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1.
PLoS Genet ; 19(8): e1010863, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37616321

RESUMO

Quantitative traits may be controlled by many loci, many alleles at each locus, and subject to genotype-by-environment interactions, making them difficult to map. One example of such a complex trait is shoot branching in the model plant Arabidopsis, and its plasticity in response to nitrate. Here, we use artificial selection under contrasting nitrate supplies to dissect the genetic architecture of this complex trait, where loci identified by association mapping failed to explain heritability estimates. We found a consistent response to selection for high branching, with correlated responses in other traits such as plasticity and flowering time. Genome-wide scans for selection and simulations suggest that at least tens of loci control this trait, with a distinct genetic architecture between low and high nitrate treatments. While signals of selection could be detected in the populations selected for high branching on low nitrate, there was very little overlap in the regions selected in three independent populations. Thus the regulatory network controlling shoot branching can be tuned in different ways to give similar phenotypes.


Assuntos
Arabidopsis , Nitratos , Alelos , Genótipo , Herança Multifatorial
2.
Arterioscler Thromb Vasc Biol ; 44(6): 1318-1329, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38634281

RESUMO

BACKGROUND: Tissue resident memory T (TRM) cells are a T-cell subset that resides at the site of prior antigen recognition to protect the body against reoccurring encounters. Besides their protective function, TRM cells have also been implicated in inflammatory disorders. TRM cells are characterized by the expression of CD69 and transcription factors Hobit (homolog of Blimp-1 [B lymphocyte-induced maturation protein 1] in T cells) and Blimp-1. As the majority of T cells in the arterial intima expresses CD69, TRM cells may contribute to the pathogenesis of atherosclerosis as well. Here, we aimed to assess the presence and potential role of TRM cells in atherosclerosis. METHODS: To identify TRM cells in human atherosclerotic lesions, a single-cell RNA-sequencing data set was interrogated, and T-cell phenotypes were compared with that of integrated predefined TRM cells. The presence and phenotype of TRM in atherosclerotic lesions was corroborated using a mouse model that enabled tracking of Hobit-expressing TRM cells. To explore the function of TRM cells during atherogenesis, RAG1-/- (recombination activating gene 1 deficient) LDLr-/- (low-density lipoprotein receptor knockout) mice received a bone marrow transplant from HobitKO/CREBlimp-1flox/flox mice, which exhibit abrogated TRM cell formation, whereafter the mice were fed a Western-type diet for 10 weeks. RESULTS: Human atherosclerotic lesions contained T cells that exhibited a TRM cell-associated gene signature. Moreover, a fraction of these T cells clustered together with predefined TRM cells upon integration. The presence of Hobit-expressing TRM cells in the atherosclerotic lesion was confirmed in mice. These lesion-derived TRM cells were characterized by the expression of CD69 and CD49α. Moreover, we demonstrated that this small T-cell subset significantly affects lesion composition, by reducing the amount of intralesional macrophages and increasing collagen content. CONCLUSIONS: TRM cells, characterized by the expression of CD69 and CD49α, constitute a minor population in atherosclerotic lesions and are associated with increased lesion stability in a Hobit and Blimp-1 knockout mouse model.


Assuntos
Aterosclerose , Modelos Animais de Doenças , Memória Imunológica , Macrófagos , Células T de Memória , Camundongos Endogâmicos C57BL , Placa Aterosclerótica , Receptores de LDL , Animais , Aterosclerose/patologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/genética , Humanos , Células T de Memória/imunologia , Células T de Memória/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/patologia , Receptores de LDL/genética , Receptores de LDL/deficiência , Camundongos , Masculino , Camundongos Knockout , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Fenótipo , Feminino , Antígenos CD/metabolismo , Antígenos CD/genética , Doenças da Aorta/patologia , Doenças da Aorta/imunologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo
3.
Arterioscler Thromb Vasc Biol ; 44(6): 1302-1314, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38511327

RESUMO

INTRODUCTION: Viral infections have been associated with the progression of atherosclerosis and CD8+ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been detected inside human atherosclerotic lesions. These virus-specific CD8+ T-cells have been hypothesized to contribute to the development of atherosclerosis; however, whether they affect disease progression directly remains unclear. In this study, we aimed to characterize the activation status of virus-specific CD8+ T-cells in the atherosclerotic lesion. METHODS: The presence, clonality, tissue enrichment, and phenotype of virus-associated CD8+ T-cells in atherosclerotic lesions were assessed by exploiting bulk T-cell receptor-ß sequencing and single-cell T-cell receptor (α and ß) sequencing datasets on human endarterectomy samples and patient-matched blood samples. To investigate if virus-specific CD8+ T-cells can be activated through T-cell receptor stimulation in the atherosclerotic lesion, the immunopeptidome of human plaques was determined. RESULTS: Virus-associated CD8+ T-cells accumulated more in the atherosclerotic lesion (mean=2.0%), compared with patient-matched blood samples (mean=1.4%; P=0.05), and were more clonally expanded and tissue enriched in the atherosclerotic lesion in comparison with nonassociated CD8+ T-cells from the lesion. Single-cell T-cell receptor sequencing and flow cytometry revealed that these virus-associated CD8+ T-cells were phenotypically highly similar to other CD8+ T-cells in the lesion and that both exhibited a more activated phenotype compared with circulating T-cells. Interestingly, virus-associated CD8+ T-cells are unlikely to be activated through antigen-specific interactions in the atherosclerotic lesion, as no virus-derived peptides were detected on HLA-I in the lesion. CONCLUSIONS: This study suggests that virus-specific CD8+ T-cells are tissue enriched in atherosclerotic lesions; however, their potential contribution to inflammation may involve antigen-independent mechanisms.


Assuntos
Linfócitos T CD8-Positivos , Ativação Linfocitária , Placa Aterosclerótica , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Aterosclerose/imunologia , Aterosclerose/virologia , Aterosclerose/patologia , Masculino , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Feminino , Pessoa de Meia-Idade , Idoso , Doenças das Artérias Carótidas/imunologia , Doenças das Artérias Carótidas/virologia , Doenças das Artérias Carótidas/patologia , Interações Hospedeiro-Patógeno
4.
Mol Ecol ; 32(21): 5742-5756, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37800849

RESUMO

Understanding the rate and extent to which populations can adapt to novel environments at their ecological margins is fundamental to predicting the persistence of biological communities during ongoing and rapid global change. Recent range expansion in response to climate change in the UK butterfly Aricia agestis is associated with the evolution of novel interactions with a larval food plant, and the loss of its ability to use an ancestral host species. Using ddRAD analysis of 61,210 variable SNPs from 261 females from throughout the UK range of this species, we identify genomic regions at multiple chromosomes that are associated with evolutionary responses, and their association with demographic history and ecological variation. Gene flow appears widespread throughout the range, despite the apparently fragmented nature of the habitats used by this species. Patterns of haplotype variation between selected and neutral genomic regions suggest that evolution associated with climate adaptation is polygenic, resulting from the independent spread of alleles throughout the established range of this species, rather than the colonization of pre-adapted genotypes from coastal populations. These data suggest that rapid responses to climate change do not depend on the availability of pre-adapted genotypes. Instead, the evolution of novel forms of biotic interaction in A. agestis has occurred during range expansion, through the assembly of novel genotypes from alleles from multiple localities.


Assuntos
Borboletas , Animais , Feminino , Borboletas/genética , Geografia , Ecossistema , Aclimatação , Reino Unido , Evolução Biológica , Mudança Climática
5.
PLoS Genet ; 15(9): e1008366, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31539368

RESUMO

The capacity of organisms to tune their development in response to environmental cues is pervasive in nature. This phenotypic plasticity is particularly striking in plants, enabled by their modular and continuous development. A good example is the activation of lateral shoot branches in Arabidopsis, which develop from axillary meristems at the base of leaves. The activity and elongation of lateral shoots depends on the integration of many signals both external (e.g. light, nutrient supply) and internal (e.g. the phytohormones auxin, strigolactone and cytokinin). Here, we characterise natural variation in plasticity of shoot branching in response to nitrate supply using two diverse panels of Arabidopsis lines. We find extensive variation in nitrate sensitivity across these lines, suggesting a genetic basis for variation in branching plasticity. High plasticity is associated with extreme branching phenotypes such that lines with the most branches on high nitrate have the fewest under nitrate deficient conditions. Conversely, low plasticity is associated with a constitutively moderate level of branching. Furthermore, variation in plasticity is associated with alternative life histories with the low plasticity lines flowering significantly earlier than high plasticity lines. In Arabidopsis, branching is highly correlated with fruit yield, and thus low plasticity lines produce more fruit than high plasticity lines under nitrate deficient conditions, whereas highly plastic lines produce more fruit under high nitrate conditions. Low and high plasticity, associated with early and late flowering respectively, can therefore be interpreted alternative escape vs mitigate strategies to low N environments. The genetic architecture of these traits appears to be highly complex, with only a small proportion of the estimated genetic variance detected in association mapping.


Assuntos
Arabidopsis/genética , Nitratos/metabolismo , Brotos de Planta/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas/genética , Genes de Plantas/genética , Meristema/crescimento & desenvolvimento , Fenótipo , Folhas de Planta/metabolismo , Raízes de Plantas/genética , Brotos de Planta/crescimento & desenvolvimento , Brotos de Planta/metabolismo
6.
Ecol Appl ; 30(3): e02062, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31863538

RESUMO

The ecological impact of artificial light at night (ALAN) on phenological events such as reproductive timing is increasingly recognized. In birds, previous experiments under controlled conditions showed that ALAN strongly advances gonadal growth, but effects on egg-laying date are less clear. In particular, effects of ALAN on timing of egg laying are found to be year-dependent, suggesting an interaction with climatic conditions such as spring temperature, which is known have strong effects on the phenology of avian breeding. Thus, we hypothesized that ALAN and temperature interact to regulate timing of reproduction in wild birds. Field studies have suggested that sources of ALAN rich in short wavelengths can lead to stronger advances in egg-laying date. We therefore tested this hypothesis in the Great Tit (Parus major), using a replicated experimental set-up where eight previously unlit forest transects were illuminated with either white, green, or red LED light, or left dark as controls. We measured timing of egg laying for 619 breeding events spread over six consecutive years and obtained temperature data for all sites and years. We detected overall significantly earlier egg-laying dates in the white and green light vs. the dark treatment, and similar trends for red light. However, there was a strong interannual variability in mean egg-laying dates in all treatments, which was explained by spring temperature. We did not detect any fitness consequence of the changed timing of egg laying due to ALAN, which suggests that advancing reproduction in response to ALAN might be adaptive.


Assuntos
Passeriformes , Reprodução , Animais , Oviposição , Estações do Ano , Temperatura
7.
Conserv Biol ; 33(5): 1120-1130, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30912605

RESUMO

Evidence of declines in insect populations has recently received considerable scientific and societal attention. However, the lack of long-term insect monitoring makes it difficult to assess whether declines are geographically widespread. By contrast, bird populations are well monitored and often used as indicators of environmental change. We compared the population trends of European insectivorous birds with those of other birds to assess whether patterns in bird population trends were consistent with declines of insects. We further examined whether declines were evident for insectivores with different habitats, foraging strata, and other ecological preferences. Bird population trends were estimated for Europe (1990-2015) and Denmark (1990-2016). On average, insectivores declined over the study period (13% across Europe and 28% in Denmark), whereas omnivores had stable populations. Seedeaters also declined (28% across Europe; 34% in Denmark), but this assessment was based on fewer species than for other groups. The effects of insectivory were stronger for farmland species (especially grassland species), for ground feeders, and for cold-adapted species. Insectivory was associated with long-distance migration, which was also linked to population declines. However, many insectivores had stable populations, especially habitat generalists. Our findings suggest that the decline of insectivores is primarily associated with agricultural intensification and loss of grassland habitat. The loss of both seed and insect specialists indicates an overall trend toward bird communities dominated by diet generalists.


Declinaciones a Largo Plazo de Poblaciones de Aves Insectívoras en Europa y las Causas Probables Resumen La evidencia de las declinaciones poblacionales de insectos ha recibido recientemente una atención considerable por parte de la comunidad científica y la sociedad. Sin embargo, la falta de un monitoreo prolongado de los insectos complica valorar si estas declinaciones tienen una distribución extensa geográficamente. Como contraste, las poblaciones de aves tienen un monitoreo constante y con frecuencia se usan como indicadores del cambio climático. Comparamos las tendencias poblacionales de las aves insectívoras de Europa con las de otras aves para valorar si los patrones en las tendencias poblacionales de aves son consistentes con las declinaciones de insectos. Además examinamos si las declinaciones eran evidentes para aves insectívoras con diferentes hábitats, estratos de alimentación, y otras preferencias ecológicas. Las tendencias poblacionales de las aves se estimaron para Europa (1990 - 2015) y para Dinamarca (1990 - 2016). En promedio, las aves insectívoras declinaron a lo largo del periodo de estudio (13% en Europa y 28% en Dinamarca) mientras que las aves omnívoras tuvieron poblaciones estables. Las poblaciones de aves que se alimentan de semillas también declinaron (28% en Europa; 34% en Dinamarca), pero esta valoración se basó en menos especies que para los otros grupos. Los efectos de la insectivoría fueron más evidentes para las especies de tierras agrícolas (especialmente las especies de pastizales), para las especies que se alimentan sobre el suelo y para las especies adaptadas al frío. La insectivoría estuvo asociada con la migración de larga distancia, la cual también estuvo ligada a las declinaciones poblacionales. Sin embargo, muchas aves insectívoras tuvieron poblaciones estables, especialmente aquellas generalistas de hábitat. Nuestros hallazgos sugieren que la declinación de las aves insectívoras está asociada principalmente con la intensificación agrícola y la pérdida de pastizales. La pérdida de aves cuya alimentación es especialista en insectos o en semillas indica una tendencia general hacia comunidades de aves dominadas por aquellas con dietas generalistas.


Assuntos
Aves , Conservação dos Recursos Naturais , Agricultura , Animais , Ecossistema , Europa (Continente) , Dinâmica Populacional
8.
Proc Biol Sci ; 284(1847)2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28100819

RESUMO

A small number of free-living viruses have been found to be obligately vertically transmitted, but it remains uncertain how widespread vertically transmitted viruses are and how quickly they can spread through host populations. Recent metagenomic studies have found several insects to be infected with sigma viruses (Rhabdoviridae). Here, we report that sigma viruses that infect Mediterranean fruit flies (Ceratitis capitata), Drosophila immigrans, and speckled wood butterflies (Pararge aegeria) are all vertically transmitted. We find patterns of vertical transmission that are consistent with those seen in Drosophila sigma viruses, with high rates of maternal transmission, and lower rates of paternal transmission. This mode of transmission allows them to spread rapidly in populations, and using viral sequence data we found the viruses in D. immigrans and C. capitata had both recently swept through host populations. The viruses were common in nature, with mean prevalences of 12% in C. capitata, 38% in D. immigrans and 74% in P. aegeria We conclude that vertically transmitted rhabdoviruses may be widespread in a broad range of insect taxa, and that these viruses can have dynamic interactions with their hosts.


Assuntos
Transmissão Vertical de Doenças Infecciosas , Insetos/virologia , Rhabdoviridae , Animais , Borboletas/virologia , Ceratitis capitata/virologia , Drosophila/virologia
9.
Glob Chang Biol ; 23(11): 4987-4994, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28597541

RESUMO

The natural nighttime environment is increasingly polluted by artificial light. Several studies have linked artificial light at night to negative impacts on human health. In free-living animals, light pollution is associated with changes in circadian, reproductive, and social behavior, but whether these animals also suffer from physiologic costs remains unknown. To fill this gap, we made use of a unique network of field sites which are either completely unlit (control), or are artificially illuminated with white, green, or red light. We monitored nighttime activity of adult great tits, Parus major, and related this activity to within-individual changes in physiologic indices. Because altered nighttime activity as a result of light pollution may affect health and well-being, we measured oxalic acid concentrations as a biomarker for sleep restriction, acute phase protein concentrations and malaria infection as indices of immune function, and telomere lengths as an overall measure of metabolic costs. Compared to other treatments, individuals roosting in the white light were much more active at night. In these individuals, oxalic acid decreased over the course of the study. We also found that individuals roosting in the white light treatment had a higher probability of malaria infection. Our results indicate that white light at night increases nighttime activity levels and sleep debt and affects disease dynamics in a free-living songbird. Our study offers the first evidence of detrimental effects of light pollution on the health of free-ranging wild animals.


Assuntos
Ritmo Circadiano/efeitos da radiação , Poluição Ambiental , Luz/efeitos adversos , Sono/efeitos da radiação , Aves Canoras/fisiologia , Animais , Metabolismo Energético/efeitos da radiação , Feminino , Imunidade Inata/efeitos da radiação , Masculino , Atividade Motora/efeitos da radiação
10.
Plant Physiol ; 166(1): 384-95, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25059707

RESUMO

The degree of shoot branching is strongly affected by environmental conditions, such as nutrient availability. Here we demonstrate that nitrate limitation reduces shoot branching in Arabidopsis (Arabidopsis thaliana) both by delaying axillary bud activation and by attenuating the basipetal sequence of bud activation that is triggered following floral transition. Ammonium supply has similar effects, suggesting that they are caused by plant nitrogen (N) status, rather than direct nitrate signaling. We identify increased auxin export from active shoot apices, resulting in increased auxin in the polar auxin transport stream of the main stem, as a likely cause for the suppression of basal branches. Consistent with this idea, in the auxin response mutant axr1 and the strigolactone biosynthesis mutant more axillary growth1, increased retention of basal branches on low N is associated with a failure to increase auxin in the main stem. The complex interactions between the hormones that regulate branching make it difficult to rule out other mechanisms of N action, such as up-regulation of strigolactone synthesis. However, the proposed increase in auxin export from active buds can also explain how reduced shoot branching is achieved without compromising root growth, leading to the characteristic shift in relative biomass allocation to the root when N is limiting.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Ácidos Indolacéticos/metabolismo , Lactonas/metabolismo , Nitratos/metabolismo , Brotos de Planta/crescimento & desenvolvimento , Arabidopsis/metabolismo , Nitrogênio/metabolismo
11.
J Exp Bot ; 66(11): 3405-16, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25883382

RESUMO

The transformation of the ovary into a fruit after successful completion of pollination and fertilization has been associated with many changes at transcriptomic level. These changes are part of a dynamic and complex regulatory network that is controlled by phytohormones, with a major role for auxin. One of the auxin-related genes differentially expressed upon fruit set and early fruit development in tomato is Solanum lycopersicum AUXIN RESPONSE FACTOR 9 (SlARF9). Here, the functional analysis of this ARF is described. SlARF9 expression was found to be auxin-responsive and SlARF9 mRNA levels were high in the ovules, placenta, and pericarp of pollinated ovaries, but also in other plant tissues with high cell division activity, such as the axillary meristems and root meristems. Transgenic plants with increased SlARF9 mRNA levels formed fruits that were smaller than wild-type fruits because of reduced cell division activity, whereas transgenic lines in which SlARF9 mRNA levels were reduced showed the opposite phenotype. The expression analysis, together with the phenotype of the transgenic lines, suggests that, in tomato, ARF9 negatively controls cell division during early fruit development.


Assuntos
Frutas/genética , Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Proteínas de Plantas/metabolismo , Solanum lycopersicum/genética , Divisão Celular , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Solanum lycopersicum/crescimento & desenvolvimento , Solanum lycopersicum/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Óvulo Vegetal/genética , Óvulo Vegetal/crescimento & desenvolvimento , Óvulo Vegetal/metabolismo , Fenótipo , Proteínas de Plantas/genética , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plantas Geneticamente Modificadas
12.
Biol Lett ; 11(8)2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26311159

RESUMO

Organisms have evolved under natural daily light/dark cycles for millions of years. These cycles have been disturbed as night-time darkness is increasingly replaced by artificial illumination. Investigating the physiological consequences of free-living organisms in artificially lit environments is crucial to determine whether nocturnal lighting disrupts circadian rhythms, changes behaviour, reduces fitness and ultimately affects population numbers. We make use of a unique, large-scale network of replicated field sites which were experimentally illuminated at night using lampposts emanating either red, green, white or no light to test effect on stress hormone concentrations (corticosterone) in a songbird, the great tit (Parus major). Adults nesting in white-light transects had higher corticosterone concentrations than in the other treatments. We also found a significant interaction between distance to the closest lamppost and treatment type: individuals in red light had higher corticosterone levels when they nested closer to the lamppost than individuals nesting farther away, a decline not observed in the green or dark treatment. Individuals with high corticosterone levels had fewer fledglings, irrespective of treatment. These results show that artificial light can induce changes in individual hormonal phenotype. As these effects vary considerably with light spectrum, it opens the possibility to mitigate these effects by selecting street lighting of specific spectra.


Assuntos
Corticosterona/sangue , Luz/efeitos adversos , Iluminação/efeitos adversos , Passeriformes/fisiologia , Animais , Escuridão , Reprodução/efeitos da radiação , Estresse Fisiológico
13.
Sci Adv ; 10(18): eadj6979, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38701204

RESUMO

Nature has devised many ways of producing males and females. Here, we report on a previously undescribed mechanism for Lepidoptera that functions without a female-specific gene. The number of alleles or allele heterozygosity in a single Z-linked gene (BaMasc) is the primary sex-determining switch in Bicyclus anynana butterflies. Embryos carrying a single BaMasc allele develop into WZ (or Z0) females, those carrying two distinct alleles develop into ZZ males, while (ZZ) homozygotes initiate female development, have mismatched dosage compensation, and die as embryos. Consequently, selection against homozygotes has favored the evolution of spectacular allelic diversity: 205 different coding sequences of BaMasc were detected in a sample of 246 females. The structural similarity of a hypervariable region (HVR) in BaMasc to the HVR in Apis mellifera csd suggests molecular convergence between deeply diverged insect lineages. Our discovery of this primary switch highlights the fascinating diversity of sex-determining mechanisms and underlying evolutionary drivers.


Assuntos
Borboletas , Processos de Determinação Sexual , Animais , Borboletas/genética , Feminino , Masculino , Processos de Determinação Sexual/genética , Alelos , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Homozigoto
14.
Nat Cardiovasc Res ; 2(2): 112-125, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38665903

RESUMO

Atherosclerosis is a lipid-driven chronic inflammatory disease; however, whether it can be classified as an autoimmune disease remains unclear. In this study, we applied single-cell T cell receptor seqencing (scTCR-seq) on human carotid artery plaques and matched peripheral blood mononuclear cell samples to assess the extent of TCR clonality and antigen-specific activation within the various T cell subsets. We observed the highest degree of plaque-specific clonal expansion in effector CD4+ T cells, and these clonally expanded T cells expressed genes such as CD69, FOS and FOSB, indicative of recent TCR engagement, suggesting antigen-specific stimulation. CellChat analysis suggested multiple potential interactions of these effector CD4+ T cells with foam cells. Finally, we integrated a published scTCR-seq dataset of the autoimmune disease psoriatic arthritis, and we report various commonalities between the two diseases. In conclusion, our data suggest that atherosclerosis has an autoimmune compondent driven by autoreactive CD4+ T cells.

15.
Cardiovasc Res ; 119(15): 2508-2521, 2023 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-37390467

RESUMO

AIMS: Aging is a dominant driver of atherosclerosis and induces a series of immunological alterations, called immunosenescence. Given the demographic shift towards elderly, elucidating the unknown impact of aging on the immunological landscape in atherosclerosis is highly relevant. While the young Western diet-fed Ldlr-deficient (Ldlr-/-) mouse is a widely used model to study atherosclerosis, it does not reflect the gradual plaque progression in the context of an aging immune system as occurs in humans. METHODS AND RESULTS: Here, we show that aging promotes advanced atherosclerosis in chow diet-fed Ldlr-/- mice, with increased incidence of calcification and cholesterol crystals. We observed systemic immunosenescence, including myeloid skewing and T-cells with more extreme effector phenotypes. Using a combination of single-cell RNA-sequencing and flow cytometry on aortic leucocytes of young vs. aged Ldlr-/- mice, we show age-related shifts in expression of genes involved in atherogenic processes, such as cellular activation and cytokine production. We identified age-associated cells with pro-inflammatory features, including GzmK+CD8+ T-cells and previously in atherosclerosis undefined CD11b+CD11c+T-bet+ age-associated B-cells (ABCs). ABCs of Ldlr-/- mice showed high expression of genes involved in plasma cell differentiation, co-stimulation, and antigen presentation. In vitro studies supported that ABCs are highly potent antigen-presenting cells. In cardiovascular disease patients, we confirmed the presence of these age-associated T- and B-cells in atherosclerotic plaques and blood. CONCLUSIONS: Collectively, we are the first to provide comprehensive profiling of aged immunity in atherosclerotic mice and reveal the emergence of age-associated T- and B-cells in the atherosclerotic aorta. Further research into age-associated immunity may contribute to novel diagnostic and therapeutic tools to combat cardiovascular disease.


Assuntos
Doenças da Aorta , Aterosclerose , Doenças Cardiovasculares , Placa Aterosclerótica , Humanos , Camundongos , Animais , Idoso , Doenças Cardiovasculares/complicações , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Leucócitos/metabolismo , Receptores de LDL/genética , Camundongos Knockout , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
17.
Nat Commun ; 13(1): 755, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35136048

RESUMO

Seasonal plasticity is accomplished via tightly regulated developmental cascades that translate environmental cues into trait changes. Little is known about how alternative splicing and other posttranscriptional molecular mechanisms contribute to plasticity or how these mechanisms impact how plasticity evolves. Here, we use transcriptomic and genomic data from the butterfly Bicyclus anynana, a model system for seasonal plasticity, to compare the extent of differential expression and splicing and test how these axes of transcriptional plasticity differ in their potential for evolutionary change. Between seasonal morphs, we find that differential splicing affects a smaller but functionally unique set of genes compared to differential expression. Further, we find strong support for the novel hypothesis that spliced genes are more susceptible than differentially expressed genes to erosion of genetic variation due to selection on seasonal plasticity. Our results suggest that splicing plasticity is especially likely to experience genetic constraints that could affect the potential of wild populations to respond to rapidly changing environments.


Assuntos
Adaptação Fisiológica/genética , Processamento Alternativo , Borboletas/fisiologia , Genes de Insetos/genética , Estágios do Ciclo de Vida/genética , Animais , Evolução Biológica , Feminino , Variação Genética , Modelos Genéticos , Estações do Ano , Transcrição Gênica
18.
Sci Rep ; 12(1): 1553, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35091579

RESUMO

Globally increasing levels of artificial light at night (ALAN) are associated with shifting rhythms of behaviour in many wild species. However, it is unclear whether changes in behavioural timing are paralleled by consistent shifts in the molecular clock and its associated physiological pathways. Inconsistent shifts between behavioural and molecular rhythms, and between different tissues and physiological systems, disrupt the circadian system, which coordinates all major body functions. We therefore compared behavioural, transcriptional and metabolomic responses of captive great tits (Parus major) to three ALAN intensities or to dark nights, recording activity and sampling brain, liver, spleen and blood at mid-day and midnight. ALAN advanced wake-up time, and this shift was paralleled by advanced expression of the clock gene BMAL1 in all tissues, suggesting close links between behaviour and clock gene expression across tissues. However, further analysis of gene expression and metabolites revealed that clock shifts were inconsistent across physiological systems. Untargeted metabolomic profiling showed that only 9.7% of the 755 analysed metabolites followed the behavioural shift. This high level of desynchronization indicates that ALAN disrupted the circadian system on a deep, easily overlooked level. Thus, circadian disruption could be a key mediator of health impacts of ALAN on wild animals.


Assuntos
Poluição Luminosa
19.
Proc Biol Sci ; 278(1706): 789-97, 2011 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-20826484

RESUMO

Polyphenisms-the expression of discrete phenotypic morphs in response to environmental variation-are examples of phenotypic plasticity that may potentially be adaptive in the face of predictable environmental heterogeneity. In the butterfly Bicyclus anynana, we examine the hormonal regulation of phenotypic plasticity that involves divergent developmental trajectories into distinct adult morphs for a suite of traits as an adaptation to contrasting seasonal environments. This polyphenism is induced by temperature during development and mediated by ecdysteroid hormones. We reared larvae at separate temperatures spanning the natural range of seasonal environments and measured reaction norms for ecdysteroids, juvenile hormones (JHs) and adult fitness traits. Timing of peak ecdysteroid, but not JH titres, showed a binary response to the linear temperature gradient. Several adult traits (e.g. relative abdomen mass) responded in a similar, dimorphic manner, while others (e.g. wing pattern) showed a linear response. This study demonstrates that hormone dynamics can translate a linear environmental gradient into a discrete signal and, thus, that polyphenic differences between adult morphs can already be programmed at the stage of hormone signalling during development. The range of phenotypic responses observed within the suite of traits indicates both shared regulation and independent, trait-specific sensitivity to the hormone signal.


Assuntos
Adaptação Fisiológica/fisiologia , Borboletas/fisiologia , Ecossistema , Animais , Ecdisteroides/metabolismo , Feminino , Hormônios Juvenis/metabolismo , Masculino , Feromônios , Pupa , Estações do Ano , Temperatura
20.
J Exp Bot ; 62(2): 617-26, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20937732

RESUMO

Transgenic tomato plants (Solanum lycopersicum L.) with reduced mRNA levels of AUXIN RESPONSE FACTOR 7 (SlARF7) form parthenocarpic fruits with morphological characteristics that seem to be the result of both increased auxin and gibberellin (GA) responses during fruit growth. This paper presents a more detailed analysis of these transgenic lines. Gene expression analysis of auxin-responsive genes show that SlARF7 may regulate only part of the auxin signalling pathway involved in tomato fruit set and development. Also, part of the GA signalling pathway was affected by the reduced levels of SlARF7 mRNA, as morphological and molecular analyses display similarities between GA-induced fruits and fruits formed by the RNAi SlARF7 lines. Nevertheless, the levels of GAs were strongly reduced compared with that in seeded fruits. These findings indicate that SlARF7 acts as a modifier of both auxin and gibberellin responses during tomato fruit set and development.


Assuntos
Frutas/crescimento & desenvolvimento , Giberelinas/metabolismo , Ácidos Indolacéticos/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Proteínas de Plantas/metabolismo , Transdução de Sinais , Solanum lycopersicum/metabolismo , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Solanum lycopersicum/genética , Solanum lycopersicum/crescimento & desenvolvimento , Proteínas de Plantas/genética
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