RESUMEN
Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy1. Clinically, it is challenging to differentiate Parkinson's disease and multiple system atrophy, especially at the early stages of disease2. Aggregates of α-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of α-synuclein that can self-propagate and spread from cell to cell3-6. Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect α-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity7,8. Here we show that the α-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson's disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of α-synuclein-PMCA, and found that the characteristics of the α-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson's disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that α-synuclein aggregates that are associated with Parkinson's disease and multiple system atrophy correspond to different conformational strains of α-synuclein, which can be amplified and detected by α-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of α-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinson's disease and multiple system atrophy.
Asunto(s)
Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Parkinson/diagnóstico , alfa-Sinucleína/líquido cefalorraquídeo , alfa-Sinucleína/química , Amiloide/química , Química Encefálica , Dicroismo Circular , Endopeptidasa K/metabolismo , Humanos , Atrofia de Múltiples Sistemas/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Conformación Proteica , Desnaturalización Proteica , Pliegue de Proteína , Espectroscopía Infrarroja por Transformada de Fourier , alfa-Sinucleína/clasificación , alfa-Sinucleína/toxicidadRESUMEN
The Protein Ensemble Database (PED) (https://proteinensemble.org), which holds structural ensembles of intrinsically disordered proteins (IDPs), has been significantly updated and upgraded since its last release in 2016. The new version, PED 4.0, has been completely redesigned and reimplemented with cutting-edge technology and now holds about six times more data (162 versus 24 entries and 242 versus 60 structural ensembles) and a broader representation of state of the art ensemble generation methods than the previous version. The database has a completely renewed graphical interface with an interactive feature viewer for region-based annotations, and provides a series of descriptors of the qualitative and quantitative properties of the ensembles. High quality of the data is guaranteed by a new submission process, which combines both automatic and manual evaluation steps. A team of biocurators integrate structured metadata describing the ensemble generation methodology, experimental constraints and conditions. A new search engine allows the user to build advanced queries and search all entry fields including cross-references to IDP-related resources such as DisProt, MobiDB, BMRB and SASBDB. We expect that the renewed PED will be useful for researchers interested in the atomic-level understanding of IDP function, and promote the rational, structure-based design of IDP-targeting drugs.
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Bases de Datos de Proteínas , Proteínas Intrínsecamente Desordenadas/química , Humanos , Motor de Búsqueda , Proteína p53 Supresora de Tumor/químicaRESUMEN
Pathology consisting of intracellular aggregates of alpha-Synuclein (α-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct α-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native α-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel α-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25α. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to α-Syn alone, a substoichiometric concentration of p25α redirects α-Syn aggregation into a unique α-Syn/p25α strain with a different structure and enhanced in vivo prodegenerative properties. The α-Syn/p25α strain induced larger inclusions in human dopaminergic neurons. In vivo, intramuscular injection of preformed fibrils (PFF) of the α-Syn/p25α strain compared to α-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of α-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the α-Syn/p25α strain was associated with an increased load of α-Syn aggregates based on a Förster resonance energy transfer immunoassay and a reduced α-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the α-Syn/p25α strain resulted in a more-pronounced motoric phenotype than α-Syn PFF and exhibited a "tropism" for nigro-striatal neurons compared to α-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25α is responsible for generating a highly prodegenerative α-Syn strain in multiple system atrophy.
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Atrofia de Múltiples Sistemas/genética , Enfermedades Neurodegenerativas/genética , Sinucleinopatías/patología , alfa-Sinucleína/genética , Animales , Línea Celular , Humanos , Cuerpos de Inclusión/patología , Ratones , Ratones Transgénicos , Atrofia de Múltiples Sistemas/patología , Proteínas del Tejido Nervioso/genética , Oligodendroglía/metabolismo , Conformación Proteica , Deficiencias en la Proteostasis/genética , Sustancia Negra/patología , alfa-Sinucleína/toxicidadRESUMEN
The formation of oligomeric soluble aggregates is related to the toxicity of amyloid peptides and proteins. In this manuscript, we report the use of a ruthenium polypyridyl complex ([Ru(bpy)2(dpqp)]2+) to track the formation of amyloid oligomers at different times using photoluminescence anisotropy. This technique is sensitive to the rotational correlation time of the molecule under study, which is consequently related to the size of the molecule. [Ru(bpy)2(dpqp)]2+ presents anisotropy values of zero when free in solution (due to its rapid rotation and long lifetime) but larger values as the size and concentration of amyloid-ß (Aß) oligomers increase. Our assays show that Aß forms oligomers immediately after the assay is started, reaching a steady state at â¼48 h. SDS-PAGE, DLS, and TEM were used to confirm and characterize the formation of oligomers. Our experiments show that the rate of formation for Aß oligomers is temperature dependent, with faster rates as the temperature of the assay is increased. The probe was also effective in monitoring the formation of α-synuclein oligomers at different times.
