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1.
Food Chem ; 439: 138128, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38071843

RESUMO

We determined δ11B values of green and roasted coffee beans from 20 locations worldwide and conducted laboratory experiments with the aim to investigate boron isotope fractionation during roasting. Authentic single origin roasted coffees were found to be isotopically lighter than their green bean counterparts, with an average difference of 1.5‰. This isotope fractionation can be explained as arising from partial dissociation of boric acid in capillary water of green beans, where 11B isotopes are preferentially partitioned into molecules of undissociated boric acid and are then volatised during roasting. However, boron isotope fractionation induced by roasting was significantly smaller than between-origin variations in δ11B values of green coffee beans that had the range of ∼54‰. This implies that δ11B isotopic composition of roasted coffee retains the geographical origin information within δ11B values of green beans when regional differences in boron isotopic composition of coffee are considered.


Assuntos
Coffea , Boro , Isótopos , Sementes , Temperatura Alta
2.
J Biomech ; 152: 111588, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37094384

RESUMO

While cyclic adenosine monophosphate (cAMP) is typically considered an intracellular signal, it has been shown to spread between adjacent cells through connexin-based gap junction channels, promoting gap junctional intercellular communication (GJIC). Gap junction-mediated signaling is critical for the coordinated function of many tissues, and have been linked with cardiovascular disease, neurogenerative disease, and cancers. In particular, it plays a complex role in tumor suppression or promotion. This work introduces a two-dimensional finite element model that can describe intercellular cAMP signaling in the presence of gap junctions on membrane interfaces. The model was utilized to simulate cAMP transfer through one and two gap junction channels on the interface of a cluster of two pulmonary microvascular endothelial cells. The simulation results were found to generally agree with what has been observed in the literature in terms of GJIC. The research outcomes suggest that the proposed model can be employed to evaluate the permeability properties of a gap junction channel if its cAMP volumetric flow rate can be experimentally measured.


Assuntos
Células Endoteliais , Junções Comunicantes , Análise de Elementos Finitos , AMP Cíclico , Conexinas , Comunicação Celular
3.
Mol Neurobiol ; 59(9): 5366-5378, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35699875

RESUMO

Monogenic forms of cerebral small vessel disease (CSVD) can be caused by both variants in nuclear DNA and mitochondrial DNA (mtDNA). Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is known to have a phenotype similar to Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL), and can be caused by variants in the mitochondrial genome and in several nuclear-encoded mitochondrial protein (NEMP) genes. The aim of this study was to screen for variants in the mitochondrial genome and NEMP genes in a NOTCH3-negative CADASIL cohort, to identify a potential link between mitochondrial dysfunction and CSVD pathology. Whole exome sequencing was performed for 50 patients with CADASIL-like symptomology on the Ion Torrent system. Mitochondrial sequencing was performed using an in-house designed protocol with sequencing run on the Ion GeneStudio S5 Plus (S5 +). NEMP genes and mitochondrial sequencing data were examined for rare (MAF < 0.001), non-synonymous variants that were predicted to have a deleterious effect on the protein. We identified 29 candidate NEMP variants that had links to either MELAS-, encephalopathy-, or Alzheimer's disease-related phenotypes. Based on these changes, variants affecting POLG, MTO1, LONP1, NDUFAF6, NDUFB3, and TCIRG1 were thought to play a potential role in CSVD pathology in this cohort. Overall, the exploration of the mitochondrial genome identified a potential role for mitochondrial related proteins and mtDNA variants contributing to CSVD pathologies.


Assuntos
CADASIL , Doenças de Pequenos Vasos Cerebrais , Leucoencefalopatias , Síndrome MELAS , Acidente Vascular Cerebral , ATPases Vacuolares Próton-Translocadoras , Proteases Dependentes de ATP/genética , Doenças de Pequenos Vasos Cerebrais/genética , DNA Mitocondrial/genética , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Mutação/genética
5.
Int J Immunogenet ; 49(1): 22-29, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34555264

RESUMO

All UK H&I laboratories and transplant units operate under a single national kidney offering policy, but there have been variations in approach regarding when to undertake the pre-transplant crossmatch test. In order to minimize cold ischaemia times for deceased donor kidney transplantation we sought to find ways to be able to report a crossmatch result as early as possible in the donation process. A panel of experts in transplant surgery, nephrology, specialist nursing in organ donation and H&I (all relevant UK laboratories represented) assessed evidence and opinion concerning five factors that relate to the effectiveness of the crossmatch process, as follows: when the result should be ready for reporting; what level of donor HLA typing is needed; crossmatch sample type and availability; fairness and equity; risks and patient safety. Guidelines aimed at improving practice based on these issues are presented, and we expect that following these will allow H&I laboratories to contribute to reducing CIT in deceased donor kidney transplantation.


Assuntos
Transplante de Rim , Tipagem e Reações Cruzadas Sanguíneas , Isquemia Fria , Antígenos HLA , Teste de Histocompatibilidade , Humanos , Rim
6.
Mol Genet Genomics ; 295(2): 515-523, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31897802

RESUMO

Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study; n = 58 and Hawaiian Ironman Triathlon 2008; n = 115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO2 max) in recreationally active individuals and a triathlon time-to-completion (Hawaiian Ironman Triathlon cohort only). A nominal significance threshold of α < 0.05 was used to identify 17 variants (11 in the Gene SMART population and six in the Hawaiian Ironman Triathlon cohort) which were significantly associated with performance gains in highly trained individuals. The variant rs1474347 located in Interleukin 6 (IL6) was the only variant with a false discovery rate < 0.05 and was found to be associated with gains in VO2 max (additional 4.016 mL/(kg min) for each G allele inherited) after training in the Gene SMART cohort. In summary, this study found further evidence to suggest that genetic variance can influence training response in a moderately trained cohort and provides an example of the potential application of genomic research in the assessment of exercise trait response.


Assuntos
Adaptação Fisiológica/genética , Desempenho Atlético/fisiologia , Exercício Físico/fisiologia , Resistência Física/genética , Adulto , Genoma Humano/genética , Genótipo , Humanos , Ácido Láctico/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética
7.
Hum Genomics ; 14(1): 2, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915071

RESUMO

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Our laboratory has been undertaking genetic diagnostic testing for CADASIL since 1997. Work originally utilised Sanger sequencing methods targeting specific NOTCH3 exons. More recently, next-generation sequencing (NGS)-based technologies such as a targeted gene panel and whole exome sequencing (WES) have been used for improved genetic diagnostic testing. In this study, data from 680 patient samples was analysed for 764 tests utilising 3 different sequencing technologies. Sanger sequencing was performed for 407 tests, a targeted NGS gene panel which includes NOTCH3 exonic regions accounted for 354 tests, and WES with targeted analysis was performed for 3 tests. In total, 14.7% of patient samples (n = 100/680) were determined to have a mutation. Testing efficacy varied by method, with 10.8% (n = 44/407) of tests using Sanger sequencing able to identify mutations, with 15.8% (n = 56/354) of tests performed using the NGS custom panel successfully identifying mutations and a likely non-NOTCH3 pathogenic variant (n = 1/3) identified through WES. Further analysis was then performed through stratification of the number of mutations detected at our facility based on the number of exons, level of pathogenicity and the classification of mutations as known or novel. A systematic review of NOTCH3 mutation testing data from 1997 to 2017 determined the diagnostic rate of pathogenic findings and found the NGS-customised panel increases our ability to identify disease-causing mutations in NOTCH3.


Assuntos
CADASIL/diagnóstico , Sequenciamento do Exoma/métodos , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Técnicas de Diagnóstico Molecular/métodos , Mutação , Receptor Notch3/genética , CADASIL/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Rev Sci Tech ; 38(2): 437-457, 2019 Sep.
Artigo em Inglês, Francês, Espanhol | MEDLINE | ID: mdl-31866683

