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Phosphorescent organic light emitting diodes (OLEDs) suffer from efficiency roll off, where device efficiency rapidly decays at higher luminance. One strategy to minimize this loss of efficiency at higher luminance is the use of non-uniform or graded guest:host blend ratios within the emissive layer. This work applies a multi-scale modeling framework to elucidate the mechanisms by which a non-uniform blend ratio can change the performance of an OLED. Mobility and exciton data are extracted from a kinetic Monte-Carlo model, which is then coupled to a drift diffusion model for fast sampling of the parameter space. The model is applied to OLEDs with uniform, linear, and stepwise graduations in the blend ratio in the emissive layer. The distribution of the guests in the film was found to affect the mobility of the charge carriers, and it was determined that having a graduated guest profile broadened the recombination zone, leading to a reduction in second order annihilation rates. That is, there was a reduction in triplet-triplet and triplet-polaron annihilation. Reducing triplet-triplet and triplet-polaron annihilation would lead to an improvement in device efficiency.
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Ram suspension-feeding fish, such as herring, use gill rakers to separate small food particles from large water volumes while swimming forward with an open mouth. The fish gill raker function was tested using 3D-printed conical models and computational fluid dynamics simulations over a range of slot aspect ratios. Our hypothesis predicting the exit of particles based on mass flow rates, dividing streamlines (i.e. stagnation streamlines) at the slots between gill rakers, and particle size was supported by the results of experiments with physical models in a recirculating flume. Particle movement in suspension-feeding fish gill raker models was consistent with the physical principles of lateral displacement arrays ('bump arrays') for microfluidic and mesofluidic separation of particles by size. Although the particles were smaller than the slots between the rakers, the particles skipped over the vortical region that was generated downstream from each raker. The particles 'bumped' on anterior raker surfaces during posterior transport. Experiments in a recirculating flume demonstrate that the shortest distance between the dividing streamline and the raker surface preceding the slot predicts the maximum radius of a particle that will exit the model by passing through the slot. This theoretical maximum radius is analogous to the critical separation radius identified with reference to the stagnation streamlines in microfluidic and mesofluidic devices that use deterministic lateral displacement and sieve-based lateral displacement. These conclusions provide new perspectives and metrics for analyzing cross-flow and cross-step filtration in fish with applications to filtration engineering.
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Conducta Alimentaria , Branquias , Animales , Biomimética , Peces , Filtración , Tamaño de la PartículaRESUMEN
Research on the suspension-feeding apparatus of fishes has led recently to the identification of novel filtration mechanisms involving vortices. Structures inside fish mouths form a series of 'backward-facing steps' by protruding medially into the mouth cavity. In paddlefish and basking shark mouths, porous gill rakers lie inside 'slots' between the protruding branchial arches. Vortical flows inside the slots of physical models have been shown to be important for the filtration process, but the complex flow patterns have not been visualised fully. Here we resolve the three-dimensional hydrodynamics by computational fluid dynamics simulation of a simplified mouth cavity including realistic flow dynamics at the porous layer. We developed and validated a modelling protocol in ANSYS Fluent software that combines a porous media model and permeability direction vector mapping. We found that vortex shape and confinement to the medial side of the gill rakers result from flow resistance by the porous gill raker surfaces. Anteriorly directed vortical flow shears the porous layer in the centre of slots. Flow patterns also indicate that slot entrances should remain unblocked, except for the posterior-most slot. This new modelling approach will enable future design exploration of fish-inspired filters.
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OBJECTIVE: To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population-based BRCA (Breast Cancer Gene)-testing. DESIGN: Cohort-study set within recruitment to GCaPPS-trial (ISRCTN73338115). SETTING: London Ashkenazi-Jewish (AJ) population. POPULATION OR SAMPLE: AJ men and women, >18 years. METHODS: Participants were self-referred, and attended recruitment clinics (clusters) for pre-test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self-identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural-Identity (JI) and Jewish Religious-identity (JR). Four-item Likert-scales analysed initial 'interest' and 'intention to test' pre-counselling. Item-Response-Theory and graded-response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI-scale, JR-scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing. MAIN OUTCOME MEASURES: Interest, intention, uptake of BRCA testing. RESULTS: In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre-test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non-practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre-counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation. CONCLUSIONS: Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population-based BRCA testing. BRCA testing was robust across all Jewish denominations. TWEETABLE ABSTRACT: Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations.
