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Emerging observational evidence suggests links between cognitive impairment and a range of gastrointestinal tract (GIT) disorders; however, the mechanisms underlying their relationships remain unclear. Leveraging large-scale genome-wide association studies' summary statistics, we comprehensively assessed genetic overlap and potential causality of cognitive traits and Alzheimer's disease (AD) with several GIT disorders. We demonstrate a strong and highly significant inverse global genetic correlation between cognitive traits and GIT disorderspeptic ulcer disease (PUD), gastritis-duodenitis, diverticulosis, irritable bowel syndrome, and gastroesophageal reflux disease (GERD), but not inflammatory bowel disease (IBD). Further analysis detects 35 significant (p < 4.37 × 10−5) bivariate local genetic correlations between cognitive traits, AD, and GIT disorders (including IBD). Mendelian randomisation analysis suggests a risk-decreasing causality of educational attainment, intelligence, and other cognitive traits on PUD and GERD, but not IBD, and a putative association of GERD with cognitive function decline. Gene-based analysis reveals a significant gene-level genetic overlap of cognitive traits with AD and GIT disorders (IBD inclusive, pbinomial-test = 1.18 × 10−3−2.20 × 10−16). Our study supports the protective roles of genetically-influenced educational attainments and other cognitive traits on the risk of GIT disorders and highlights a putative association of GERD with cognitive function decline. Findings from local genetic correlation analysis provide novel insights, indicating that the relationship of IBD with cognitive traits (and AD) will depend largely on their local effects across the genome.
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Doença de Alzheimer , Refluxo Gastroesofágico , Doenças Inflamatórias Intestinais , Humanos , Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Cognição , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: MYCN is amplified in small cell lung cancers and several pediatric tumors, including alveolar rhabdomyosarcomas and neuroblastomas. MYCN protein is known to play a key oncogenic role in both alveolar rhabdomyosarcomas and neuroblastomas. MYCN opposite strand (MYCNOS) is a gene located on the antisense strand to MYCN that encodes alternatively spliced transcripts, two of which (MYCNOS-01 and MYCNOS-02) are known to be expressed in neuroblastoma and small cell lung cancer with reciprocal regulation between MYCNOS-02 and MYCN reported for neuroblastomas. We sought to determine a functional role for MYCNOS-01 in alveolar rhabdomyosarcoma and neuroblastoma cells and identify any associated regulatory effects between MYCN and MYCNOS-01. METHODS: MYCNOS-01, MYCNOS-02 and MYCN expression levels were assessed in alveolar rhabdomyosarcoma and neuroblastoma cell lines and tumor samples from patients using Affymetrix microarray data and quantitative RT-PCR. Following MYCNOS-01 or MYCN siRNA knockdown and MYCNOS-01 overexpression, transcript levels were assayed by quantitative RT-PCR and MYCN protein expression assessed by Western blot and immunofluorescence. Additionally, effects on cell growth, apoptosis and cell cycle profiles were determined by a metabolic assay, caspase activity and flow cytometry, respectively. RESULTS: MYCNOS-01 transcript levels were generally higher in NB and RMS tumor samples and cell lines with MYCN genomic amplification. RNA interference of MYCNOS-01 expression did not alter MYCN transcript levels but decreased MYCN protein levels. Conversely, MYCN reduction increased MYCNOS-01 transcript levels, creating a negative feedback loop on MYCN protein levels. Reduction of MYCNOS-01 or MYCN expression decreased cell growth in MYCN-amplified alveolar rhabdomyosarcoma and neuroblastoma cell lines. This is consistent with MYCNOS-01-mediated regulation of MYCN contributing to the phenotype observed. CONCLUSIONS: An alternative transcript of MYCNOS, MYCNOS-01, post-transcriptionally regulates MYCN levels and affects growth in MYCN-amplified rhabdomyosarcoma and neuroblastoma cells.
