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Acta Derm Venereol ; 104: adv12430, 2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38323497


There are regional differences in the prevalence of psoriasis between countries, as well as within countries. However, regional determinants of differences in prevalence are not yet understood. The aim of this study was to identify sociodemographic and environmental determinants of regional prevalence rates for psoriasis. Analyses were based on German outpatient billing data from statutory health insurance, together with data from databases on sociodemographic and environment factors at the county level (N = 402) for 2015-2017. Descriptive statistics were calculated for all variables. To identify determinants for prevalence at the county level, spatiotemporal regression analysis was performed, with prevalence as the dependent variable, and the number of physicians, mean age, mean precipitation, sunshine hours, mean temperature, level of urbanity, and the German Index of Socioeconomic Deprivation (GISD) as independent variables. Mean prevalence of psoriasis increased from 168.63 per 10,000 in 2015 to 173.54 per 10,000 in 2017 for Germany as a whole, with high regional variation. Five determinants were detected (p < 0.05). The prevalence increased by 4.18 per 10,000 persons with SHI with each GISD unit, and by 3.76 per 10,000 with each year increase in age. Each additional hour of sunshine resulted in a decrease of 0.04 and each °C increase in mean temperature resulted in an increase of 4.22. Each additional dermatologist per 10,000 inhabitants resulted in a decrease of 0.07. In conclusion, sociodemographic and environmental factors result in significant differences in prevalence of psoriasis, even within-country.

Programas Nacionales de Salud , Psoriasis , Humanos , Prevalencia , Alemania/epidemiología , Bases de Datos Factuales
J Biol Chem ; 299(9): 105102, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37507021


The Vps10p domain receptor SorCS2 is crucial for the development and function of the nervous system and essential for brain-derived neurotrophic factor (BDNF)-induced changes in neuronal morphology and plasticity. SorCS2 regulates the subcellular trafficking of the BDNF signaling receptor TrkB as well as selected neurotransmitter receptors in a manner that is dependent on the SorCS2 intracellular domain (ICD). However, the cellular machinery and adaptor protein (AP) interactions that regulate receptor trafficking via the SorCS2 ICD are unknown. We here identify four splice variants of human SorCS2 differing in the insertion of an acidic cluster motif and/or a serine residue within the ICD. We show that each variant undergoes posttranslational proteolytic processing into a one- or two-chain receptor, giving rise to eight protein isoforms, the expression of which differs between neuronal and nonneuronal tissues and is affected by cellular stressors. We found that the only variants without the serine were able to rescue BDNF-induced branching of SorCS2 knockout hippocampal neurons, while variants without the acidic cluster showed increased interactions with clathrin-associated APs AP-1, AP-2, and AP-3. Using yeast two-hybrid screens, we further discovered that all variants bound dynein light chain Tctex-type 3; however, only variants with an acidic cluster motif bound kinesin light chain 1. Accordingly, splice variants showed markedly different trafficking properties and localized to different subcellular compartments. Taken together, our findings demonstrate the existence of eight functional SorCS2 isoforms with differential capacity for interactions with cytosolic ligands dynein light chain Tctex-type 3 and kinesin light chain 1, which potentially allows cell-type specific SorCS2 trafficking and BDNF signaling.

Empalme Alternativo , Sistema Nervioso Central , Receptores de Superficie Celular , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Empalme Alternativo/fisiología , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Dineínas/metabolismo , Cinesinas/metabolismo , Unión Proteica , Isoformas de Proteínas/metabolismo , Receptor trkB/metabolismo , Receptores de Superficie Celular/metabolismo , Sistema Nervioso Central/crecimiento & desarrollo , Procesamiento Proteico-Postraduccional , Transporte de Proteínas/genética
Nat Commun ; 14(1): 2409, 2023 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-37100772


Viruses mimic host short linear motifs (SLiMs) to hijack and deregulate cellular functions. Studies of motif-mediated interactions therefore provide insight into virus-host dependencies, and reveal targets for therapeutic intervention. Here, we describe the pan-viral discovery of 1712 SLiM-based virus-host interactions using a phage peptidome tiling the intrinsically disordered protein regions of 229 RNA viruses. We find mimicry of host SLiMs to be a ubiquitous viral strategy, reveal novel host proteins hijacked by viruses, and identify cellular pathways frequently deregulated by viral motif mimicry. Using structural and biophysical analyses, we show that viral mimicry-based interactions have similar binding strength and bound conformations as endogenous interactions. Finally, we establish polyadenylate-binding protein 1 as a potential target for broad-spectrum antiviral agent development. Our platform enables rapid discovery of mechanisms of viral interference and the identification of potential therapeutic targets which can aid in combating future epidemics and pandemics.

Bacteriófagos , Proteínas Intrínsecamente Desordenadas , Virus , Bacteriófagos/genética , Virus/genética , Proteínas Intrínsecamente Desordenadas/metabolismo , Secuencias de Aminoácidos , Interacciones Huésped-Patógeno/genética
Nat Commun ; 13(1): 4755, 2022 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-35963857


Determining the levels of protein-protein interactions is essential for the analysis of signaling within the cell, characterization of mutation effects, protein function and activation in health and disease, among others. Herein, we describe MolBoolean - a method to detect interactions between endogenous proteins in various subcellular compartments, utilizing antibody-DNA conjugates for identification and signal amplification. In contrast to proximity ligation assays, MolBoolean simultaneously indicates the relative abundances of protein A and B not interacting with each other, as well as the pool of A and B proteins that are proximal enough to be considered an AB complex. MolBoolean is applicable both in fixed cells and tissue sections. The specific and quantifiable data that the method generates provide opportunities for both diagnostic use and medical research.

Mapeo de Interacción de Proteínas , Proteínas , Mapeo de Interacción de Proteínas/métodos , Proteínas/metabolismo , Transducción de Señal
Exp Cell Res ; 380(1): 69-79, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-30970237


The role of plasma membrane composition and dynamics in the activation process of receptor tyrosine kinases (RTKs) is still poorly understood. In this study we have investigated how signaling via the RTK, platelet-derived growth factor ß-receptor (PDGFR-ß) is affected by Dynasore or Dyngo-4a, which are commonly used dynamin inhibitors. PDGFR-ß preferentially internalizes via clathrin-coated pits and in this pathway, Dynamin II has a major role in the formation and release of vesicles from the plasma membrane by performing the membrane scission. We have found that dynamin inhibitors impedes the activation of PDGFR-ß by impairing ligand-induced dimerization of the receptor monomers, which leads to a subsequent lack of phosphorylation and activation both of receptors and downstream effectors, such as ERK1/2 and AKT. In contrast, dynamin inhibitors did not affect epidermal growth factor receptor (EGFR) dimerization and phosphorylation. Our findings suggest that there is a link between plasma membrane dynamics and PDGFR-ß activation, and that this link is not shared with the epidermal growth factor receptor.

Dinaminas/genética , Multimerización de Proteína/efectos de los fármacos , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Dinaminas/antagonistas & inhibidores , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Fibroblastos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Humanos , Hidrazonas/farmacología , Ligandos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Naftoles/farmacología , Fosforilación/efectos de los fármacos , Multimerización de Proteína/genética , Proteínas Proto-Oncogénicas c-akt/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/química , Transducción de Señal/genética