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Pruebas Genéticas , Judíos , Estudios de Cohortes , Femenino , Humanos , Judíos/genética , Modelos Logísticos , Londres/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
To assess potential filtration mechanisms, scanning electron microscopy was used in a comprehensive quantification and analysis of the morphology and surface ultrastructure for all five branchial arches in the ram suspension-feeding fish, American shad (Alosa sapidissima, Clupeidae). The orientation of the branchial arches and the location of mucus cells on the gill rakers were more consistent with mechanisms of crossflow filtration and cross-step filtration rather than conventional dead-end sieving. The long, thin gill rakers could lead to a large area for the exit of water from the oropharyngeal cavity during suspension feeding (high fluid exit ratio). The substantial elongation of gill rakers along the dorsal-ventral axis formed d-type ribs with a groove aspect ratio of 0.5 and a Reynolds number of approximately 500, consistent with the potential operation of cross-step filtration. Mucus cell abundance differed significantly along the length of the raker and the height of the raker. The mucus cell abundance data and the observed sloughing of denticles along the gill raker margins closest to the interior of the oropharyngeal cavity suggest that gill raker growth may occur primarily at the raker tips, the denticle bases, and the internal raker margins along the length of the raker. These findings will be applied in ongoing experiments with 3D-printed physical models of fish oral cavities in flow tanks, and in future ecological studies on the diet and nutrition of suspension-feeding fishes.
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Conducta Alimentaria , Peces/anatomía & histología , Orofaringe/anatomía & histología , Animales , Peces/fisiología , BranquiasRESUMEN
OBJECTIVE: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. DESIGN: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. SETTING: North London Ashkenazi-Jewish (AJ) population. POPULATION/SAMPLE: AJ women/men. METHODS: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. INCLUSION CRITERIA: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. INTERVENTIONS: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years. MAIN OUTCOME MEASURES: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. RESULTS: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%). CONCLUSION: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. TWEETABLE ABSTRACT: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.
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Ansiedad , Detección Precoz del Cáncer , Genes BRCA1 , Genes BRCA2 , Síndrome de Cáncer de Mama y Ovario Hereditario , Calidad de Vida , Adulto , Ansiedad/fisiopatología , Ansiedad/prevención & control , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/psicología , Femenino , Predisposición Genética a la Enfermedad/psicología , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Síndrome de Cáncer de Mama y Ovario Hereditario/diagnóstico , Síndrome de Cáncer de Mama y Ovario Hereditario/etnología , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/psicología , Humanos , Judíos/genética , Judíos/estadística & datos numéricos , Londres/epidemiología , Masculino , Anamnesis/estadística & datos numéricos , IncertidumbreRESUMEN
A new filter was developed to collect harmful algae colonies by adapting the cross-step filtration structures and mechanisms discovered recently in filter-feeding fish. Extending beyond previously published models that closely emulated the basic morphology of the fish, the new cross-step filter's major innovations are helical slots, radial symmetry, and rotation as an active anti-clogging mechanism. These innovations enable the transport of concentrated particles to the downstream end of the filter. This advance was made possible by recognizing that biologically imposed constraints such as bilateral symmetry do not apply to human-made filters. The use of helical slots was developed in a series of iterative tests that used water-tracing dye and algae-sized microspheres. The major products of the iterative tests were refinements in the helical design and an understanding of how varying the major structural parameters qualitatively influenced fluid flow and filter performance. Following the iterative tests, the clogging behavior of select filters was quantified at high particle concentrations. Vortices in the helical filter were effective at reducing clogging in the center of the slots. By considering the design space that is free of the biological constraints on the system and exploring the effects of variations in major structural parameters, our work has identified promising new directions for cross-step filtration and provided key insights into the biological system.
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Materiales Biomiméticos/química , Eutrofización/fisiología , Peces/anatomía & histología , Animales , RotaciónRESUMEN
OBJECTIVE: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ). DESIGN: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115). SETTING: North London AJ population. POPULATION OR SAMPLE: Ashkenazi Jews women/men >18 years, recruited through self-referral. METHODS: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire. MAIN OUTCOME MEASURES: Interest, intention, uptake, attitude towards BRCA testing. RESULTS: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing. CONCLUSIONS: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing. TWEETABLE ABSTRACT: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making.
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Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Síndrome de Cáncer de Mama y Ovario Hereditario , Judíos , Adulto , Actitud Frente a la Salud/etnología , Características Culturales , Femenino , Asesoramiento Genético/psicología , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/psicología , Pruebas Genéticas/economía , Pruebas Genéticas/estadística & datos numéricos , Síndrome de Cáncer de Mama y Ovario Hereditario/etnología , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/psicología , Humanos , Judíos/genética , Judíos/psicología , Londres , Masculino , Mutación , Participación del Paciente/estadística & datos numéricos , Factores SocioeconómicosRESUMEN
Vortical cross-step filtration in suspension-feeding fish has been reported recently as a novel mechanism, distinct from other biological and industrial filtration processes. Although crossflow passing over backward-facing steps generates vortices that can suspend, concentrate, and transport particles, the morphological factors affecting this vortical flow have not been identified previously. In our 3D-printed models of the oral cavity for ram suspension-feeding fish, the angle of the backward-facing step with respect to the model's dorsal midline affected vortex parameters significantly, including rotational, tangential, and axial speed. These vortices were comparable to those quantified downstream of the backward-facing steps that were formed by the branchial arches of preserved American paddlefish in a recirculating flow tank. Our data indicate that vortices in cross-step filtration have the characteristics of forced vortices, as the flow of water inside the oral cavity provides the external torque required to sustain forced vortices. Additionally, we quantified a new variable for ram suspension feeding termed the fluid exit ratio. This is defined as the ratio of the total open pore area for water leaving the oral cavity via spaces between branchial arches that are not blocked by gill rakers, divided by the total area for water entering through the gape during ram suspension feeding. Our experiments demonstrated that the fluid exit ratio in preserved paddlefish was a significant predictor of the flow speeds that were quantified anterior of the rostrum, at the gape, directly dorsal of the first ceratobranchial, and in the forced vortex generated by the first ceratobranchial. Physical modeling of vortical cross-step filtration offers future opportunities to explore the complex interactions between structural features of the oral cavity, vortex parameters, motile particle behavior, and particle morphology that determine the suspension, concentration, and transport of particles within the oral cavity of ram suspension-feeding fish.
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Conducta Alimentaria/fisiología , Peces/fisiología , Animales , Región Branquial/fisiología , Filtración/métodos , Branquias/fisiología , Boca/fisiología , Fenómenos Físicos , Estados UnidosRESUMEN
Ram suspension-feeding fishes swim with an open mouth to force water through the oral cavity and extract prey items that are too small to be pursued individually. Recent research has indicated that, rather than using a dead-end mechanical sieve, American paddlefish (Polyodon spathula) employ vortical cross-step filtration. In this filtration mechanism, vortical flow that is generated posterior to the branchial arches organizes crossflow filtration processes into a spatial structure across the gill rakers. Despite the known impact of locomotor kinematics on fluid flow around the bodies of swimming fish, the effects of locomotor kinematics on filtration mechanisms in ram suspension feeders are unknown. Potential temporal organization of filtration mechanisms in ram suspension-feeding fish has not been studied previously. We investigated the effects of locomotor kinematics associated with undulatory swimming on intra-oral flow patterns and food particle transport. A mechanized model of the oral cavity was used to simulate the swimming kinematics of suspension-feeding paddlefish. We recorded fluctuations of flow speed and pressure within the model, which occurred at a frequency that corresponded with the frequency of the model's strides. Using the mechanized model in a flow tank seeded with Artemia cysts, we also showed that swimming kinematics aided the transport of this simulated food to the posterior margins of the gill slots, although the time scale of this transport is expected to vary with prey parameters such as size and concentration. Dye stream experiments revealed that, although stable vortical flow formed because of flow separation downstream of backward-facing steps in control trials, vortical flow structures in mechanized trials repeatedly formed and shed. These findings suggest strong integration between locomotor and feeding systems in ram suspension-feeding fishes.
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Conducta Alimentaria , Peces/anatomía & histología , Peces/fisiología , Boca/fisiología , Natación , Animales , Fenómenos Biomecánicos , Filtración , Boca/anatomía & histología , Impresión TridimensionalRESUMEN
Suspension-feeding fishes such as goldfish and whale sharks retain prey without clogging their oral filters, whereas clogging is a major expense in industrial crossflow filtration of beer, dairy foods and biotechnology products. Fishes' abilities to retain particles that are smaller than the pore size of the gill-raker filter, including extraction of particles despite large holes in the filter, also remain unexplained. Here we show that unexplored combinations of engineering structures (backward-facing steps forming d-type ribs on the porous surface of a cone) cause fluid dynamic phenomena distinct from current biological and industrial filter operations. This vortical cross-step filtration model prevents clogging and explains the transport of tiny concentrated particles to the oesophagus using a hydrodynamic tongue. Mass transfer caused by vortices along d-type ribs in crossflow is applicable to filter-feeding duck beak lamellae and whale baleen plates, as well as the fluid mechanics of ventilation at fish gill filaments.
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Bioingeniería , Filtración , Carpa Dorada/anatomía & histología , Boca/anatomía & histología , Tiburones/anatomía & histología , Animales , Región Branquial/fisiología , Conducta Alimentaria , Hidrodinámica , Modelos Biológicos , Presión , CostillasRESUMEN
Assays designed to select transplant recipients for immunosuppression withdrawal have met with limited success, perhaps because they measure events downstream of T cell-alloantigen interactions. Using in vitro time-lapse microscopy in a mouse transplant model, we investigated whether transplant outcome would result in changes in the proportion of CD4(+) T cells forming prolonged interactions with donor dendritic cells. By blocking CD4-MHC class II and CD28-B7 interactions, we defined immunologically relevant interactions as those ≥500 s. Using this threshold, T cell-dendritic cell (T-DC) interactions were examined in rejection, tolerance and T cell control mediated by regulatory T cells. The frequency of T-DC contacts ≥500 s increased with T cells from mice during acute rejection and decreased with T cells from mice rendered unresponsive to alloantigen. Regulatory T cells reduced prolonged T-DC contacts. Importantly, this effect was replicated with human polyclonally expanded naturally occurring regulatory T cells, which we have previously shown can control rejection of human tissues in humanized mouse models. Finally, in a proof-of-concept translational context, we were able to visualize differential allogeneic immune synapse formation in polyclonal CD4(+) T cells using high-throughput imaging flow cytometry.
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Linfocitos T CD4-Positivos/inmunología , Rechazo de Injerto/diagnóstico , Trasplante de Corazón/efectos adversos , Sinapsis Inmunológicas/inmunología , Isoantígenos/inmunología , Linfocitos T Reguladores/inmunología , Imagen de Lapso de Tiempo/métodos , Animales , Células Dendríticas/inmunología , Rechazo de Injerto/etiología , Supervivencia de Injerto/inmunología , Tolerancia Inmunológica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBARESUMEN
This study developed and applied an approach to calculate the proportion of fish gut content composed of mucus secreted by the oropharyngeal cavity and gut. The amount of nitrogen in the contents of the foregut (oesophagus and gizzard) and the epibranchial organs of suspension-feeding American gizzard shad Dorosoma cepedianum was significantly higher than the nitrogen in the homogeneous food source. Using data collected from suspension-feeding experiments and the nitrogen content of D. cepedianum mucus, a series of equations illustrated that mucus constituted c. 10% of D. cepedianum foregut content and 12% of epibranchial organ content by dry mass. Future quantification of fish feeding selectivity and absorption efficiency can use this approach to take into account the contribution of fish mucus to the nutrients in the gut contents. This study supports the conclusion that suspension-feeding D. cepedianum in a heterogeneous environment selectively ingest nutrient-rich particles, even when gut nutrient content is adjusted to take into account the contribution of mucus.
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Alimentación Animal , Peces , Moco/química , Nitrógeno/química , Animales , Esófago/metabolismo , Conducta Alimentaria , Molleja No Aviar/metabolismoAsunto(s)
Predisposición Genética a la Enfermedad/psicología , Neoplasias Pulmonares/genética , Penetrancia , Fumar/efectos adversos , Adolescente , Demografía , Femenino , Pruebas Genéticas , Glutatión Transferasa/genética , Educación en Salud , Humanos , Neoplasias Pulmonares/psicología , Masculino , Fumar/psicología , Adulto JovenRESUMEN
The suspension-feeding cichlids Oreochromis aureus (blue tilapia) and Oreochromis esculentus (ngege tilapia) are able to selectively retain small food particles. The gill rakers and microbranchiospines of these species have been assumed to function as filters. However, surgical removal of these oral structures, which also removed associated mucus, did not significantly affect the total number of 11-200 µm particles ingested by the fish. This result supports the hypothesis that the branchial arch surfaces themselves play an important role in crossflow filtration. Both species selectively retained microspheres greater than 50 µm with gill rakers and microbranchiospines intact as well as removed, demonstrating that neither these structures nor mucus are necessary for size selectivity to occur during biological crossflow filtration. After removal of the gill rakers and microbranchiospines, O. esculentus retained significantly more microspheres 51-70 µm in diameter and fewer 91-130 µm microspheres compared to retention with intact structures, but the particle size selectivity of O. aureus was not affected significantly. These results support conclusions from previous computational fluid dynamics simulations indicating that particle size can have marked effects on particle trajectory and retention inside the fish oropharyngeal cavity during crossflow filtration. The substantial inter-individual variability in particle retention by suspension-feeding fish is an unexplored area of research with the potential to increase our understanding of the factors influencing particle retention during biological filtration.
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Región Branquial/anatomía & histología , Cíclidos/anatomía & histología , Cíclidos/fisiología , Dieta/veterinaria , Tamaño de la Partícula , Animales , Región Branquial/cirugía , Conducta Alimentaria , Filtración , Branquias/anatomía & histología , Microscopía Electrónica de RastreoRESUMEN
OBJECTIVE: Allelic variation (rs738409CâG) in adiponutrin (patatin-like phospholipase domain-containing protein 3, PNPLA3) has been associated with hepatic steatosis and liver fibrosis. The physiologic impact of the PNPLA3 G allele may be exacerbated in patients with severe obesity. In this study, we investigated the interactions of PNPLA3 rs738409 with a broad panel of metabolic and histologic characteristics of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) in patients with medically complicated obesity. DESIGN AND METHODS: Consecutive patients undergoing bariatric surgery were selected for a prospective study. They underwent extensive laboratory and histologic (liver biopsy) assessment, as well as evaluation of rs738409 polymorphism by TaqMan assay. RESULTS: Only 12 (8.3%) of the 144 patients had normal liver histology, with 72 (50%) NASH, of whom 15 (10.4% of total patients) had fibrosis stage 2-3. PNPLA3 GG genotype correlated positively (P < 0.05) with serum levels of alanine aminotransferase (ALT), asparate aminotransferase (AST), glucose, fibrinogen, and insulin-dependent diabetes mellitus, homeostasis model assessment-insulin resistance, and presence of NASH. Multivariate analysis indicated that PNPLA3 rs738409 G versus C allele remained an (independent) risk factor for NASH, in addition to CK-18 >145 IU/l, glucose >100 mg/dl, and C-reactive protein (CRP) >0.8 mg/dl. The probability of NASH increased from 9% (no risk factor) to 82% if all four risk factors were present. CONCLUSIONS: In this cohort of patients with medically complicated obesity, PNPLA3 rs738409 G allelic expression is associated with hepatic (NASH) and nonhepatic complications of obesity, such as insulin resistance. These novel findings may be related to a greater impact of PNPLA3 variant in magnitude and scope in patients with severe obesity than in less obese populations. Further studies are needed to characterize the nature of these associations.
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Alelos , Hígado Graso/genética , Variación Genética , Genotipo , Lipasa/genética , Hígado/patología , Proteínas de la Membrana/genética , Obesidad Mórbida/genética , Adulto , Glucemia/metabolismo , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 1/genética , Hígado Graso/etiología , Hígado Graso/metabolismo , Femenino , Fibrinógeno/metabolismo , Fibrosis , Humanos , Resistencia a la Insulina/genética , Hígado/enzimología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Enfermedad del Hígado Graso no Alcohólico , Obesidad Mórbida/complicaciones , Obesidad Mórbida/metabolismo , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: New genetic associations with obesity are rapidly being discovered. People's causal beliefs about obesity may influence their obesity-related behaviors. Little is known about genetic compared to lifestyle causal beliefs regarding obesity, and obesity-related diseases, among minority populations. This study examined genetic and lifestyle causal beliefs about obesity and 3 obesity-related diseases among a low-income, ethnically diverse patient sample. METHODS: Structured interviews were conducted with patients attending an inner-city hospital outpatient clinic. Participants (n=205) were asked how much they agreed that genetics influence the risk of obesity, type 2 diabetes, heart disease, and cancer. Similar questions were asked regarding lifestyle causal beliefs (overeating, eating certain types of food, chemicals in food, not exercising, smoking). In this study, 48% of participants were non-Hispanic Black, 29% Hispanic and 10% non-Hispanic White. RESULTS: Over two-thirds (69%) of participants believed genetics cause obesity 'some' or 'a lot', compared to 82% for type 2 diabetes, 79% for heart disease and 75% for cancer. Participants who held genetic causal beliefs about obesity held more lifestyle causal beliefs in total than those who did not hold genetic causal beliefs about obesity (4.0 vs. 3.7 lifestyle causal beliefs, respectively, possible range 0-5, p=0.025). There were few associations between causal beliefs and sociodemographic characteristics. CONCLUSIONS: Higher beliefs in genetic causation of obesity and related diseases are not automatically associated with decreased lifestyle beliefs. Future research efforts are needed to determine whether public health messages aimed at reducing obesity and its consequences in racially and ethnically diverse urban communities may benefit from incorporating an acknowledgement of the role of genetics in these conditions.
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Etnicidad , Estilo de Vida , Obesidad/etiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Obesidad/etnología , Obesidad/genética , Obesidad/psicología , Adulto JovenRESUMEN
The apicomplexan parasite, Theileria annulata, is the causative agent of tropical theileriosis, a devastating lymphoproliferative disease of cattle. The schizont stage transforms bovine leukocytes and provides an intriguing model to study host/pathogen interactions. The genome of T. annulata has been sequenced and transcriptomic data are rapidly accumulating. In contrast, little is known about the proteome of the schizont, the pathogenic, transforming life cycle stage of the parasite. Using one-dimensional (1-D) gel LC-MS/MS, a proteomic analysis of purified T. annulata schizonts was carried out. In whole parasite lysates, 645 proteins were identified. Proteins with transmembrane domains (TMDs) were under-represented and no proteins with more than four TMDs could be detected. To tackle this problem, Triton X-114 treatment was applied, which facilitates the extraction of membrane proteins, followed by 1-D gel LC-MS/MS. This resulted in the identification of an additional 153 proteins. Half of those had one or more TMD and 30 proteins with more than four TMDs were identified. This demonstrates that Triton X-114 treatment can provide a valuable additional tool for the identification of new membrane proteins in proteomic studies. With two exceptions, all proteins involved in glycolysis and the citric acid cycle were identified. For at least 29% of identified proteins, the corresponding transcripts were not present in the existing expressed sequence tag databases. The proteomics data were integrated into the publicly accessible database resource at EuPathDB (www.eupathdb.org) so that mass spectrometry-based protein expression evidence for T. annulata can be queried alongside transcriptional and other genomics data available for these parasites.
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Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Esquizontes/metabolismo , Theileria annulata/crecimiento & desarrollo , Theileria annulata/metabolismo , Theileriosis/parasitología , Animales , Bovinos , Espectrometría de Masas , Datos de Secuencia Molecular , Proteómica , Proteínas Protozoarias/genética , Esquizontes/química , Esquizontes/crecimiento & desarrollo , Theileria annulata/química , Theileria annulata/genéticaRESUMEN
The presence of preformed donor-specific HLA antibodies (DSA) in liver transplant recipients is increasingly recognized; however, the prevalence of DSA and their impact on early allograft function remains unknown. We prospectively followed serum DSA levels of 90 consecutive liver transplant recipients from baseline to 4 months. Twenty recipients (22.2%) had preformed DSA. No antibody-targeting treatments were undertaken. Seven days after transplantation, DSA levels decreased markedly in all but three patients. Day 7 protocol biopsies showed diffuse C4d deposition along the portal stroma, central vein, subendothelial and stromal space in the patients with persistent high DSA levels. The rate of acute cellular rejection was not significantly different in patients with DSA. The transaminase and bilirubin levels remained comparable during the first year despite the presence of DSA. The three patients with persistently high DSA levels continue to have normal allograft function. We conclude that in most cases, DSA disappear after liver transplant, however in rare instances where they persist, there is evidence of complement activation in the liver allograft, without significant clinical impact in the first year.