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The objective of this study was to assess the growth, apparent total-tract digestibility of nutrients, the prevalence of coccidia, and purine derivatives in postweaning heifers when limit-fed a diet supplemented with sodium butyrate (SB). A 12 wk randomized complete block experiment was conducted using 24 Holstein heifers (92.8 d ± 1.9 d of age and initial body weight [BW] of 99.6 ± 15.2 kg [mean ± standard deviation]). Treatments were 100 g soybean meal (control; CON) and 0.75 g of SB/kg of BW + 100 g soybean meal (SB). Diets were formulated to contain 16.4% crude protein, 2.27 Mcal/kg metabolizable energy (ME), and fed at a feed out rate of 2.15% of BW on a dry matter basis. Intakes were recorded daily while growth measurements and BW were recorded weekly. Urine and fecal samples were taken every 2 wk. On d 42 through d 49 an apparent total-tract digestibility phase took place using acid detergent insoluble ash as a marker. Growth measurements were similar among treatments except CON heifers grew longer and tended to be taller at the withers. A trend was observed for CON animals to have lower levels of coccidian oocytes by week. Heifers fed SB had lower blood glucose levels and higher levels of ketones in their blood. Urinary volume was greater for heifers fed SB throughout the 12 wk study. Total purine derivatives were greater in CON heifers. Dry matter, organic matter and acid detergent fiber digestibilities were greater for heifers fed SB compared with CON heifers. Crude protein, neutral detergent fiber, and ash digestibilities tended to be greater in heifers fed SB than in CON heifers. These results suggested no growth benefit of supplementing SB to limit-fed heifers; however, apparent total-tract fiber, ash, and crude protein digestibilities were improved in the SB fed heifers likely due to improved ruminal and intestinal development.
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Enfermedades de los Bovinos , Coccidiosis , Bovinos , Animales , Femenino , Ácido Butírico/metabolismo , Digestión , Detergentes/metabolismo , Alimentación Animal/análisis , Dieta/veterinaria , Nutrientes , Peso Corporal , Vitaminas/metabolismo , Coccidiosis/metabolismo , Coccidiosis/veterinaria , Purinas , Rumen/metabolismo , Enfermedades de los Bovinos/metabolismoRESUMEN
AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.
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Aterosclerosis , Infarto del Miocardio , Oxazolidinonas , Adulto , Aterosclerosis/tratamiento farmacológico , Atorvastatina/uso terapéutico , Método Doble Ciego , Humanos , Infarto del Miocardio/tratamiento farmacológico , Oxazolidinonas/efectos adversos , Resultado del TratamientoRESUMEN
Behavioural responses to heat and desiccation stress in ectotherms are crucial for their survival in habitats where environmental temperatures are close to or even exceed their upper thermal limits. During low tide periods when pools in intertidal sediments heat up, a novel shell lifting behaviour (when hermit crabs crawl out of pools and lift up their shells) was observed in the hermit crab, Diogenes deflectomanus, on tropical sandy shores. On-shore measurements revealed that the hermit crabs left pools and lifted their shells predominantly when pool water exceeded 35.4 °C. Standing on emersed substrates above the pool water, the hermit crabs maintained their body temperatures at 26 - 29 °C, â¼ 10 °C lower than temperatures at which their physiological performances (as measured using heart rate) reached the maximum. This mismatch between preferred body temperatures and temperatures at maximal physiological performance was also observed under a laboratory controlled thermal gradient, where hermit crabs spent more time at 22 - 26 °C as compared to > 30 °C. These behaviours suggest a thermoregulatory function of the shell lifting behaviour, where the hermit crabs can avoid further increase in body temperatures when pools heat up during low tide periods. Such a behavioural decision allows the hermit crabs to be less prone to the strong temporal fluctuation in temperatures experienced during emersion periods on thermally dynamic tropical sandy shores.
