RESUMEN
Parapanteles Ashmead (Braconidae: Microgastrinae) is a medium-sized genus of microgastrine wasps that was erected over a century ago and lacks a unique synapomorphic character, and its monophyly has not been tested by any means. Parapanteles usually are parasitoids of large, unconcealed caterpillars (macrolepidoptera) and have been reared from an unusually large diversity of hosts for a relatively small microgastrine genus. We used Cytochrome Oxidase I sequences ("DNA barcodes") available for Parapanteles and other microgastrines to sample the generic diversity of described and undescribed species currently placed in Parapanteles, and then sequenced four additional genes for this subsample (wingless, elongation factor 1-alpha, ribosomal subunit 28s, and NADH dehydrogenase subunit 1). We constructed individual gene trees and concatenated Bayesian and maximum-likelihood phylogenies for this 5-gene subsample. In these phylogenies, most Parapanteles species formed a monophyletic clade within another genus, Dolichogenidea, while the remaining Parapanteles species were recovered polyphyletically within several other genera. The latter likely represent misidentified members of other morphologically similar genera. Species in the monophyletic clade containing most Parapanteles parasitized caterpillars from only five families - Erebidae (Arctiinae), Geometridae, Saturniidae, Notodontidae, and Crambidae. We do not make any formal taxonomic decisions here because we were not able to include representatives of type species for Parapanteles or other relevant genera, and because we feel such decisions should be reserved until a comprehensive morphological analysis of the boundaries of these genera is accomplished.
Asunto(s)
Himenópteros/clasificación , Animales , Teorema de Bayes , Complejo IV de Transporte de Electrones/clasificación , Complejo IV de Transporte de Electrones/genética , Himenópteros/genética , Proteínas de Insectos/clasificación , Proteínas de Insectos/genética , NADH Deshidrogenasa/clasificación , NADH Deshidrogenasa/genética , Filogenia , ARN Ribosómico 28S/clasificación , ARN Ribosómico 28S/genéticaRESUMEN
Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.
Asunto(s)
Cromosomas Humanos Par 10/genética , Abuso de Marihuana/genética , Adulto , Negro o Afroamericano/genética , Alelos , Cannabis , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Población Blanca/genética , Adulto JovenRESUMEN
KEY POINTS: Oral consumption of nitrate (NO3(-)) in beetroot juice has been shown to decrease the oxygen cost of submaximal exercise; however, the mechanism of action remains unresolved. We supplemented recreationally active males with beetroot juice to determine if this altered mitochondrial bioenergetics. Despite reduced submaximal exercise oxygen consumption, measures of mitochondrial coupling and respiratory efficiency were not altered in muscle. In contrast, rates of mitochondrial hydrogen peroxide (H2O2) emission were increased in the absence of markers of lipid or protein oxidative damage. These results suggest that improvements in mitochondrial oxidative metabolism are not the cause of beetroot juice-mediated improvements in whole body oxygen consumption. ABSTRACT: Ingestion of sodium nitrate (NO3(-)) simultaneously reduces whole body oxygen consumption (VÌO2) during submaximal exercise while improving mitochondrial efficiency, suggesting a causal link. Consumption of beetroot juice (BRJ) elicits similar decreases in VÌO2 but potential effects on the mitochondria remain unknown. Therefore we examined the effects of 7-day supplementation with BRJ (280 ml day(-1), â¼26 mmol NO3(-)) in young active males (n = 10) who had muscle biopsies taken before and after supplementation for assessments of mitochondrial bioenergetics. Subjects performed 20 min of cycling (10 min at 50% and 70% VÌO2 peak) 48 h before 'Pre' (baseline) and 'Post' (day 5 of supplementation) biopsies. Whole body VÌO2 decreased (P < 0.05) by â¼3% at 70% VÌO2 peak following supplementation. Mitochondrial respiration in permeabilized muscle fibres showed no change in leak respiration, the content of proteins associated with uncoupling (UCP3, ANT1, ANT2), maximal substrate-supported respiration, or ADP sensitivity (apparent Km). In addition, isolated subsarcolemmal and intermyofibrillar mitochondria showed unaltered assessments of mitochondrial efficiency, including ADP consumed/oxygen consumed (P/O ratio), respiratory control ratios and membrane potential determined fluorometrically using Safranine-O. In contrast, rates of mitochondrial hydrogen peroxide (H2O2) emission were increased following BRJ. Therefore, in contrast to sodium nitrate, BRJ supplementation does not alter key parameters of mitochondrial efficiency. This occurred despite a decrease in exercise VÌO2, suggesting that the ergogenic effects of BRJ ingestion are not due to a change in mitochondrial coupling or efficiency. It remains to be determined if increased mitochondrial H2O2 contributes to this response.
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Beta vulgaris/química , Mitocondrias Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Consumo de Oxígeno , Extractos Vegetales/farmacología , Ejercicio Físico , Jugos de Frutas y Vegetales , Humanos , Masculino , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Extractos Vegetales/administración & dosificación , Adulto JovenRESUMEN
A taxonomic review of the genus Hypomicrogaster Ashmead is presented with the redescription and redelimitation of the already named species Hypomicrogaster ecus Nixon, H. imitator (Ashmead), H. tydeus Nixon and H. zonaria (Say). The review also implies eleven new synonymies, and a new combination for the species H. areolaris (Blanchard). Also, the present revision identified 40 new Hypomicrogaster species: Hypomicrogaster aodous n. sp., H. aplebis n. sp., H. cernus n. sp., H. crocinus n. sp., H. daktulios n. sp., H. deltis n. sp., H. duo n. sp., H. epipagis n. sp., H. espera n. sp., H. evrys n. sp., H. guille n. sp., H. hektos n. sp., H. hupsos n. sp., H. ingensis n. sp., H. insolitus n. sp., H. inversalis n. sp., H. koinos n. sp., H. largus n. sp., H. laxus n. sp., H. linearis n. sp., H. lineatus n. sp., H. luisi n. sp., H. masoni n. sp., H. mesos n. sp., H. mikrosus n. sp., H. multus n. sp., H. pectinatus n. sp., H. plagios n. sp., H. pollex n. sp., H. rugosus n. sp., H. scindus n. sp., H. sicingens n. sp., H. sicpollex n. sp., H. sicscindus n. sp., H. siderion n. sp., H. spatulae n. sp., H. specialis n. sp., H. tantillus n. sp., H. tetra n. sp., H. zan n. sp. The Hypomicrogaster species are using as hosts 11 families of Lepidoptera, and 52 confirmed lepidopteran species feeding on 34 families of plants. Additionally, a fully illustrated key to all known described species of Hypomicrogaster is presented.
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Himenópteros/anatomía & histología , Himenópteros/clasificación , Distribución Animal , Animales , Femenino , Himenópteros/genética , Masculino , Especificidad de la EspecieRESUMEN
Studies have shown increased incorporation of omega-3 fatty acids into whole skeletal muscle following supplementation, although little has been done to investigate the potential impact on the fatty acid composition of mitochondrial membranes and the functional consequences on mitochondrial bioenergetics. Therefore, we supplemented young healthy male subjects (n = 18) with fish oils [2 g eicosapentaenoic acid (EPA) and 1 g docosahexanoic acid (DHA) per day] for 12 weeks and skeletal muscle biopsies were taken prior to (Pre) and following (Post) supplementation for the analysis of mitochondrial membrane phospholipid composition and various assessments of mitochondrial bioenergetics. Total EPA and DHA content in mitochondrial membranes increased (P < 0.05) â¼450 and â¼320%, respectively, and displaced some omega-6 species in several phospholipid populations. Mitochondrial respiration, determined in permeabilized muscle fibres, demonstrated no change in maximal substrate-supported respiration, or in the sensitivity (apparent Km) and maximal capacity for pyruvate-supported respiration. In contrast, mitochondrial responses during ADP titrations demonstrated an enhanced ADP sensitivity (decreased apparent Km) that was independent of the creatine kinase shuttle. As the content of ANT1, ANT2, and subunits of the electron transport chain were unaltered by supplementation, these data suggest that prolonged omega-3 intake improves ADP kinetics in human skeletal muscle mitochondria through alterations in membrane structure and/or post-translational modification of ATP synthase and ANT isoforms. Omega-3 supplementation also increased the capacity for mitochondrial reactive oxygen species emission without altering the content of oxidative products, suggesting the absence of oxidative damage. The current data strongly emphasize a role for omega-3s in reorganizing the composition of mitochondrial membranes while promoting improvements in ADP sensitivity.
Asunto(s)
Ácidos Grasos Omega-3/administración & dosificación , Músculo Cuádriceps/metabolismo , Translocador 1 del Nucleótido Adenina/metabolismo , Translocador 2 del Nucleótido Adenina/metabolismo , Adenosina Difosfato/metabolismo , Respiración de la Célula/fisiología , Suplementos Dietéticos , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/farmacocinética , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/farmacocinética , Metabolismo Energético , Ácidos Grasos Omega-3/farmacocinética , Humanos , Peróxido de Hidrógeno/metabolismo , Cinética , Masculino , Mitocondrias Musculares/metabolismo , Membranas Mitocondriales/metabolismo , Estrés Oxidativo , Fosfolípidos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adulto JovenRESUMEN
Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2)î¶ 0.95), have previously been associated with risk for bipolar disorder.
Asunto(s)
Alcoholismo/genética , Cromosomas Humanos Par 15/genética , Estudio de Asociación del Genoma Completo , Sistemas de Lectura Abierta/genética , Evaluación de Síntomas , Alcoholismo/diagnóstico , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Endofenotipos , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer's disease (AD) is driven by the overproduction and spreading of first Amyloid-ßx-42 (Aß42) and later hyperphosphorylated (hp)-Tau oligomeric "infectious seeds". Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aß peptides specifically bind and activate the Ca(2+)-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aß42. While the Aß-exposed neurons start dying, astrocytes survive and keep oversecreting Aß42, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons' demise. Moreover, we have found that a highly selective allosteric CaSR agonist ("calcimimetic"), NPS R-568, mimics the just mentioned neurotoxic actions triggered by AßâCaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist ("calcilytic"), fully suppresses all the AßâCaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aß42 oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aß42 oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aß/CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology.
RESUMEN
Host-parasite systems have been models for understanding the connection between shifts in resource use and diversification. Despite theoretical expectations, ambiguity remains regarding the frequency and importance of host switches as drivers of speciation in herbivorous insects and their parasitoids. We examine phylogenetic patterns with multiple genetic markers across three trophic levels using a diverse lineage of geometrid moths (Eois), specialist braconid parasitoids (Parapanteles) and plants in the genus Piper. Host-parasite associations are mapped onto phylogenies, and levels of cospeciation are assessed. We find nonrandom patterns of host use within both the moth and wasp phylogenies. The moth-plant associations in particular are characterized by small radiations of moths associated with unique host plants in the same geographic area (i.e. closely related moths using the same host plant species). We suggest a model of diversification that emphasizes an interplay of factors including host shifts, vicariance and adaptation to intraspecific variation within hosts.
Asunto(s)
Cadena Alimentaria , Interacciones Huésped-Patógeno/genética , Mariposas Nocturnas/genética , Mariposas Nocturnas/parasitología , Piper/genética , Árboles , Avispas/genética , Animales , Secuencia de Bases , Teorema de Bayes , Biología Computacional , Costa Rica , ADN Mitocondrial/genética , Ecuador , Evolución Molecular , Especiación Genética , Interacciones Huésped-Patógeno/fisiología , Larva/parasitología , Larva/fisiología , Modelos Genéticos , Datos de Secuencia Molecular , Mariposas Nocturnas/clasificación , Mariposas Nocturnas/fisiología , Filogenia , Análisis de Secuencia de ADN , Avispas/fisiologíaRESUMEN
BACKGROUND: Point-of-care (POC) SARS-CoV-2 lateral-flow antigen detection (LFD) testing in the emergency department (ED) could inform rapid infection control decisions but requirements for safe deployment have not been fully defined. METHODS: Review of LFD test results, laboratory and POC-RT-PCR results and ED-performance metrics during a two-week high SARS-CoV-2 prevalence period followed by several months of falling prevalence. AIM: Determine whether LFD testing can be safely deployed in ED to provide an effective universal SARS-CoV-2 testing capability. FINDINGS: 93% (345/371) of COVID-19 patients left ED with a virological diagnosis during the 2-week universal LFD evaluation period compared to 77% with targeted POC-RT-PCR deployment alone, on background of approximately one-third having an NHS Track and Trace RT-PCR test-result at presentation. LFD sensitivity and specificity was 70.7% and 99.1% respectively providing a PPV of 97.7% and NPV of 86.4% with disease prevalence of 34.7%. ED discharge-delays (breaches) attributable to COVID-19 fell to 33/3532 (0.94%) compared with the preceding POC-RT-PCR period (107/4114 (2.6%); p=<0.0001). Importantly, LFD testing identified 1 or 2 clinically-unsuspected COVID-19 patients/day. Three clinically-confirmed LFD false positive patients were appropriately triaged based on LFD action-card flowchart, and only 5 of 95 false-negative LFD results were inappropriately admitted to non-COVID-19 areas where no onward-transmission was identified. LFD testing was restricted to asymptomatic patients when disease prevalence fell below 5% and detected 1-3 cases/week. CONCLUSION: Universal SARS-CoV-2 LFD testing can be safely and effectively deployed in ED alongside POC-RT-PCR testing during periods of high and low disease prevalence.
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AIMS/HYPOTHESIS: There has been much focus on the potential role of mitochondria in the aetiology of type 2 diabetes and the metabolic syndrome, and many case-control mitochondrial association studies have been undertaken for these conditions. We tested for a potential association between common mitochondrial variants and a number of quantitative traits related to type 2 diabetes in a large sample of >2,000 healthy Australian adolescent twins and their siblings, many of whom were measured on more than one occasion. METHODS: To the best of our knowledge, this is the first mitochondrial association study of quantitative traits undertaken using family data. The maternal inheritance pattern of mitochondria means established association methodologies are unsuitable for analysis of mitochondrial data in families. We present a methodology, implemented in the freely available program Sib-Pair for performing such an analysis. RESULTS: Despite our study having the power to detect variants with modest effects on these phenotypes, only one significant association was found after correction for multiple testing in any of four age groups. This was for mt14365 with triacylglycerol levels (unadjusted p = 0.0006). This association was not replicated in other age groups. CONCLUSIONS/INTERPRETATION: We find little evidence in our sample to suggest that common European mitochondrial variants contribute to variation in quantitative phenotypes related to diabetes. Only one variant showed a significant association in our sample, and this association will need to be replicated in a larger cohort. Such replication studies or future meta-analyses may reveal more subtle effects that could not be detected here because of limitations of sample size.
Asunto(s)
ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Síndrome Metabólico/genética , Adolescente , Glucemia/análisis , Niño , Diabetes Mellitus Tipo 2/sangre , Familia , Femenino , Geografía , Humanos , Lípidos/sangre , Masculino , Síndrome Metabólico/sangre , Grupos Raciales , HermanosRESUMEN
We provide the first phylogenetic evidence supporting complementary sex determination (CSD) as the ancestral mechanism for haplodiploidy in the Hymenoptera. It is currently not possible, however, to distinguish the evolutionary polarity of single locus (sl) CSD and multiple-locus (ml) CSD given the available data. In this light, we discuss the seemingly maladaptive hypothesis of ml-CSD ancestry, suggesting that collapse from ml-CSD to sl-CSD should remain a viable evolutionary hypothesis based on (i) likely weakening of frequency-dependent selection on sex alleles under ml-CSD and (ii) recent findings with respect to the evolutionary novelty of the complementary sex determiner gene in honeybees. Our findings help provide a phylogenetically informed blueprint for future sampling of sex determination mechanisms in the Hymenoptera, as they yield hypotheses for many unsampled or ambiguous taxa and highlight taxa whose further sampling will influence reconstruction of the evolutionary polarity of sex determination mechanisms in major clades.
Asunto(s)
Himenópteros/genética , Procesos de Determinación del Sexo , Animales , Femenino , Himenópteros/clasificación , Masculino , FilogeniaRESUMEN
Osteocytes and articular chondrocytes sense and respond to the strains imposed on bones and joints by various activities such as breathing and walking. This mechanoresponsiveness is needed to maintain bone and cartilage microstructure and strength. In bone the large number of osteocytes form a vast osteointernet in which the gap junctionally interconnected members are lodged in an extensive lacunocanalicular network. The much smaller number of articular chondrocytes are not interconnected in a chondrointernet. Instead, they are separately lodged in capsules called chondrons. While there are many possible strain-sensing devices, it now appears that the non-motile solitary (primary) cilia protruding like aerials from osteocytes (as well as osteoblasts) and chondrocytes are switches that when toggled by cyclical pulses of lacunocanalicular fluid or cartilage compression send signals such as Ca(2+) surges into the cell to trigger a cascade of events that include appropriate gene activations to maintain and strengthen bone and cartilage. Moreover, the chondrocyte cilium with its Ihh(Indian hedgehog)-activated Smo receptor is a key player along with PTHrP in endochondral bone formation.
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Condrocitos/metabolismo , Mecanotransducción Celular , Osteocitos/metabolismo , Animales , Huesos/citología , Señalización del Calcio , Cartílago/citología , Cilios/metabolismoRESUMEN
Sympathetic neurons require nerve growth factor for survival and die by apoptosis in its absence. Key steps in the death pathway include c-Jun activation, mitochondrial cytochrome c release, and caspase activation. Here, we show that neurons rescued from NGF withdrawal-induced apoptosis by expression of dominant-negative c-Jun do not release cytochrome c from their mitochondria. Furthermore, we find that the mRNA for BIM(EL), a proapoptotic BCL-2 family member, increases in level after NGF withdrawal and that this is reduced by dominant-negative c-Jun. Finally, overexpression of BIM(EL) in neurons induces cytochrome c redistribution and apoptosis in the presence of NGF, and neurons injected with Bim antisense oligonucleotides or isolated from Bim(-/-) knockout mice die more slowly after NGF withdrawal.
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Proteínas Portadoras/genética , Supervivencia Celular , Grupo Citocromo c/metabolismo , Quinasa 1 de Quinasa de Quinasa MAP , Proteínas de la Membrana , Mitocondrias/metabolismo , Neuronas/fisiología , Proteínas Proto-Oncogénicas c-jun/fisiología , Proteínas Proto-Oncogénicas , Adenoviridae/genética , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis , Proteína 11 Similar a Bcl2 , Proteínas Portadoras/fisiología , Caspasas/metabolismo , Células Cultivadas , Activación Enzimática , Expresión Génica , Ratones , Ratones Noqueados , Microinyecciones , Factor de Crecimiento Nervioso/administración & dosificación , Factor de Crecimiento Nervioso/fisiología , Neuronas/ultraestructura , Oligonucleótidos Antisentido/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-jun/genética , Ratas , Ratas Sprague-Dawley , Ganglio Cervical Superior/citología , TransfecciónRESUMEN
Sympathetic neurons depend on nerve growth factor (NGF) for survival and die by apoptosis in its absence. We have investigated the pattern of expression of the Jun and Fos family of transcription factors in dying sympathetic neurons using antibodies specific for each family member. When sympathetic neurons are deprived of NGF, the level of c-Jun protein significantly increases, whereas the levels of the other members of the Jun and Fos family remain relatively constant. c-Jun also becomes more phosphorylated, probably on its amino terminal transactivation domain. When microinjected into sympathetic neurons, an expression vector for a c-Jun dominant negative mutant protects them against NGF withdrawal-induced death, indicating that AP-1 activity is essential for neuronal cell death. Furthermore, overexpression of the full-length c-Jun protein is, in itself, sufficient to induce apoptosis in sympathetic neurons.