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Regulação Neoplásica da Expressão Gênica , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/metabolismo , RNA Longo não Codificante/metabolismo , Rabdomiossarcoma Alveolar/metabolismo , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/fisiopatologia , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/fisiopatologiaRESUMO
Public health emergency preparedness (PHEP) all too often focusses only on institutional capabilities, including their technical expertise and political influence, while overlooking community capabilities. However, the success of institutional emergency preparedness plans depends upon communities and institutions working together to ensure successful anticipation, response and recovery. Broader community engagement is therefore recommended worldwide. This literature review was carried out to identify enablers and barriers to community and institutional synergies in emergency preparedness. Searches were undertaken across bibliographic databases and grey literature sources. The literature identified was qualitative in nature. A qualitative, 'best fit' framework approach using a pre-existing framework was used to analyse the literature, whereby themes were added and changed as analysis progressed. A working definition of community was identified, based on a 'whole community' approach, inclusive of the whole multitude of stakeholders including community residents and emergency management staff. Given the diversity in community make-up, the types of emergencies that could be faced, the socio-economic, environmental and political range of communities, there are no set practices that will be effective for all communities. The most effective way of engaging communities in emergency preparedness is context-dependent and the review did draw out some important key messages for institutions to consider.
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Participação da Comunidade , Planejamento em Desastres , Saúde Pública , Competência Cultural , HumanosRESUMO
Predicting how species will respond to the rapid climatic changes predicted this century is an urgent task. Species distribution models (SDMs) use the current relationship between environmental variation and species' abundances to predict the effect of future environmental change on their distributions. However, two common assumptions of SDMs are likely to be violated in many cases: (i) that the relationship of environment with abundance or fitness is constant throughout a species' range and will remain so in future and (ii) that abiotic factors (e.g. temperature, humidity) determine species' distributions. We test these assumptions by relating field abundance of the rainforest fruit fly Drosophila birchii to ecological change across gradients that include its low and high altitudinal limits. We then test how such ecological variation affects the fitness of 35 D. birchii families transplanted in 591 cages to sites along two altitudinal gradients, to determine whether genetic variation in fitness responses could facilitate future adaptation to environmental change. Overall, field abundance was highest at cooler, high-altitude sites, and declined towards warmer, low-altitude sites. By contrast, cage fitness (productivity) increased towards warmer, lower-altitude sites, suggesting that biotic interactions (absent from cages) drive ecological limits at warmer margins. In addition, the relationship between environmental variation and abundance varied significantly among gradients, indicating divergence in ecological niche across the species' range. However, there was no evidence for local adaptation within gradients, despite greater productivity of high-altitude than low-altitude populations when families were reared under laboratory conditions. Families also responded similarly to transplantation along gradients, providing no evidence for fitness trade-offs that would favour local adaptation. These findings highlight the importance of (i) measuring genetic variation in key traits under ecologically relevant conditions, and (ii) considering the effect of biotic interactions when predicting species' responses to environmental change.
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Aclimatação , Drosophila , Floresta Úmida , Altitude , Animais , Evolução Biológica , Aptidão GenéticaRESUMO
The threat of serious, cross-border communicable disease outbreaks in Europe poses a significant challenge to public health and emergency preparedness because the relative likelihood of these threats and the pathogens involved are constantly shifting in response to a range of changing disease drivers. To inform strategic planning by enabling effective resource allocation to manage the consequences of communicable disease outbreaks, it is useful to be able to rank and prioritise pathogens. This paper reports on a literature review which identifies and evaluates the range of methods used for risk ranking. Searches were performed across biomedical and grey literature databases, supplemented by reference harvesting and citation tracking. Studies were selected using transparent inclusion criteria and underwent quality appraisal using a bespoke checklist based on the AGREE II criteria. Seventeen studies were included in the review, covering five methodologies. A narrative analysis of the selected studies suggests that no single methodology was superior. However, many of the methods shared common components, around which a 'best-practice' framework was formulated. This approach is intended to help inform decision makers' choice of an appropriate risk-ranking study design.
