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Hidradenitis suppurativa (HS) is characterized by deep-seated, highly inflamed, and painful lumps/abscesses, fistulae, and sinus tracts that grow extensively deep in the dermis and are highly immunogenic in nature. In about one-third of the HS patients there is strong evidence for the role of γ-secretase mutations along with dysregulated Notch signaling. However, the contribution of dysregulated Notch signaling in HS pathogenesis in relation to hair follicle alterations and hyper-activation of the immune system remains undefined. A genome-wide association study (GWAS), proteomic data and functional investigations of identified sequence variants in HS pathology are not fully revealing. The disease initiation or progression may involve bacterial infection besides intrinsic functional defects in keratinocytes, which may be key to further exacerbate immune cell infiltration and cytokine production in and around the lesional tissue. The absence of a suitable animal model that could fully recapitulate the pathogenesis of HS is a major impediment for proper understanding the underlying mechanisms and development of effective treatments. The presence of extracellular matrix (ECM) degradation products along with dysregulation in keratinocytes and, dermal fibroblasts ultimately affect immune regulation and are various components of HS pathogenesis. Bacterial infection further exacerbates the complexity of the disease progression. While anti-TNFα therapy shows partial efficacy, treatment to cure HS is absent. Multiple clinical trials targeting various cytokines, complement C5a and ECM products are in progress. This review provides state-of-the-art information on these aspects with a focus on dysregulated keratinocyte and immune cells; and role of ECM, and Keratin functions in this regard.
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Hidradenitis Supurativa , Animales , Proteínas del Citoesqueleto/metabolismo , Estudio de Asociación del Genoma Completo , Hidradenitis Supurativa/genética , Hidradenitis Supurativa/patología , Humanos , Queratinas/genética , Queratinas/metabolismo , Proteómica , Transducción de Señal/genéticaRESUMEN
NPR1 is a key transcriptional coregulator in plant defense responses. In this issue, Spoel et al. (2009) demonstrate that proteasome-mediated degradation of NPR1 in the nucleus promotes efficient expression of defense response genes following infection and prevents spurious activation of defensive responses in the absence of infection.
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Proteínas de Arabidopsis/inmunología , Arabidopsis/inmunología , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
In this Letter, an incorrect version of the Supplementary Information file was inadvertently used, which contained several errors. The details of references 59-65 were missing from the end of the Supplementary Discussion section on page 4. In addition, the section 'Text 3. Y2H on ICD interactions' incorrectly referred to 'Extended Data Fig. 4d' instead of 'Extended Data Fig. 3d' on page 3. Finally, the section 'Text 4. Interaction network analysis' incorrectly referred to 'Fig. 1b and Extended Data Fig. 6' instead of 'Fig. 2b and Extended Data Fig. 7' on page 3. These errors have all been corrected in the Supplementary Information.
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The cells of multicellular organisms receive extracellular signals using surface receptors. The extracellular domains (ECDs) of cell surface receptors function as interaction platforms, and as regulatory modules of receptor activation. Understanding how interactions between ECDs produce signal-competent receptor complexes is challenging because of their low biochemical tractability. In plants, the discovery of ECD interactions is complicated by the massive expansion of receptor families, which creates tremendous potential for changeover in receptor interactions. The largest of these families in Arabidopsis thaliana consists of 225 evolutionarily related leucine-rich repeat receptor kinases (LRR-RKs), which function in the sensing of microorganisms, cell expansion, stomata development and stem-cell maintenance. Although the principles that govern LRR-RK signalling activation are emerging, the systems-level organization of this family of proteins is unknown. Here, to address this, we investigated 40,000 potential ECD interactions using a sensitized high-throughput interaction assay, and produced an LRR-based cell surface interaction network (CSILRR) that consists of 567 interactions. To demonstrate the power of CSILRR for detecting biologically relevant interactions, we predicted and validated the functions of uncharacterized LRR-RKs in plant growth and immunity. In addition, we show that CSILRR operates as a unified regulatory network in which the LRR-RKs most crucial for its overall structure are required to prevent the aberrant signalling of receptors that are several network-steps away. Thus, plants have evolved LRR-RK networks to process extracellular signals into carefully balanced responses.