RESUMO

The growth of aquaculture over the past 50 years has been accompanied by the emergence of aquatic animal diseases, many of which have spread to become pandemic in countries or continents. An analysis of 400 emerging disease events in aquatic animals that were logged by the Centre for Environment, Fisheries and Aquaculture Science between 2002 and 2017 revealed that more than half were caused by viruses. However, in molluscs, most events were parasitic. Categorising these events indicated that the key processes underpinning emergence were the movement of live animals and host switching. Profiles of key pathogens further illustrate the importance of wild aquatic animals as the source of new infections in farmed animals. It is also clear that the spread of new diseases through the largescale movement of aquatic animals for farming, for food and for the ornamental trade has allowed many to achieve pandemic status. Many viral pathogens of fish (e.g. infectious salmon anaemia, viral haemorrhagic septicaemia) and shrimp (e.g. white spot syndrome virus) affect a large proportion of the global production of key susceptible species. Wild aquatic animal populations have also been severely affected by pandemic diseases, best exemplified by Batrachochytrium dendrobatidis, a fungal infection of amphibians, whose emergence and spread were driven by the movement of animals for the ornamental trade. Batrachochytrium dendrobatidis is now widespread in the tropics and subtropics and has caused local extinctions of susceptible amphibian hosts. Given the rising demand for seafood, aquacultural production will continue to grow and diseases will continue to emerge. Some will inevitably achieve pandemic status, having significant impacts on production and trade, unless there are considerable changes in global monitoring and the response to aquatic animal diseases.


Au cours des 50 dernières années, la forte croissance qu'a connue l'aquaculture est allée de pair avec l'émergence de nombreuses maladies affectant les animaux aquatiques, dont certaines se sont propagées jusqu'à devenir pandémiques à l'échelle nationale ou continentale. L'analyse de 400 événements sanitaires survenus chez des animaux aquatiques et consignés entre 2002 et 2017 par le Centre for Environment, Fisheries and Aquaculture Science a déterminé l'origine virale de plus de la moitié d'entre eux. Toutefois, chez les mollusques la plupart des événements analysés étaient d'ordre parasitaire. Le classement des événements par catégories a montré que les principaux processus sous-jacents à cette émergence étaient liés aux transferts d'animaux vivants et à la colonisation de nouveaux hôtes par les agents pathogènes. Les profils des agents pathogènes majeurs illustrent le rôle des espèces aquatiques sauvages en tant que sources d'infections nouvelles chez les animaux aquatiques d'élevage. Il apparaît clairement que la propagation de nouvelles maladies à la faveur des transferts massifs d'animaux aquatiques à des fins d'élevage, de production alimentaire ou de commerce d'espèces d'ornement a conféré un statut pandémique à nombre de ces maladies. De nombreux virus affectant les poissons (par ex., le virus de l'anémie infectieuse du saumon, le virus de la septicémie hémorragique virale) et les crevettes (par ex., le virus du syndrome des points blancs) ont une incidence majeure sur de vastes segments de la production mondiale d'espèces sensibles cruciales. Les populations sauvages d'animaux aquatiques sont également touchées par des maladies pandémiques, dont l'exemple type est l'infection à Batrachochytrium dendrobatidis, une affection fongique des amphibiens dont l'émergence et la propagation sont le fruit des transferts d'animaux aquatiques destinés au commerce aquariophile. Batrachochytrium dendrobatidis est désormais largement présent dans les eaux tropicales et subtropicales où il est responsable d'extinctions locales parmi les espèces d'amphibiens sensibles. La croissance de la production aquacole se poursuivra afin de répondre à une demande toujours plus forte en poissons et fruits de mer, entraînant l'émergence continue de nouvelles maladies. Si des changements déterminants ne sont pas introduits dans la surveillance exercée au niveau mondial sur les maladies des animaux aquatiques et dans la réponse qui leur est apportée, certaines de ces maladies vont inéluctablement acquérir une dimension pandémique avec des conséquences importantes sur la production et le commerce.