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Controle de Doenças Transmissíveis/normas , Doenças Transmissíveis/classificação , Doenças Transmissíveis/epidemiologia , Planejamento em Desastres/normas , Guias de Prática Clínica como Assunto , Medição de Risco/normas , Benchmarking/métodos , Controle de Doenças Transmissíveis/métodos , Europa (Continente) , Medição de Risco/métodosRESUMO
Studies suggest links between diabetes and gastrointestinal (GI) traits; however, their underlying biological mechanisms remain unclear. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and GI disorders. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). We identify several positive local genetic correlations (negative for T2D - IBD) contributing to T2D's relationship with GI disorders. Univariable and multivariable Mendelian randomisation analyses suggest causal effects of T2D on PUD and gastritis-duodenitis and bidirectionally with GERD. Gene-based analyses reveal a gene-level genetic overlap between T2D and GI disorders and identify several shared genes reaching genome-wide significance. Pathway-based study implicates leptin (T2D - IBD), thyroid, interferon, and notch signalling (T2D - IBS), abnormal circulating calcium (T2D - PUD), cardiovascular, viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. These findings support a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared biological pathways with putative causality for certain T2D - GI pairs, and identify targets for further investigation.
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Diabetes Mellitus Tipo 2 , Gastroenteropatias , Estudo de Associação Genômica Ampla , Diabetes Mellitus Tipo 2/genética , Humanos , Gastroenteropatias/genética , Predisposição Genética para Doença , Análise da Randomização MendelianaRESUMO
The response of spinal motoneurons to synaptic input greatly depends on the activation of persistent inward currents (PICs), the contribution of which can be estimated through the paired motor unit technique. Yet, the intra-session test-retest reliability of this measurement remains to be fully established. Twenty males performed isometric triangular dorsiflexion contractions to 20 and 50 % of maximal torque at baseline and after a 15-min resting period. High-density electromyographic signals (HD-EMG) of the tibialis anterior were recorded with a 64-electrode matrix. HD-EMG signals were decomposed, and motor units tracked across time points to estimate the contribution of PICs to motoneuron firing through quantification of motor unit recruitment-derecruitment hysteresis (ΔF). A good intraclass correlation coefficient (ICC = 0.75 [0.63, 0.83]) and a large repeated measures correlation coefficient (rrm = 0.65 [0.49, 0.77]; p < 0.001) were found between ΔF values obtained at both time points for 20 % MVC ramps. For 50 % MVC ramps, a good ICC (0.77 [0.65, 0.85]) and a very large repeated measures correlation coefficient (rrm = 0.73 [0.63, 0.80]; p < 0.001) were observed. Our data suggest that ΔF scores can be reliably investigated in tibialis anterior motor units during both low- and moderate-intensity contractions within a single experimental session.
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Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer's disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-ß and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia.
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BACKGROUND: Rhabdomyosarcomas (RMS) are predominantly paediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (< 30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumours. RESULTS: We demonstrate combining inhibition of the epigenetic modulator EZH2 with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3-FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signalling resulting in differentiation. In both subtypes, EZH2 is significantly associated with enrichment of trimethylated lysine 27 on histone 3 (H3K27me3) in genes that are downregulated in untreated RMS cells and upregulated with EZH2 inhibitor treatment. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS. CONCLUSIONS: The results of this study demonstrate the potential utility of combining EZH2 inhibitors with differentiation agents for the treatment of paediatric rhabdomyosarcomas. As EZH2 inhibitors are currently undergoing clinical trials for adult and paediatric solid tumours and retinoic acid differentiation agents are already in clinical use this presents a readily translatable potential therapeutic strategy. Moreover, as inhibition of EZH2 in the poor prognosis FPRMS subtype results in an inflammatory response, it is conceivable that this strategy may also synergise with immunotherapies for a more effective treatment in these patients.
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Proteína Potenciadora do Homólogo 2 de Zeste , Rabdomiossarcoma , Humanos , Criança , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Tretinoína/farmacologia , Tretinoína/metabolismo , Metilação de DNA , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Diferenciação Celular , Inibidores Enzimáticos/farmacologia , Apoptose , Linhagem Celular TumoralRESUMO
Models of local adaptation to spatially varying selection predict that maximum rates of evolution are determined by the interaction between increased adaptive potential owing to increased genetic variation, and the cost genetic variation brings by reducing population fitness. We discuss existing and new results from our laboratory assays and field transplants of rainforest Drosophila and UK butterflies along environmental gradients, which try to test these predictions in natural populations. Our data suggest that: (i) local adaptation along ecological gradients is not consistently observed in time and space, especially where biotic and abiotic interactions affect both gradient steepness and genetic variation in fitness; (ii) genetic variation in fitness observed in the laboratory is only sometimes visible to selection in the field, suggesting that demographic costs can remain high without increasing adaptive potential; and (iii) antagonistic interactions between species reduce local productivity, especially at ecological margins. Such antagonistic interactions steepen gradients and may increase the cost of adaptation by increasing its dimensionality. However, where biotic interactions do evolve, rapid range expansion can follow. Future research should test how the environmental sensitivity of genotypes determines their ecological exposure, and its effects on genetic variation in fitness, to predict the probability of evolutionary rescue at ecological margins. This article is part of the theme issue 'Species' ranges in the face of changing environments (Part II)'.
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Borboletas , Adaptação Fisiológica/genética , Animais , Evolução Biológica , Borboletas/genética , Drosophila/genética , Floresta ÚmidaRESUMO
Consistent with the concept of the gut-brain phenomenon, observational studies suggest a relationship between Alzheimer's disease (AD) and gastrointestinal tract (GIT) disorders; however, their underlying mechanisms remain unclear. Here, we analyse several genome-wide association studies (GWAS) summary statistics (N = 34,652-456,327), to assess the relationship of AD with GIT disorders. Findings reveal a positive significant genetic overlap and correlation between AD and gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), gastritis-duodenitis, irritable bowel syndrome and diverticulosis, but not inflammatory bowel disease. Cross-trait meta-analysis identifies several loci (Pmeta-analysis < 5 × 10-8) shared by AD and GIT disorders (GERD and PUD) including PDE4B, BRINP3, ATG16L1, SEMA3F, HLA-DRA, SCARA3, MTSS2, PHB, and TOMM40. Colocalization and gene-based analyses reinforce these loci. Pathway-based analyses demonstrate significant enrichment of lipid metabolism, autoimmunity, lipase inhibitors, PD-1 signalling, and statin mechanisms, among others, for AD and GIT traits. Our findings provide genetic insights into the gut-brain relationship, implicating shared but non-causal genetic susceptibility of GIT disorders with AD's risk. Genes and biological pathways identified are potential targets for further investigation in AD, GIT disorders, and their comorbidity.
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Doença de Alzheimer , Refluxo Gastroesofágico , Doença de Alzheimer/genética , Refluxo Gastroesofágico/complicações , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Evidence that long non-coding RNAs (lncRNAs) participate in DNA repair is accumulating, however, whether they can control DNA repair pathway choice is unknown. Here we show that the small Cajal body-specific RNA 2 (scaRNA2) can promote HR by inhibiting DNA-dependent protein kinase (DNA-PK) and, thereby, NHEJ. By binding to the catalytic subunit of DNA-PK (DNA-PKcs), scaRNA2 weakens its interaction with the Ku70/80 subunits, as well as with the LINP1 lncRNA, thereby preventing catalytic activation of the enzyme. Inhibition of DNA-PK by scaRNA2 stimulates DNA end resection by the MRN/CtIP complex, activation of ATM at DNA lesions and subsequent repair by HR. ScaRNA2 is regulated in turn by WRAP53ß, which binds this RNA, sequestering it away from DNA-PKcs and allowing NHEJ to proceed. These findings reveal that RNA-dependent control of DNA-PK catalytic activity is involved in regulating whether the cell utilizes NHEJ or HR.
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Proteínas Quinases , RNA , DNA/genética , DNA/metabolismo , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Autoantígeno Ku/genética , Autoantígeno Ku/metabolismo , Proteínas Quinases/metabolismoRESUMO
Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aß) pathology through the modulation of microglial activation and Aß clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.
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Doença de Alzheimer , Humanos , Feminino , Animais , Camundongos , Doença de Alzheimer/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Estudo de Associação Genômica Ampla , Apolipoproteína E4/genética , Peptídeos beta-Amiloides/genéticaRESUMO
Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer's disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast "resilient" unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.
