RESUMO
Event boundaries impose structure on how events are stored in long-term memory. Research with young adults has shown that associations within events are stronger than those that cross event boundaries. Recently, this effect was observed in both young and old adults using movie stimuli (Davis, Chemnitz, et al., 2021). Here, we test whether this effect extends to written narratives. Young and old participants read a series of narratives that were interspersed with temporal shifts in the storyline meant to elicit the perception of an event boundary. Later, participants were cued with sentences and were asked to recall the sentence that immediately followed. We expected participants would have worse memory when a cue and correct answer flanked a boundary than when it did not. In Experiment 1, we found that despite older adults' lower performance overall, both age groups had lower accuracy for cues that flanked a boundary, compared to cues that elicited a response from within the same event. Experiment 2 replicated the results from Experiment 1. Our results support past work that did not find age differences in event perception and demonstrate that older and younger adults may store events similarly in long-term memory.
Assuntos
Memória de Longo Prazo , Rememoração Mental , Adulto Jovem , Humanos , Idoso , Memória de Longo Prazo/fisiologia , Rememoração Mental/fisiologia , Sinais (Psicologia) , Idioma , Transtornos da Memória , Envelhecimento/fisiologiaRESUMO
Skeletal dysplasias are challenging to diagnose because of their phenotypic variability, genetic heterogeneity, and diverse inheritance patterns. We conducted whole exome sequencing of a Turkish male with a suspected X-linked skeletal dysplasia of unknown etiology as well as his unaffected mother and maternal uncle. Bioinformatic filtering of variants implicated in skeletal system development revealed a novel hemizygous mutation, c.341-(11_9)delAAT, in an intron of TRAPPC2, the causative locus of spondyloepiphyseal dysplasia tarda (SEDT). We show that this deletion leads to the loss of wild-type TRAPPC2 and the generation of two functionally impaired mRNAs in patient cells. These consequences are predicted to disrupt function of SEDLIN/TRAPPC2. The clinical and research data were returned, with appropriate caveats, to the patient and informed his disease status and reproductive choices. Our findings expand the allelic repertoire of SEDT and show how prior filtering of the morbid human genome informed by inheritance pattern and phenotype, when combined with appropriate functional tests in patient-derived cells, can expedite discovery, overcome issues of missing data and help interpret variants of unknown significance. Finally, this example shows how the return of a clinically confirmed mutational finding, supported by research allele pathogenicity data, can assist individuals with inherited disorders with life choices.
Assuntos
Proteínas de Membrana Transportadoras/genética , Mutação , Osteocondrodisplasias/genética , Fatores de Transcrição/genética , Adulto , Éxons , Feminino , Humanos , Recém-Nascido , Íntrons , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Linhagem , Fatores de Transcrição/metabolismoRESUMO
Bardet-Biedl syndrome (BBS) is a rare pediatric ciliopathy characterized by marked clinical variability and extensive genetic heterogeneity. Typical diagnosis of BBS is secured at a median of 9 years of age, and sometimes well into adolescence. Here, we report a patient in whom prenatal detection of increased nuchal fold, enlarged echogenic kidneys, and polydactyly prompted us to screen the most commonly mutated genes in BBS and the phenotypically and genetically overlapping ciliopathy, Meckel-Gruber syndrome (MKS). We identified the common Met390Arg mutation in BBS1 in compound heterozygosity with a novel intronic variant of unknown significance (VUS). Testing of mRNA harvested from primary foreskin fibroblasts obtained shortly after birth revealed the VUS to induce a cryptic splice site, which in turn led to a premature termination and mRNA degradation. To our knowledge, this is the earliest diagnosis of BBS in the absence of other affected individuals in the family, and exemplifies how combining clinical assessment with genetic and timely assays of variant pathogenicity can inform clinical diagnosis and assist with patient management in the prenatal and neonatal setting.
Assuntos
Síndrome de Bardet-Biedl/genética , Testes Genéticos/métodos , Proteínas Associadas aos Microtúbulos/genética , Mutação , Ultrassonografia Pré-Natal , Sequência de Aminoácidos , Síndrome de Bardet-Biedl/diagnóstico , Sequência de Bases , Células Cultivadas , Análise Mutacional de DNA , Feminino , Fibroblastos/metabolismo , Prepúcio do Pênis/citologia , Humanos , Recém-Nascido , Masculino , GravidezRESUMO
Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.
Assuntos
Síndrome de Bardet-Biedl/diagnóstico , Síndrome de Bardet-Biedl/genética , Mutação , Adulto , Idoso , Cromatografia Líquida de Alta Pressão , Mapeamento Cromossômico , Árvores de Decisões , Feminino , Deleção de Genes , Duplicação Gênica , Frequência do Gene , Testes Genéticos , Homozigoto , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNARESUMO
BACKGROUND: Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive disorder characterised by the five cardinal features retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity and hypogenitalism. In addition, renal cysts and other anomalies of the kidney and urinary tract can be present. To date, mutations in 12 BBS genes as well as in MKS1 and CEP290 have been identified as causing BBS. The vast genetic heterogeneity of BBS renders molecular genetic diagnosis difficult in terms of the time and cost required to screen all 204 coding exons. METHOD: Here, the use of genome-wide homozygosity mapping as a tool to identify homozygous segments at known BBS loci, in BBS individuals from inbred and outbred background, is reported. RESULTS: In a worldwide cohort of 45 families, causative homozygous mutations in 20 families were identified via direct exon sequencing. Eleven of these mutations were novel, thereby increasing the number of known BBS mutations by 5% (11/218). CONCLUSIONS: Thus, in the presence of extreme genetic locus heterogeneity, homozygosity mapping provides a valuable approach to the molecular genetic diagnosis of BBS and will facilitate the discovery of novel pathogenic mutations.
Assuntos
Síndrome de Bardet-Biedl/genética , Mutação , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico/métodos , Estudos de Coortes , Consanguinidade , Estudos de Associação Genética , Genoma Humano , Homozigoto , Humanos , Dados de Sequência Molecular , Fenótipo , Proteínas/genéticaRESUMO
Hydrothermal circulation within the sea floor, through lithosphere older than one million years (Myr), is responsible for 30% of the energy released from plate cooling, and for 70% of the global heat flow anomaly (the difference between observed thermal output and that predicted by conductive cooling models). Hydrothermal fluids remove significant amounts of heat from the oceanic lithosphere for plates typically up to about 65 Myr old. But in view of the relatively impermeable sediments that cover most ridge flanks, it has been difficult to explain how these fluids transport heat from the crust to the ocean. Here we present results of swath mapping, heat flow, geochemistry and seismic surveys from the young eastern flank of the Juan de Fuca ridge, which show that isolated basement outcrops penetrating through thick sediments guide hydrothermal discharge and recharge between sites separated by more than 50 km. Our analyses reveal distinct thermal patterns at the sea floor adjacent to recharging and discharging outcrops. We find that such a circulation through basement outcrops can be sustained in a setting of pressure differences and crustal properties as reported in independent observations and modelling studies.
RESUMO
Intravenous administration of a humanized monoclonal antibody of IgE (E25) attenuates the early and late phase response to inhaled allergen in allergic asthmatic subjects. To test whether direct delivery of E25 to the airway might have the same effect, we conducted a randomized, double-blind, three group study in 33 subjects with mild allergic asthma (20 to 46 yr of age, 21 men, FEV(1) > 70% predicted). The airway responses to aerosolized allergen were determined at baseline, after 2 and 8 wk of once daily treatment with aerosolized placebo (n = 11), aerosolized E25 1 mg (n = 12), or aerosolized E25 10 mg (n = 10), and after 4 wk of treatment withdrawal. We found that E25 was detectable in the serum during aerosol treatment, although serum IgE did not change significantly in any of the three groups during treatment. In addition, both doses of E25 were no more effective than placebo in attenuating the early phase responses to allergen at both times during treatment. Although aerosolized E25 was generally well tolerated, one subject receiving aerosolized E25 10 mg daily was found to have serum IgG and IgA antibodies to E25. We conclude that aerosol administration of an anti-IgE monoclonal antibody does not inhibit the airway responses to inhaled allergen in allergic asthmatic subjects. We speculate that the observed lack of efficacy may be due to the inability of aerosol route of delivery to result in high enough concentrations of E25 in the tissue compartments surrounding IgE effector cells to neutralize IgE arising from local airway and pulmonary sources and IgE arising from the vascular space. Additionally, the aerosol route of delivery of monoclonal antibodies may be more immunogenic than the parenteral route.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Asma/terapia , Imunoglobulina E/imunologia , Administração por Inalação , Adulto , Aerossóis , Alérgenos/imunologia , Anticorpos Monoclonais/administração & dosagem , Área Sob a Curva , Asma/imunologia , Asma/fisiopatologia , Testes de Provocação Brônquica , Método Duplo-Cego , Feminino , Humanos , Hipersensibilidade Tardia/fisiopatologia , Hipersensibilidade Tardia/terapia , Hipersensibilidade Imediata/fisiopatologia , Hipersensibilidade Imediata/terapia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Estatísticas não ParamétricasRESUMO
BACKGROUND: Regular use of salmeterol has been associated with reduced bronchoprotective effect against methacholine as early as 24 hours after initiating treatment. OBJECTIVE: To determine whether loss of the bronchoprotective effect measured one hour after salmeterol could be demonstrated 12 hours following one previous dose. METHODS: Ten subjects with stable, mild asthma were enrolled in a randomized, placebo-controlled, double-blind, crossover study comparing two 2-dose treatment periods: (1) blinded salmeterol 50 microg inhaled at bedtime, followed by unblinded salmeterol 50 microg inhaled 12 hours later and (2) blinded placebo inhaled at bedtime, followed by unblinded salmeterol 50 microg inhaled 12 hours later. The methacholine PC20 was measured one hour after the morning salmeterol; FEV1 was measured just prior to the morning salmeterol dose and at the start of the methacholine inhalation test. RESULTS: The mean log methacholine PC20 recorded one hour after a single dose of salmeterol (1.20 +/- 0.17 SE) was significantly higher than the mean log methacholine PC20 recorded after two doses of salmeterol at 12-hour intervals (1.00 +/- 0.16 SE; P = .024). The mean FEV1 12 hours after salmeterol was significantly higher than the mean FEV1 recorded 12 hours after placebo (P = .0017), however, there was no significant difference between the FEV1 recordings one hour after the two unblinded doses of salmeterol. CONCLUSIONS: Tolerance to the bronchoprotective effect of salmeterol against methacholine induced bronchoconstriction occurs extremely quickly as it is evident 12 hours after starting twice daily treatment.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Albuterol/análogos & derivados , Asma/fisiopatologia , Brônquios/efeitos dos fármacos , Administração por Inalação , Adulto , Albuterol/administração & dosagem , Asma/tratamento farmacológico , Brônquios/fisiopatologia , Testes de Provocação Brônquica , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Tolerância a Medicamentos , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Cloreto de Metacolina , Pessoa de Meia-Idade , Xinafoato de SalmeterolRESUMO
The following papers will tell us much about our current knowledge of certain aspects of the olfactory control of mosquito behaviour-specifically host-locating behaviour. More importantly, as we read the papers, we should pay attention to the insights they will provide about what is not known and to the questions that our lack of knowledge should raise. The authors will also provide us with some new approaches and methodologies that we can apply to the study of mosquito physiology and behaviour.
Assuntos
Comportamento Apetitivo , Culicidae/fisiologia , Condutos Olfatórios , Oviposição , Animais , Feminino , HumanosRESUMO
Hematophagous insects use air-borne chemical cues to guide them to resources such as blood-meal hosts, plants, and oviposition sites. Research that combines behavioral and electrophysiological approaches to the study of how insects find these resources can result in useful information about what chemical signals a mosquito can detect and at what airborne concentrations such compounds are effective. Such studies have helped clarify the role of lactic acid, ammonia, carbon dioxide, octenol, phenols, temperature, and humidity in the attraction of mosquitoes, tsetse flies, and ticks to blood-meal hosts. Egg raft pheromone, indoles, cresols, methyl cyclohexanol, 2-butoxy ethanol, and fatty acid esters have been examined with respect to oviposition site location and selection. Plant volatiles have received less attention but electrophysiological responses to terpenes and green plant volatiles have been observed. Information from studies of this type can be useful in the design of both attractants and more effective repellents.
Assuntos
Comportamento Animal , Culicidae/fisiologia , Animais , Eletrofisiologia , Humanos , Células Receptoras SensoriaisRESUMO
The insect repellent, N,N-diethyl-m-toluamide (deet), interferes with detection of the host attractant, lactic acid (LA), by LA-excited neurons on the antennae of female Aedes aegypti (L.) mosquitoes. In the current laboratory behavioral experiment, the attraction of gravid female mosquitoes to a source of ethyl propionate, an oviposition attractant, was reduced by a factor of two when deet was present. Similarly, when deet was presented together with ethyl propionate in electrophysiological experiments, sensitivity of the neural response to ethyl propionate was depressed in a transient, dose-dependent manner that could account for the reduction in behavioral attraction of gravid females to ethyl propionate. Electrophysiologically, the sensitivity of oviposition attractant receptors to ethyl propionate on gravid females was not different from that on nongravid host-seeking females. The similarity between the depression of sensitivity of the oviposition attractant-sensitive neurons induced by deet and that observed in the host attractant-sensitive neurons suggest a common mode of action of deet on peripheral chemoreceptor neurons that mediate these behaviors.
Assuntos
Aedes , DEET , Oviposição/efeitos dos fármacos , Animais , Eletrofisiologia , FemininoRESUMO
Auditory, visual and somatosensory evoked potentials (EPs), recorded epidurally from 31 chronically implanted male Long-Evans rats, were studied to examine the pattern of sensory effects caused by hypercapnia. Recordings were obtained before exposures, 10-20 min after the beginning of exposure to CO2 in synthetic air, and 30 min after the end of exposure. Previous recordings revealed no substantial effects of the extended recording period itself. Blood pH during an average exposure of 18.8% CO2 was about 7.1. During this level of CO2 exposure the somatosensory response was almost completely abolished, but the latencies of early detectable components were not affected. In contrast, the latencies of all brainstem auditory evoked response components and the 1-5 interwave time increased, whereas amplitudes were only slightly affected. Amplitudes and latencies of early and late components of the flash EP were decreased and lengthened, but the after-discharge components appeared to be most sensitive to CO2. Concentration-response relationships were examined by exposure of rats to 8 and 16% CO2. The most sensitive EP parameter was average amplitude of the late somatosensory EP components. These results suggest that EPs might be useful for assessing acute metabolic disturbances as well as more commonly assessed neurologic disorders.
Assuntos
Acidose Respiratória/fisiopatologia , Encéfalo/fisiopatologia , Animais , Potenciais Evocados Auditivos , Potenciais Somatossensoriais Evocados , Potenciais Evocados Visuais , Masculino , Ratos , Tempo de ReaçãoRESUMO
Host-seeking behaviour in newly emerged Aedes aegypti (L.) females is not expressed immediately after adult eclosion but develops gradually over a period of approximately 3-4 days. This development is accompanied by an apparent maturation of the antennal chemosensory afferent neurons involved in the detection of the airborne host attractant lactic acid. Since these events coincide in time with juvenile hormone-dependent previtellogenic ovarian growth and since the expression of other reproduction-associated behaviour has previously been shown to be dependent on juvenile hormone, the effects of juvenile hormone removal and replacement on the development of host-seeking behaviour and the response characteristics of the lactic acid-sensitive receptors were investigated. No effect of juvenile hormone removal by allatectomy or juvenile hormone replacement or augmentation by topical application of the juvenile hormone mimic methoprene was found. It was concluded that this hormone is not involved in the appearance of host-seeking behaviour or the apparent maturation of the lactic acid receptors that occurs during early imaginal life.
Assuntos
Aedes/fisiologia , Corpora Allata/fisiologia , Hormônios Juvenis/fisiologia , Lactatos/metabolismo , Animais , Feminino , Interações Hospedeiro-Parasita , Ácido Láctico , Metoprene/farmacologiaRESUMO
The occurrence of a genital sex pheromone in the anterior reproductive tract of partially fed femaleDermacentor variabilis was demonstrated by extraction and bioassay. A new type of bioassay, the "neutered" female assay, was developed to test the potency of extracts or chemically defined fractions to stimulate males to copulate. Electrophysiological tests confirmed the ability of males to detect the pheromone with sensilla on their cheliceral digits. Males of bothD. variabilis andD. andersoni exhibited neuronal excitation when stimulated with extracts of theD. variabilis reproductive tissues. The pheromone, which is soluble in methanol, was fractionated and found to contain at least two fractions that stimulated copulation by sexually excited males. Evidently, the pheromone is a mixture of two or more compounds. Histologic, ultrastructural, and histochemical studies suggest the vestibular vagina as the site of genital sex pheromone occurrence, presumably from secretions of the surrounding lobular accessory gland. The identity of the compounds that comprise the pheromone remains unknown.
RESUMO
A high-strength, high-ductility, austenitic stainless steel has been evaluated for use in surgical implants by performing in vivo tests in rats, rabbits, dogs, and rhesus monkeys. This stainless steel, a TRIP (Transformation Induced Plasticity) steel containing about 4% Mo, was compared with two alloys in current clinical use: Type 316L stainless steel and cast Vitallium. Compared with the other two alloys, cast Vitallium generally had higher resistance to corrosion and superior biocompatibility in all animals. The tests in rats and dogs indicated that the corrosion resistances of the TRIP steel and the Type 316L stainless steel were similar and that the tissue reactions caused by these alloys were also similar. However, in rhesus monkeys, the TRIP steel was shown to be susceptible to stress-corrosion cracking and much more susceptible to crevice corrosion than Type 316L stainless steel. Limited tests in rabbits supported the observation that the TRIP steel is susceptible to stress-corrosion cracking. These inconsistencies in the in vivo tests underline the need for a reevaluation of the popular test techniques and of the animals commonly chosen for assessing the suitability of candidate implant materials. The "worst case" results from the rhesus monkey tests were entirely consistent with previous results obtained from in vitro studies. However, further work must be performed before the behavior of metals in humans, rhesus monkeys, or any other animal, can be predicted with confidence from an in vitro test program.