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Detecting microevolutionary responses to natural selection by observing temporal changes in individual breeding values is challenging. The collection of suitable datasets can take many years and disentangling the contributions of the environment and genetics to phenotypic change is not trivial. Furthermore, pedigree-based methods of obtaining individual breeding values have known biases. Here, we apply a genomic prediction approach to estimate breeding values of adult weight in a 35-year dataset of Soay sheep (Ovis aries). Comparisons are made with a traditional pedigree-based approach. During the study period, adult body weight decreased, but the underlying genetic component of body weight increased, at a rate that is unlikely to be attributable to genetic drift. Thus cryptic microevolution of greater adult body weight has probably occurred. Genomic and pedigree-based approaches gave largely consistent results. Thus, using genomic prediction to study microevolution in wild populations can remove the requirement for pedigree data, potentially opening up new study systems for similar research.
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Genoma , Genómica , Animales , Peso Corporal , Genotipo , Modelos Genéticos , Linaje , Fenotipo , OvinosRESUMEN
PURPOSE: All-inside meniscal repair devices have evolved to allow surgeons to undertake complex repairs in a timely and efficient manner. This is advantageous in active patients, where meniscus preservation is critical in preserving joint function and stability. The aim of the study was to evaluate the failure rate of all-inside meniscal repair performed in patients undergoing reconstructive ligament surgery using a particular meniscal repair device. METHODS: Patients were identified using a single-site prospectively maintained patient registry. Primary outcome was failure, defined as return to surgery with documented failure of repair. Complication rates and functional scores were also recorded. Patients in whom meniscal repair failure was identified were further assessed, to identify any common features. RESULTS: Over an 8-year period, 323 patients underwent meniscal repair at the time of ligament reconstruction, compared to 244 meniscectomies. Of these, 286 patients underwent repair using an all-inside suture device. One-hundred and twenty-seven repairs were to the medial meniscus only, 124 were lateral, and in 35 patients both menisci were repaired. Follow-up was to a median of 51.5 months. There were 31 (9.7%) failures reported at a median of 22 months post-operatively (IQR 13.5-41.5). Medial repair failures were seen more frequently than lateral (13.6% versus 5.6% OR 2.62 95% CI 1.17-5.88 p = 0.022). Failure of ACL reconstruction was associated with meniscal repair failure (OR 5.83 95% CI 1.55-21.95 p = 0.0039). Multi-ligament reconstruction was undertaken in 70/286 patients receiving meniscal repair and was not associated with failure (OR 1.3 95% CI 0.57-2.98 p = 0.51). Mode number of all-inside sutures used was 3 in both medial and lateral repairs (Range 1-9 lateral; 1-7 medial). CONCLUSIONS: All-inside repair is a safe and versatile technique which can be used in the majority of meniscal tears encountered during ligament reconstruction with excellent mid-term success. Failure is seen more commonly in medial sided repairs and with failure of ACL reconstruction. LEVEL OF EVIDENCE: IV.
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Articulación de la Rodilla/cirugía , Ligamentos Articulares/cirugía , Procedimientos de Cirugía Plástica/métodos , Lesiones de Menisco Tibial/cirugía , Adolescente , Adulto , Anciano , Ligamento Cruzado Anterior/cirugía , Lesiones del Ligamento Cruzado Anterior/cirugía , Reconstrucción del Ligamento Cruzado Anterior/métodos , Niño , Femenino , Humanos , Traumatismos de la Rodilla/cirugía , Masculino , Meniscectomía/métodos , Meniscos Tibiales/cirugía , Persona de Mediana Edad , Estudios Prospectivos , Suturas , Adulto JovenRESUMEN
The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive. Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell-neurite complexes. It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron; however, major aspects of touch sensation remain intact without Merkel cell activity. Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.
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Canales Iónicos/metabolismo , Mecanotransducción Celular/fisiología , Piel/inervación , Tacto/fisiología , Animales , Canales Iónicos/genética , Mecanorreceptores/metabolismo , Mecanotransducción Celular/genética , Células de Merkel/fisiología , Ratones , Ratones Noqueados , Células Receptoras Sensoriales/fisiología , Tacto/genéticaRESUMEN
The vertebrate stress response enables individuals to react to and cope with environmental challenges. A crucial aspect of the stress response is the elevation of circulating glucocorticoids. However, continued activation of the stress response under repeated exposure to stressors can be damaging to fitness. Under certain circumstances it may therefore be adaptive to habituate to repeated exposures to a particular stressor by reducing the magnitude of any associated release of glucocorticoids. Here, we investigate whether Trinidadian guppies (Poecilia reticulata) habituate to repeated exposure to a mild stressor, using a waterborne hormone sampling approach that has previously been shown to elicit a stress response in small fish. We also test for individual variation in the extent of habituation to this stressor. Concentrating on freely circulating cortisol, we found that the first exposure to the assay induced high cortisol release rates but that guppies tended to habituate quickly to subsequent exposures. There were consistent differences among individuals in their average cortisol release rate (after accounting for effects of variables such as body size) over repeated exposures. Our analyses did not find evidence of individual differences in habituation rate, although limitations in statistical power could account for this finding. We repeated the analysis for free 11-ketotestosterone, which can also respond to stressors, but found no obvious habituation pattern and no among-individual variation. We also present data on conjugated forms of both hormones, which were repeatable but did not show the expected time-lagged habituation effect. We discuss consistent individual differences around the general pattern of habituation in the flexible stress response, and highlight the potential for individual variation in habituation to facilitate selection against the deleterious effects of chronic stress.
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Hidrocortisona/metabolismo , Trastornos Relacionados con Sustancias/metabolismo , Animales , Hidrocortisona/análisis , Individualidad , Masculino , PoeciliaRESUMEN
When estimating heritability in free-living populations, it is common practice to account for common environment effects, because of their potential to generate phenotypic covariance among relatives thereby biasing heritability estimates. In quantitative genetic studies of natural populations, however, philopatry, which results in relatives being clustered in space, is rarely accounted for. The two studies that have been carried out so far suggest absolute declines in heritability estimates of up to 43% when accounting for space sharing by relatives. However, due to methodological limitations these estimates may not be representative. We used data from the St. Kilda Soay sheep population to estimate heritabilities with and without accounting for space sharing for five traits for which there is evidence for additive genetic variance (birthweight, birth date, lamb August weight, and female post-mortem jaw and metacarpal length). We accounted for space sharing by related females by separately incorporating spatial autocorrelation, and a home range similarity matrix. Although these terms accounted for up to 18% of the variance in these traits, heritability estimates were only reduced by up to 7%. Our results suggest that the bias caused by not accounting for space sharing may be lower than previously thought. This suggests that philopatry does not inevitably lead to a large bias if space sharing by relatives is not accounted for. We hope our work stimulates researchers to model shared space when relatives in their study population share space, as doing so will enable us to better understand when bias may be of particular concern.
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Variación Genética , Fenotipo , Ovinos/genética , Animales , Peso al Nacer , Peso Corporal , Femenino , Patrón de Herencia , Ovinos/anatomía & histología , Oveja DomésticaRESUMEN
Male fitness is dependent on sexual traits that influence mate acquisition (precopulatory sexual selection) and paternity (post-copulatory sexual selection), and although many studies have documented the form of selection in one or the other of these arenas, fewer have done it for both. Nonetheless, it appears that the dominant form of sexual selection is directional, although theoretically, populations should converge on peaks in the fitness surface, where selection is stabilizing. Many factors, however, can prevent populations from reaching adaptive peaks. Genetic constraints can be important if they prevent the development of highest fitness phenotypes, as can the direction of selection if it reverses across episodes of selection. In this study, we examine the evidence that these processes influence the evolution of the multivariate sex comb morphology of male Drosophila simulans. To do this, we conduct a quantitative genetic study together with a multivariate selection analysis to infer how the genetic architecture and selection interact. We find abundant genetic variance and covariance in elements of the sex comb. However, there was little evidence for directional selection in either arena. Significant nonlinear selection was detected prior to copulation when males were mated to nonvirgin females, and post-copulation during sperm offence (again with males mated to nonvirgins). Thus, contrary to our predictions, the evolution of the D. simulans sex comb is limited neither by genetic constraints nor by antagonistic selection between pre- and post-copulatory arenas, but nonlinear selection on the multivariate phenotype may prevent sex combs from evolving to reach some fitness maximizing optima.
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Evolución Biológica , Fenotipo , Caracteres Sexuales , Conducta Sexual Animal , Animales , Copulación , Drosophila , Drosophila simulans , Femenino , Variación Genética , Masculino , Selección GenéticaRESUMEN
Gap mode surface-enhanced Raman scattering (SERS) substrates are created when a single nanoparticle is deposited on a thin metal film, creating a region of significant electromagnetic field enhancement in the gap between the nanoparticle and the film due to excitation of a vertically-oriented, out-of-plane dipole plasmon mode, e.g. the gap plasmon. When molecules are located in the gap and couple to the gap plasmon mode, the resulting emission is polarized perpendicular to the thin film, generating SERS emission patterns that have a characteristic donut shape. We analyze these SERS emission patterns using a dipole emission model and extract out-of-plane and in-plane emission angles associated with the gap plasmon mode. Fluctuations in both of these angles reveal dynamic heterogeneity due to molecular motion within the hot spot that changes as a function of molecular coverage. We also reveal static heterogeneity associated with structural defects in the thin film component of the gap mode substrates, indicating that even nanometer-scale surface roughness can impact the quality of gap mode emission.
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The Fisherian sexual selection paradigm has been called the null model of sexual selection. At its heart is the expectation of a genetic correlation (rG ) between female preference and male trait. However, recent meta-analysis has shown estimated correlations are often extremely weak and not statistically significant. We show here that systematic failure of studies to reject the null hypothesis that rG = 0 is almost certainly due to the low power of most experimental designs used. We provide an easy way to assess experimental power a priori and suggest that current data make it difficult to definitively test a key component of the Fisher effect.
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Evolución Biológica , Preferencia en el Apareamiento Animal , Modelos Estadísticos , Animales , Femenino , Masculino , Fenotipo , Selección Genética , Conducta Sexual , Conducta Sexual AnimalRESUMEN
Responses to sexually antagonistic selection are thought to be constrained by the shared genetic architecture of homologous male and female traits. Accordingly, adaptive sexual dimorphism depends on mechanisms such as genotype-by-sex interaction (G×S) and sex-specific plasticity to alleviate this constraint. We tested these mechanisms in a population of Xiphophorus birchmanni (sheepshead swordtail), where the intensity of male competition is expected to mediate intersexual conflict over age and size at maturity. Combining quantitative genetics with density manipulations and analysis of sex ratio variation, we confirm that maturation traits are dimorphic and heritable, but also subject to large G×S. Although cross-sex genetic correlations are close to zero, suggesting sex-linked genes with important effects on growth and maturation are likely segregating in this population, we found less evidence of sex-specific adaptive plasticity. At high density, there was a weak trend towards later and smaller maturation in both sexes. Effects of sex ratio were stronger and putatively adaptive in males but not in females. Males delay maturation in the presence of mature rivals, resulting in larger adult size with subsequent benefit to competitive ability. However, females also delay maturation in male-biased groups, incurring a loss of reproductive lifespan without apparent benefit. Thus, in highly competitive environments, female fitness may be limited by the lack of sex-specific plasticity. More generally, assuming that selection does act antagonistically on male and female maturation traits in the wild, our results demonstrate that genetic architecture of homologous traits can ease a major constraint on the evolution of adaptive dimorphism.
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Ciprinodontiformes/fisiología , Modelos Genéticos , Conducta Sexual Animal , Factores de Edad , Animales , Tamaño Corporal/genética , Conducta Competitiva , Ciprinodontiformes/genética , Femenino , Variación Genética , Genotipo , Masculino , Fenotipo , Reproducción/fisiología , Caracteres Sexuales , Razón de MasculinidadRESUMEN
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a costimulatory molecule that negatively regulates T-cell activation. Originally identified in murine CD8(+) T cells, it has been found to be rapidly induced on human T cells. Furthermore, CTLA-4 is expressed on regulatory T cells. Clinically, targeting CTLA-4 has clinical utility in the treatment of melanoma. Whether the expression of CTLA-4 is differentially regulated in CD8(+) vs CD4(+) human T cells is unclear. Here, we analyzed CTLA-4 in normal human CD4(+) and CD8(+) T-cell subsets and show for the first time that CTLA-4 is expressed significantly higher in the CD4(+) T cells than in CD8(+) T cells. CTLA-4 is higher at the protein and the transcriptional levels in CD4(+) T cells. This increase is due to the activation of the CTLA-4 promoter, which undergoes acetylation at the proximal promoter. Furthermore, we show that blocking CTLA-4 on CD4(+) T cells permits greater proliferation in CD4(+) vs CD8(+) cells. These findings demonstrate a differential regulation of CTLA-4 on CD4(+) and CD8(+) T-cell subsets, which is likely important to the clinical efficacy for anti-CTLA-4 therapies. The findings hint to strategies to modulate CTLA-4 expression by targeting epigenetic transcription to alter the immune response.
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Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Antígeno CTLA-4/metabolismo , Factores de Transcripción NFATC/metabolismo , Acetilación , Antígeno CTLA-4/genética , Proliferación Celular , Células Cultivadas , Regulación de la Expresión Génica , Histonas/metabolismo , Humanos , Activación de Linfocitos , Regiones Promotoras Genéticas , Linfocitos T Reguladores/metabolismo , Regulación hacia ArribaRESUMEN
Competition among individuals is central to our understanding of ecology and population dynamics. However, it could also have major implications for the evolution of resource-dependent life history traits (for example, growth, fecundity) that are important determinants of fitness in natural populations. This is because when competition occurs, the phenotype of each individual will be causally influenced by the phenotypes, and so the genotypes, of competitors. Theory tells us that indirect genetic effects arising from competitive interactions will give rise to the phenomenon of 'evolutionary environmental deterioration', and act as a source of evolutionary constraint on resource-dependent traits under natural selection. However, just how important this constraint is remains an unanswered question. This article seeks to stimulate empirical research in this area, first highlighting some patterns emerging from life history studies that are consistent with a competition-based model of evolutionary constraint, before describing several quantitative modelling strategies that could be usefully applied. A recurrent theme is that rigorous quantification of a competition's impact on life history evolution will require an understanding of the causal pathways and behavioural processes by which genetic (co)variance structures arise. Knowledge of the G-matrix among life history traits is not, in and of itself, sufficient to identify the constraints caused by competition.
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Conducta , Evolución Biológica , Personalidad/genética , Selección Genética , Animales , Genética de Población , Humanos , Reproducción/genéticaRESUMEN
BACKGROUND: Regular physical activity is associated with a range of physical and psychological health benefits. In North America the majority of adolescents are insufficiently active. PURPOSE: The purpose of this study was to examine the prospective relationship between adolescents' perceptions of transformational leadership displayed by their school physical education teachers and their own physical activity behaviors, both with respect to within-class physical activity (WCPA) and also leisure time physical activity (LTPA). METHOD: The study used a prospective observational design. Using multilevel structural equation modeling (MSEM), we examined the extent to which adolescents' affective attitudes mediated the effects of teachers' behaviors on adolescents' physical activity responses. Two thousand nine hundred and forty-eight adolescents (M age = 14.33, SD = 1.00, N female = 1,641, 55.7 %) from 133 Grade 8-10 classes in British Columbia (Canada) provided ratings of their physical education teachers' behaviors midway through the school year. Two months later, students completed measures of affective attitudes, WCPA, and LTPA. RESULTS: The results indicated that adolescents' perceptions of transformational teaching explained significant variance in both WCPA and LTPA, and these effects were fully mediated by adolescents' affective attitudes (total indirect effect: b = 0.581, p < 0.001). CONCLUSION: The findings suggest that transformational leadership behaviors displayed by physical education teachers may be an important source of adolescent enjoyment of physical education as well as health-enhancing physical activity involvement within school and outside of school.
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Conocimientos, Actitudes y Práctica en Salud , Relaciones Interpersonales , Liderazgo , Actividad Motora , Educación y Entrenamiento Físico , Estudiantes/psicología , Adolescente , Colombia Británica , Docentes , Femenino , Humanos , Actividades Recreativas , Masculino , Modelos Estadísticos , Estudios Prospectivos , Psicología del Adolescente , Estudiantes/estadística & datos numéricosRESUMEN
PURPOSE: This article summarises the history and evolution of osteotomy around the knee, examining the changes in principles, operative technique and results over three distinct periods: Historical (pre 1940), Modern Early Years (1940-2000) and Modern Later Years (2000-Present). We aim to place the technique in historical context and to demonstrate its evolution into a validated procedure with beneficial outcomes whose use can be justified for specific indications. MATERIALS AND METHODS: A thorough literature review was performed to identify the important steps in the development of osteotomy around the knee. RESULTS: The indications and surgical technique for knee osteotomy have never been standardised, and historically, the results were unpredictable and at times poor. These factors, combined with the success of knee arthroplasty from the 1980s onward, led to knee osteotomy being regarded as an irrelevant surgical option by many surgeons. Despite its fluctuating reputation, this article demonstrates the reasons for the enduring practice of osteotomy, not least because achieving the appropriate alignment is now recognised as the foundation step when planning any surgical intervention. CONCLUSIONS: With appropriate patient selection, accurate pre-operative planning, modern surgical fixation techniques and rapid rehabilitation, osteotomy around the knee is now an effective biological treatment for degenerative disease, deformity, knee instability and also as an adjunct to other complex joint surface and meniscal cartilage surgery. LEVEL OF EVIDENCE: V.
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Fémur/cirugía , Deformidades Adquiridas de la Articulación/historia , Inestabilidad de la Articulación/historia , Articulación de la Rodilla/cirugía , Osteoartritis de la Rodilla/historia , Osteotomía/historia , Tibia/cirugía , Artroplastia de Reemplazo de Rodilla/historia , Europa (Continente) , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Historia Antigua , Humanos , Deformidades Adquiridas de la Articulación/cirugía , Inestabilidad de la Articulación/cirugía , Osteoartritis de la Rodilla/cirugía , Osteotomía/instrumentación , Osteotomía/métodos , Osteotomía/mortalidad , Cuidados Preoperatorios/historia , Estados UnidosRESUMEN
It is generally assumed that the male:female (M:F) ratio in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey, however, revealed that high incidence countries (mainly European) have a high M:F ratio and low incidence ones (Asian and African) have a low M:F ratio. We have now analysed the M:F ratio according to genotype at the major locus, the major histocompatibility complex (MHC; IDDM1). There are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases. We report here that in medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence is largely restricted to the DR3/X category of patients (X not = DR4) with a M:F ratio of 1.7 (P=9.3x10(-7)), compared with a ratio of 1.0 in the DR4/Y category (Y;DR3). This is additional evidence for significant heterogeneity between the aetiology of 'DR4-associated' and 'DR3-associated' diabetes. We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13-p11 was in the DR3/X affected sibpair families (n=97; peak multipoint MLS at DXS1068=3.5, P=2.7x10(-4); single point MLS=4.5, P=2.7x10(-5)). This is evidence for aetiological heterogeneity at the IDDM1/MHC locus and, therefore, in the search for non-MHC loci in type 1 diabetes, conditioning of linkage data by HLA type is advised.
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Diabetes Mellitus Tipo 1/genética , Ligamiento Genético , Antígeno HLA-DR3/genética , Cromosoma X , Adolescente , Adulto , Femenino , Humanos , Masculino , Caracteres SexualesRESUMEN
Genetic analysis of a mouse model of major histocompatability complex (MHC)-associated autoimmune type 1 (insulin-dependent) diabetes mellitus (IDDM) has shown that the disease is caused by a combination of a major effect at the MHC and at least ten other susceptibility loci elsewhere in the genome. A genome-wide scan of 93 affected sibpair families (ASP) from the UK (UK93) indicated a similar genetic basis for human type 1 diabetes, with the major genetic component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease (lambda(s)=2.5; refs 3,4). In the present report, we have analysed a further 263 multiplex families from the same population (UK263) to provide a total UK data set of 356 ASP families (UK356). Only four regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded at lambda(s)=3 and lod=-2, of which two showed evidence of linkage: chromosome 10p13-p11 (maximum lod score (MLS)=4.7, P=3x10(-6), lambda(s)=1.56) and chromosome 16q22-16q24 (MLS=3.4, P=6.5x10(-5), lambda(s)=1.6). These and other novel regions, including chromosome 14q12-q21 and chromosome 19p13-19q13, could potentially harbour disease loci but confirmation and fine mapping cannot be pursued effectively using conventional linkage analysis. Instead, more powerful linkage disequilibrium-based and haplotype mapping approaches must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage.
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Diabetes Mellitus Tipo 1/genética , Adolescente , Adulto , Mapeo Cromosómico , Predisposición Genética a la Enfermedad , Humanos , Reino UnidoRESUMEN
The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.
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Diabetes Mellitus Tipo 1/genética , Insulina/genética , Alelos , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Variación Genética , Genética de Población , Homocigoto , Humanos , MasculinoRESUMEN
Advanced systemic mastocytosis (AdvSM) is a rare, life-limiting mast cell (MC) neoplasm, with approximately 70% patients having an associated haematological neoplasm (AHN). Avapritinib, a selective tyrosine kinase inhibitor targeting KIT D816V, has shown potent activity translating clinically into durable responses in the phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) studies. We report three patients with AdvSM-AHN on avapritinib who achieved complete remission (CR) of SM and were successfully bridged to allogeneic haematopoietic cell transplant (allo-HCT). Two cases additionally highlight the risk of clonal evolution within the AHN component and requirement for close monitoring while on targeted therapy.
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Insects with complex life-cycles should optimize age and size at maturity during larval development. When inhabiting seasonal environments, organisms have limited reproductive periods and face fundamental decisions: individuals that reach maturity late in season have to either reproduce at a small size or increase their growth rates. Increasing growth rates is costly in insects because of higher juvenile mortality, decreased adult survival or increased susceptibility to parasitism by bacteria and viruses via compromised immune function. Environmental changes such as seasonality can also alter the quantitative genetic architecture. Here, we explore the quantitative genetics of life history and immunity traits under two experimentally induced seasonal environments in the cricket Gryllus bimaculatus. Seasonality affected the life history but not the immune phenotypes. Individuals under decreasing day length developed slower and grew to a bigger size. We found ample additive genetic variance and heritability for components of immunity (haemocyte densities, proPhenoloxidase activity, resistance against Serratia marcescens), and for the life history traits, age and size at maturity. Despite genetic covariance among traits, the structure of G was inconsistent with genetically based trade-off between life history and immune traits (for example, a strong positive genetic correlation between growth rate and haemocyte density was estimated). However, conditional evolvabilities support the idea that genetic covariance structure limits the capacity of individual traits to evolve independently. We found no evidence for G × E interactions arising from the experimentally induced seasonality.
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Gryllidae/genética , Gryllidae/inmunología , Animales , Femenino , Variación Genética , Gryllidae/microbiología , Gryllidae/fisiología , Hemolinfa/inmunología , Hemolinfa/microbiología , Inmunidad , Luz , Masculino , Fotoperiodo , Reproducción , Estaciones del Año , Serratia marcescens/fisiologíaRESUMEN
Anatomic placement of the femoral tunnel in anterior cruciate ligament (ACL) reconstruction confers biomechanical advantages over the traditional tunnel position. The anteromedial portal technique for anatomic ACL reconstruction has many well-described technical challenges. This paper describes the TransLateral technique. The technique produces anatomic femoral tunnel placement using direct measurement of the medial wall of the lateral femoral condyle and out to in drilling. All work is carried out through the lateral portal with all viewing via the medial portal. There is no need for an accessory medial portal or hyperflexion of the knee. Level of evidence Expert opinion, Level V.
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Reconstrucción del Ligamento Cruzado Anterior/métodos , Ligamento Cruzado Anterior/cirugía , Fémur/cirugía , Tendones/trasplante , Lesiones del Ligamento Cruzado Anterior , Artroscopía/instrumentación , Artroscopía/métodos , HumanosRESUMEN
Parasites detrimentally affect host fitness, leading to expectations of positive selection on host parasite resistance. However, as immunity is costly, host fitness may be maximized at low, but nonzero, parasite infection intensities. These hypotheses are rarely tested on natural variation in free-living populations. We investigated selection on a measure of host parasite resistance in a naturally regulated Soay sheep population using a longitudinal data set and found negative correlations between parasite infection intensity and annual fitness in lambs, male yearlings and adult females. However, having accounted for confounding effects of body weight, the effect was only significant in lambs. Associations between fitness and parasite resistance were environment-dependent, being strong during low-mortality winters, but negligible during harsher high-mortality winters. There was no evidence for stabilizing selection. Our findings reveal processes that may shape variation in parasite resistance in natural populations and illustrate the importance of accounting for correlated traits in selection analysis.