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1.
Plant Cell ; 29(2): 310-330, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-28123107

RESUMEN

Across the plant kingdom, phytochrome (PHY) photoreceptors play an important role during adaptive and developmental responses to light. In Arabidopsis thaliana, light-activated PHYs accumulate in the nucleus, where they regulate downstream signaling components, such as phytochrome interacting factors (PIFs). PIFs are transcription factors that act as repressors of photomorphogenesis; their inhibition by PHYs leads to substantial changes in gene expression. The nuclear function of PHYs, however, has so far been investigated in only a few non-seed plants. Here, we identified putative target genes of PHY signaling in the moss Physcomitrella patens and found light-regulated genes that are putative orthologs of PIF-controlled genes in Arabidopsis. Phylogenetic analyses revealed that an ancestral PIF-like gene was already present in streptophyte algae, i.e., before the water-to-land transition of plants. The PIF homologs in the genome of P. patens resemble Arabidopsis PIFs in their protein domain structure, molecular properties, and physiological effects, albeit with notable differences in the motif-dependent PHY interaction. Our results suggest that P. patens PIFs are involved in PHY signaling. The PHY-PIF signaling node that relays light signals to target genes has been largely conserved during land plant evolution, with evidence of lineage-specific diversification.


Asunto(s)
Bryopsida/metabolismo , Proteínas de Plantas/fisiología , Factores de Transcripción/fisiología , Secuencias de Aminoácidos , Arabidopsis/genética , Secuencia Conservada , Genes de Plantas , Filogenia , Fitocromo/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Alineación de Secuencia , Transducción de Señal , Factores de Transcripción/química , Factores de Transcripción/metabolismo
2.
Proc Natl Acad Sci U S A ; 111(8): 3044-9, 2014 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-24516157

RESUMEN

Determining the molecular changes that give rise to functional innovations is a major unresolved problem in biology. The paucity of examples has served as a significant hindrance in furthering our understanding of this process. Here we used experimental evolution with the bacterium Escherichia coli to quantify the molecular changes underlying functional innovation in 68 independent instances ranging over 22 different metabolic functions. Using whole-genome sequencing, we show that the relative contribution of regulatory and structural mutations depends on the cellular context of the metabolic function. In addition, we find that regulatory mutations affect genes that act in pathways relevant to the novel function, whereas structural mutations affect genes that act in unrelated pathways. Finally, we use population genetic modeling to show that the relative contributions of regulatory and structural mutations during functional innovation may be affected by population size. These results provide a predictive framework for the molecular basis of evolutionary innovation, which is essential for anticipating future evolutionary trajectories in the face of rapid environmental change.


Asunto(s)
Adaptación Biológica/genética , Escherichia coli/genética , Evolución Molecular , Redes y Vías Metabólicas/genética , Modelos Genéticos , Fenotipo , Secuencia de Bases , ADN Intergénico/genética , Evolución Molecular Dirigida/métodos , Escherichia coli/metabolismo , Genética de Población , Datos de Secuencia Molecular , Mutación/genética , Densidad de Población , Análisis de Secuencia de ADN
3.
Plant J ; 79(3): 530-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24889180

RESUMEN

The moss Physcomitrella patens is an important model organism for studying plant evolution, development, physiology and biotechnology. Here we have generated microarray gene expression data covering the principal developmental stages, culture forms and some environmental/stress conditions. Example analyses of developmental stages and growth conditions as well as abiotic stress treatments demonstrate that (i) growth stage is dominant over culture conditions, (ii) liquid culture is not stressful for the plant, (iii) low pH might aid protoplastation by reduced expression of cell wall structure genes, (iv) largely the same gene pool mediates response to dehydration and rehydration, and (v) AP2/EREBP transcription factors play important roles in stress response reactions. With regard to the AP2 gene family, phylogenetic analysis and comparison with Arabidopsis thaliana shows commonalities as well as uniquely expressed family members under drought, light perturbations and protoplastation. Gene expression profiles for P. patens are available for the scientific community via the easy-to-use tool at https://www.genevestigator.com. By providing large-scale expression profiles, the usability of this model organism is further enhanced, for example by enabling selection of control genes for quantitative real-time PCR. Now, gene expression levels across a broad range of conditions can be accessed online for P. patens.


Asunto(s)
Bryopsida/crecimiento & desarrollo , Bryopsida/genética , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico/genética , Transcriptoma/genética , Bryopsida/fisiología , Perfilación de la Expresión Génica , Filogenia , Reacción en Cadena en Tiempo Real de la Polimerasa
4.
Nat Commun ; 14(1): 2057, 2023 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-37045813

RESUMEN

Mutations in glucocerebrosidase cause the lysosomal storage disorder Gaucher's disease and are the most common risk factor for Parkinson's disease. Therapies to restore the enzyme's function in the brain hold great promise for treating the neurological implications. Thus, we developed blood-brain barrier penetrant therapeutic molecules by fusing transferrin receptor-binding moieties to ß-glucocerebrosidase (referred to as GCase-BS). We demonstrate that these fusion proteins show significantly increased uptake and lysosomal efficiency compared to the enzyme alone. In a cellular disease model, GCase-BS rapidly rescues the lysosomal proteome and lipid accumulations beyond known substrates. In a mouse disease model, intravenous injection of GCase-BS leads to a sustained reduction of glucosylsphingosine and can lower neurofilament-light chain plasma levels. Collectively, these findings demonstrate the potential of GCase-BS for treating GBA1-associated lysosomal dysfunction, provide insight into candidate biomarkers, and may ultimately open a promising treatment paradigm for lysosomal storage diseases extending beyond the central nervous system.


Asunto(s)
Enfermedad de Gaucher , Enfermedad de Parkinson , Animales , Ratones , Enfermedad de Gaucher/genética , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Encéfalo/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Lisosomas/metabolismo , Mutación , alfa-Sinucleína/metabolismo
5.
Life Sci Alliance ; 5(9)2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35580987

RESUMEN

MAPK inhibitors (MAPKi) remain an important component of the standard of care for metastatic melanoma. However, acquired resistance to these drugs limits their therapeutic benefit. Tumor cells can become refractory to MAPKi by reactivation of ERK. When this happens, tumors often become sensitive to drug withdrawal. This drug addiction phenotype results from the hyperactivation of the oncogenic pathway, a phenomenon commonly referred to as oncogene overdose. Several feedback mechanisms are involved in regulating ERK signaling. However, the genes that serve as gatekeepers of oncogene overdose in mutant melanoma remain unknown. Here, we demonstrate that depletion of the ERK phosphatase, DUSP4, leads to toxic levels of MAPK activation in both drug-naive and drug-resistant mutant melanoma cells. Importantly, ERK hyperactivation is associated with down-regulation of lineage-defining genes including MITF Our results offer an alternative therapeutic strategy to treat mutant melanoma patients with acquired MAPKi resistance and those unable to tolerate MAPKi.


Asunto(s)
Melanoma , Proteínas Proto-Oncogénicas B-raf , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Fosfatasas de Especificidad Dual/genética , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Humanos , Melanoma/genética , Melanoma/patología , Proteínas de la Membrana/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Oncogenes , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética
6.
Plant Physiol ; 153(3): 1123-34, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20427465

RESUMEN

Ultraviolet-B (UV-B) radiation present in sunlight is an important trigger of photomorphogenic acclimation and stress responses in sessile land plants. Although numerous moss species grow in unshaded habitats, our understanding of their UV-B responses is very limited. The genome of the model moss Physcomitrella patens, which grows in sun-exposed open areas, encodes signaling and metabolic components that are implicated in the UV-B response in flowering plants. In this study, we describe the response of P. patens to UV-B radiation at the morphological and molecular levels. We find that P. patens is more capable of surviving UV-B stress than Arabidopsis (Arabidopsis thaliana) and describe the differential expression of approximately 400 moss genes in response to UV-B radiation. A comparative analysis of the UV-B response in P. patens and Arabidopsis reveals both distinct and conserved pathways.


Asunto(s)
Bryopsida/genética , Bryopsida/fisiología , Rayos Ultravioleta , Adaptación Fisiológica/efectos de la radiación , Antocianinas/biosíntesis , Arabidopsis/crecimiento & desarrollo , Arabidopsis/efectos de la radiación , Teorema de Bayes , Bryopsida/crecimiento & desarrollo , Bryopsida/efectos de la radiación , Flavonoles/biosíntesis , Regulación de la Expresión Génica de las Plantas/efectos de la radiación , Genes de Plantas/genética , Genotipo , Células Germinativas de las Plantas/crecimiento & desarrollo , Células Germinativas de las Plantas/efectos de la radiación , Modelos Genéticos , Morfogénesis/efectos de la radiación , Filogenia , Reproducibilidad de los Resultados , Esporas/crecimiento & desarrollo , Esporas/efectos de la radiación , Estrés Fisiológico/efectos de la radiación
7.
J Phys Chem B ; 124(45): 10219-10225, 2020 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-33140644

RESUMEN

The binding dynamics of the trans-1-methyl-4-(4-hydroxystyryl)pyridinium cation (HSP+) to cucurbit[6]uril (CB[6]) in the presence of Na+ cations were studied to establish the effect of the relative concentrations of the system's components (HSP+, CB[6], and Na+) on these dynamics. The formation of the HSP+@CB[6] complex was temporally uncoupled from the photoisomerization of trans-HSP+, while a nonlinear effect of the Na+ cation concentration on the HSP+@CB[6] dynamics was observed. This nonlinearity is a consequence of Na+ having the opposite effect on the association and dissociation rate constants for the HSP+@CB[6] complex, creating a conceptual framework for using such nonlinearities to control multistep reactions in cucurbit[n]uril chemistry.

8.
Sci Rep ; 9(1): 5013, 2019 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-30899034

RESUMEN

Identification of novel antibiotics remains a major challenge for drug discovery. The present study explores use of phenotypic readouts beyond classical antibacterial growth inhibition adopting a combined multiparametric high content screening and genomic approach. Deployment of the semi-automated bacterial phenotypic fingerprint (BPF) profiling platform in conjunction with a machine learning-powered dataset analysis, effectively allowed us to narrow down, compare and predict compound mode of action (MoA). The method identifies weak antibacterial hits allowing full exploitation of low potency hits frequently discovered by routine antibacterial screening. We demonstrate that BPF classification tool can be successfully used to guide chemical structure activity relationship optimization, enabling antibiotic development and that this approach can be fruitfully applied across species. The BPF classification tool could be potentially applied in primary screening, effectively enabling identification of novel antibacterial compound hits and differentiating their MoA, hence widening the known antibacterial chemical space of existing pharmaceutical compound libraries. More generally, beyond the specific objective of the present work, the proposed approach could be profitably applied to a broader range of diseases amenable to phenotypic drug discovery.


Asunto(s)
Antibacterianos/uso terapéutico , Bacterias/efectos de los fármacos , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Antibacterianos/química , Bacterias/patogenicidad , Evaluación Preclínica de Medicamentos/métodos , Humanos , Aprendizaje Automático
9.
PLoS One ; 11(6): e0156853, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27286033

RESUMEN

BACKGROUND: Due to increased resistance and safety concerns with insecticide-based pediculicides, there is growing demand for head lice treatments with a physical mode of action. Certain mineral oils kill lice by blocking spiracles or by disrupting the epicuticular wax layer. The present study was performed to evaluate efficacy and safety of a mineral oil-based shampoo. METHODS: This randomized, controlled, investigator-blinded, monocentric study (EudraCT registration no. 2014-002918-23) was performed from October 2014-June 2015 in Germany. A mineral oil shampoo (Mosquito® Med Läuse Shampoo 10 in Germany, Paranix or Silcap shampoo elsewhere), registered as medical device, was compared to a conventional, locally reimbursed, pyrethroid-based pediculicide (Goldgeist® Forte solution). In total, 107 patients (>1 year) with confirmed head lice infestation were included (test arm: n = 53; control arm: n = 54). All subjects received two applications of either test or control product at day 0 and day 7, according to the instructions for use. Efficacy and safety was evaluated directly, 1h and 24h after first application, before and after second treatment, and at day 10. The main objective was demonstrating a cure rate for the test product, being superior to 70% at day 10. RESULTS: Cure rates at day 10 (corrected for re-infestation) for the test product (96.1%) and control (94%) significantly exceeded the pre-defined target (70%) (p < 0.001, 2-sided, 1-sample, chi-square test) with confirmed non-inferiority for the test product. Over all visits, cure rates were consistently higher for the test product, whereas more initially-cured subjects remained lice-free until end of study (78%; control: 60%). Both products were safe and well tolerated, offering good esthetical effects. CONCLUSION: This study showed that substance-based medical devices (including the tested mineral oil shampoo) can be safe and effective alternatives for insecticide-based pediculicides, with less risk for development of resistance because of the physical mode of action. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00009753 and EudraCT database 2014-002918-23.


Asunto(s)
Preparaciones para el Cabello/administración & dosificación , Preparaciones para el Cabello/efectos adversos , Infestaciones por Piojos/tratamiento farmacológico , Aceite Mineral/administración & dosificación , Aceite Mineral/efectos adversos , Pediculus/efectos de los fármacos , Administración Tópica , Adolescente , Adulto , Animales , Niño , Preescolar , Femenino , Humanos , Insecticidas/administración & dosificación , Insecticidas/efectos adversos , Masculino , Persona de Mediana Edad , Dermatosis del Cuero Cabelludo/tratamiento farmacológico , Resultado del Tratamiento , Adulto Joven
10.
Elife ; 42015 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-26080931

RESUMEN

Although it is often tacitly assumed that gene regulatory interactions are finely tuned, how accurate gene regulation could evolve from a state without regulation is unclear. Moreover, gene expression noise would seem to impede the evolution of accurate gene regulation, and previous investigations have provided circumstantial evidence that natural selection has acted to lower noise levels. By evolving synthetic Escherichia coli promoters de novo, we here show that, contrary to expectations, promoters exhibit low noise by default. Instead, selection must have acted to increase the noise levels of highly regulated E. coli promoters. We present a general theory of the interplay between gene expression noise and gene regulation that explains these observations. The theory shows that propagation of expression noise from regulators to their targets is not an unwanted side-effect of regulation, but rather acts as a rudimentary form of regulation that facilitates the evolution of more accurate regulation.


Asunto(s)
Evolución Molecular , Regulación de la Expresión Génica/fisiología , Modelos Genéticos , Selección Genética , Evolución Molecular Dirigida/métodos , Escherichia coli/genética , Regiones Promotoras Genéticas/genética , Procesos Estocásticos
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