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Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimología , Leucina/metabolismo , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Arabidopsis/citología , Arabidopsis/inmunología , Arabidopsis/microbiología , Unión Proteica , Dominios Proteicos , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Superficie Celular/química , Receptores de Superficie Celular/metabolismo , Reproducibilidad de los Resultados , Transducción de SeñalRESUMEN
Understanding of cancer with the help of ever-expanding cutting edge technological tools and bioinformatics is revolutionizing modern cancer research by broadening the space of discovery window of various genomic and epigenomic processes. Genomics data integrated with multi-omics layering have advanced cancer research. Uncovering such layers of genetic mutations/modifications, epigenetic regulation and their role in the complex pathophysiology of cancer progression could lead to novel therapeutic interventions. Although a plethora of literature is available in public domain defining the role of various tumor driver gene mutations, understanding of epigenetic regulation of cancer is still emerging. This review focuses on epigenetic regulation association with the pathogenesis of non-melanoma skin cancer (NMSC). NMSC has higher prevalence in Caucasian populations compared to other races. Due to lack of proper reporting to cancer registries, the incidence rates for NMSC worldwide cannot be accurately estimated. However, this is the most common neoplasm in humans, and millions of new cases per year are reported in the United States alone. In organ transplant recipients, the incidence of NMSC particularly of squamous cell carcinoma (SCC) is very high and these SCCs frequently become metastatic and lethal. Understanding of solar ultraviolet (UV) light-induced damage and impaired DNA repair process leading to DNA mutations and nuclear instability provide an insight into the pathogenesis of metastatic neoplasm. This review discusses the recent advances in the field of epigenetics of NMSCs. Particularly, the role of DNA methylation, histone hyperacetylation and non-coding RNA such as long-chain noncoding (lnc) RNAs, circular RNAs and miRNA in the disease progression are summarized.
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Carcinoma de Células Escamosas , ARN Largo no Codificante , Neoplasias Cutáneas , Carcinoma de Células Escamosas/genética , Metilación de ADN , Epigénesis Genética , Humanos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Rayos UltravioletaRESUMEN
Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.
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Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Tumores Neuroectodérmicos/tratamiento farmacológico , Fosfoproteínas/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/genética , Quinasa 5 Dependiente de la Ciclina/metabolismo , Xenoinjertos , Humanos , Ratones , Neoplasias/genética , Tumores Neuroectodérmicos/genética , Tumores Neuroectodérmicos/metabolismo , Fosfoproteínas/análisis , Fosfoproteínas/genética , FosforilaciónRESUMEN
Drought is one of the most serious abiotic stressors in the environment, restricting agricultural production by reducing plant growth, development, and productivity. To investigate such a complex and multifaceted stressor and its effects on plants, a systems biology-based approach is necessitated, entailing the generation of co-expression networks, identification of high-priority transcription factors (TFs), dynamic mathematical modeling, and computational simulations. Here, we studied a high-resolution drought transcriptome of Arabidopsis. We identified distinct temporal transcriptional signatures and demonstrated the involvement of specific biological pathways. Generation of a large-scale co-expression network followed by network centrality analyses identified 117 TFs that possess critical properties of hubs, bottlenecks, and high clustering coefficient nodes. Dynamic transcriptional regulatory modeling of integrated TF targets and transcriptome datasets uncovered major transcriptional events during the course of drought stress. Mathematical transcriptional simulations allowed us to ascertain the activation status of major TFs, as well as the transcriptional intensity and amplitude of their target genes. Finally, we validated our predictions by providing experimental evidence of gene expression under drought stress for a set of four TFs and their major target genes using qRT-PCR. Taken together, we provided a systems-level perspective on the dynamic transcriptional regulation during drought stress in Arabidopsis and uncovered numerous novel TFs that could potentially be used in future genetic crop engineering programs.