El crecimiento de la acuicultura en los últimos 50 años se ha acompañado de la aparición de enfermedades de los animales acuáticos, que en muchos casos se han propagado hasta llegar a ser pandémicas en ciertos países o continentes. Tras analizar 400 episodios de enfermedades emergentes de animales acuáticos registrados entre 2002 y 2017 por el Centre for the Environment, Fisheries and Aquaculture Science, los autores constataron que más de la mitad de esos episodios fueron causados por virus, si bien en el caso de los moluscos la mayoría de ellos eran parasitarios. De la clasificación de esos episodios se desprende que los procesos básicos que subyacen a su aparición son los desplazamientos de animales vivos y los cambios de anfitrión. El perfil de los principales patógenos revela además la importancia que revisten los animales acuáticos silvestres como fuente de nuevas infecciones de los animales de acuicultura. También está claro que la propagación de nuevas enfermedades por el movimiento a gran escala de animales acuáticos con fines de producción acuícola, consumo alimentario o comercio de animales ornamentales ha propiciado que muchas de ellas adquieran carácter pandémico. Muchos patógenos víricos de los peces (como el virus de la anemia infecciosa del salmón o el de la septicemia hemorrágica viral) y camarones (como el virus del síndrome de las manchas blancas) afectan a una gran parte de la producción mundial de las principales especies sensibles. Las poblaciones silvestres de animales acuáticos también se han visto afectadas de gravedad por enfermedades pandémicas, como ejemplifica perfectamente la infección por Batrachochytrium dendrobatidis, micosis de los anfibios cuya aparición y propagación fue alimentada por el comercio y el consiguiente movimiento de animales con fines ornamentales. Este hongo, muy extendido ahora en las regiones tropicales y subtropicales, ha causado la extinción en ciertas áreas de especies anfibias sensibles. Habida cuenta de la creciente demanda de alimentos de origen marino, la producción acuícola seguirá creciendo y también seguirán surgiendo enfermedades. Inevitablemente, algunas de ellas se harán pandémicas y resultarán muy dañinas para la producción y el comercio, a menos que haya cambios de calado en los sistemas mundiales de vigilancia y respuesta ante las enfermedades de los animales acuáticos.


Assuntos
Anfíbios/microbiologia , Doenças dos Peixes/epidemiologia , Pandemias/veterinária , Frutos do Mar , Animais , Aquicultura , Quitridiomicetos , Micoses/microbiologia , Micoses/veterinária , Frutos do Mar/microbiologia , Frutos do Mar/parasitologia , Frutos do Mar/virologia
9.
J Geophys Res Space Phys ; 124(4): 3100-3109, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32874820

RESUMO

Previous observations have shown that electron density and temperature in the dayside ionosphere of Mars vary between strongly and weakly magnetized regions of the planet. Here we use data from the Neutral Gas and Ion Mass Spectrometer (NGIMS) on the Mars Atmosphere and Volatile EvolutioN (MAVEN) spacecraft to examine whether dayside ion densities and ionospheric composition also vary. We find that O+, O 2 + , and CO 2 + densities above ~200 km are greater in strongly magnetized regions than in weakly magnetized regions. Fractional abundances of ion species are also affected. The O + / O 2 + ratio at 300-km altitude increases from ~0.5 in strongly magnetized regions to ~0.8 in weakly magnetized regions. Consequently, the plasma reservoir available for escape is fundamentally different between strongly magnetized and weakly magnetized regions.

10.
J Dairy Sci ; 101(9): 8159-8168, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29908805

RESUMO

The objective of this field trial was to evaluate the effect of a vaccine protocol using a commercially available trivalent vaccine designed for intranasal use. Experimental challenge studies have demonstrated varying efficacies of vaccines administered via the intranasal route. A total of 468 calves from 3 herds were enrolled and randomized into 3 treatment groups (positive control, PC, n = 211; intranasal vaccine, IN, n = 215; negative control, NC, n = 42) and followed for 8 to 12 wk. The PC consisted of one dose of commercially available multivalent injectable vaccine against bovine respiratory syncytial virus, infectious bovine rhinotracheitis, parainfluenza 3, and bovine viral diarrhea administered subcutaneously at 6 wk of age. The IN was administered at enrollment and 6 wk of age, and contained antigen against bovine respiratory syncytial virus, infectious bovine rhinotracheitis, and parainfluenza 3. The NC was sterile saline administered intranasally and subcutaneously at enrollment and 6 wk of age. Clinical illness was assessed using systematic respiratory scoring, and thoracic ultrasonography was used to identify the lung consolidation associated with pneumonia. Rib fractures were identified in 6% of calves, and an association was observed between rib fractures and calving ease. Overall, 54% of the calves had at least one episode of an abnormal respiratory score (ILL). Vaccination protocol did not affect the occurrence of ILL. Similarly, 54% of the calves had at least one episode of lung consolidation ≥3 cm (CON). Vaccine protocol affected the odds of CON. The odds of CON in PC were 1.63 (95% confidence interval: 1.04-2.56) times the odds of CON in IN, and 0.38 (95% confidence interval: 0.16-0.93) times the odds of CON in NC. The odds of CON in IN were 0.23 (95% confidence interval: 0.09-0.59) times the odds of CON in NC. The outcomes ILL and CON were associated; however, the measure of agreement was only fair (kappa = 0.38). Multivariable linear regression revealed an interaction between vaccine protocol and herd on average daily gain (ADG); therefore, these data were stratified. In herd 1, IN (0.53 ± 0.03 kg/d) decreased ADG compared with PC (0.63 ± 0.03 kg/d). In herd 2, IN increased ADG (0.41 ± 0.03 kg/d) compared with PC (0.38 ± 0.03 kg/d). In contrast, none of the protocols affected ADG at herd 3. In conclusion, this commercially available trivalent IN vaccine protocol did not alter the incidence of ILL, reduced the risk of lung lesions associated with pneumonia, and improved the ADG of the calves in one of the commercial study herds.


