responses based on pre-vaccination multi-omic profiles. Over 30 models adopted from the literature were tested, but only one was predictive, and was based on age alone. The performance of new models built using CMI-PB training data was much better, but varied significantly based on the choice of pre-vaccination features used and the model building strategy. This suggests that previously published models developed for other vaccines do not generalize well to Pertussis Booster vaccination. Overall, these results reinforced the need for comparative analysis across models and datasets that CMI-PB aims to achieve. We are seeking wider community engagement for our first public prediction contest, which will open in early 2024.
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The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seen multiple anti-SARS-CoV-2 antibodies being generated globally. It is difficult, however, to assemble a useful compendium of these biological properties if they are derived from experimental measurements performed at different sites under different experimental conditions. The Coronavirus Immunotherapeutic Consortium (COVIC) circumvents these issues by experimentally testing blinded antibodies side by side for several functional activities. To collect these data in a consistent fashion and make it publicly available, we established the COVIC database (COVIC-DB, https://covicdb.lji.org/). This database enables systematic analysis and interpretation of this large-scale dataset by providing a comprehensive view of various features such as affinity, neutralization, in vivo protection and effector functions for each antibody. Interactive graphs enable direct comparisons of antibodies based on select functional properties. We demonstrate how the COVIC-DB can be utilized to examine relationships among antibody features, thereby guiding the design of therapeutic antibody cocktails. Database URL https://covicdb.lji.org/.
Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Anticorpos Antivirais , ImunoterapiaRESUMO
We examined the efficacy and adverse events of continuous l-asparaginase administration in dogs with large cell lymphoma of presumedgastrointestinal (GI) origin. We retrospectively reviewed medical records of dogs with large cell lymphoma of presumed GI origin treated with continuous l-asparaginase administration from 2009 to 2018. We collected information on the signalment, lesion site, complete blood count, serum biochemical profile, diagnostic imaging findings, cytological and histopathological findings, immunophenotype, l-asparaginase administration frequency, treatment response, adverse events, rescue protocol, and patient outcomes. Clinical outcomes were assessed using medical records or by contacting the owner or referring veterinarian. Thirty-two dogs with large cell lymphoma of presumed GI origin received weekly l-asparaginase administration. The median number of l-asparaginase injections was seven (range: 1-30). Although two of the 32 dogs had GI toxicity of grade 3 or higher, none developed a hypersensitivity reaction. The response rate based on ultrasonographic findings was 18/32 (56%) and that based on clinical signs was 30/32 (94%). The median overall progression-free survival was 50 days (range: 2-214 days), and median overall survival was 147 days (range: 2-482 days). Adverse events associated with continuous l-asparaginase administration were rare. Clinical signs at diagnosis improved in most cases. Based on these results, continuous l-asparaginase administration appears to be a reasonable treatment option for dogs with large cell lymphoma of presumed GI origin.
Assuntos
Doenças do Cão , Linfoma não Hodgkin , Linfoma , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Doenças do Cão/induzido quimicamente , Doenças do Cão/tratamento farmacológico , Cães , Linfoma/veterinária , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/veterinária , Estudos RetrospectivosRESUMO
OBJECTIVES: Primary copper-associated hepatopathy (PCH) has been reported in young cats. Although our group recently reported a young cat with PCH harbouring single-nucleotide variations in ATP7B, limited information is available regarding its association with the pathogenesis of feline PCH. The objective of this study was to investigate the prevalence of ATP7B variations in cats with PCH. METHODS: Rhodanine staining was performed to detect hepatic copper accumulation (HCA) in intraoperative liver tissue specimens from 54 cats. In cats with HCA, variations in ATP7B and COMMD1 and serum ceruloplasmin activity were analysed. RESULTS: Based on age, liver histopathological findings and hepatic distribution of accumulated copper, PCH was suspected in 4/54 cats. Sequence analysis of ATP7B and COMMD1 revealed single-nucleotide variations in ATP7B in 3/4 cats with PCH. Among the cats with PCH, one showed remarkably low serum ceruloplasmin activity, while the other three did not. CONCLUSIONS AND RELEVANCE: The results of this study suggest that some cats with PCH harbour single-nucleotide variations in ATP7B, suggesting that feline PCH is an equivalent disorder to human Wilson's disease. This study provides basic evidence facilitating further studies of the pathophysiology and treatment of feline PCH.
Assuntos
Doenças do Gato/genética , ATPases Transportadoras de Cobre/genética , Degeneração Hepatolenticular/veterinária , Fígado/enzimologia , Animais , Gatos , Cobre/sangue , ATPases Transportadoras de Cobre/metabolismo , Feminino , Degeneração Hepatolenticular/genética , Fígado/patologia , MasculinoRESUMO
A 9-month-old intact crossbred female cat was presented with jaundice, intermittent anorexia and lethargy, increased hepatic enzyme activities, and hyperammonemia. Abdominal ultrasound and computed tomographic examinations determined that the liver had a rounded and irregular margin, and histopathological examination identified excessive accumulation of copper hepatocytes in the liver. Concentrations of both blood and urine copper were higher than in healthy cats. The patient responded well to treatment with penicillamine. Clinicopathological abnormalities and clinical signs improved within 2 months, and the patient was alive for >9 months after starting treatment. Genetic examination determined that the patient and its littermate had a single-nucleotide variation (SNV, p. T1297R) that impaired the function of the ATP7B gene product; the gene that is mutated in patients with Wilson's disease (WD). Hepatic copper accumulation was believed to be associated with the SNV of the ATP7B gene, and the patient had a genetic disorder of copper metabolism equivalent to WD in humans.
Assuntos
Doenças do Gato/genética , ATPases Transportadoras de Cobre/genética , Cobre/metabolismo , Degeneração Hepatolenticular/veterinária , Animais , Doenças do Gato/tratamento farmacológico , Doenças do Gato/metabolismo , Gatos , Quelantes/uso terapêutico , Cobre/sangue , Cobre/urina , Feminino , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/genética , Fígado/metabolismo , Mutação , Penicilamina/uso terapêuticoRESUMO
A novel flexible sensor was developed for the noninvasive oxygen metabolism measurement of cultivated cells and tissues. This device is composed of a transparent double-layered polymer sheet of ethylene-vinyl alcohol (EVOH) and poly(dimethylsiloxane) (PDMS) having an array of microhole structures of 90 µm diameter and 50 µm depth on its surface. All the microhole structures were equipped with a 1-µm-thick optical chemical sensing layer of platinum porphyrin-fluoropolymer on their bottom. The three-dimensional microstructures of the sensor were fabricated by a newly developed simple and low-cost production method named self-aligned hot embossing. The device was designed to be attached slightly above the cells cultivated on a dish to form a temporarily closed microspace over the target cells during measurement. Since the change in oxygen concentration is relatively fast in the microcompartmentalized culture medium, a rapid evaluation of the oxygen consumption rate is possible by measuring the phosphorescence lifetime of the platinum porphyrin-fluoropolymer. The combined use of the device and an automated optical measurement system enabled the high-throughput sensing of cellular oxygen consumption (100 points/min). We monitored the oxygen metabolism of the human breast cancer cell line MCF7 on a Petri dish and evaluated the oxygen consumption rate to be 0.72 ± 0.12 fmol/min/cell. Furthermore, to demonstrate the utility of the developed sensing system, we demonstrated the mapping of the oxygen consumption rate of rat brain slices and succeeded in visualizing a clear difference among the layer structures of the hippocampus, i.e., the cornu ammonis (CA1 and CA3) and dentate gyrus (DG).