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Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , Redes Reguladoras de Genes , Sequías , Factores de Transcripción/metabolismo , Biología de Sistemas , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico/genéticaRESUMEN
Biological networks are often large and complex, making it difficult to accurately identify the most important nodes. Node prioritization algorithms are used to identify the most influential nodes in a biological network by considering their relationships with other nodes. These algorithms can help us understand the functioning of the network and the role of individual nodes. We developed CentralityCosDist, an algorithm that ranks nodes based on a combination of centrality measures and seed nodes. We applied this and four other algorithms to protein-protein interactions and co-expression patterns in Arabidopsis thaliana using pathogen effector targets as seed nodes. The accuracy of the algorithms was evaluated through functional enrichment analysis of the top 10 nodes identified by each algorithm. Most enriched terms were similar across algorithms, except for DIAMOnD. CentralityCosDist identified more plant-pathogen interactions and related functions and pathways compared to the other algorithms.
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Aberrant activation of multiple complex signaling pathways underlies the pathogenesis of rhabdomyosarcoma (RMS), which remains a cause of mortality in approximately 30% of children with RMS. Bromodomain and extraterminal (BET) domain chromatin remodeling regulates several of these pathways. Here, we targeted bromodomain 4 (BRD4) in combination with another molecular metabolic tumor driver, the Akt/mTOR signaling pathway, to provide a highly effective treatment for this neoplasm. We demonstrated that a nexus of these two molecular pathways underlies RMS pathogenesis. Our data show that the combined inhibition of the BET bromodomain and mTORC1/2 signaling abrogates aggressive RMS growth. Thus, the bromodomain inhibitor RVX-208 significantly augmented the therapeutic effects of the dual mTORC1/2 inhibitors, OSI-027 and PP242, both in vitro and in a human xenograft murine model. Drug-treated residual tumors showed a decrease in the activation of underlying signaling mechanisms characterized by a reduction in the expression of p-AKT, p-mTOR, p-p70S6K, cyclin D1, and proliferation. Our ChIP-seq data demonstrated that RVX-208 effectively blocked BRD4 occupancy on its target promoters. ChIP-qPCR assays further confirmed that RVX-208 treatment resulted in a significant decrease in H3K27ac and H4K8ac signals at their target loci. While single RVX-208 treatment induces apoptosis and a single mTORC1/2 inhibitor induces macropinocytosis, their combined treatment led to necroptosis-mediated cell death. These data suggest that combined treatment with drugs targeting BRD4 and mTORC1/2 may be an effective therapeutic intervention for drug-resistant RMS.
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Proteínas Nucleares , Rabdomiosarcoma , Animales , Apoptosis , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Niño , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cultivated cotton (Gossypium hirsutum) is the most important fibre crop in the world. Cotton leaf curl disease (CLCuD) is the major limiting factor and a threat to textile industry in India and Pakistan. All the local cotton cultivars exhibit moderate to no resistance against CLCuD. In this study, we evaluated an exotic cotton accession Mac7 as a resistance source to CLCuD by challenging it with viruliferous whiteflies and performing qPCR to evaluate the presence/absence and relative titre of CLCuD-associated geminiviruses/betasatellites. The results indicated that replication of pathogenicity determinant betasatellite is significantly attenuated in Mac7 and probably responsible for resistance phenotype. Afterwards, to decipher the genetic basis of CLCuD resistance in Mac7, we performed RNA sequencing on CLCuD-infested Mac7 and validated RNA-Seq data with qPCR on 24 independent genes. We performed co-expression network and pathway analysis for regulation of geminivirus/betasatellite-interacting genes. We identified nine novel modules with 52 hubs of highly connected genes in network topology within the co-expression network. Analysis of these hubs indicated the differential regulation of auxin stimulus and cellular localization pathways in response to CLCuD. We also analysed the differential regulation of geminivirus/betasatellite-interacting genes in Mac7. We further performed the functional validation of selected candidate genes via virus-induced gene silencing (VIGS). Finally, we evaluated the genomic context of resistance responsive genes and found that these genes are not specific to A or D sub-genomes of G. hirsutum. These results have important implications in understanding CLCuD resistance mechanism and developing a durable resistance in cultivated cotton.
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Begomovirus , Resistencia a la Enfermedad , Gossypium/genética , Enfermedades de las Plantas/genética , Silenciador del Gen , Genes de Plantas , Gossypium/virología , India , Pakistán , Enfermedades de las Plantas/virologíaRESUMEN
Systems biology is an inclusive approach to study the static and dynamic emergent properties on a global scale by integrating multiomics datasets to establish qualitative and quantitative associations among multiple biological components. With an abundance of improved high throughput -omics datasets, network-based analyses and machine learning technologies are playing a pivotal role in comprehensive understanding of biological systems. Network topological features reveal most important nodes within a network as well as prioritize significant molecular components for diverse biological networks, including coexpression, protein-protein interaction, and gene regulatory networks. Machine learning techniques provide enormous predictive power through specific feature extraction from biological data. Deep learning, a subtype of machine learning, has plausible future applications because a domain expert for feature extraction is not needed in this algorithm. Inspired by diverse domains of biology, we here review classic systems biology techniques applied in plant immunity thus far. We also discuss additional advanced approaches in both graph theory and machine learning, which may provide new insights for understanding plant-microbe interactions. Finally, we propose a hybrid approach in plant immune systems that harnesses the power of both network biology and machine learning, with a potential to be applicable to both model systems and agronomically important crop plants.
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Interacciones Huésped-Patógeno , Aprendizaje Automático , Biología de Sistemas , Algoritmos , Redes Reguladoras de Genes , Modelos BiológicosRESUMEN
One layer of the innate immune system allows plants to recognize pathogen-associated molecular patterns (PAMPS), activating a defense response known as PAMP-triggered immunity (PTI). Maintaining an active immune response, however, comes at the cost of plant growth and development; accordingly, optimization of the balance between defense and development is critical to plant fitness. The TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) transcription factor family consists of well-characterized transcriptional regulators of plant development and morphogenesis. The three closely related class I TCP transcription factors TCP8, TCP14, and TCP15 have also been implicated in the regulation of effector-triggered immunity, but there has been no previous characterization of PTI-related phenotypes. To identify TCP targets involved in PTI, we screened a PAMP-induced gene promoter library in a yeast one-hybrid assay and identified interactions of these three TCPs with the EF-Tu RECEPTOR (EFR) promoter. The direct interactions between TCP8 and EFR were confirmed to require an intact TCP binding site in planta. A tcp8 tcp14 tcp15 triple mutant was impaired in EFR-dependent PTI and exhibited reduced levels of PATHOGENESIS-RELATED PROTEIN 2 and induction of EFR expression after elicitation with elf18 but also increased production of reactive oxygen species relative to Col-0. Our data support an increasingly complex role for TCPs at the nexus of plant development and defense.
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Proteínas de Arabidopsis , Arabidopsis , Inmunidad de la Planta , Arabidopsis/inmunología , Proteínas de Arabidopsis/genética , Regulación de la Expresión Génica de las Plantas , Factor Tu de Elongación Peptídica/genética , Inmunidad de la Planta/genética , Factores de Transcripción/genéticaRESUMEN
HopAF1 is a type III effector protein of unknown function encoded in the genomes of several strains of Pseudomonas syringae and other plant pathogens. Structural modeling predicted that HopAF1 is closely related to deamidase proteins. Deamidation is the irreversible substitution of an amide group with a carboxylate group. Several bacterial virulence factors are deamidases that manipulate the activity of specific host protein substrates. We identified Arabidopsis methylthioadenosine nucleosidase proteins MTN1 and MTN2 as putative targets of HopAF1 deamidation. MTNs are enzymes in the Yang cycle, which is essential for the high levels of ethylene biosynthesis in Arabidopsis We hypothesized that HopAF1 inhibits the host defense response by manipulating MTN activity and consequently ethylene levels. We determined that bacterially delivered HopAF1 inhibits ethylene biosynthesis induced by pathogen-associated molecular patterns and that Arabidopsis mtn1 mtn2 mutant plants phenocopy the effect of HopAF1. Furthermore, we identified two conserved asparagines in MTN1 and MTN2 from Arabidopsis that confer loss of function phenotypes when deamidated via site-specific mutation. These residues are potential targets of HopAF1 deamidation. HopAF1-mediated manipulation of Yang cycle MTN proteins is likely an evolutionarily conserved mechanism whereby HopAF1 orthologs from multiple plant pathogens contribute to disease in a large variety of plant hosts.
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Arabidopsis/microbiología , Proteínas Bacterianas/fisiología , Etilenos/antagonistas & inhibidores , Metionina/metabolismo , Pseudomonas syringae/metabolismo , Acilación , Secuencia de Aminoácidos , Arabidopsis/inmunología , Proteínas Bacterianas/química , Dominio Catalítico , Membrana Celular/metabolismo , Evolución Molecular , Duplicación de Gen , Filogenia , Pseudomonas syringae/genética , Homología de Secuencia de AminoácidoRESUMEN
Cytokinin is a phytohormone that is well known for its roles in numerous plant growth and developmental processes, yet it has also been linked to abiotic stress response in a less defined manner. Arabidopsis (Arabidopsis thaliana) Cytokinin Response Factor 6 (CRF6) is a cytokinin-responsive AP2/ERF-family transcription factor that, through the cytokinin signaling pathway, plays a key role in the inhibition of dark-induced senescence. CRF6 expression is also induced by oxidative stress, and here we show a novel function for CRF6 in relation to oxidative stress and identify downstream transcriptional targets of CRF6 that are repressed in response to oxidative stress. Analysis of transcriptomic changes in wild-type and crf6 mutant plants treated with H2O2 identified CRF6-dependent differentially expressed transcripts, many of which were repressed rather than induced. Moreover, many repressed genes also show decreased expression in 35S:CRF6 overexpressing plants. Together, these findings suggest that CRF6 functions largely as a transcriptional repressor. Interestingly, among the H2O2 repressed CRF6-dependent transcripts was a set of five genes associated with cytokinin processes: (signaling) ARR6, ARR9, ARR11, (biosynthesis) LOG7, and (transport) ABCG14. We have examined mutants of these cytokinin-associated target genes to reveal novel connections to oxidative stress. Further examination of CRF6-DNA interactions indicated that CRF6 may regulate its targets both directly and indirectly. Together, this shows that CRF6 functions during oxidative stress as a negative regulator to control this cytokinin-associated module of CRF6-dependent genes and establishes a novel connection between cytokinin and oxidative stress response.
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Proteínas de Arabidopsis/genética , Arabidopsis/genética , Citocininas/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica de las Plantas/genética , Estrés Oxidativo , Factores de Transcripción/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Clorofila/química , Clorofila/metabolismo , Fluorescencia , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Ontología de Genes , Peróxido de Hidrógeno/farmacología , Mutación , Oxidantes/farmacología , Hojas de la Planta/genética , Hojas de la Planta/metabolismo , Plantas Modificadas Genéticamente , Unión Proteica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Plantones/genética , Plantones/metabolismo , Factores de Transcripción/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
PURPOSE: The achievement of shoulder balance is an important measure of successful scoliosis surgery. No previously described classification system has taken shoulder balance into account. We propose a simple classification system for AIS based on two components which include the curve type and shoulder level. METHODS: Altogether, three curve types have been defined according to the size and location of the curves, each curve pattern is subdivided into type A or B depending on the shoulder level. This classification was tested for interobserver reproducibility and intraobserver reliability. A retrospective analysis of the radiographs of 232 consecutive cases of AIS patients treated surgically between 2005 and 2009 was also performed. RESULTS: Three major types and six subtypes were identified. Type I accounted for 30 %, type II 28 % and type III 42 %. The retrospective analysis showed three patients developed a decompensation that required extension of the fusion. One case developed worsening of shoulder balance requiring further surgery. This classification was tested for interobserver and intraobserver reliability. The mean kappa coefficients for interobserver reproducibility ranged from 0.89 to 0.952, while the mean kappa value for intraobserver reliability was 0.964 indicating a good-to-excellent reliability. CONCLUSIONS: The treatment algorithm guides the spinal surgeon to achieve optimal curve correction and postoperative shoulder balance whilst fusing the smallest number of spinal segments. The high interobserver reproducibility and intraobserver reliability makes it an invaluable tool to describe scoliosis curves in everyday clinical practice.