Assuntos
Doenças dos Bovinos/prevenção & controle , Rinotraqueíte Infecciosa Bovina/prevenção & controle , Infecções por Vírus Respiratório Sincicial/veterinária , Vacinas Virais/administração & dosagem , Administração Intranasal/métodos , Administração Intranasal/veterinária , Animais , Anticorpos Antivirais , Bovinos , Herpesvirus Bovino 1 , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Bovino
11.
Osteoporos Int ; 29(2): 451-457, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29063214

RESUMO

Geisinger Health System (GHS) high-risk osteoporosis clinic (HiROC), which treats patients with low-trauma, fragility fractures, reports their 2013-2015 performance measures in secondary fracture prevention. This fracture liaison service (FLS) pathway treats 75% of high-risk, drug eligible patients, compared to 13.8% in GHS primary care. This performance points to the need for more FLS programs throughout the world. INTRODUCTION: The purpose of this study is to analyze and report ongoing performance measures in outpatient and inpatient high-risk osteoporosis clinic (HiROC) program designed for patients with low-trauma, fragility fractures. METHODS: Retrospective chart review of outpatient HiROC (511 patients) and inpatient HiROC (1279 patients) performance from 2013 to 2015 is reported within Geisinger Health System (GHS). RESULTS: Similar to a prior report, we document that Geisinger's branded outpatient and inpatient HiROC pathways continue to function as an all-fracture FLS. Importantly, this analysis emphasizes the importance of FLS care that HiROC's treatment rate of 75% was markedly superior to GHS-PCP care of 13.8%. However, a large percentage of patients (37.8%) were lost to follow-up care. This led to the identification of multiple care gaps/barriers to ideal best practice. CONCLUSIONS: FLS programs use case finding strategies and address secondary fracture prevention. GHS HiROC's performance and initiation of drug therapy in this fracture patient population contrasts with GHS-PCP care's much lower rate of treatment, documenting the need for ongoing FLS care. Importantly, the results of this analysis have prompted the beginnings of GHS programmatic changes, designed to narrow the reported care gaps in this mature FLS.


Assuntos
Instituições de Assistência Ambulatorial/normas , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Prevenção Secundária/normas , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial/organização & administração , Conservadores da Densidade Óssea/uso terapêutico , Procedimentos Clínicos/organização & administração , Procedimentos Clínicos/normas , Feminino , Pesquisa sobre Serviços de Saúde/métodos , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico , Pennsylvania , Melhoria de Qualidade/organização & administração , Estudos Retrospectivos , Medição de Risco/métodos , Prevenção Secundária/métodos , Prevenção Secundária/organização & administração , Adulto Jovem
12.
Am J Med Genet A ; 173(3): 611-617, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28139025

RESUMO

Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A>G) and clinical features of the rare FG syndrome-4 (FGS4). We provide further characterization of genotype-phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. There is considerable variability in clinical phenotype among patients with a CASK mutation, even among variants predicted to have similar functionality. Our patient presented with developmental delay, nystagmus, and severe gastrointestinal and gastroesophageal complications. From a cognitive and neuropsychological perspective, language skills and IQ are within normal range, although visual-motor, motor development, behavior, and working memory were impaired. The c.2521-2A>G splice mutation leads to skipping of exon 26 and a 9 base-pair deletion associated with a cryptic splice site, leading to a 28-AA and a 3-AA in-frame deletion, respectively (p.Ala841_Lys843del and p.Ala841_Glu868del). The predominant mutant transcripts contain an aberrant guanylate kinase domain and thus are predicted to degrade CASK's ability to interact with important neuronal and ocular development proteins, including FRMD7. Upregulation of CASK as well as dysregulation among a number of interactors is also evident by RNA-seq. This is the second CASK mutation known to us as cause of FGS4. © 2017 Wiley Periodicals, Inc.


Assuntos
Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/genética , Anus Imperfurado/diagnóstico , Anus Imperfurado/genética , Constipação Intestinal/diagnóstico , Constipação Intestinal/genética , Guanilato Quinases/genética , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Hipotonia Muscular/congênito , Mutação , Nistagmo Congênito/diagnóstico , Nistagmo Congênito/genética , Sítios de Splice de RNA , Adolescente , Criança , Pré-Escolar , Fácies , Feminino , Expressão Gênica , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Masculino , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Testes Neuropsicológicos , Fenótipo , Polimorfismo de Nucleotídeo Único
13.
Respir Med Case Rep ; 20: 137-140, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28217439

RESUMO

Specific oncogenes with driver mutations, such as the Epidermal Growth Factor Receptor (EGFR 1) gene can lead to non-small-cell lung cancer formation. Identification of these oncogenes, their driver mutations and downstream effects allow the targeting of these pathways by drugs. Such personalised therapy has become an important strategy in combating lung cancer and highlights the need to test for these mutations. Tyrosine Kinase Inhibitors (TKIs) against EGFR, such as Erlotinib, are able to halt these tumour promoting properties in non-small-cell lung cancers. Third generation EGFR TKIs, such as Osimertinib, are focussing on resulting acquired TKI resistance. Here we report the clinical course of a patient with metastatic non-small-cell lung cancer who has undergone EGFR targeted therapy and been further challenged by TKI acquired resistance. Her extended survival and maintained quality of life are a consequence of these modern, genotype-targeted, personalised metastatic non-small-cell lung cancer therapies.

14.
Heredity (Edinb) ; 116(5): 466-76, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26860199

RESUMO

Genes of the major histocompatibility complex (MHC) encode receptor molecules that are responsible for recognition of intracellular and extracellular pathogens (class I and class II genes, respectively) in vertebrates. Given the different roles of class I and II MHC genes, one might expect the strength of selection to differ between these two classes. Different selective pressures may also promote different rates of gene conversion at each class. Despite these predictions, surprisingly few studies have looked at differences between class I and II genes in terms of both selection and gene conversion. Here, we investigated the molecular evolution of MHC class I and II genes in five closely related species of prairie grouse (Centrocercus and Tympanuchus) that possess one class I and two class II loci. We found striking differences in the strength of balancing selection acting on MHC class I versus class II genes. More than half of the putative antigen-binding sites (ABS) of class II were under positive or episodic diversifying selection, compared with only 10% at class I. We also found that gene conversion had a stronger role in shaping the evolution of MHC class II than class I. Overall, the combination of strong positive (balancing) selection and frequent gene conversion has maintained higher diversity of MHC class II than class I in prairie grouse. This is one of the first studies clearly demonstrating that macroevolutionary mechanisms can act differently on genes involved in the immune response against intracellular and extracellular pathogens.


Assuntos
Evolução Molecular , Galliformes/genética , Conversão Gênica , Genes MHC da Classe II , Genes MHC Classe I , Seleção Genética , Alelos , Sequência de Aminoácidos , Animais , Galliformes/classificação , Variação Genética , Dados de Sequência Molecular , Filogenia , Análise de Sequência de DNA
15.
Science ; 350(6261): aad0210, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26542576

RESUMO

Coupling between the lower and upper atmosphere, combined with loss of gas from the upper atmosphere to space, likely contributed to the thin, cold, dry atmosphere of modern Mars. To help understand ongoing ion loss to space, the Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft made comprehensive measurements of the Mars upper atmosphere, ionosphere, and interactions with the Sun and solar wind during an interplanetary coronal mass ejection impact in March 2015. Responses include changes in the bow shock and magnetosheath, formation of widespread diffuse aurora, and enhancement of pick-up ions. Observations and models both show an enhancement in escape rate of ions to space during the event. Ion loss during solar events early in Mars history may have been a major contributor to the long-term evolution of the Mars atmosphere.

16.
Science ; 350(6261): aad0459, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26542579

RESUMO

The Mars Atmosphere and Volatile Evolution (MAVEN) mission, during the second of its Deep Dip campaigns, made comprehensive measurements of martian thermosphere and ionosphere composition, structure, and variability at altitudes down to ~130 kilometers in the subsolar region. This altitude range contains the diffusively separated upper atmosphere just above the well-mixed atmosphere, the layer of peak extreme ultraviolet heating and primary reservoir for atmospheric escape. In situ measurements of the upper atmosphere reveal previously unmeasured populations of neutral and charged particles, the homopause altitude at approximately 130 kilometers, and an unexpected level of variability both on an orbit-to-orbit basis and within individual orbits. These observations help constrain volatile escape processes controlled by thermosphere and ionosphere structure and variability.

17.
Int J Immunogenet ; 42(5): 361-3, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26212036

RESUMO

Seven new HLA class I alleles have been identified in the New Zealand population in the process of routine HLA typing and they are described here. Unusual bead positivity in Luminex typing identified potential new alleles in a bone marrow registry donor (B*40:285) and two HIV patients prior to abacavir prescription (B*14:02:09, B*41:29). In addition, four new class I alleles were identified through class I sequencing-based typing (SBT) outside of exons 2 and 3. One mutation was identified in exon 4 (new allele C*12:125) and three have been found in exon 5, an exon rarely sequenced. Two stem cell transplant recipients (B*07:02:45, C*03:279) had novel mutations in exon 5 and one was found in exon 5 of a potentially matched unrelated donor from DKMS, previously thought to be B*40:02:01 (B*40:303).


Assuntos
Alelos , Antígenos de Histocompatibilidade Classe I/genética , Teste de Histocompatibilidade , Humanos , Dados de Sequência Molecular , Nova Zelândia
18.
Dis Aquat Organ ; 110(1-2): 101-11, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25060502

RESUMO

Bonamiasis, caused by Bonamia ostreae, was confirmed in native flat oysters Ostrea edulis L. in England in 1982. Hudson & Hill (1991; Aquaculture 93:279-285) documented investigations into the initial spread of the disease in wild and cultivated stocks of native oysters in the UK. They also described the controls that were initially applied to prevent the further spread of the pathogen. This paper reports on subsequent controls and associated monitoring applied in the UK and reports on the epidemiology of the disease in the 30 yr from 1982 to 2012. Bonamiasis remained confined to the zones in England as documented by Hudson & Hill (1991) until 2005, when it was confirmed in Lough Foyle, Northern Ireland. In 2006 it was found in 2 new areas, one in Wales and one in Scotland. Subsequent further spread to additional areas in all parts of the UK has resulted in 9 zones being currently designated as infected with the disease. In addition, a single oyster from one area has tested positive for the closely related B. exitiosa. In general, analysis of the results of the monitoring programme in England and Wales shows no clear trend in infection levels over time, although there has been an apparent decrease in the level of infection in some fishery areas. In an autumn sampling programme the highest levels of infection were detected in October.


Assuntos
Haplosporídios/fisiologia , Ostrea/parasitologia , Animais , Interações Hospedeiro-Parasita , Reino Unido
19.
J Evol Biol ; 27(5): 982-91, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24731149

RESUMO

Females often possess ornaments that appear smaller and duller than homologous traits in males. These ornaments may arise as nonfunctional by-products of sexual selection in males and cause negative viability or fecundity selection in females in proportion to the cost of their production and maintenance. Alternatively, female ornaments may function as signals of quality that are maintained by sexual or social selection. In a 4-year study of 83 female common yellowthroats (Geothlypis trichas) and their 222 young, we found strong viability and fecundity selection on the yellow bib, a carotenoid-based plumage ornament that is a target of sexual selection in males. Females with larger bibs were older, larger and more fecund than females with smaller bibs. However, bib size positively covaried with bib total brightness and carotenoid chroma, aspects of bib coloration that were under negative viability and fecundity selection. Females with more colourful bibs laid fewer eggs in their first clutch, were more likely to suffer total brood loss due to predation and were less likely to return to the study area. Selection against bib coloration limits the value of bib size as a quality indicator in females and may constrain the elaboration of bib attributes in males.


Assuntos
Plumas/metabolismo , Preferência de Acasalamento Animal/fisiologia , Passeriformes/fisiologia , Pigmentação/fisiologia , Caracteres Sexuais , Fatores Etários , Animais , Tamanho Corporal , Carotenoides/metabolismo , Tamanho da Ninhada , Feminino , Masculino , Seleção Genética
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