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Anomuros , Animales , Anomuros/fisiología , Temperatura Corporal , Temperatura , Agua , Respuesta al Choque TérmicoRESUMEN
Schistosomiasis, or also generally known as bilharzia or snail fever, is a parasitic disease that is caused by trematode flatworms of the genus Schistosoma. It is considered by the World Health Organisation as the second most prevalent parasitic disease after malaria and affects more than 230 million people in over 70 countries. People are infected via a variety of activities ranging from agricultural, domestic, occupational to recreational activities, where the freshwater snails Biomphalaria release Schistosoma cercariae larvae that penetrate the skin of humans when exposed in water. Understanding the biology of the intermediate host snail Biomphalaria is thus important to reveal the potential spread of schistosomiasis. In this article, we present an overview of the latest molecular studies focused on the snail Biomphalaria, including its ecology, evolution, and immune response; and propose using genomics as a foundation to further understand and control this disease vector and thus the transmission of schistosomiasis.
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Biomphalaria , Esquistosomiasis mansoni , Esquistosomiasis , Animales , Humanos , Schistosoma mansoni/genética , Biomphalaria/genética , Caracoles , GenómicaRESUMEN
In thermally extreme environments, it is challenging for organisms to maximize performance due to risks associated with stochastic variation in temperature and, subsequently, over evolutionary time minimizing the exposure to risk can serve as one of the mechanisms that result in organisms preferring suboptimal temperatures. We tested this hypothesis in a slow-moving intertidal snail on tropical rocky shores, where temperature variability increases with time from 30 min to 20 hr when recorded at 30 min intervals (due to short-term environmental autocorrelation where temperatures closer in time are more similar as compared to temperatures over a long period of time). Failure to accommodate temporal variation in thermal stress by selecting cool habitats can result in mortality. Thermal performance curves for different traits (heart rate and locomotion) were measured and compared to the snail's thermal preferences in both the field and laboratory. Predicted performances of the snails were simulated based on thermal performance curves for different traits over multiple time-scales and simulated carryover effects. A strong mismatch was found between physiological and behavioural thermal maxima of the snails (physiological thermal maximum being higher by ~7°C), but the snails avoided these maxima and sought temperatures 7-14°C cooler. Such a risk-averse strategy can be explained by their predicted performances where the snails should make decisions about preferred temperatures based on time periods ≥5 hr to avoid underestimating the temporal variation in body temperature. In extreme and stochastic environments, where the temporal variation in environmental conditions can lead to substantial divergence between instantaneous and time-averaged thermal performances, 'cooler is better' and 'suboptimal' body temperatures are preferred as they provide sufficient buffer to reduce mortality risk from heat stress.
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Ecosistema , Caracoles , Animales , Evolución Biológica , TemperaturaRESUMEN
[This corrects the article DOI: 10.1371/journal.pbio.2005359.].
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Placozoans are a phylum of nonbilaterian marine animals currently represented by a single described species, Trichoplax adhaerens, Schulze 1883. Placozoans arguably show the simplest animal morphology, which is identical among isolates collected worldwide, despite an apparently sizeable genetic diversity within the phylum. Here, we use a comparative genomics approach for a deeper appreciation of the structure and causes of the deeply diverging lineages in the Placozoa. We generated a high-quality draft genome of the genetic lineage H13 isolated from Hong Kong and compared it to the distantly related T. adhaerens. We uncovered substantial structural differences between the two genomes that point to a deep genomic separation and provide support that adaptation by gene duplication is likely a crucial mechanism in placozoan speciation. We further provide genetic evidence for reproductively isolated species and suggest a genus-level difference of H13 to T. adhaerens, justifying the designation of H13 as a new species, Hoilungia hongkongensis nov. gen., nov. spec., now the second described placozoan species and the first in a new genus. Our multilevel comparative genomics approach is, therefore, likely to prove valuable for species distinctions in other cryptic microscopic animal groups that lack diagnostic morphological characters, such as some nematodes, copepods, rotifers, or mites.
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Genómica , Placozoa/genética , Alelos , Animales , Secuencia de Bases , ADN Ribosómico/genética , Duplicación de Gen , Reordenamiento Génico/genética , Especiación Genética , Variación Genética , Genoma , Anotación de Secuencia Molecular , Filogenia , Placozoa/ultraestructura , Aislamiento ReproductivoRESUMEN
AbstractAnticipatory changes in organismal responses, triggered by reliable environmental cues for future conditions, are key to species' persistence in temporally variable environments. Such responses were tested by measuring the physiological performance of a tropical high-shore oyster in tandem with the temporal predictability of environmental temperature. Heart rate of the oyster increased with environmental temperatures until body temperature reached â¼37°C, when a substantial depression occurred (â¼60%) before recovery between â¼42° and 47°C, after which cardiac function collapsed. The sequential increase, depression, and recovery in cardiac performance aligned with temporal patterns in rock surface temperatures, where the risk of reaching temperatures close to the oysters' lethal limit accelerates if the rock heats up beyond â¼37°C, coinciding closely with the body temperature at which the oysters initiate metabolic depression. The increase in body temperature over a critical threshold serves as an early-warning cue to initiate anticipatory shifts in physiology and energy conservation before severe thermal stress occurs on the shore. Cross-correlating the onset of physiological mechanisms and temporal structures in environmental temperatures, therefore, reveals the potential role of reliable real-time environmental cues for future conditions in driving the evolution of anticipatory responses.
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Frecuencia Cardíaca , Calor , Ostreidae/metabolismo , Animales , Corazón/fisiopatología , Ostreidae/fisiologíaRESUMEN
Despite extensive research, the pathophysiology and prevention of pre-eclampsia remain elusive, diagnosis is challenging, and pre-eclampsia remains associated with adverse maternal and perinatal outcomes. Angiogenic biomarkers, including placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), have been identified as valuable biomarkers for preterm pre-eclampsia, accelerating diagnosis and reducing maternal adverse outcomes by risk stratification, with enhanced surveillance for high-risk women. PlGF-based testing is increasingly being implemented in clinical practice in several countries. This review provides healthcare providers with an understanding of the evidence for PlGF-based testing and describes the practicalities and challenges to implementation. TWEETABLE ABSTRACT: Placental growth factor in pre-eclampsia: evidence and implementation of testing.
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Factor de Crecimiento Placentario/sangre , Preeclampsia/sangre , Preeclampsia/diagnóstico , Femenino , Predicción , Humanos , Pruebas Inmunológicas , EmbarazoRESUMEN
Soft sediment shores in the tropics are highly dynamic environments, where behavioural patterns of organisms are constrained by tidal conditions, and environmental temperatures during an organisms' activity periods can exceed their thermal tolerance levels. In such extreme habitats, behavioural responses to environmental changes are key to survival, driving differential performance. We investigated sponging behaviour (water uptake from sediments) of the deposit-feeding crab, Scopimera intermedia, on tropical sandy shores to determine its thermoregulatory function. The thermal physiology of the crabs and their habitat conditions were quantified by measuring thermal performance curves and recording environmental temperatures during the crabs' activity periods. Environmental temperatures were combined with experimental data to investigate the role of sponging on the thermal performances of the crabs by simulating field body temperatures. Sponging rate was strongly and positively correlated with feeding rate, as sponging replenishes water for flotation feeding. Sponging, however, also reduced body temperatures on average by 1.3 °C. Simulated populations of crabs which were unable to sponge had more variable body temperatures, which exceeded the critical thermal maximum of the crabs (~ 39 °C) nearly 2000 times more often than crabs able to sponge. Sponging is, therefore, a multifunctional behavioural trait important for both feeding and thermoregulation. The evolution of such multifunctional traits is likely to be a widespread, but overlooked phenomenon in intertidal species, as maintaining a functional body temperature is energetically costly in habitats where environmental conditions fluctuate strongly such as on tropical shores.
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Braquiuros , Animales , Temperatura Corporal , Regulación de la Temperatura Corporal , Ecosistema , TemperaturaRESUMEN
OBJECTIVES: Canada's Indian Residential School (IRS) system aimed to annihilate Indigenous culture among Indigenous children. Negative health impacts have been documented not only among survivors but also among their descendants. Reconnection with culture has been promoted as a means to recovery for people affected by this historical trauma. This study aimed to assess whether cultural connectedness has a specific protective effect on mental health among the descendants of IRS survivors. STUDY DESIGN: Cross-sectional survey. METHODS: A randomly selected cross section of Anishinabe people, aged 18-39 years, from one community were invited to complete a brief questionnaire. Associations were calculated between IRS attendance, cultural connectedness, and mental health. RESULTS: A total of 147 people participated. Among participants without a family history of IRS attendance, cultural connectedness was not significantly associated with improved mental health. Among participants with a family history of IRS attendance, a high level of cultural connectedness was significantly associated with a 31% greater probability of reporting high mental health and mental health status similar to those with no family history of IRS attendance. CONCLUSIONS: Cultural connectedness appears to act as a strong and specific protective factor against the intergenerational effects of IRS on the mental health of Anishinabe young adults, providing epidemiological support for the notion of 'culture as treatment.'
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Trauma Histórico/psicología , Pueblos Indígenas/psicología , Salud Mental/estadística & datos numéricos , Identificación Social , Adolescente , Adulto , Canadá , Estudios Transversales , Características Culturales , Femenino , Humanos , Pueblos Indígenas/estadística & datos numéricos , Masculino , Instituciones Académicas , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Stroke/death rates within 30 days of carotid endarterectomy (CEA) and carotid artery stenting (CAS) in RCTs inform current clinical guidelines. However, the risks may have changed in recent years with wider use of effective stroke prevention therapies, especially statins, improved patient selection and growing operator expertise. The aim of this study was to investigate whether the procedural stroke/death risks from CEA and CAS have changed over time. METHODS: MEDLINE and Embase were searched systematically from inception to May 2016 for observational cohort studies of CEA and CAS. Studies included reported on more than 1000 patients, with 30-day outcomes after the procedure according to patients' symptom status (recent stroke or transient ischaemic attack). Restricted maximum likelihood random-effects and meta-regressions methods were used to synthesize procedural stroke/death rates of CEA and CAS according to year of study recruitment completion. RESULTS: Fifty-one studies, including 223 313 patients undergoing CEA and 72 961 undergoing CAS, were reviewed. Procedural stroke/death risks of CEA decreased over time in symptomatic and asymptomatic patients. Risks were substantially lower in studies completing recruitment in 2005 or later, both in symptomatic (5·11 per cent before 2005 versus 2·68 per cent from 2005 onwards; P = 0·002) and asymptomatic (3·17 versus 1·50 per cent; P < 0·001) patients. Procedural stroke/death rates of CAS did not change significantly over time (4·77 per cent among symptomatic and 2·59 per cent among asymptomatic patients). There was substantial heterogeneity in event rates and recruitment periods were long. CONCLUSIONS: Risks of procedural stroke/death following CEA appear to have decreased substantially. There was no evidence of a change in stroke/death rates following CAS.
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Estenosis Carotídea/cirugía , Endarterectomía Carotidea , Complicaciones Posoperatorias , Stents , Accidente Cerebrovascular/etiología , Endarterectomía Carotidea/efectos adversos , Endarterectomía Carotidea/mortalidad , Humanos , Modelos Estadísticos , Complicaciones Posoperatorias/epidemiología , Riesgo , Stents/efectos adversos , Accidente Cerebrovascular/epidemiología , Resultado del TratamientoRESUMEN
AIM: Glucose-lowering interventions in Type 2 diabetes mellitus have demonstrated reductions in microvascular complications and modest reductions in macrovascular complications. However, the degree to which targeting different HbA1c reductions might reduce risk is unclear. METHODS: Participant-level data for Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) participants with established cardiovascular disease were used in a Type 2 diabetes-specific simulation model to quantify the likely impact of different HbA1c decrements on complication rates. Ten-year micro- and macrovascular rates were estimated with HbA1c levels fixed at 86, 75, 64, 53 and 42 mmol/mol (10%, 9%, 8%, 7% and 6%) while holding other risk factors constant at their baseline levels. Cumulative relative risk reductions for each outcome were derived for each HbA1c decrement. RESULTS: Of 5717 participants studied, 72.0% were men and 74.2% White European, with a mean (sd) age of 66.2 (7.9) years, systolic blood pressure 134 (16.9) mmHg, LDL-cholesterol 2.3 (0.9) mmol/l, HDL-cholesterol 1.13 (0.3) mmol/l and median Type 2 diabetes duration 9.6 (5.1-15.6) years. Ten-year cumulative relative risk reductions for modelled HbA1c values of 75, 64, 53 and 42 mmol/mol, relative to 86 mmol/mol, were 4.6%, 9.3%, 15.1% and 20.2% for myocardial infarction; 6.0%, 12.8%, 19.6% and 25.8% for stroke; 14.4%, 26.6%, 37.1% and 46.4% for diabetes-related ulcer; 21.5%, 39.0%, 52.3% and 63.1% for amputation; and 13.6%, 25.4%, 36.0% and 44.7 for single-eye blindness. CONCLUSIONS: These simulated complication rates might help inform the degree to which complications might be reduced by targeting particular HbA1c reductions in Type 2 diabetes.
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Enfermedades Cardiovasculares/complicaciones , Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/metabolismo , Hipoglucemiantes/uso terapéutico , Anciano , Amputación Quirúrgica/estadística & datos numéricos , Ceguera/epidemiología , Ceguera/etiología , Complicaciones de la Diabetes/etiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Pie Diabético/epidemiología , Pie Diabético/etiología , Retinopatía Diabética/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Planificación de Atención al Paciente , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiologíaRESUMEN
BACKGROUND AND OBJECTIVES: During storage, red blood cells (RBCs) undergo physicochemical changes which affect the quality, function, and in vivo survival of transfused packed RBCs (pRBC). Changes include decreased 2,3-diphosphoglycerate (2,3-DPG) levels, decreased ATP, changes in mechanical properties and oxidative injury. RBC rejuvenation is a method used to increase levels of 2,3-DPG and ATP in pRBCs. This process requires incubating the pRBCs with a rejuvenation solution and subsequent washing. Standard blood bank protocols using the COBE 2991 Cell Processor require several hours of preparation. The objective of this study was to verify if a bedside protocol for rejuvenating pRBC and washing with the Sorin Xtra autologous cell salvage system could be used. MATERIALS AND METHODS: Outdated pRBC units were obtained and rejuvenated in a model operating suite using a dry air incubator for 1 h at 37°C. Six units of pRBCs were pre-diluted with saline (1000 ml) and six units were not pre-diluted with saline. All units were washed with normal saline (1000 ml) using an apheresis-design cell salvage device in manual mode and wash volume set to 3000 ml. Samples were collected and analyzed for standard RBC quality parameters at baseline and post-wash. RESULTS: Total pRBC wash efficiency was 94% ± 12% at a final hematocrit of 67.7 ± 5.9% while maintaining post-wash hemolysis 0.24 ± 0.12 %. Pre-dilution prior to washing did not confer statistically significant differences in final RBC quality parameters with the notable exceptions of calculated hemolysis and supernatant potassium levels (P < 0.05). The washing process can be completed within 10 min. The post-wash RBC parameters are appropriate for immediate transfusion to patients.
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OBJECTIVES: To estimate maximum jaw-opening forces in healthy participants of diverse ancestry and to estimate whether opening forces are associated with sex, age and anthropometric parameters such as height, weight and BMI. SETTING AND SAMPLE POPULATION: One hundred and forty-nine participants aged 20-60 years with overall good oral and general health. Exclusion criteria included myofascial or neck pain, symptomatic temporomandibular joint disorders (TMD), current orthodontic treatment or the absence of a natural dentition. MATERIAL AND METHODS: Jaw-opening forces were measured with an adjustable rigid extra-oral device connected to a 1000 N load cell. Seven attempts were recorded, with 10 seconds interval. Median force values were obtained after discarding the first and last attempt. The height and weight of each participant were measured and recorded, alongside age, sex and ethnicity. RESULTS: Men had greater maximum opening force median values than women (P < .001). Median (IQR) values for women were 41.16 N (30.44) and 79.00 N for men (63.86). Jaw-opening force values were poorly associated with biological and anthropometric parameters. CONCLUSION: In this study, which included a large sample of participants of broad age range and from a demographically diverse background, jaw-opening force values were greater in males than in females; however, force values were poorly associated with biological and anthropometric parameters. Future studies should explore the potential of this method as a screening tool for TMJ disorders and other conditions.
