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Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.
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Respiración de la Célula , Ratones Noqueados , Contracción Muscular , Músculo Esquelético , Enfisema Pulmonar , Succinato Deshidrogenasa , Animales , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/genética , Enfisema Pulmonar/patología , Enfisema Pulmonar/etiología , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/genética , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Complejo II de Transporte de Electrones/metabolismo , Complejo II de Transporte de Electrones/genética , Modelos Animales de Enfermedad , Ratones Transgénicos , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/patología , Consumo de OxígenoRESUMEN
Natural prokaryotic gene repression systems often exploit DNA looping to increase the local concentration of gene repressor proteins at a regulated promoter via contributions from repressor proteins bound at distant sites. Using principles from the Escherichia coli lac operon we design analogous repression systems based on target sequence-programmable Transcription Activator-Like Effector dimer (TALED) proteins. Such engineered switches may be valuable for synthetic biology and therapeutic applications. Previous TALEDs with inducible non-covalent dimerization showed detectable, but limited, DNA loop-based repression due to the repressor protein dimerization equilibrium. Here, we show robust DNA loop-dependent bacterial promoter repression by covalent TALEDs and verify that DNA looping dramatically enhances promoter repression in E. coli. We characterize repression using a thermodynamic model that quantitates this favorable contribution of DNA looping. This analysis unequivocally and quantitatively demonstrates that optimized TALED proteins can drive loop-dependent promoter repression in E. coli comparable to the natural LacI repressor system. This work elucidates key design principles that set the stage for wide application of TALED-dependent DNA loop-based repression of target genes.
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Escherichia coli , Regulación Bacteriana de la Expresión Génica , Represoras Lac , Regiones Promotoras Genéticas , Represoras Lac/metabolismo , Represoras Lac/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Operón Lac , Efectores Tipo Activadores de la Transcripción/metabolismo , Efectores Tipo Activadores de la Transcripción/genética , Ingeniería de Proteínas/métodos , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Multimerización de Proteína , Conformación de Ácido Nucleico , ADN/metabolismo , ADN/genética , ADN/química , ADN Bacteriano/metabolismo , ADN Bacteriano/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/química , TermodinámicaRESUMEN
The occurrence of DNA looping is ubiquitous. This process plays a well-documented role in the regulation of prokaryotic gene expression, such as in regulation of the Escherichia coli lactose (lac) operon. Here we present two complementary methods for high-resolution in vivo detection of DNA/protein binding within the bacterial nucleoid by using either chromatin immunoprecipitation combined with phage λ exonuclease digestion (ChIP-exo) or chromatin endogenous cleavage (ChEC), coupled with ligation-mediated polymerase chain reaction (LM-PCR) and Southern blot analysis. As an example, we apply these in vivo protein-mapping methods to E. coli to show direct binding of architectural proteins in the Lac repressor-mediated DNA repression loop.
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Inmunoprecipitación de Cromatina , ADN Bacteriano , Escherichia coli , ADN Bacteriano/metabolismo , ADN Bacteriano/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Inmunoprecipitación de Cromatina/métodos , Unión Proteica , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Operón Lac , Reacción en Cadena de la Polimerasa/métodos , Southern Blotting , Bacteriófago lambda/genética , Bacteriófago lambda/metabolismoRESUMEN
In this issue of Cell Chemical Biology, Bush et al.1 report an in vitro selection method for optimizing CRISPR-Cas9 single-guide RNAs. This approach may be useful in targeting previously intractable genomic sequences. The results also provide insights into which positions in single-guide RNAs are most amenable to modification.
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Sistemas CRISPR-Cas , Genómica , Sistemas CRISPR-Cas/genética , ARN Guía de Sistemas CRISPR-CasRESUMEN
Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and ß-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. ß-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals ß-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa.
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Neoplasias de la Próstata , Regulador Transcripcional ERG , Proteína p53 Supresora de Tumor , Animales , Humanos , Masculino , Ratones , beta Catenina/genética , beta Catenina/metabolismo , Mutación con Ganancia de Función , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Proto-Oncogenes , Pirimidinas/biosíntesis , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The efficient and specific delivery of functional cargos such as small-molecule drugs, proteins, or nucleic acids across lipid membranes and into subcellular compartments is a significant unmet need in nanomedicine and molecular biology. Systematic Evolution of Ligands by EXponential enrichment (SELEX) exploits vast combinatorial nucleic acid libraries to identify short, nonimmunogenic single-stranded DNA molecules (aptamers) capable of recognizing specific targets based on their 3D structures and molecular interactions. While SELEX has previously been applied to identify aptamers that bind specific cell types or gain cellular uptake, selection of aptamers capable of carrying cargos to specific subcellular compartments is challenging. Here, we describe peroxidase proximity selection (PPS), a generalizable subcellular SELEX approach. We implement local expression of engineered ascorbate peroxidase APEX2 to biotinylate naked DNA aptamers capable of gaining access to the cytoplasm of living cells without assistance. We discovered DNA aptamers that are preferentially taken up into endosomes by macropinocytosis, with a fraction apparently accessing APEX2 in the cytoplasm. One of these selected aptamers is capable of endosomal delivery of an IgG antibody.
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Polyploidization is an evolutionary process by which a species acquires multiple copies of its complete set of chromosomes. The reticulate nature of the signal left behind by it means that phylogenetic networks offer themselves as a framework to reconstruct the evolutionary past of species affected by it. The main strategy for doing this is to first construct a so-called multiple-labelled tree and to then somehow derive such a network from it. The following question therefore arises: How much can be said about that past if such a tree is not readily available? By viewing a polyploid dataset as a certain vector which we call a ploidy (level) profile, we show that among other results, there always exists a phylogenetic network in the form of a beaded phylogenetic tree with additional arcs that realizes a given ploidy profile. Intriguingly, the two end vertices of almost all of these additional arcs can be interpreted as having co-existed in time thereby adding biological realism to our network, a feature that is, in general, not enjoyed by phylogenetic networks. In addition, we show that our network may be viewed as a generator of ploidy profile space, a novel concept similar to phylogenetic tree space that we introduce to be able to compare phylogenetic networks that realize one and the same ploidy profile. We illustrate our findings in terms of a publicly available Viola dataset.
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Conceptos Matemáticos , Modelos Biológicos , Filogenia , Evolución Biológica , Tiempo , Modelos Genéticos , AlgoritmosRESUMEN
Advances in peroxidase and biotin ligase-mediated signal amplification have enabled high-resolution subcellular mapping of endogenous RNA localization and protein-protein interactions. Application of these technologies has been limited to RNA and proteins because of the reactive groups required for biotinylation in each context. Here we report several novel methods for proximity biotinylation of exogenous oligodeoxyribonucleotides by application of well-established and convenient enzymatic tools. We describe approaches using simple and efficient conjugation chemistries to modify deoxyribonucleotides with "antennae" that react with phenoxy radicals or biotinoyl-5'-adenylate. In addition, we report chemical details of a previously undescribed adduct between tryptophan and a phenoxy radical group. These developments have potential application in the selection of exogenous nucleic acids capable of unaided entry into living cells.
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The histone chaperone FACT (facilitates chromatin transcription) enhances transcription in eukaryotic cells, targeting DNA-protein interactions. FACT, a heterodimer in humans, comprises SPT16 and SSRP1 subunits. We measure nucleosome stability and dynamics in the presence of FACT and critical component domains. Optical tweezers quantify FACT/subdomain binding to nucleosomes, displacing the outer wrap of DNA, disrupting direct DNA-histone (core site) interactions, altering the energy landscape of unwrapping, and increasing the kinetics of DNA-histone disruption. Atomic force microscopy reveals nucleosome remodeling, while single-molecule fluorescence quantifies kinetics of histone loss for disrupted nucleosomes, a process accelerated by FACT. Furthermore, two isolated domains exhibit contradictory functions; while the SSRP1 HMGB domain displaces DNA, SPT16 MD/CTD stabilizes DNA-H2A/H2B dimer interactions. However, only intact FACT tethers disrupted DNA to the histones and supports rapid nucleosome reformation over several cycles of force disruption/release. These results demonstrate that key FACT domains combine to catalyze both nucleosome disassembly and reassembly.
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Chaperonas de Histonas , Nucleosomas , Humanos , Cromatina , ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Factores de Elongación Transcripcional/genéticaRESUMEN
Polyploidization, whereby an organism inherits multiple copies of the genome of their parents, is an important evolutionary event that has been observed in plants and animals. One way to study such events is in terms of the ploidy number of the species that make up a dataset of interest. It is therefore natural to ask: How much information about the evolutionary past of the set of species that form a dataset can be gleaned from the ploidy numbers of the species? To help answer this question, we introduce and study the novel concept of a ploidy profile which allows us to formalize it in terms of a multiplicity vector indexed by the species the dataset is comprised of. Using the framework of a phylogenetic network, we present a closed formula for computing the hybrid number (i.e. the minimal number of polyploidization events required to explain a ploidy profile) of a large class of ploidy profiles. This formula relies on the construction of a certain phylogenetic network from the simplification sequence of a ploidy profile and the hybrid number of the ploidy profile with which this construction is initialized. Both of them can be computed easily in case the ploidy numbers that make up the ploidy profile are not too large. To help illustrate the applicability of our approach, we apply it to a simplified version of a publicly available Viola dataset.
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Genoma , Ploidias , Animales , FilogeniaRESUMEN
The quantitative polymerase chain reaction (qPCR) with detection of duplex DNA yield by intercalator fluorescence is a common and essential technique in nucleic acid analysis. We encountered unexpected results when applying standard qPCR methods to the quantitation of random DNA libraries flanked by regions of fixed sequence, a configuration essential for in vitro selection experiments. Here we describe the results of experiments revealing why conventional qPCR methods can fail to allow automated analysis in such cases, and simple solutions to this problem. In particular we show that renaturation of PCR products containing random regions is incomplete in late PCR cycles when extension fails due to reagent depletion. Intercalator fluorescence can then be lost at standard interrogation temperatures. We show that qPCR analysis of random DNA libraries can be achieved simply by adjusting the step at which intercalator fluorescence is monitored so that the yield of annealed constant regions is detected rather than the yield of full duplex DNA products.
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Aptámeros de Nucleótidos , Aptámeros de Nucleótidos/genética , ADN/análisis , ADN/genética , Biblioteca de Genes , Sustancias Intercalantes , Reacción en Cadena de la Polimerasa/métodosRESUMEN
Aims To evaluate the impact of Allura Clarity technology on radiation exposure in patients undergoing diagnostic coronary angiography. Methods A retrospective analysis was undertaken of invasive coronary angiograms performed by a single experienced operator in Cork University Hospital (CUH) (Allura Xper FD10 angiography system). In order to reduce operator variability, we also analysed cases performed by the same operator in the Bon Secours Hospital Cork (BSHC) (Allura Clarity FD10 angiography system). Cases were selected consecutively, having excluded those involving percutaneous coronary intervention, graft studies, aortography, ventriculography, right heart studies or fractional flow reserve studies. Results A total of 178 patients were included, equally distributed between the CUH arm (n=89) and the BSHC arm (n=89). Cohorts were very well matched in terms of age, gender, Body Mass Index, and procedural approach. The median radiation dose in CUH was a Dose Area Product (DAP) of 10,460 mGy.cm2 vs. median DAP of 12,795 mGy.cm2 in BSHC (p=0.148). The median fluoroscopy time in CUH was 2.25mins vs. median fluoroscopy time of 2.17mins in BSHC (p=0.675). Conclusion The use of the Allura Clarity system for diagnostic coronary angiography did not result in a significant difference in radiation dose or fluoroscopy time when compared to the reference Allura Xper system. Further research is needed to investigate the benefit of this new image noise reduction technology in diagnostic coronary angiography.
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Reducción Gradual de Medicamentos , Reserva del Flujo Fraccional Miocárdico , Angiografía Coronaria/efectos adversos , Fluoroscopía/efectos adversos , Humanos , Dosis de Radiación , Estudios RetrospectivosRESUMEN
Successful use of biomedical forms of HIV risk-reduction may have predisposed many gay and bisexual men (GBM) to vaccination against COVID-19, which may, in turn, affect their sexual behavior. A total of 622 Australian GBM provided weekly data on COVID-19 vaccination history and sexual behaviour between 17 January 2021 and 22 June 2021. We identify factors associated with COVID-19 vaccination, and compare sexual behavior before and since vaccination. Mean age was 47.3 years (SD 14.0). At least one-dose vaccination coverage had reached 57.2%, and 61.3% reported that the majority of their friends intended to be vaccinated. Vaccinated men reported a mean of 1.11 (SD 2.10) weekly non-relationship sex partners before vaccination and 1.62 (SD 3.42) partners following vaccination. GBM demonstrated high confidence in COVID-19 vaccines. Their sexual activity increased following vaccination suggesting that greater sexual freedom may be a specific motivation for vaccine uptake among some men.
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COVID-19 , Infecciones por VIH , Minorías Sexuales y de Género , Australia/epidemiología , Bisexualidad , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Humanos , Masculino , Persona de Mediana Edad , Conducta Sexual , Parejas SexualesRESUMEN
Architectural proteins alter the shape of DNA. Some distort the double helix by introducing sharp kinks. This can serve to relieve strain in tightly-bent DNA structures. Here, we design and test artificial architectural proteins based on a sequence-specific Transcription Activator-like Effector (TALE) protein, either alone or fused to a eukaryotic high mobility group B (HMGB) DNA-bending domain. We hypothesized that TALE protein binding would stiffen DNA to bending and twisting, acting as an architectural protein that antagonizes the formation of small DNA loops. In contrast, fusion to an HMGB domain was hypothesized to generate a targeted DNA-bending architectural protein that facilitates DNA looping. We provide evidence from Escherichia coli Lac repressor gene regulatory loops supporting these hypotheses in living bacteria. Both data fitting to a thermodynamic DNA looping model and sophisticated molecular modeling support the interpretation of these results. We find that TALE protein binding inhibits looping by stiffening DNA to bending and twisting, while the Nhp6A domain enhances looping by bending DNA without introducing twisting flexibility. Our work illustrates artificial approaches to sculpt DNA geometry with functional consequences. Similar approaches may be applicable to tune the stability of small DNA loops in eukaryotes.
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ADN Bacteriano/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Operón Lac , Conformación de Ácido Nucleico , Regiones Promotoras Genéticas , Unión ProteicaRESUMEN
BACKGROUND: Comorbidity is the presence of at least two disorders in one person at one time. This study examined the frequency of gastrointestinal (GI) symptoms, sleep problems, comorbid psychopathology, challenging behaviour and autism spectrum disorder (ASD) symptoms in children and adolescents with duplication 15q syndrome (Dup15q), aged 3-17 years. This study also examined whether challenging behaviour in Dup15q is predicted by age, gender, presence of an intellectual disability, sleep problems, GI symptoms and comorbid psychopathology. METHOD: Parental measures were completed by 101 parents of children and adolescents with Dup15q. Questionnaires were composed of the Children's Sleep Habits Questionnaire, Behavior Problems Inventory - Short Form, GI Symptom Inventory, Social Communication Questionnaire and the Child Behavior Checklist. RESULTS: Sleep problems (94%), GI symptoms (87%) and challenging behaviour (100%) were common comorbidities represented in the sample in this study. Significant relationships were found between challenging behaviour and the presence of co-occurring sleep problems, GI symptoms, comorbid psychopathology and ASD symptoms. Further analysis revealed that these comorbidities also predicted challenging behaviour. CONCLUSION: This research demonstrated the importance of studying the relationships between GI symptoms, sleep problems, comorbid psychopathology, ASD symptoms and challenging behaviour in Dup15q and how these conditions can shape the Dup15q phenotype.
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Trastorno del Espectro Autista/genética , Enfermedades Gastrointestinales/genética , Trastornos Mentales/genética , Problema de Conducta/psicología , Sueño/fisiología , Adolescente , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/psicología , Niño , Preescolar , Duplicación Cromosómica , Cromosomas Humanos Par 15/genética , Comorbilidad , Femenino , Enfermedades Gastrointestinales/epidemiología , Humanos , Masculino , Trastornos Mentales/epidemiología , Psicopatología , Trastornos del Sueño-Vigilia/epidemiología , TrisomíaRESUMEN
Recent advances in peroxidase-mediated biotin tyramide (BT) signal amplification technology have resulted in high-resolution and subcellular compartment-specific mapping of protein and RNA localization. Horseradish peroxidase (HRP) in the presence of H2 O2 is known to activate phenolic compounds for phenoxy radical reaction with nucleic acids, where biotinylation by BT is a practical example. BT reactivity with RNA and DNA is not understood in detail. We report that BT phenoxy radicals react in a sequence-independent manner with guanosine bases in RNA. In contrast, DNA reactivity with BT cannot be detected by our methods under the same conditions. Remarkably, we show that fluorescein conjugates DNA rapidly and selectively reacts with BT phenoxy radicals, allowing convenient and practical biotinylation of DNA on fluorescein with retention of fluorescence.
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Ácidos Nucleicos/metabolismo , Fenoles/metabolismo , Biotina/análogos & derivados , Biotina/química , Biotina/metabolismo , Biotinilación , ADN/química , ADN/metabolismo , Estructura Molecular , Ácidos Nucleicos/química , Fenoles/química , Tiramina/análogos & derivados , Tiramina/química , Tiramina/metabolismoRESUMEN
Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre-mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a compartment where PPGL is known to originate. We report that while there is modest expansion of TH+ glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondiabetic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH+ cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.
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Neoplasias de las Glándulas Suprarrenales/genética , Modelos Animales de Enfermedad , Síndromes Neoplásicos Hereditarios/genética , Obesidad/genética , Fenotipo , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , Neoplasias de las Glándulas Suprarrenales/patología , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Síndromes Neoplásicos Hereditarios/patología , Obesidad/patología , Feocromocitoma/patología , Succinato Deshidrogenasa/deficienciaRESUMEN
Gene regulation by control of transcription initiation is a fundamental property of living cells. Much of our understanding of gene repression originated from studies of the Escherichia coli lac operon switch, in which DNA looping plays an essential role. To validate and generalize principles from lac for practical applications, we previously described artificial DNA looping driven by designed transcription activator-like effector dimer (TALED) proteins. Because TALE monomers bind the idealized symmetrical lac operator sequence in two orientations, our prior studies detected repression due to multiple DNA loops. We now quantitatively characterize gene repression in living E. coli by a collection of individual TALED loops with systematic loop length variation. Fitting of a thermodynamic model allows unequivocal demonstration of looping and comparison of the engineered TALED repression system with the natural lac repressor system.
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Proteínas de Escherichia coli , Efectores Tipo Activadores de la Transcripción , ADN Bacteriano , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Regulación Bacteriana de la Expresión Génica , Operón Lac/genética , Represoras Lac/genética , Represoras Lac/metabolismo , Conformación de Ácido NucleicoRESUMEN
BACKGROUND: Numerous models, tools and frameworks have been produced to improve the sustainability of evidence-based interventions. Due to the vast number available, choosing the most appropriate one is increasingly difficult for researchers and practitioners. To understand the value of such approaches, evidence warranting their use is needed. However, there is limited understanding of how sustainability approaches have been used and how they have impacted research or practice. This review aims to consolidate evidence on the application and impact of sustainability approaches in healthcare settings. METHODS: A systematic scoping review was designed to search for peer-reviewed publications detailing the use of sustainability approaches in practice. A 5-stage framework for scoping reviews directed the search strategy, and quality assessment was performed using the Mixed Method Appraisal Tool. Searches were performed through electronic citation tracking and snowballing of references. Articles were obtained through Web of Science, PubMed and Google Scholar. Six outcome variables for sustainability were explored to ascertain impact of approaches. RESULTS: This review includes 68 articles demonstrating the application of sustainability approaches in practice. Results show an increase in the use of sustainability approaches in peer-reviewed studies. Approaches have been applied across a range of healthcare settings, including primary, secondary, tertiary and community healthcare. Approaches are used for five main purposes, namely analysis, evaluation, guidance, assessment and planning. Results outline benefits (e.g. improved conceptualisation of sustainability constructs and improved ability to interpret sustainability data) and challenges (e.g. issues with approach constructs and difficulty in application) associated with using a sustainability approach in practice. Few articles (14/68) reported the sustainability outcome variables explored; therefore, the impact of approaches on sustainability remains unclear. Additional sustainability outcome variables reported in retrieved articles are discussed. CONCLUSIONS: This review provides practitioners and researchers with a consolidated evidence base on sustainability approaches. Findings highlight the remaining gaps in the literature and emphasise the need for improved rigour and reporting of sustainability approaches in research studies. To guide future assessment and study of sustainability in healthcare settings an updated list of sustainability outcome variables is proposed. TRIAL REGISTRATION: This review was registered on the PROSPERO database CRD 42016040081 in June 2016.
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Atención a la Salud , Servicios de Salud , Instituciones de Salud , Humanos , Proyectos de Investigación , InvestigadoresRESUMEN
Mitochondrial disorders arise from defects in nuclear genes encoding enzymes of oxidative metabolism. Mutations of metabolic enzymes in somatic tissues can cause cancers due to oncometabolite accumulation. Paraganglioma and pheochromocytoma are examples, whose etiology and therapy are complicated by the absence of representative cell lines or animal models. These tumors can be driven by loss of the tricarboxylic acid cycle enzyme succinate dehydrogenase. We exploit the relationship between succinate accumulation, hypoxic signaling, egg-laying behavior, and morphology in C. elegans to create genetic and pharmacological models of succinate dehydrogenase loss disorders. With optimization, these models may enable future high-throughput screening efforts.