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Doença de Alzheimer , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Fatores de RiscoRESUMO
Many plants regenerate after fire from a canopy-stored seed bank, in which seed are housed in fire resistant confructescences (cones) that remain on maternal plants. This strategy would be favoured if plants accumulate a sufficiently large and genetically diverse seed bank during interfire intervals. We use a 16-year demographic study and surveys of microsatellite variation to quantify and explain the rate of accumulation of genetic diversity within the canopy seed bank of the shrub Banksia spinulosa. Flowering and fruit set were highly variable. An initial sample in 1991 of 354 reproductively mature plants generated 426 cones over 16 years, of which only 55 cones from 40 maternal plants persisted until 2005. By genotyping seed from these 55 cones we demonstrated that genetic diversity accumulated rapidly within the seed bank. Resampling revealed that diversity was determined by the number, not the age, of cones. Cones were widely distributed among plants, outcrossing rates were high (mean t(m) = 1.00 +/- 0.04) and biparental inbreeding low. Adults displayed little evidence of isolation by distance and the genotypic diversity of seed cohorts was independent of the density of neighbouring potential sires. We therefore estimate that within at least 13 individual years the number of cones produced per year (14-63) would have contained 100% of the adult genetic diversity. We conclude that a highly outcrossed mating system and relatively widespread pollen dispersal ensure the rapid development of a genetically diverse and spatially and temporally homogeneous seed bank.
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Variação Genética , Genética Populacional , Proteaceae/genética , Sementes/genética , Austrália , DNA de Plantas/genética , Flores/crescimento & desenvolvimento , Frutas/crescimento & desenvolvimento , Genótipo , Repetições de Microssatélites , Reprodução/genética , Análise de Sequência de DNARESUMO
The clinically aggressive alveolar rhabdomyosarcoma (RMS) subtype is characterized by expression of the oncogenic fusion protein PAX3-FOXO1, which is critical for tumorigenesis and cell survival. Here, we studied the mechanism of cell death induced by loss of PAX3-FOXO1 expression and identified a novel pharmacologic combination therapy that interferes with PAX3-FOXO1 biology at different levels. Depletion of PAX3-FOXO1 in fusion-positive (FP)-RMS cells induced intrinsic apoptosis in a NOXA-dependent manner. This was pharmacologically mimicked by the BH3 mimetic navitoclax, identified as top compound in a screen from 208 targeted compounds. In a parallel approach, and to identify drugs that alter the stability of PAX3-FOXO1 protein, the same drug library was screened and fusion protein levels were directly measured as a read-out. This revealed that inhibition of Aurora kinase A most efficiently negatively affected PAX3-FOXO1 protein levels. Interestingly, this occurred through a novel specific phosphorylation event in and binding to the fusion protein. Aurora kinase A inhibition also destabilized MYCN, which is both a functionally important oncogene and transcriptional target of PAX3-FOXO1. Combined treatment with an Aurora kinase A inhibitor and navitoclax in FP-RMS cell lines and patient-derived xenografts synergistically induced cell death and significantly slowed tumor growth. These studies identify a novel functional interaction of Aurora kinase A with both PAX3-FOXO1 and its effector MYCN, and reveal new opportunities for targeted combination treatment of FP-RMS. SIGNIFICANCE: These findings show that Aurora kinase A and Bcl-2 family proteins are potential targets for FP-RMS.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aurora Quinase A/metabolismo , Proteína Proto-Oncogênica N-Myc/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Rabdomiossarcoma Alveolar/tratamento farmacológico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Aurora Quinase A/antagonistas & inibidores , Sinergismo Farmacológico , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Camundongos , Mutagênese Sítio-Dirigida , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/metabolismo , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/patologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Genomic imprinting shapes the genotype-phenotype relationship by creating an asymmetry between the influences of paternally and maternally inherited gene copies. Consequently, imprinting can impact heritable and nonheritable variation, resemblance of relatives, and evolutionary dynamics. Although previous analyses have identified some of the quantitative genetic consequences of imprinting, we lack a framework that cleanly separates the influence of imprinting from other components of variation, particularly dominance. Here we apply a simple orthogonal genetic model to evaluate the roles of genetic (additive and dominance) and epigenetic (imprinting) effects. Imprinting increases the resemblance of relatives who share the expressed allele, and therefore increases variance among families of full or half-siblings. However, only part of this increased variance is heritable and contributes to selection responses. When selection is within, or among, families sharing only a single parent (half-siblings), which is common in selective breeding programs, imprinting can alter overall responses. Selection is more efficient when it acts among families sharing the expressed parent, or within families sharing the parent with lower expression. Imprinting also affects responses to sex-specific selection. When selection is on the sex whose gene copy has lower expression, the response is diminished or delayed the next generation, although the long-term response is unaffected. Our findings have significant implications for understanding patterns of variation, interpretation of short-term selection responses, and the efficacy of selective breeding programs, demonstrating the importance of considering the independent influence of genomic imprinting in quantitative genetics.
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Evolução Molecular , Impressão Genômica , Modelos Genéticos , Animais , Feminino , Variação Genética , Humanos , MasculinoRESUMO
Proper repair of DNA double-strand breaks is critical for maintaining genome integrity and avoiding disease. Modification of damaged chromatin has profound consequences for the initial signaling and regulation of repair. One such modification involves ubiquitination by E3 ligases RNF8 and RNF168 within minutes after DNA double-strand break formation, altering chromatin structure and recruiting factors such as 53BP1 and BRCA1 for repair via non-homologous end-joining (NHEJ) and homologous recombination (HR), respectively. The WD40 protein WRAP53ß plays an essential role in localizing RNF8 to DNA breaks by scaffolding its interaction with the upstream factor MDC1. Loss of WRAP53ß impairs ubiquitination at DNA lesions and reduces downstream repair by both NHEJ and HR. Intriguingly, WRAP53ß depletion attenuates repair of DNA double-strand breaks more than depletion of RNF8, indicating functions other than RNF8-mediated ubiquitination. WRAP53ß plays key roles with respect to the nuclear organelles Cajal bodies, including organizing the genome to promote associated transcription and collecting factors involved in maturation of the spliceosome and telomere elongation within these organelles. It is possible that similar functions may aid also in DNA repair. Here we describe the involvement of WRAP53ß in Cajal bodies and DNA double-strand break repair in detail and explore whether and how these processes may be linked. We also discuss the possibility that the overexpression of WRAP53ß detected in several cancer types may reflect its normal participation in the DNA damage response rather than oncogenic properties.
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Imprinted genes are peculiar in that expression of the two copies differs depending on whether the copy was maternally or paternally inherited. The discovery of this striking pattern of gene expression inspired myriad evolutionary theories, the most successful of which identify scenarios that create an asymmetry between the maternally and paternally inherited gene copies that favors silencing of one of the copies. Most notably, imprinting can evolve when gene dosage affects kin interactions (typically involving conflict) or when silencing enhances coadaptation by coordinating traits expressed by interacting kin. Although we have a well-established theory for the former process (the "Kinship Theory"), the coadaptation process has only been explored for the specific case of interactions between mothers and offspring. Here, we fill this critical gap in our understanding by developing a general "Coadaptation Theory" that explains how imprinting can evolve to coordinate interactions between all types of relatives. Using a simple model in which fitness of an individual is determined by an interaction between its own phenotype (and hence genotype) and that of its social partner(s), we find that when the relatedness of interactants differs through their maternally versus paternally inherited gene copies, then selection favors expression of the allele through which relatedness is higher. The predictions of this Coadaptation Theory potentially apply whenever a gene underlies traits that mediate the outcome of conspecific interactions, regardless of their mechanism or the type of organism, and therefore provide a potential explanation for enigmatic patterns of imprinting, including those underlying adult traits. By providing simple testable predictions that often directly contrast with those derived from alternative theories, our model should play an important role in consolidating our understanding of the evolution of imprinting across genes and species, which will ultimately provide crucial insights into imprinted gene function and dysfunction.
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Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P < 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies.