RESUMO
BACKGROUND: Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn. Recently, parkinsonian features were reported in a study of European patients and Lewy bodies have been demonstrated pathologically in a similar series of patients. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease. METHODS: Based on the finding that α-Syn has been found to be a prion-like protein, we have utilized a validated α-Synuclein seed amplification assay to determine if seed-competent α-Syn could be detected in the spinal fluid of patients with ALS. RESULTS: Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assays (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects. CONCLUSIONS: Our findings suggest that a sub-group of ALS occurs in which self-replicating α-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.
Assuntos
Esclerose Lateral Amiotrófica , alfa-Sinucleína , Humanos , alfa-Sinucleína/metabolismo , Esclerose Lateral Amiotrófica/patologia , Corpos de Lewy/metabolismo , Corpos de Lewy/patologia , Superóxido Dismutase-1RESUMO
Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.
Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/genética , Humanos , Neurônios Motores/metabolismo , Ligação Proteica , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
OBJECTIVES: The island of New Guinea was settled by modern human over 50,000 years ago, and is currently characterized by a complex landscape and contains one-seventh of the world's languages. The Eastern Highlands of New Guinea were also the home to the devastating prion disease called kuru that primarily affected Fore-speaking populations, with some 68% of cases involving adult females. We characterized the mitochondrial DNA (mtDNA) diversity of highlanders from Papua New Guinea (PNG) to: (a) gain insight into the coevolution of genes and languages in situ over mountainous landscapes; and (b) evaluate the recent influence of kuru mortality on the pattern of female gene flow. MATERIALS AND METHODS: We sequenced the mtDNA hypervariable segment 1 of 870 individuals from the Eastern and Southern Highlands of PNG using serums collected in the 1950s to 1960s. These highlanders were selected from villages representing 15 linguistic groups within the Trans-New Guinea phylum. Genetic, linguistic, and geographic distances were calculated separately and correlations among those distance matrices were assessed using the Mantel test. RESULTS: Geographic, genetic, and linguistic patterns were independently correlated with each other (p < .05). Increased mtDNA diversity in kuru-affected populations and low Fst estimates between kuru-affected linguistic groups were observed. DISCUSSION: In general, the genetic structure among the Highland populations was shaped by both geography and language, and language is a good predictor of mtDNA affinity in the PNG Highlands. High kuru female mortality increased female gene flow locally, disrupting coevolutionary pattern among genes, languages, and geography.
Assuntos
Coevolução Biológica , Fluxo Gênico , Kuru , Idioma , DNA Mitocondrial/análise , Meio Ambiente , Feminino , Humanos , Masculino , Papua Nova Guiné , Fatores SexuaisRESUMO
OBJECTIVE: The present study evaluates the use of multiple correspondence analysis (MCA), a type of exploratory factor analysis designed to reduce the dimensionality of large categorical data sets, in identifying behaviours associated with measures of overweight/obesity in Vanuatu, a rapidly modernizing Pacific Island country. DESIGN: Starting with seventy-three true/false questions regarding a variety of behaviours, MCA identified twelve most significantly associated with modernization status and transformed the aggregate binary responses of participants to these twelve questions into a linear scale. Using this scale, individuals were separated into three modernization groups (tertiles) among which measures of body fat were compared and OR for overweight/obesity were computed. SETTING: Vanuatu.ParticipantsNi-Vanuatu adults (n 810) aged 20-85 years. RESULTS: Among individuals in the tertile characterized by positive responses to most of or all the twelve modernization questions, weight and measures of body fat and the likelihood that measures of body fat were above the US 75th percentile were significantly greater compared with individuals in the tertiles characterized by mostly or partly negative responses. CONCLUSIONS: The study indicates that MCA can be used to identify individuals or groups at risk for overweight/obesity, based on answers to simply-put questions. MCA therefore may be useful in areas where obtaining detailed information about modernization status is constrained by time, money or manpower.