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Apoptosis/genética , Ganglios Simpáticos/citología , Genes jun , Mutación , Neuronas/fisiología , Animales , Secuencia de Bases , Células Cultivadas , Expresión Génica , Datos de Secuencia Molecular , Factores de Crecimiento Nervioso/farmacología , Factores de Crecimiento Nervioso/fisiología , Proteínas Proto-Oncogénicas c-jun/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
We have undertaken a study on variations in cholinesterase (ChE) genes in relation to cardiovascular (CV) function and the metabolic syndrome. Peripheral and central nervous system control of cardiovascular (CV) function mediated through cholinergic pathways is critical in homeostatic maintenance of blood pressure and responsiveness to stress. For acetylcholinesterase (AChE; EC 3.1.1.7) our focus is to identify single nucleotide polymorphisms (SNPs) in the gene that are linked to cardiovascular function. For butyrylcholinesterase (BChE; EC 3.1.1.8) we examined whether BChE activity correlated with parameters of the metabolic syndrome and cardiovascular function. ChE can be found in whole blood enabling a characterization of biochemical phenotype in addition to correlating genotype with phenotypic physiologic responses. Analysis of enzymatic activity was determined spectrophotometrically in blood samples from twin and other subject registries. Correlation analysis revealed significant relationships between enzyme activity and certain CV endpoints. Linkage analysis with data from a dizygotic (DZ) twin set showed a suggestive linkage at the BChE locus, and statistical analysis revealed a high correlation between BChE activity and variables associated with cardiovascular risk and the metabolic syndrome. Pattern of within-pair twin correlations by zygosity and the ACE model-fitting findings suggest the major source of this variation (65%) is attributable to an additive genetic component. To date 19 SNPs have been identified by the re-sequencing of AChE including four nonsynonymous coding SNPs (cSNPs).
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Acetilcolinesterasa/genética , Butirilcolinesterasa/genética , Farmacogenética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
NRK rat kidney cells infected with a temperature-sensitive mutant of the Kirsten sarcoma virus (ts371) were transformed at 36 degrees C but were phenotypically nontransformed at 41 degrees C because of the abnormal thermolability of the oncogenic 21-kilodalton product of the viral Ki-ras gene. Thus tsK-NRK cells were rendered quiescent in a G0-G1 state by a 48-h incubation in serum-free medium at the nonpermissive, p21-inactivating temperature of 41 degrees C. The serum-starved cells could then be stimulated to transit G1 either as nontransformed cells by adding serum at 41 degrees C or as transformed cells by lowering the temperature to a p21-activating 36 degrees C. The viral p21 protein was as effective as serum in stimulating tsK-NRK cells to transit G1 and to start replicating DNA. While p21 effectively stimulated cells to transit G1 even in unconditioned, serum-free medium, they still needed cell-derived conditioning factors to subsequently divide. The p21 protein also enabled the cells to transit G1 in spite of an extracellular Ca2+ deficiency that inhibited the G1 transit of serum-stimulated cells. p21 activity was needed to stimulate both early and late G1 events. In contrast to serum, p21 did not stimulate total RNA or protein synthesis, but some RNA and protein synthesis must have been needed for the p21-driven G1 transit because it could be stopped by actinomycin D or cycloheximide.
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Transformación Celular Neoplásica , Genes Virales , Virus del Sarcoma Murino de Kirsten/genética , Proteínas Oncogénicas Virales/genética , Oncogenes , Virus del Sarcoma Murino/genética , Animales , Ciclo Celular , Línea Celular , Replicación del ADN , Interfase , Cinética , Mitógenos , Proteína Oncogénica p21(ras) , Proteínas Oncogénicas Virales/fisiología , Biosíntesis de Proteínas , Ratas , Transcripción GenéticaRESUMEN
NRK cells infected with a temperature-sensitive Kirsten sarcoma virus (ts371 KSV) are transformed at 36 degrees C, but are untransformed at 41 degrees C which inactivates the abnormally thermolabile oncogenic p21Ki product of the viral Ki-ras gene. At 41 degrees C, tsKSV-infected NRK cells were arrested in G0/G1 when incubated in serum-free medium, but could then be stimulated to transit G1, replicate DNA, and divide by adding serum at 41 degrees C or dropping the temperature to a p21-activating 36 degrees C without adding serum. When quiescent cells at 41 degrees C were stimulated to transit G1 in serum-free medium by activating p21 at 36 degrees C and then shifted back to the p21-inactivating 41 degrees C in the mid-S phase, they continued replicating DNA but could not transit G2. Reactivating p21 in the G2-arrested cells by once again lowering the temperature to 36 degrees C stimulated a rapid entry into mitosis. By contrast, while serum-stimulated quiescent G0 cells at 41 degrees C replicate DNA and divide, serum did not induce G2-arrested cells to enter mitosis, indicating that serum growth factors may trigger events in the G1 phase that ultimately determine G2 transit. These observations made with the viral ras product suggest that cellular ras proto-oncogene products have a role in G2 transit of normal cells.
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Transformación Celular Neoplásica , Genes Virales , Interfase , Virus del Sarcoma Murino de Kirsten/genética , Oncogenes , Virus del Sarcoma Murino/genética , Animales , Ciclo Celular , Línea Celular , Medios de Cultivo , Riñón , Cinética , Mitosis , Ratas , TemperaturaRESUMEN
Kuru is a prion disease which became epidemic among the Fore and surrounding linguistic groups in Papua New Guinea, peaking in the late 1950s. It was transmitted during the transumption (endocannibalism) of dead family members at mortuary feasts. In this study, we aimed to explain the historical spread and the changing epidemiological patterns of kuru by analysing factors that affected its transmission. We also examined what cultural group principally determined a family's behaviour during mortuary rituals. Our investigations showed that differences in mortuary practices were responsible for the initial pattern of the spread of kuru and the ultimate shape of the epidemic, and for subsequent spatio-temporal differences in the epidemiology of kuru. Before transumption stopped altogether, the South Fore continued to eat the bodies of those who had died of kuru, whereas other linguistic groups, sooner or later, stopped doing so. The linguistic group was the primary cultural group that determined behaviour but at linguistic boundaries the neighbouring group's cultural practices were often adopted. The epidemiological changes were not explained by genetic differences, but genetic studies led to an understanding of genetic susceptibility to kuru and the selection pressure imposed by kuru, and provided new insights into human history and evolution.
RESUMEN
Evidence is accumulating that suggests that Ca2+-calmodulin (Ca2+-CaM) and the protein kinase Cs (PKCs) obstruct each other's actions because of the embedding of PKC phosphorylation sites in CaM or Ca2+-CaM-binding domains of a growing number of crucial substrates in neurons (and other cells). These substrates include the CaM storage proteins (neurogranin, neuromodulin), the membrane-associated MARCKS (myristoylated alanine-rich C-kinase substrate) protein, the NMDA receptor RI subunit and the autoinhibitory domain of the plasma membrane Ca2+ pump. In this review, the emerging data are woven into a hypothetical picture of the conflicting, timing-dependent convergence of two major signalers on neuronal functions.
Asunto(s)
Calcio/metabolismo , Calmodulina/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana , Modelos Neurológicos , Proteína Quinasa C/metabolismo , Secuencia de Aminoácidos/genética , Animales , Proteínas de Unión a Calmodulina/genética , Proteína GAP-43/genética , Datos de Secuencia Molecular , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada , Proteínas del Tejido Nervioso/genética , Neurogranina , Proteínas/genética , Especificidad por SustratoRESUMEN
Cells from the thigh muscles of normal fetal rats proliferated rapidly and indefinitely in a medium containing adult rat "plasma" and a normal free-calcium concentration, but they could not proliferate in calcium-deficient plasma medium. As the animals grew older, the cells became increasingly less able to proliferate even in normal (high-calcium) plasma medium, though they retained the potential to proliferate in a more conventional medium containing fetal bovine serum. By contrast, neoplastic adult cells from malignant rhabdomyosarcomas (induced by Ni3S2) proliferated rapidly and indefinitely in both normal and low-calcium plasma medium