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Escoliosis/clasificación , Escoliosis/cirugía , Hombro/diagnóstico por imagen , Columna Vertebral/diagnóstico por imagen , Adolescente , Femenino , Estudios de Seguimiento , Humanos , Masculino , Variaciones Dependientes del Observador , Radiografía , Reproducibilidad de los Resultados , Estudios Retrospectivos , Fusión VertebralRESUMEN
BACKGROUND: Heterotrimeric G-proteins are important signalling switches, present in all eukaryotic kingdoms. In plants they regulate several developmental functions and play an important role in plant-microbe interactions. The current knowledge on plant G-proteins is mostly based on model angiosperms and little is known about the G-protein repertoire and function in other lineages. In this study we investigate the heterotrimeric G-protein subunit repertoire in Pinaceae, including phylogenetic relationships, radiation and sequence diversity levels in relation to other plant linages. We also investigate functional diversification of the G-protein complex in Picea abies by analysing transcriptional regulation of the G-protein subunits in different tissues and in response to pathogen infection. RESULTS: A full repertoire of G-protein subunits in several conifer species were identified in silico. The full-length P. abies coding regions of one Gα-, one Gß- and four Gγ-subunits were cloned and sequenced. The phylogenetic analysis of the Gγ-subunits showed that PaGG1 clustered with A-type-like subunits, PaGG3 and PaGG4 clustered with C-type-like subunits, while PaGG2 and its orthologs represented a novel conifer-specific putative Gγ-subunit type. Gene expression analyses by quantitative PCR of P. abies G-protein subunits showed specific up-regulation of the Gα-subunit gene PaGPA1 and the Gγ-subunit gene PaGG1 in response to Heterobasidion annosum sensu lato infection. CONCLUSIONS: Conifers possess a full repertoire of G-protein subunits. The differential regulation of PaGPA1 and PaGG1 indicates that the heterotrimeric G-protein complex represents a critical linchpin in Heterobasidion annosum s.l. perception and downstream signaling in P. abies.
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Basidiomycota/fisiología , Regulación de la Expresión Génica de las Plantas , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Picea/metabolismo , Enfermedades de las Plantas/inmunología , Proteínas de Plantas/metabolismo , Secuencia de Aminoácidos , Dimerización , Proteínas de Unión al GTP Heterotriméricas/química , Proteínas de Unión al GTP Heterotriméricas/genética , Datos de Secuencia Molecular , Filogenia , Picea/química , Picea/clasificación , Picea/genética , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/química , Proteínas de Plantas/genética , Subunidades de Proteína/química , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Alineación de SecuenciaRESUMEN
An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.
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Síndrome de Cockayne/tratamiento farmacológico , Síndrome de Cockayne/patología , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Niacina/uso terapéutico , Proteínas Nucleares/genética , Pelagra/patología , Factores de Transcripción/genética , Xerodermia Pigmentosa/tratamiento farmacológico , Xerodermia Pigmentosa/patología , Secuencia de Bases , Preescolar , Síndrome de Cockayne/genética , Ensayo Cometa , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Exoma/genética , Resultado Fatal , Femenino , Humanos , Lactante , Datos de Secuencia Molecular , Niacina/farmacología , Linaje , Análisis de Secuencia de ADN , Xerodermia Pigmentosa/genéticaRESUMEN
Leishmaniasis remains a serious health problem. The outcome of Leishmania infection depends on the early innate response. In this study, whole blood samples of 40 patients with visceral leishmaniasis (VL), 10 leishmanin skin test-negative (LST-ve) controls and 10 leishmanin skin test-positive (LST+ve) controls were stimulated by live L. donovani promastigotes. Also, THP1 human cell line was infected with L. donovani. The production of interleukin 10 (IL-10), tumour necrosis factor alpha (TNF) and interferon gamma (IFNG) cytokines was measured, and the expression of Toll-like receptors (TLR2, TLR4 and TLR9) was done in the blood samples and also in the THP1 cell line. IL-10 was found to be higher in LST+ve controls compared with VL patients. TNF was moderately produced with no variation between patients, controls and THP1 cells. IFNG was higher in LST+ve controls also in THP1 cells. TLR4 and TLR9 were found to be highly expressed in patients with VL. L. donovani increases the expression of TLR4 and TLR9 in patients with VL and TLR2 in THP1 cells, suggesting a TLRs relation in induction of a mixed cytokine response. TLR9 was markedly recognized by L. donovani DNA.
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Interferón gamma/inmunología , Interleucina-10/inmunología , Leishmaniasis Visceral/inmunología , Macrófagos/inmunología , Receptores Toll-Like/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adulto , Antígenos de Protozoos/análisis , Sangre/inmunología , Línea Celular , Femenino , Humanos , Leishmania donovani/inmunología , Macrófagos/parasitología , Masculino , Sudán , Receptor Toll-Like 2/sangre , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/sangre , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 9/sangre , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunología , Receptores Toll-Like/sangre , Receptores Toll-Like/genéticaAsunto(s)
Complicaciones de la Diabetes , Diabetes Mellitus , Proteína HMGB1/genética , Infarto del Miocardio , Receptor para Productos Finales de Glicación Avanzada/genética , Proteína X Asociada a bcl-2/genética , Expresión Génica , Marcadores Genéticos , Humanos , Infarto del Miocardio/complicaciones , Infarto del Miocardio/genética , PakistánRESUMEN
BACKGROUND: Plants respond to diverse environmental cues including microbial perturbations by coordinated regulation of thousands of genes. These intricate transcriptional regulatory interactions depend on the recognition of specific promoter sequences by regulatory transcription factors. The combinatorial and cooperative action of multiple transcription factors defines a regulatory network that enables plant cells to respond to distinct biological signals. The identification of immune-related modules in large-scale transcriptional regulatory networks can reveal the mechanisms by which exposure to a pathogen elicits a precise phenotypic immune response. RESULTS: We have generated a large-scale immune co-expression network using a comprehensive set of Arabidopsis thaliana (hereafter Arabidopsis) transcriptomic data, which consists of a wide spectrum of immune responses to pathogens or pathogen-mimicking stimuli treatments. We employed both linear and non-linear models to generate Arabidopsis immune co-expression regulatory (AICR) network. We computed network topological properties and ascertained that this newly constructed immune network is densely connected, possesses hubs, exhibits high modularity, and displays hallmarks of a "real" biological network. We partitioned the network and identified 156 novel modules related to immune functions. Gene Ontology (GO) enrichment analyses provided insight into the key biological processes involved in determining finely tuned immune responses. We also developed novel software called OCCEAN (One Click Cis-regulatory Elements ANalysis) to discover statistically enriched promoter elements in the upstream regulatory regions of Arabidopsis at a whole genome level. We demonstrated that OCCEAN exhibits higher precision than the existing promoter element discovery tools. In light of known and newly discovered cis-regulatory elements, we evaluated biological significance of two key immune-related functional modules and proposed mechanism(s) to explain how large sets of diverse GO genes coherently function to mount effective immune responses. CONCLUSIONS: We used a network-based, top-down approach to discover immune-related modules from transcriptomic data in Arabidopsis. Detailed analyses of these functional modules reveal new insight into the topological properties of immune co-expression networks and a comprehensive understanding of multifaceted plant defense responses. We present evidence that our newly developed software, OCCEAN, could become a popular tool for the Arabidopsis research community as well as potentially expand to analyze other eukaryotic genomes.