Assuntos
Obesidade/psicologia , Sobrepeso/psicologia , Mudança Social , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Comportamento do Consumidor , Dieta , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Vanuatu , Adulto JovemRESUMO
Parkinsonism-dementia complex of Guam (Guam PDC) is a neurodegenerative disease with parkinsonism and early onset Alzheimer-like dementia. Guam PDC belongs to the family of neurodegenerative disorders, known as tauopathies, which are histopathologically characterized by abnormal deposition of microtubule-associated protein tau. While changes in the blood-brain barrier (BBB) in Alzheimer's disease are increasingly recognized, dysfunction of BBB in Guam PDC has not been extensively studied. In this study, we characterized cerebrovascular changes in the patients with Guam PDC. The brain tissue from ten post-mortem Guam PDC patients and six non-demented controls were assessed for structural and functional changes in BBB. Entorhinal cortex sections were immunostained for the markers of brain endothelial cells (claudin-5, occludin, and collagen IV) and inflammation (VCAM-1, ICAM-1, P-Selectin, and E-Selectin). The ultrastructure of brain capillaries was investigated by confocal microscopy and morphological changes and intensity alterations were evaluated. We found a significant decrease of tight junction proteins and the upregulation of adhesion molecules that correlated with the presence of neurofibrillary tangles. In addition, we showed the presence of CD3+-positive cells in the brain areas affected by pathological lesions. Our findings indicate that pathological lesions in Guam PDC are associated with inflammatory changes of brain capillaries and could mediate transmigration of cells to the brain parenchyma.
Assuntos
Barreira Hematoencefálica/patologia , Demência/patologia , Inflamação/patologia , Transtornos Parkinsonianos/patologia , Proteínas tau , Adulto , Idoso , Feminino , Guam , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologiaRESUMO
OBJECTIVES: To determine whether (1) maximal handgrip strength (HGS) is associated with inter-island level of economic development in Vanuatu, (2) how associations between island of residence and HGS are mediated by age, sex, body size/composition, and individual sociodeomographic variation, and (3) whether HGS is predictive of hypertension. MATERIAL AND METHODS: HGS was collected from 833 adult (aged 18 and older) men and women on five islands representing a continuum of economic development in Vanuatu. HGS was measured using a handheld dynamometer. Participants were administered in an extensive sociobehavioral questionnaire and were also assessed for height, weight, percent body fat, forearm skinfold thickness, forearm circumference, and blood pressure. RESULTS: HGS was significantly greater in men than in women regardless of island of residence. HGS was also significantly positively associated with inter-island level of economic development. Grip strength-to-weight ratio was not different across islands except in older individuals, where age-related decline occurred primarily on islands with greater economic development. HGS significantly declined with age in both men and women. CONCLUSION: HGS is positively associated with modernization in Vanuatu, but the relationship between HGS and modernization is largely due to an association of both variables with increased body size on more modernized islands. Further research on the role of individual variation in diet and physical activity are necessary to clarify the relationship between HGS and modernization.
Assuntos
Força da Mão/fisiologia , Transição Epidemiológica , Adulto , Antropometria , Estudos Transversais , Suscetibilidade a Doenças/epidemiologia , Desenvolvimento Econômico , Feminino , Mãos/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Vanuatu/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: The Republic of Vanuatu, like many developing nations, is undergoing a rapid health transition. Our previous study identified several behavioral risk factors for the rising prevalence of obesity. Unexpectedly, daily time spent using television and radio was revealed as a protective factor for obesity in 2007. In this study, we sought to explore associations between ownership of consumer electronics (CE) and measures of adiposity in Vanuatu in 2011. METHODS: We surveyed 873 adults from five islands varying in level of economic development. Height, weight, and waist circumferences; triceps, subscapular, and suprailiac skinfolds; and percent body fat by bioelectrical impedance were measured. Ownership of eight types of CE, diet through 24-h dietary recall and leisure-time activity patterns were assessed using a questionnaire. RESULTS: Participants from more developed islands owned more types of CE, and revealed higher measures of adiposity on average as well as higher prevalence of obesity/central obesity. When controlling for demographic factors, and dietary and activity patterns, increased measures of adiposity and risk for obesity/central obesity were associated with ownership of cellphones, music players, televisions, video players, microwaves, and/or refrigerators. Positive correlations between CE ownership and measures of adiposity were mainly observed among men on the two most developed islands. CONCLUSIONS: The results of this study indicate a possible role of CE use in the rising prevalence of obesity and the shift to a sedentary lifestyle in Vanuatu and many other modernizing regions, where prevention efforts including education on healthy use of CE are imperative.
Assuntos
Transição Epidemiológica , Obesidade/epidemiologia , Rádio , Comportamento Sedentário , Televisão , Adiposidade , Adulto , Idoso , Feminino , Humanos , Atividades de Lazer , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Propriedade , Prevalência , Fatores de Risco , Vanuatu/epidemiologiaRESUMO
OBJECTIVE: To determine whether: (1) there is a secular increase in adult stature in Vanuatu, and (2) whether adult stature is positively associated with modernization in Vanuatu. METHODS: This study reports on stature measurements collected on 650 adult (age > 17 years) men and women from four islands of varying economic development in Vanuatu. Measurements were collected as part of the Vanuatu Health Transitions Research Project in 2007 and 2011. RESULTS: Stature increased significantly in adults born between the 1940s and 1960s in Vanuatu, before leveling off in those born between the 1970s and 1990s. Adults are significantly taller on Efate, the most modernized island in the study sample, than on the less economically developed islands. CONCLUSIONS: Modernization is likely associated with improvements in child growth in Vanuatu, as assessed by gains in adult stature.
Assuntos
Estatura , Mudança Social , Adulto , Idoso , Idoso de 80 Anos ou mais , Desenvolvimento Econômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vanuatu , Adulto JovemRESUMO
Parkinsonism-dementia (PD) of Guam is a neurodegenerative disease with parkinsonism and early-onset Alzheimer-like dementia associated with neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein, tau. ß-N-methylamino-l-alanine (BMAA) has been suspected of being involved in the etiology of PD, but the mechanism by which BMAA leads to tau hyperphosphorylation is not known. We found a decrease in protein phosphatase 2A (PP2A) activity associated with an increase in inhibitory phosphorylation of its catalytic subunit PP2Ac at Tyr(307) and abnormal hyperphosphorylation of tau in brains of patients who had Guam PD. To test the possible involvement of BMAA in the etiopathogenesis of PD, we studied the effect of this environmental neurotoxin on PP2A activity and tau hyperphosphorylation in mouse primary neuronal cultures and metabolically active rat brain slices. BMAA treatment significantly decreased PP2A activity, with a concomitant increase in tau kinase activity resulting in elevated tau hyperphosphorylation at PP2A favorable sites. Moreover, we found an increase in the phosphorylation of PP2Ac at Tyr(307) in BMAA-treated rat brains. Pretreatment with metabotropic glutamate receptor 5 (mGluR5) and Src antagonists blocked the BMAA-induced inhibition of PP2A and the abnormal hyperphosphorylation of tau, indicating the involvement of an Src-dependent PP2A pathway. Coimmunoprecipitation experiments showed that BMAA treatment dissociated PP2Ac from mGluR5, making it available for phosphorylation at Tyr(307). These findings suggest a scenario in which BMAA can lead to tau pathology by inhibiting PP2A through the activation of mGluR5, the consequent release of PP2Ac from the mGluR5-PP2A complex, and its phosphorylation at Tyr(307) by Src.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Regulação Enzimológica da Expressão Gênica , Proteína Fosfatase 2/metabolismo , Proteínas tau/metabolismo , Idoso , Animais , Encéfalo/enzimologia , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurotoxinas/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptor de Glutamato Metabotrópico 5/metabolismo , Fatores de Tempo , Tirosina/química , Quinases da Família src/metabolismoRESUMO
OBJECTIVES: This study compares forced vital capacity (FVC) and Forced Expiratory Volume at 1 Second (FEV1 ) of Tibetans with those of Han who were born and raised at high altitude. MATERIALS AND METHODS: FVC and FEV1 tests were conducted among 1,063 children and adolescents between the ages of 6 and 20 years, and 184 adults between the ages of 21 and 39 years who had lived their entire lives at 3200 m, 3800 m and 4300 m in Qinghai Provence, Peoples Republic of China. RESULTS: Even though FVC and FEV1 values of Han born and raised at high altitude are generally lower than those of Tibetans through age 15 in girls and age 16 in boys, differences are largely explained by variation in stature (height-squared) and chest circumference. Among older adolescents and adults, the FVC and FEV1 values of Tibetans are significantly larger than those of Han born and raised at high altitude; and are much larger than would be predicted, based on stature and chest circumference. DISCUSSION: These results indicate that the large FVC and FEV1 values of Tibetan adults develop primarily from an accelerated pattern of lung growth that begins during mid-to-late adolescence and possibly extends into young adulthood. This developmental pattern is not only distinct from that of Han born and raised at high altitude, but also from those of Andean Quechua and Aymara. The pace of lung function growth may therefore represent another feature distinguishing the Tibetan from the Andean pattern of adaptation to high altitude hypoxia. Because of this, a search for features in the Tibetan genome related to this lung function growth phenotype might be productive and important.
Assuntos
Etnicidade/estatística & dados numéricos , Volume Expiratório Forçado/fisiologia , Capacidade Vital/fisiologia , Adolescente , Adulto , Altitude , Antropologia Física , Antropometria , Criança , Etnicidade/etnologia , Feminino , Humanos , Masculino , Tórax/anatomia & histologia , Tórax/fisiologia , Tibet/etnologia , Adulto JovemRESUMO
OBJECTIVE: The Republic of Vanuatu, similar to other South Pacific island nations, is undergoing a rapid health transition as a consequence of modernization. The pace of modernization is uneven across Vanuatu's 63 inhabited islands, resulting in differential impacts on overall body composition and prevalence of obesity among islands, and between men and women. In this study, we investigated (1) how modernization impacts body composition between adult male and female Melanesians living on four islands of varying economic development in Vanuatu, and (2) how body composition differs between adult Melanesians and Polynesians living on rural islands in Vanuatu. METHODS: Anthropometric measurements were taken on adult male and female Melanesians aged 18 years and older (n = 839) on the islands of Ambae (rural), Aneityum (rural with tourism), Nguna (rural with urban access), and Efate (urban) in Vanuatu, in addition to Polynesian adults on Futuna (rural). RESULTS: Mean measurements of body mass and fatness, and prevalence of obesity, were greatest on the most modernized islands in our sample, particularly among women. Additionally, differences between men and women became more pronounced on islands that were more modernized. Rural Polynesians on Futuna exhibited greater body mass, adiposity, and prevalence of obesity than rural Melanesians on Ambae. CONCLUSIONS: We conclude that Vanuatu is undergoing an uneven and rapid health transition resulting in increased prevalence of obesity, and that women are at greatest risk for developing obesity-related chronic diseases in urbanized areas in Vanuatu.
Assuntos
Pesos e Medidas Corporais , Desenvolvimento Econômico/estatística & dados numéricos , Obesidade/epidemiologia , Características de Residência , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Fatores Socioeconômicos , VanuatuRESUMO
Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscore the role of α-Syn's mitochondrial localization in inducing TOM40 degradation. Parkinson's Disease related etiological factors, such as 6-hydroxy dopamine or ROS/metal ions stress, which promote α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.
RESUMO
TDP-43 mislocalization and aggregation are key pathological features of motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, transgenic hTDP-43 WT or ΔNLS-overexpression animal models mainly capture late-stages TDP-43 proteinopathy, and do not provide a complete understanding of early motor neuron-specific pathology during pre-symptomatic phases. We have now addressed this shortcoming by generating a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43ΔNLS variant of mouse Tdp-43. This variant is either expressed conditionally in whole mice or specifically in the motor neurons. The mice exhibit loss of nuclear Tdp-43 concomitant with its cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation and DNA damage-associated cellular senescence. Notably, unlike WT Tdp43 which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43ΔNLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mice brain. The mutant mice also exhibit myogenic degeneration in limb muscles and distinct motor deficits, consistent with the characteristics of MND. Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43ΔNLS mutant, independent of TDP-43 overexpression or other confounding etiological factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to further characterize the early-stage progression of MND and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.
RESUMO
TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.
RESUMO
Until 50 years ago, high-altitude terrestrial research was conducted largely within the realm of environmental physiology, where interests were focused on physiological mechanisms and mountain exploration. Scientists from the United States, Europe, and Peru had developed sophisticated physiological models of adaptation and acclimatization to the hypoxia of high altitude, but very little research had been conducted on permanent residents, particularly natives of high altitude in the two major regions of the world-the Andes and the Himalayas. In 1962, Raul T. Baker initiated a project at the Pennsylvania State University to explore the responses of indigenous Peruvians to the major stresses at altitude: hypoxia and cold. Approaches to this early research were anthropological in perspective and centered on population-level studies with an evolutionary approach. Studies were conducted by applying a combination of physiological experimental methods, simulated field experiments, and extended anthropological field observations. Early hypotheses at this time were that heredity played a major role in the adaptive complexes in native high-altitude residents. These early hypotheses were later modified to incorporate or replace the genetic hypotheses with developmental adaptation models. A half century of research within anthropology and research in other fields has presented a vastly more complex and integrated picture of high-altitude adaptation in native residents. Recent studies incorporate physiology and oxygen transport, population and molecular genetics, reproduction, growth, and development. The history and current status of high-altitude research and its anthropological applications are treated in papers from this plenary symposium.
Assuntos
Aclimatação , Evolução Biológica , Oxigênio/metabolismo , Adaptação Fisiológica , Altitude , Temperatura Baixa , HumanosRESUMO
While many studies have compared Tibetans and low-altitude born Han living at high altitude, few have carefully controlled the chronological age at which lowlanders migrated, the length of time they had lived at high altitude, their nutrition, and their socio-economic status. This has produced an array of results that frequently do not support the hypothesis that Tibetans and Han show fundamental differences in their response to hypoxia. Unlike the situation in the Andes, only one study has tested the developmental adaptation hypothesis on the Qinghai-Tibetan plateau. This study shows that Tibetans and Han of the same age, who were born and raised in the same towns at the same altitudes, show considerable overlap in the individual distribution of [Hb], SaO2 and lung volumes. These results indicate that second-generation Han make substantial developmental adjustments to hypoxia that are not reflected in studies of first-generation migrants. Thus, there is a great need for further developmental studies to determine whether and/or how Han and Tibetan responses to hypoxia diverge, as well as for studies exploring whether Han and Tibetans who show similar responses also share genetic adaptations.
Assuntos
Aclimatação , Emigrantes e Imigrantes , Pulmão/anatomia & histologia , Pulmão/fisiologia , Oxigênio/metabolismo , Altitude , Povo Asiático , Humanos , Tamanho do Órgão , TibetRESUMO
BACKGROUND: Archaeological and linguistic evidence suggests the Marianas Islands were settled around 3,600 years before present (ybp) from Island Southeast Asia (ISEA). Around 1,000 ybp latte stone pillars and the first evidence of rice cultivation appear in the Marianas. Both traditions are absent in the rest of prehistoric Oceania. OBJECTIVE: To examine the genetic origins and postsettlement gene flow of Chamorros of the Marianas Islands. METHODS: To infer the origins of the Chamorros we analyzed â¼360 base pairs of the hypervariable-region 1 (HVS1) of mitochondrial DNA from 105 Chamorros from Guam, Rota, and Saipan, and the complete mitochondrial genome of 32 Guamanian Chamorros, and compared them to lineages from ISEA and neighboring Pacific archipelagoes from the database. RESULTS: Results reveal that 92% of Chamorros belong to haplogroup E, also found in ISEA but rare in Oceania. The two most numerous E lineages were identical to lineages currently found in Indonesia, while the remaining E lineages differed by only one or two mutations and all were unique to the Marianas. Seven percent of the lineages belonged to a single Chamorro-specific lineage within haplogroup B4, common to ISEA as well as Micronesia and Polynesia. CONCLUSIONS: These patterns suggest a small founding population had reached and settled the Marianas from ISEA by 4,000 ybp, and developed unique mutations in isolation. A second migration from ISEA may have arrived around 1,000 ybp, introducing the latte pillars, rice agriculture and the homogeneous minority B4 lineage.
Assuntos
DNA Mitocondrial/genética , Fluxo Gênico , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Emigração e Imigração , Guam , Haplótipos , Humanos , Dados de Sequência Molecular , Mutação , Filogenia , PolinésiaRESUMO
OBJECTIVE: Rapid economic development and subsequent changes in lifestyle and disease burdens ('health transition') is associated with increasing prevalence of obesity among both adults and children. However, because of continued infectious diseases and undernutrition during the early stages of transition, monitoring childhood obesity has not been prioritized in many countries and the scope of the problem is unknown. Therefore we sought to characterize patterns of childhood overweight and obesity in an early transitional area, the South Pacific archipelago of Vanuatu. DESIGN: We completed an anthropometric survey among children from three islands with varying levels of economic development, from rural areas (where adult obesity prevalence is low) to urban areas (where adult obesity prevalence is high). SETTING: The islands of Ambae (rural), Aneityum (rural with tourism) and Efate (urban). SUBJECTS: Boys and girls (n 513) aged 6-17 years. RESULTS: Height-, weight- and BMI-for-age did not vary among islands, and prevalence of overweight/obesity based on BMI was low. However, girls from Aneityum - a rural island where the tourism industry increased rapidly after malaria eradication - had increased central adiposity compared with girls from the other islands. This is contrary to adult patterns, which indicate higher obesity prevalence in urban areas. Multiple factors might contribute, including stunting, biological responses after malaria control, sleeping patterns, diet and physical activity levels. CONCLUSIONS: Measures of central adiposity highlight an emerging obesity risk among girls in Vanuatu. The data highlight the synergistic relationship among infectious diseases, undernutrition and obesity during the early stages of health transition.
Assuntos
Transição Epidemiológica , Desnutrição/epidemiologia , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Adolescente , Composição Corporal , Estatura , Índice de Massa Corporal , Peso Corporal , Criança , Pré-Escolar , Intervalos de Confiança , Dieta , Feminino , Humanos , Lactente , Estilo de Vida , Masculino , Desnutrição/complicações , Estado Nutricional , Obesidade/complicações , Sobrepeso/complicações , Prevalência , População Rural/estatística & dados numéricos , Fatores Socioeconômicos , População Urbana/estatística & dados numéricos , Vanuatu/epidemiologiaRESUMO
Lyme disease (LD) is the most common vector-borne disease in the USA. Beyond its tick-borne nature, however, risk factors for LD are poorly understood. We used an online questionnaire to compare LD patients and non-LD counterparts and elucidate factors associated with LD. We investigated demographic, lifestyle, and household characteristics and use of prevention measures. Associations with LD were modeled using logistic regression, and average marginal effects were estimated. In total, 185 active or past LD patients and 139 non-patients participated. The majority of respondents were white (95%) and female (65%). Controlling for age, sex, and type of residential area, pet ownership was associated with an 11.1% (p = 0.038) increase in the probability of LD. This effect was limited to cat owners (OR: 2.143, p = 0.007; dog owners, OR: 1.398, p = 0.221). Living in rural areas was associated with a 36% (p = 0.001) increase in the probability of LD compared to living in an urban area. Participants who reported knowing someone with Lyme Disease were more likely to wear insect repellant and perform tick checks. This study suggests opportunities for improved LD prevention, including advising cat owners of their increased risk. Although patterns in adoption of LD prevention methods remain poorly understood, concern about LD risk does motivate their use.
Assuntos
Doença de Lyme , Carrapatos , Animais , Gatos , Cães , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Doença de Lyme/epidemiologia , Doença de Lyme/prevenção & controle , New England/epidemiologia , Propriedade , Prevalência , Fatores de RiscoRESUMO
Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disease found in the Chamorro people of Guam and other Pacific Island populations. The etiology is unknown, although both genetic and environmental factors appear important. To identify loci for ALS/PDC, we conducted both genome-wide linkage and association analyses, using approximately 400 microsatellite markers, in the largest sample assembled to date, comprising a nearly complete sample of all living and previously sampled deceased cases. A single, large, complex pedigree was ascertained from a village on Guam, with smaller families and a case-control sample ascertained from the rest of Guam by population-based neurological screening and archival review. We found significant evidence for two regions with novel ALS/PDC loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. D12S1617 on 12p gave the strongest evidence of linkage (maximum LOD score, Z(max) = 4.03) in our initial scan, with additional support in the complete case-control sample in the form of evidence of allelic association at this marker and another nearby marker. D12S79 on 12q also provided significant evidence of linkage (Z(max) = 3.14) with support from flanking markers. Our results suggest that ALS/PDC may be influenced by as many as three loci, while illustrating challenges that are intrinsic in genetic analyses of isolated populations, as well as analytical strategies that are useful in this context. Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS.