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OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.
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Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Hipocampo , Esclerose , Humanos , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Esclerose/genética , Esclerose/patologia , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/patologia , Feminino , Masculino , Adulto , Adulto Jovem , Adolescente , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/patologia , Criança , Filaminas/genética , Pessoa de Meia-Idade , Pré-Escolar , Variação Genética/genética , Esclerose HipocampalRESUMO
OBJECTIVE: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.
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Diabetes Mellitus Tipo 2 , Fragilidade , Idoso , Glicemia , Pressão Sanguínea , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
The World Trade Organization (WTO) is in the final stages of negotiating an agreement to prohibit harmful fisheries subsidies, thereby achieving UN Sustainable Development Goal (SDG) 14.6. An effective agreement should be viewed as an opportunity for nations to proactively transition towards sustainable and equitable fisheries and pave the path for other SDGs. Supporting fishers does not require harmful subsidies, and we provide evidence-based options for reform that highlight equity needs while reducing environmental harm. Subsidy reforms need clear goals, co-design, transparency, and fair implementation. An agreement on SDG 14.6 could be a turning point for the oceans and for the well-being of those that depend on the oceans for livelihoods and nutrition. Responsible seafood production will require international cooperation not only at WTO, but among governments, fisher organizations, civil society, and the wider public.
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Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.
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Epilepsia/genética , Testes Genéticos/métodos , Deficiência Intelectual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Comorbidade , Hibridização Genômica Comparativa/métodos , Hibridização Genômica Comparativa/normas , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Feminino , Testes Genéticos/normas , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Sensibilidade e Especificidade , Sequenciamento do Exoma/métodos , Sequenciamento do Exoma/normasRESUMO
The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.
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This paper estimates the price changes in global bluefin tuna (BFT) markets in response to shifts in regional and global landings to evaluate the conservation and economic incentives from changes in the Total Allowable Catch (TAC) managed by all three Regional Fisheries Management Organizations. A fisherman's income, and thus the financial incentive to accept management measures controlling catch levels, depends in part on how responsive price is to overall catch. Individual fisherman, with their own best interest in mind, used to wish to increase their individual landings and create an incentive to ask to increase the TAC for the industry, without realizing the possible revenue loss due to the resulting falling prices. To protect the value of all stakeholders' property rights, a consensus to avoid abruptly raising the TAC, without first considering the potential loss due to market response, is needed. Alternatively, if revenue increases with lower TAC, a positive economic incentive for conservation is created if price increasing proportionately more than the lower supply, with harvest profits boosted by lower costs of production. To capture the complexity of substituting across various sources of supply and product form, a general synthetic inverse demand system is estimated to identify the impact of overall landings on BFT prices. This system estimates price flexibilities of both fresh and frozen longline-caught sashimi-grade tunas (Pacific, Atlantic and southern bluefins, and bigeye) at the Tokyo Center Market in Japan, including the Tsukiji Market, the world's largest fish auction market that served as the single global price leader for BFT. The resulting estimation shows that own-quantity price flexibilities of every type of fresh and frozen BFTs are less than unity and inflexible in their own consumption. This creates poor individual producer incentives for fishermen to reduce wild or farmed BFT supply, as there is a chance to increase their own revenue, under the unlikely condition that the total supply is fixed. However, by observing the rapid increases in the TAC of Eastern Atlantic bluefin tuna (EABFT) in the coming years, suppliers may not be better off as price will drop proportionally faster and total revenue if the estimated scale flexibility is greater than one. Based on the estimated scale flexibility of frozen BFT, which is slightly less than unity, the frozen subsector of EABFT suppliers is the only winner under the supply increases. Suppliers of frozen BFT in other regions, fresh BFT (in the Atlantic and elsewhere), and southern BFT and bigeye tuna will all be harmed through lower revenue by the supply increases. Additionally, while total revenue might stay the same for frozen BFT suppliers, fishermen will potentially receive lower profits due to higher operating costs associated with increased landings when the supply of EABFT increases. Given the number of sectors that ultimately lose financially in the short term and given the ecological (and production) risks accompanying an abrupt increase in fishing pressure in the long term, the global economic losses resulting from an increase in the allowable catch of Atlantic bluefin tuna will outweigh any potential increases to revenue.
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Pesqueiros/economia , Alimentos Marinhos/economia , Atum , Animais , Comércio/economia , Humanos , Japão , TóquioRESUMO
INTRODUCTION: Globally, the prevalence of uncontrolled hypertension is high, particularly in low- and middle-income countries. There is a critical need for strategies to improve hypertension control. The early use of a fixed low-dose combination of three antihypertensive drugs (triple pill) has the potential to significantly improve hypertension control. The TRI ple Pill vs. U sual care M anagement for P atients with mild-to- moderate H ypertension (TRIUMPH) randomised controlled trial (RCT) is designed to test the effects of this strategy compared with usual care in patients with mild-to-moderate hypertension. This paper reports the protocol of a process evaluation of the TRIUMPH RCT. The objectives are to understand factors related to implementation of the intervention, mechanisms of effect, contextual factors that underpin the effectiveness of the triple pill strategy and the potential barriers and facilitators to implementing the strategy in clinical practice. METHODS AND ANALYSIS: Face-to-face semistructured in-depth interviews with a purposive sample of TRIUMPH RCT participants and healthcare professionals in Sri Lanka will be conducted. Healthcare professionals will include physicians and their staff who were involved in conducting the TRIUMPH RCT. Interviewees will be recruited sequentially until thematic saturation is achieved. Interviews will be audio recorded, transcribed verbatim and analysed in NVivo using framework analysis methods. ETHICS AND DISSEMINATION: The TRIUMPH RCT and process evaluation have received approval from the relevant Ethics Review Committee. All participants will be asked to provide written consent before participation. Findings from the study will be disseminated through publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12612001120864 , SLCTR/2015/020 ; Pre-results.
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Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Melhoria de Qualidade , Protocolos Clínicos , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pesquisa Qualitativa , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normasRESUMO
BACKGROUND: Identifying simple, low-cost and scalable means of supporting lifestyle change and medication adherence for patients following a cardiovascular (CV) event is important. OBJECTIVE: The TEXTMEDS (TEXT messages to improve MEDication adherence and Secondary prevention) study aims to investigate whether a cardiac education and support programme sent via mobile phone text message improves medication adherence and risk factor levels in patients following an acute coronary syndrome (ACS). STUDY DESIGN: A single-blind, multicentre, randomised clinical trial of 1400 patients after an ACS with 12 months follow-up. The intervention group will receive multiple weekly text messages that provide information, motivation, support to adhere to medications, quit smoking (if relevant) and recommendations for healthy diet and exercise. The primary endpoint is the percentage of patients who are adherent to cardioprotective medications and the key secondary outcomes are mean systolic blood pressure (BP) and low-density lipoprotein cholesterol. Secondary outcomes will also include total cholesterol, mean diastolic BP, the percentage of participants who are adherent to each cardioprotective medication class, the percentage of participants who achieve target levels of CV risk factors, major vascular events, hospital readmissions and all-cause mortality. The study will be augmented by formal economic and process evaluations to assess acceptability, utility and cost-effectiveness. SUMMARY: The study will provide multicentre randomised trial evidence of the effects of a text message-based programme on cardioprotective medication adherence and levels of CV risk factors. ETHICS AND DISSEMINATION: Primary ethics approval was received from Western Sydney Local Health District Human Research Ethics Committee (HREC2012/12/4.1 (3648) AU RED HREC/13/WMEAD/15). Results will be disseminated via peer-reviewed publications and presentations at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12613000793718; Pre-results.
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Síndrome Coronariana Aguda/tratamento farmacológico , Promoção da Saúde/métodos , Adesão à Medicação , Educação de Pacientes como Assunto/métodos , Prevenção Secundária/métodos , Telemedicina/métodos , Envio de Mensagens de Texto , Pressão Sanguínea , Telefone Celular , LDL-Colesterol/sangue , Dieta , Exercício Físico , Feminino , Humanos , Estilo de Vida , Masculino , Motivação , Readmissão do Paciente , Sistemas de Alerta , Projetos de Pesquisa , Fatores de Risco , Método Simples-CegoRESUMO
INTRODUCTION: Extracellular material (ECM) surrounding Enterococcus faecalis may play a role in increasing resistance to environmental stresses. Our aim was to determine ECM levels in response to subminimal inhibitory concentrations of sodium hypochlorite (sub-MIC/NaOCl) or anaerobic growth and determine the impact on biofilm development. METHODS: From 37 E. faecalis clinical strains, 19 were selected according to their biofilm-producing ability by using a crystal violet biofilm assay: 10 strong, 4 intermediate, and 5 non-biofilm producers. Biofilm assays were subsequently performed on all strains when subjected to sub-MIC/NaOCl. All strains were evaluated for ECM production under aerobic and anaerobic conditions and with sub-MIC/NaOCl. ECM production was assessed by using scanning electron microscopy. Double-blinded independent assessors were used to score levels of ECM production. The esp gene was detected by using polymerase chain reaction. Gelatinase activity was determined by using Todd-Hewitt and gelatin agar. RESULTS: In aerobic conditions, ECM was expressed in all strains. In the presence of sub-MIC/NaOCl, of the 10 strong biofilm producers, 5 increased their ECM production, and 4 showed increased biofilm growth. Two strains had less ECM production and showed decreased biofilm growth. One isolate demonstrated no observable changes. Most non-biofilm producers demonstrated no observable differences in ECM production, although 1 strain increased biofilm growth. ECM production in anaerobic conditions was highly variable. The esp gene (n = 15) and gelatinase activity (n = 7) were evident among the isolates. CONCLUSIONS: Clonal diversity among strains of E. faecalis suggests that some strong biofilm producers can upregulate ECM production and increase biofilm growth in response to sub-MIC/NaOCl.
Assuntos
Biofilmes/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Hipoclorito de Sódio/farmacologia , Proteínas de Bactérias/genética , Biofilmes/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Enterococcus faecalis/genética , Enterococcus faecalis/metabolismo , Gelatinases/metabolismo , Proteínas de Membrana/genética , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Reação em Cadeia da PolimeraseRESUMO
OBJECTIVE: The associations of discontinuation of the study medication on major outcomes were assessed in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Trial. METHODS: ADVANCE was a factorial randomized controlled trial of blood pressure lowering (a fixed combination of perindopril and indapamide vs. placebo) and intensive glucose control (vs. standard glucose control) in patients with type 2 diabetes. Patients who permanently discontinued the randomized blood pressure-lowering medication during the study period (nâ=â1557) were compared with others (nâ=â9583). Cox's proportional hazards models were used to estimate the effects of the discontinuation on the risks of macrovascular events, microvascular events together and separately and all-cause mortality, using discontinuation as a time-dependent covariate. RESULTS: In multivariable analyses, discontinuation was associated with increased risks of combined macro and microvascular events (hazard ratio 2.24, 95% CI 1.96-2.57), macrovascular events (3.23, 2.75-3.79), microvascular events (1.38, 1.11-1.71), and all-cause mortality (7.99, 6.92-9.21) compared to continuing administration of randomized medications during the trial period, which were highest in the first year after discontinuation. These associations were similar in active and placebo groups, except in the first year after discontinuation during which event rates were lower in the active group than in the placebo group (Pâ≤â0.01). CONCLUSION: Discontinuation of study medication is a potent risk marker for identifying high-risk patients. Thus it is important that clinicians seek to identify such patients early after discontinuation of treatment. Although some short-term residual effects of previous active treatment can be expected, patients who discontinue require further urgent investigation and management.
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Anti-Hipertensivos , Diabetes Mellitus Tipo 2 , Hipertensão , Adesão à Medicação/estatística & dados numéricos , Idoso , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , RiscoRESUMO
Businesses may be missing opportunities to account for ecosystem services in their decisions, because they do not have methods to quantify and value ecosystem services. We developed a method to quantify and value coastal protection and other ecosystem services in the context of a cost-benefit analysis of hurricane risk mitigation options for a business. We first analyze linked biophysical and economic models to examine the potential protection provided by marshes. We then applied this method to The Dow Chemical Company's Freeport, Texas facility to evaluate natural (marshes), built (levee), and hybrid (marshes and a levee designed for marshes) defenses against a 100-y hurricane. Model analysis shows that future sea-level rise decreases marsh area, increases flood heights, and increases the required levee height (12%) and cost (8%). In this context, marshes do not provide sufficient protection to the facility, located 12 km inland, to warrant a change in levee design for a 100-y hurricane. Marshes do provide some protection near shore and under smaller storm conditions, which may help maintain the coastline and levee performance in the face of sea-level rise. In sum, the net present value to the business of built defenses ($217 million [2010 US$]) is greater than natural defenses ($15 million [2010 US$]) and similar to the hybrid defense scenario ($229 million [2010 US$]). Examination of a sample of public benefits from the marshes shows they provide at least $117 million (2010 US$) in coastal protection, recreational value, and C sequestration to the public, while supporting 12 fisheries and more than 300 wildlife species. This study provides information on where natural defenses may be effective and a replicable approach that businesses can use to incorporate private, as well as public, ecosystem service values into hurricane risk management at other sites.
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Conservação dos Recursos Naturais/economia , Tempestades Ciclônicas , Ecossistema , Análise Custo-Benefício , Modelos Teóricos , Risco , Áreas AlagadasRESUMO
Enterococcus faecalis is often involved in the aetiology of apical periodontitis after endodontic treatment. This project aimed to establish, on dentine in vitro, a multi-species biofilm containing E. faecalis, and to determine if the organism had an increased resistance to sodium hypochlorite compared with an axenic biofilm. Biofilms were established on dentine discs in flow cells with either E. faecalis alone (axenic) or together with Fusobacterium nucleatum and Streptococcus sanguinis. Following treatment with either 0.9% sodium hypochlorite or saline, the viability of E. faecalis was determined by serial plating and qualitative analysis was performed by scanning electron microscopy and confocal laser scanning microscopy. Viable counts indicated that 0.9% NaOCl is highly effective against E. faecalis grown alone and as part of a multi-species biofilm (P = 0.0005 and P = 0.001, respectively). No significant difference in its survival in the two biofilm types was found (P = 0.8276).
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Biofilmes/efeitos dos fármacos , Dentina/microbiologia , Enterococcus faecalis/efeitos dos fármacos , Irrigantes do Canal Radicular/farmacologia , Hipoclorito de Sódio/farmacologia , Técnicas Bacteriológicas , Fusobacterium nucleatum/efeitos dos fármacos , Humanos , Teste de Materiais , Consórcios Microbianos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Microscopia Confocal , Microscopia Eletrônica de Varredura , Irrigantes do Canal Radicular/administração & dosagem , Hipoclorito de Sódio/administração & dosagem , Streptococcus sanguis/efeitos dos fármacosRESUMO
When a duplicate gene has no apparent loss-of-function phenotype, it is commonly considered that the phenotype has been masked as a result of functional redundancy with the remaining paralog. This is supported by indirect evidence showing that multi-copy genes show loss-of-function phenotypes less often than single-copy genes and by direct tests of phenotype masking using select gene sets. Here we take a systematic genome-wide RNA interference approach to assess phenotype masking in paralog pairs in the Caenorhabditis elegans genome. Remarkably, in contrast to expectations, we find that phenotype masking makes only a minor contribution to the low knockdown phenotype rate for duplicate genes. Instead, we find that non-essential genes are highly over-represented among duplicates, leading to a low observed loss-of-function phenotype rate. We further find that duplicate pairs derived from essential and non-essential genes have contrasting evolutionary dynamics: whereas non-essential genes are both more often successfully duplicated (fixed) and lost, essential genes are less often duplicated but upon successful duplication are maintained over longer periods. We expect the fundamental evolutionary duplication dynamics presented here to be broadly applicable.
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Caenorhabditis elegans/genética , Evolução Molecular , Genes Duplicados , Família Multigênica/genética , Interferência de RNA , Animais , Técnicas de Silenciamento de Genes , Genes Essenciais , Genoma , Modelos Genéticos , Mutação , FenótipoRESUMO
OBJECTIVE: Alcohol-related admissions are increasing. A significant number of these admissions are attributable to a small number of complex patients with other comorbidities who do not engage well with mainstream services. Assertive outreach teams have been used in the field of psychiatry to engage patients who are poorly compliant. This study examines whether an alcohol assertive outreach team (AAOT) can engage with this group and reduce hospital admissions. DESIGN: The AAOT is a multidisciplinary team with medical, psychiatric, substance misuse, psychology, nursing and social work specialists. The team worked with patients with the highest number of alcohol-related admissions and case managed in a community setting for 6â months. The admission and emergency department attendances of the cohort were compared for the 3-month period before and after the intervention. Christo inventory for substance misuse services (CISS) scores were determined pre and post the intervention period. RESULTS: 54 patients were case managed. The total number of admissions in 3â months fell from 151 prior to the intervention period to 50 following the intervention. Emergency department attendances also fell from 360 in 3â months to 146 following the intervention period. CISS scores fell from 11 preintervention to eight postintervention. CONCLUSIONS: An AAOT model appears to reduce hospital admissions and emergency department attendances in a complex group of patients that display high alcohol-related admissions.
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Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution.
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Evolução Molecular , Especiação Genética , Genoma/genética , Gorilla gorilla/genética , Animais , Feminino , Regulação da Expressão Gênica , Variação Genética/genética , Genômica , Humanos , Macaca mulatta/genética , Dados de Sequência Molecular , Pan troglodytes/genética , Filogenia , Pongo/genética , Proteínas/genética , Alinhamento de Sequência , Especificidade da Espécie , Transcrição GênicaRESUMO
Fusobacterium nucleatum is a Gram-negative anaerobic organism that plays a central role in the development of periodontal diseases. The progression of periodontitis is associated with a rise in pH of the gingival sulcus which promotes the growth and expression of virulence factors by periodontopathic bacteria. We have previously reported that the expression of specific cytoplasmic proteins is altered by a shift in growth pH. In the present study we have compared cell envelope protein expression of F. nucleatum during chemostat growth at pH 7.2 and 7.8. From a total of 176 proteins resolved from the cell envelope, 15 were found to have altered expression in response to an increase in growth pH and were identified by MS. Upregulated proteins included an outer membrane porin which has been identified as playing a role in virulence, a periplasmic chaperone which assists in the folding of outer membrane proteins, and a transporter thought to be involved with iron uptake. Proteins downregulated at pH 7.8 were consistent with our previous findings that the bacterium reduces its catabolism of energy-yielding substrates in favour of energy-storage pathways. Among the downregulated proteins, two transporters which are involved in the uptake of C4 dicarboxylates and phosphate were identified. A putative protease and an enzyme associated with the metabolism of glutamate were also identified. A high proportion of the cell envelope proteins suggested by these data to play a role in the organism's response to alkaline growth pH may have arisen by lateral gene transfer. This would support the hypothesis that genes that provide an ability to adapt to the changing conditions of the oral environment may be readily shared between oral bacteria.
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Proteínas da Membrana Bacteriana Externa/análise , Proteínas da Membrana Bacteriana Externa/metabolismo , Fusobacterium nucleatum/crescimento & desenvolvimento , Fusobacterium nucleatum/metabolismo , Regulação Bacteriana da Expressão Gênica , Gengiva/microbiologia , Proteoma/análise , Proteínas da Membrana Bacteriana Externa/genética , Fusobacterium nucleatum/genética , Concentração de Íons de Hidrogênio , Periplasma/genética , Periplasma/metabolismo , VirulênciaRESUMO
WormBase (http://www.wormbase.org) is a central data repository for nematode biology. Initially created as a service to the Caenorhabditis elegans research field, WormBase has evolved into a powerful research tool in its own right. In the past 2 years, we expanded WormBase to include the complete genomic sequence, gene predictions and orthology assignments from a range of related nematodes. This comparative data enrich the C. elegans data with improved gene predictions and a better understanding of gene function. In turn, they bring the wealth of experimental knowledge of C. elegans to other systems of medical and agricultural importance. Here, we describe new species and data types now available at WormBase. In addition, we detail enhancements to our curatorial pipeline and website infrastructure to accommodate new genomes and an extensive user base.
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Caenorhabditis elegans/genética , Caenorhabditis/genética , Biologia Computacional/métodos , Bases de Dados Genéticas , Bases de Dados de Ácidos Nucleicos , Alelos , Animais , Biologia Computacional/tendências , Bases de Dados de Proteínas , Armazenamento e Recuperação da Informação/métodos , Internet , Fenótipo , Estrutura Terciária de Proteína , Software , Fatores de TranscriçãoRESUMO
Thoracic aortic aneurysms (TAA) have remained a formidable operative challenge. Open surgical techniques have been associated with high rates of morbidity and mortality. Thoracic endovascular aneurysm repair (TEVAR) has produced results equal to or better than the traditional open surgical approach. This report presents a patient with a complex thoracic aortic aneurysm involving the ascending, transverse, and proximal descending thoracic aorta. This patient was successfully managed by the creation of Landing Zone-Zero, arch vessel debranching, and endografting the entire aortic arch without the need for hypothermic circulatory arrest or cerebral perfusion strategies. Computer tomographic images demonstrate the repair to be durable at 18 months.
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Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular/métodos , Prótese Vascular , Idoso , Humanos , MasculinoRESUMO
Type B aortic dissections have remained a difficult management problem. Open surgical techniques have had a very high perioperative mortality, and medical management has not produced satisfactory long-term results. Endovascular grafting techniques may provide a favorable alternative therapy. However, there are currently no endovascular stents approved by the United States Food and Drug Administration for treating Type B aortic dissections. Also, there is very little data from United States centers on the long-term efficacy of endovascular stents used "off-label" to treat aortic dissections. This report discusses the care of a patient with a Type B aortic dissection successfully treated by an endograft in a community hospital. In addition, serial follow-up computerized tomography demonstrates the durability of this repair at three years.
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Angioplastia , Aneurisma Aórtico/cirurgia , Dissecção Aórtica/cirurgia , Implante de Prótese Vascular , Stents , Idoso , Dissecção Aórtica/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Feminino , Humanos , Tomografia Computadorizada por Raios XRESUMO
WormBase (www.wormbase.org) is the major publicly available database of information about Caenorhabditis elegans, an important system for basic biological and biomedical research. Derived from the initial ACeDB database of C. elegans genetic and sequence information, WormBase now includes the genomic, anatomical and functional information about C. elegans, other Caenorhabditis species and other nematodes. As such, it is a crucial resource not only for C. elegans biologists but the larger biomedical and bioinformatics communities. Coverage of core areas of C. elegans biology will allow the biomedical community to make full use of the results of intensive molecular genetic analysis and functional genomic studies of this organism. Improved search and display tools, wider cross-species comparisons and extended ontologies are some of the features that will help scientists extend their research and take advantage of other nematode species genome sequences.