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Rango del Movimiento Articular/fisiología , Articulación Temporomandibular/fisiología , Adulto , Fenómenos Biomecánicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
Organisms can mitigate the effects of long term variation in environmental conditions through acclimation, which involves changes in various physiological responses. To elucidate the possible effects of temperature and food concentrations on acclimation capacity, physiological responses of the mussel, Perna viridis, were measured after individuals were held for six weeks under varying temperatures and food availability. Warm-acclimated mussels experiencing higher food levels had significantly greater upper thermal limits than those maintained on lower food levels. In contrast, the upper thermal limits of cold-acclimated mussels were not affected by food levels. For warm-acclimated mussels, differences in upper thermal limits were likely due to rapid depletion of energy storage as predicted by Dynamic Energy Budget model simulations for P. viridis exposed to lower food levels. Clearance rates of cold-acclimated mussels were significantly lower than warm-acclimated mussels, regardless of food availability. The impacts of lower food acquisition on energy storage, however, could be compensated by lower metabolic rates of the cold-acclimated mussels. The availability and the ability to acquire food are not, therefore, the main drivers differentiating between the upper thermal tolerances of cold- and warm-acclimated mussels, but these differences are driven by the past thermal history the mussels experienced. The temperature tolerance range of P. viridis showed a positive shift to tolerate higher temperatures after acclimation. Such flexibility in thermal tolerance implies P. viridis has high capacity to acclimate to novel environments, which will enhance its future success given its commercial importance as an aquaculture species.
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Dieta , Perna/fisiología , Termotolerancia , Animales , Metabolismo EnergéticoRESUMEN
There is considerable need to develop tailored approaches to psychiatric treatment. Numerous researchers have proposed using functional magnetic resonance imaging (fMRI) biomarkers to predict therapeutic response, in particular by measuring task-evoked subgenual anterior cingulate (sgACC) and amygdala activation in mood and anxiety disorders. Translating this to the clinic relies on the assumption that blood-oxygen-level dependent (BOLD) responses in these regions are stable within individuals. To test this assumption, we scanned a group of 29 volunteers twice (mean test-retest interval=14.3 days) and calculated the within-subject reliability of the amplitude of the amygdalae and sgACC BOLD responses to emotional faces using three paradigms: emotion identification; emotion matching; and gender classification. We also calculated the reliability of activation in a control region, the right fusiform face area (FFA). All three tasks elicited robust group activations in the amygdalae and sgACC (which changed little on average over scanning sessions), but within-subject reliability was surprisingly low, despite excellent reliability in the control right FFA region. Our findings demonstrate low statistical reliability of two important putative treatment biomarkers in mood and anxiety disorders.
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Mapeo Encefálico/métodos , Encéfalo/diagnóstico por imagen , Reconocimiento Facial/fisiología , Imagen por Resonancia Magnética/métodos , Adulto , Emociones/fisiología , Femenino , Humanos , Masculino , Trastornos Mentales/diagnóstico , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
PRKAG2 encodes the γ2-subunit isoform of 5'-AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in the regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload, ventricular preexcitation, and hypertrophy. We identified a novel, de novo PRKAG2 mutation (K475E) in a neonate with prenatal onset of HCM. We aimed to investigate the cellular impact, signaling pathways involved, and therapeutic options for K475E mutation using cells stably expressing human wild-type (WT) or the K475E mutant. In human embryonic kidney-293 cells, the K475E mutation induced a marked increase in the basal phosphorylation of T172 and AMPK activity, reduced sensitivity to AMP in allosteric activation, and a loss of response to phenformin. In H9c2 cardiomyocytes, the K475E mutation induced inhibition of AMPK and reduced the response to phenformin and increases in the phosphorylation of p70S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). Primary fibroblasts from the patient with the K475E mutation also showed marked increases in the phosphorylation of p70S6K and 4E-BP1 compared with those from age-matched, nondiseased controls. Moreover, overexpression of K475E induced hypertrophy in H9c2 cells, which was effectively reversed by treatment with rapamycin. Taken together, we have identified a novel, de novo infantile-onset PRKAG2 mutation causing HCM. Our study suggests the K475E mutation induces alteration in basal AMPK activity and results in a hypertrophy phenotype involving the mechanistic target of rapamycin signaling pathway, which can be reversed with rapamycin.NEW & NOTEWORTHY We identified a novel, de novo PRKAG2 mutation (K475E) in the cystathionine ß-synthase 3 repeat, a region critical for AMP binding but with no previous reported mutation. Our data suggest the mutation affects AMP-activated protein kinase activity, activates cell growth pathways, and results in cardiac hypertrophy, which can be reversed with rapamycin.
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Proteínas Quinasas Activadas por AMP/genética , Cardiomiopatía Hipertrófica/genética , Mutación Missense , Miocitos Cardíacos/enzimología , Transducción de Señal , Proteínas Quinasas Activadas por AMP/química , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Monofosfato/metabolismo , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Cardiomiopatía Hipertrófica/enzimología , Cardiomiopatía Hipertrófica/fisiopatología , Proteínas Portadoras/metabolismo , Estudios de Casos y Controles , Análisis Mutacional de ADN , Activación Enzimática , Fibroblastos/enzimología , Fibroblastos/patología , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular , Modelos Moleculares , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Fenformina/farmacología , Fenotipo , Fosfoproteínas/metabolismo , Fosforilación , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , TransfecciónRESUMEN
Behavioural decisions are often context-dependent, where information from immediate experience is incorporated into an individual's decision-making, particularly in complex environments. To test whether such mechanism is adopted by foragers in heterogeneous environments, we investigated the foraging behaviour of the deposit-feeding sand-bubbler crab, Scopimera intermedia An individual-based model was constructed, based on an optimal-patch selection criterion, which implicitly assumed that individuals adjust foraging decisions based on immediate past experience. The model's predictions were tested on the shore by manipulating the location of food patches, where the crab showed a strong context-dependent foraging pattern. When resources were randomly distributed, the crab responded by spending 56% of time in enriched patches compared with only 28% in the same area when patches were composed of natural sediments. Shore manipulations varying resource distribution supported the underlying principles of the model mechanism, and highlighted the benefits of such a strategy in heterogeneous environments such as intertidal sediments where food resources vary at different spatial and temporal scales. The proposed model therefore provides a mechanistic process, based on optimal foraging, to predict foraging decisions and movement patterns of animals feeding in heterogeneous landscapes.
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Conducta Apetitiva , Braquiuros/fisiología , Conducta Alimentaria , Animales , Toma de Decisiones , Ambiente , AprendizajeRESUMEN
Biogeographic distributions are driven by cumulative effects of smaller scale processes. Thus, vulnerability of animals to thermal stress is the result of physiological sensitivities to body temperature (Tb), microclimatic conditions, and behavioural thermoregulation. To understand interactions among these variables, we analysed the thermal tolerances of three species of intertidal snails from different latitudes along the Chinese coast, and estimated potential Tb in different microhabitats at each site. We then empirically determined the temperatures at which heart rate decreased sharply with rising temperature (Arrhenius breakpoint temperature, ABT) and at which it fell to zero (flat line temperature, FLT) to calculate thermal safety margins (TSM). Regular exceedance of FLT in sun-exposed microhabitats, a lethal effect, was predicted for only one mid-latitude site. However, ABTs of some individuals were exceeded at sun-exposed microhabitats in most sites, suggesting physiological impairment for snails with poor behavioural thermoregulation and revealing inter-individual variations (physiological polymorphism) of thermal limits. An autocorrelation analysis of Tb showed that predictability of extreme temperatures was lowest at the hottest sites, indicating that the effectiveness of behavioural thermoregulation is potentially lowest at these sites. These results illustrate the critical roles of mechanistic studies at small spatial scales when predicting effects of climate change.