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Amiloide/química , Mediciones Luminiscentes/métodos , Polímeros/química , Anisotropía , Procesos Fotoquímicos , Compuestos de Rutenio/químicaRESUMEN
It has been proposed that epithelial cells can acquire invasive properties through exposure to paracrine signals originated from mesenchymal cells within the tumor microenvironment. Transforming growth factor-ß (TGF-ß) has been revealed as an active factor that mediates the epithelial-stroma cross-talk that facilitates cell invasion and metastasis. TGF-ß signaling is modulated by the coreceptor Endoglin (Eng), which shows a tumor suppressor activity in epithelial cells and regulates the ALK1-Smad1,5,8 as well as the ALK5-Smad2,3 signaling pathways. In the current work, we present evidence showing that cell surface Eng abundance in epithelial MCF-7 breast cancer cells is inversely related with cell motility. Shedding of Eng in MCF-7 cell surface by soluble matrix metalloproteinase-14 (MMP-14) derived from the HS-5 bone-marrow-derived cell line induces a motile epithelial phenotype. On the other hand, restoration of full-length Eng expression blocks the stromal stimulus on migration. Processing of surface Eng by stromal factors was demonstrated by biotin-neutravidin labeling of cell surface proteins and this processing generated a shift in TGF-ß signaling through the activation of Smad2,3 pathway. Stromal MMP-14 abundance was stimulated by TGF-ß secreted by MCF-7 cells acting in a paracrine manner. In turn, the stromal proteolytic activity of soluble MMP-14, by inducing Eng shedding, promoted malignant progression. From these data, and due to the capacity of TGF-ß to regulate malignancy in epithelial cancer, we propose that stromal-dependent epithelial Eng shedding constitutes a putative mechanism that exerts an environmental control of cell malignancy.
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Antígenos CD/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular , Células Epiteliales/patología , Metaloproteinasa 14 de la Matriz/metabolismo , Células Madre Mesenquimatosas/patología , Receptores de Superficie Celular/metabolismo , Antígenos CD/genética , Western Blotting , Neoplasias de la Mama/genética , Proliferación Celular , Medios de Cultivo Condicionados/farmacología , Endoglina , Células Epiteliales/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunoprecipitación , Metaloproteinasa 14 de la Matriz/genética , Células Madre Mesenquimatosas/metabolismo , Microscopía Fluorescente , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Superficie Celular/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Proteínas Smad/genética , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Hard consistency, developed under the influence of tumor cell factors, is a characteristic feature of a breast tumor. Activation of resident fibroblasts leading to a myofibroblast phenotype is the principal feature that orchestrates this fibrotic process. The aim of this study was to assess the effects induced by TGF-ß1, a growth factor abundantly present in tumor microenvironment, on the molecular mechanisms that mediate myofibroblastic differentiation of normal human mammary fibroblasts. METHODS: We used an immortalized fibroblastic cell line derived from normal mammary tissue (RMF-EG cells) to study the effect of TGF-ß1 in the expression of α-SMA and CTGF as markers of myofibroblastic differentiation. The influence of redox status and JNK activity on TGF-ß1-induced transcriptional activity was measured by a luciferase reporter assay. We also used a shRNA approach to evaluate the influence of NOX4 in myofibroblastic differentiation. RESULTS: TGF-ß1 stimulates the expression of myofibroblast markers α-SMA and CTGF. Using a NOX inhibitor (DPI) and cells expressing a shRNA for NOX4, we demonstrated that TGF-ß1 promotes an oxidative environment that favors myofibroblastic differentiation. We also found that activation of c-Jun N-terminal kinase is required for TGF-ß1-dependent expression of CTGF, NOX4 and α-SMA. CONCLUSIONS: Human mammary stromal fibrosis, evaluated by the expression of early and late markers as CTGF and α-SMA, depends on the activation of JNK signaling pathway. Our results show that JNK activation is an early event that precedes the increase in ROS levels leading to myofibroblastic differentiation and tumor fibrosis, suggesting that inhibition of JNK may be used a method to interrupt the development of tumor desmoplasia.
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Mama/citología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Miofibroblastos/metabolismo , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Actinas/metabolismo , Mama/metabolismo , Mama/patología , Diferenciación Celular , Línea Celular , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , NADPH Oxidasa 4 , Células del Estroma/metabolismoRESUMEN
BACKGROUND: Several epidemiological data revealed an association between Alzheimer's disease (AD) and type 2 diabetes. Researchers concentrated on brain insulin resistance with little emphasis on the link between systemic insulin resistance and AD, despite the fact that the incidence of type 2 diabetes is higher in AD patients and that impairment in insulin signaling is a risk factor for AD. OBJECTIVE: The goal of this study is to determine the role of systemic insulin resistance in the pathogenesis of Alzheimer's disease by evaluating the consequences of tau loss-of-function on peripheral insulin sensitivity. METHODS: Primary hepatocytes isolated from transgenic mouse models (Tau KO, P301âL) and wild type mice (C57BL/6) were evaluated for their insulin sensitivity using glucose uptake assays as well as biochemical analysis of insulin signaling markers. RESULTS: Our data show that tau deletion or loss of function promotes peripheral insulin resistance as seen in primary hepatocytes isolated from Tau KO and P301âL mice, respectively. Furthermore, exposure of wild-type primary hepatocytes to sub-toxic concentrations of tau oligomers results in a dose-dependent inhibition of glucose uptake, associated with downregulation of insulin signaling. Tau oligomers-induced inactivation of insulin signaling proteins was rescued by inhibition of p38 MAPK, suggesting the involvement of p38 MAPK. CONCLUSIONS: This is the first study testing tau role in peripheral insulin resistance at the cellular level using multiple transgenic mouse models. Moreover, this study suggests that tau should be functional for insulin sensitivity, therefore, any loss of function by deletion or aggregation would result in insulin resistance.
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Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Ratones , Animales , Resistencia a la Insulina/genética , Insulina/metabolismo , Enfermedad de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Proteínas tau/genética , Proteínas tau/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Glucosa/metabolismoRESUMEN
This article describes a method for quantifying various cellular features (e.g., volume, curvature, total and sub-cellular fluorescence localization) of individual cells from sets of microscope images, and for tracking them over time-course microscopy experiments. One purposely defocused transmission image (sometimes referred to as bright-field or BF) is used to segment the image and locate each cell. Fluorescence images (one for each of the color channels or z-stacks to be analyzed) may be acquired by conventional wide-field epifluorescence or confocal microscopy. This method uses a set of R packages called rcell2. Relative to the original release of Rcell (Bush et al., 2012), the updated version bundles, into a single software suite, the image-processing capabilities of Cell-ID, offers new data analysis tools for cytometry, and relies on the widely used data analysis and visualization tools of the statistical programming framework R. © 2023 Wiley Periodicals LLC. Basic Protocol: Extracting quantitative information from single cells Support Protocol 1: Obtaining and installing Cell-ID and R Support Protocol 2: Preparing cells for imaging.
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Procesamiento de Imagen Asistido por Computador , Programas Informáticos , Microscopía Confocal/métodos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
Although synthetic colorants are widely used in many industries due to their high stability at different conditions in industrial processes, evidence of its negative impact on health and the environment is undeniable. Filamentous fungi are well known for their use as alternative sources to produce natural pigments. However, an adequate comparison of the productivity parameters between the fermentation systems could be limited to their heterogeneous conditions. Even though Solid-State Fermentations (SSF) on natural substrates are widely used for pigments production, complex media, and non-controlled variables (T, pH, medium composition), these systems could not only hamper the finding of accurate productivity parameters, but also mathematical modeling and genomics-based optimization. In this context, the present study screened five pigment-producing fungi by comparing Submerged (SmF) and Surface Adhesion Fermentation [biofilm (BF) and Solid-State (SSF)] with defined media and controlled variables. For this purpose, we used the same defined media with sucrose as the carbon source for pigment production on SmF, BF, and SSF, and BF and SSF were carried out on inert supports. Five molecularly identified Penicillium and Talaromyces strains isolated from the Peruvian rainforest were selected for their ability to produce yellowish-orange colorants. Highest productivities were obtained from T. brunneus LMB-HP43 in SmF (0.18 AU/L/h) and SSF (0.17 AU/L/h), and P. mallochii LMB-HP37 in SSF (0.18 AU/L/h). Both strains also exhibited the highest yields (AU/g biomass) in the three fermentation systems, reaching values greater than 18-folds in SSF compared to the other strains. Conversely, T. wortmannii LMB-HP14 and P. maximae LMB-HP33 showed no ability to produce pigments in the SSF system. The performed experiments accurately compared the effect of the fermentation system on yield and productivity. From this, further genomics approaches can be considered for an extensive analysis of pigment synthesis pathways and a genomics-driven optimization in the best fermentation system.
RESUMEN
Linear motifs are short protein subsequences that mediate protein interactions. Hundreds of motif classes including thousands of motif instances are known. Our theory estimates how many motif classes remain undiscovered. As commonly done, we describe motif classes as regular expressions specifying motif length and the allowed amino acids at each motif position. We measure motif specificity for a pair of motif classes by quantifying how many motif-discriminating positions prevent a protein subsequence from matching the two classes at once. We derive theorems for the maximal number of motif classes that can simultaneously maintain a certain number of motif-discriminating positions between all pairs of classes in the motif universe, for a given amino acid alphabet. We also calculate the fraction of all protein subsequences that would belong to a motif class if all potential motif classes came into existence. Naturally occurring pairs of motif classes present most often a single motif-discriminating position. This mild specificity maximizes the potential number of coexisting motif classes, the expansion of the motif universe due to amino acid modifications and the fraction of amino acid sequences that code for a motif instance. As a result, thousands of linear motif classes may remain undiscovered.
Asunto(s)
Secuencias de Aminoácidos , Análisis de Secuencia de Proteína/métodos , Humanos , Sensibilidad y Especificidad , Análisis de Secuencia de Proteína/normasRESUMEN
A hallmark feature of Alzheimer's disease (AD) and other tauopathies is the misfolding, aggregation and cerebral accumulation of tau deposits. Compelling evidence indicates that misfolded tau aggregates are neurotoxic, producing synaptic loss and neuronal damage. Misfolded tau aggregates are able to spread the pathology from cell-to-cell by a prion like seeding mechanism. The factors implicated in the initiation and progression of tau misfolding and aggregation are largely unclear. In this study, we evaluated the effect of DNA extracted from diverse prokaryotic and eukaryotic cells in tau misfolding and aggregation. Our results show that DNA from various, unrelated gram-positive and gram-negative bacteria results in a more pronounced tau misfolding compared to eukaryotic DNA. Interestingly, a higher effect in promoting tau aggregation was observed for DNA extracted from certain bacterial species previously detected in the brain, CSF or oral cavity of patients with AD. Our findings indicate that microbial DNA may play a previously overlooked role in the propagation of tau protein misfolding and AD pathogenesis, providing a new conceptual framework that positions the compromised blood-brain and intestinal barriers as important sources of microbial DNA in the CNS, opening novel opportunities for therapeutic interventions.
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ADN Bacteriano/química , Pliegue de Proteína/efectos de los fármacos , Proteínas tau/química , ADN Bacteriano/farmacología , ADN de Hongos/química , ADN de Hongos/farmacología , Bacterias Gramnegativas/química , Bacterias Grampositivas/química , PolimerizacionRESUMEN
It is known that residents at high altitude (HA) have a lower basal glycemia than residents at sea level (SL). However, whether such a difference is maintained throughout the full day remains unknown. We compared 12-h blood glucose profiles from 10 healthy males native residents at HA (3250 m) and 8 male residents at SL. Glucose profile at HA was lower throughout the glucose monitoring than that at SL (mean profile: 50.6 +/- 3.7 and 73.4 +/- 4.0 mg/dL, respectively; p < 0.001). Basal and postprandial insulin and triacylglycerol values were similar in both groups. In conclusion, HA natives resident have a lower blood glucose profile than SL residents throughout 12-h continuous monitoring.
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Aclimatación/fisiología , Altitud , Glucemia/análisis , Insulina/sangre , Montañismo/fisiología , Adulto , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Monitoreo Fisiológico , Periodo Posprandial , Valores de ReferenciaRESUMEN
IMPORTANCE: Parkinson disease (PD) is a highly prevalent and incurable neurodegenerative disease associated with the accumulation of misfolded α-synuclein (αSyn) aggregates. An important problem in this disease is the lack of a sensitive, specific, and noninvasive biochemical diagnosis to help in clinical evaluation, monitoring of disease progression, and early differential diagnosis from related neurodegenerative diseases. OBJECTIVE: To develop a novel assay with high sensitivity and specificity to detect small quantities of αSyn aggregates circulating in cerebrospinal fluid (CSF) of patients affected by PD and related synucleinopathies. DESIGN, SETTING, AND PARTICIPANTS: The strategy evaluated in this proof-of-concept study uses the protein misfolding cyclic amplification (PMCA) technology that detects minute amounts of misfolded oligomers by taking advantage of their ability to nucleate further aggregation, enabling a very high amplification of the signal. The technology was first adapted with synthetic αSyn oligomers prepared in vitro and used to screen in 2 blinded cohorts of CSF samples from German and Japanese patients with PD (n = 76) and individuals serving as controls affected by other neurologic disorders (n = 65), neurodegenerative diseases (n = 18), and Alzheimer disease (n = 14). The kinetics of αSyn aggregation were measured by αSyn-PMCA in the presence of CSF samples from the participants to detect αSyn oligomeric seeds present in this biological fluid. The assays were conducted from November 15, 2013, to August 28, 2015. MAIN OUTCOMES AND MEASURES: Kinetic parameters correlated with disease severity at the time of sample collection, measured by the Hoehn and Yahr scale, with the lowest grade indicating unilateral involvement with minimal or no functional impairment, and the highest grade defining patients with complete confinement to wheelchair or bed. RESULTS: Studies with synthetic αSyn aggregates showed that αSyn-PMCA enabled to detect as little as 0.1 pg/mL of αSyn oligomers. The αSyn-PMCA signal was directly proportional to the amount of αSyn oligomers added to the reaction. A blinded study of CSF samples correctly identified patients affected by PD with an overall sensitivity of 88.5% (95% CI, 79.2%-94.6%) and specificity of 96.9% (95% CI, 89.3%-99.6%). The αSyn-PMCA results for different patients correlated with the severity of the clinical symptoms of PD (Japanese cohort: rs = -0.54, P = .006; German cohort: rs = -0.36, P = .02). CONCLUSIONS AND RELEVANCE: The findings suggest that detection of αSyn oligomers by αSyn-PMCA in the CSF of patients affected by PD may offer a good opportunity for a sensitive and specific biochemical diagnosis of the disease. Further studies are needed to investigate the usefulness of αSyn-PMCA to monitor disease progression and for preclinical identification of patients who may develop PD.
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Enfermedad de Parkinson , Agregación Patológica de Proteínas/complicaciones , Deficiencias en la Proteostasis/complicaciones , alfa-Sinucleína/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/química , Fenómenos Bioquímicos , Pruebas Diagnósticas de Rutina , Femenino , Humanos , Técnicas In Vitro , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Masculino , Atrofia de Múltiples Sistemas/líquido cefalorraquídeo , Evaluación de Resultado en la Atención de Salud , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/etiología , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/química , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/químicaRESUMEN
SUMMARY: The objective of this review was to identify original studies describing radiographic methods for dental age estimation applied in Chilean children, considering that it is a country with a long history of natural disasters and it has shown an unprecedented increase in the number of migrants in recent years, with significant percentages of individuals under 18 years of age. A scoping review was carried out following the methodology for the Joanna Briggs Institute scoping reviews and PRISMA guidelines. A specific search strategy was implemented in PubMed/Medline database, with complementary use of the Google Scholar website searching for full articles in English and Spanish. Five documents responded to the search objective, of which only 3 were published in refereed journals. Two documents focused their study on the maturation of upper and lower third molars, one on the maturation of the second and lower third molars, and two documents on the maturation of the seven mandibular teeth according to classical methodologies. The scarce existing literature, the almost absence of validated methods for the Chilean population, as well as the reported mass immigration phenomenon make a new and profound scientific research approach necessary for the application of updated methods.
RESUMEN: El objetivo de esta revisión fue identificar estudios originales que describan métodos radiográficos para la estimación de la edad dental aplicados en niños chilenos, considerando que Chile es un país con una larga historia de desastres naturales y que ha mostrado un aumento sin precedentes en el número de inmigrantes en los últimos años, con porcentajes significativos de individuos menores de 18 años. Se llevó a cabo una revisión con búsqueda sistemática siguiendo la metodología del Instituto Joanna Briggs y las pautas PRISMA. Se implementó una estrategia de búsqueda específica en la base de datos PubMed/Medline, con uso complementario de Google Scholar, buscando artículos completos en inglés y español. Cinco documentos respondieron al objetivo de búsqueda, de los cuales solo 3 fueron publicados en revistas arbitradas. Dos documentos centraron su estudio en la maduración de los terceros molares superiores e inferiores, uno en la maduración de los segundos y terceros molares inferiores y dos documentos en la maduración de los siete dientes mandibulares según metodologías clásicas. La escasa literatura existente, la casi ausencia de métodos validados para la población chilena, así como el fenómeno de inmigración masiva reportado, hacen necesario un nuevo y profundo enfoque de investigación científica para la apli- cación de métodos actualizados.
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Humanos , Determinación de la Edad por los Dientes/métodos , Radiografía Dental , Emigración e Inmigración , Odontología Forense , ChileRESUMEN
Although a large proportion of patients with type 2 diabetes (T2D) accumulate misfolded aggregates composed of the islet amyloid polypeptide (IAPP), its role in the disease is unknown. Here, we show that pancreatic IAPP aggregates can promote the misfolding and aggregation of endogenous IAPP in islet cultures obtained from transgenic mouse or healthy human pancreas. Islet homogenates immunodepleted with anti-IAPP-specific antibodies were not able to induce IAPP aggregation. Importantly, intraperitoneal inoculation of pancreatic homogenates containing IAPP aggregates into transgenic mice expressing human IAPP dramatically accelerates IAPP amyloid deposition, which was accompanied by clinical abnormalities typical of T2D, including hyperglycemia, impaired glucose tolerance, and a substantial reduction on ß cell number and mass. Finally, induction of IAPP deposition and diabetic abnormalities were also induced in vivo by administration of IAPP aggregates prepared in vitro using pure, synthetic IAPP. Our findings suggest that some of the pathologic and clinical alterations of T2D might be transmissible through a similar mechanism by which prions propagate in prion diseases.
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Diabetes Mellitus Tipo 2/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/metabolismo , Animales , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Islotes Pancreáticos/patología , Masculino , Ratones , Ratones Transgénicos , Priones/metabolismo , Agregado de Proteínas , Deficiencias en la Proteostasis/metabolismoRESUMEN
Nanostructured porous silica coatings were synthesized on titanium by the combined sol-gel and evaporation-induced self-assembly process. The silica-coating structures were characterized by X-ray diffraction, transmission electron microscopy, scanning electron microscopy, and nitrogen sorptometry. The effect of the nanoporous surface on apatite formation in simulated body fluid, protein adsorption, osteoblast cell adhesion behavior, and osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) is reported. Silica coatings with highly ordered sub-10 nm porosity accelerate early osteoblast adhesive response, a favorable cell response that is attributed to an indirect effect due to the high protein adsorption observed on the large-specific surface area of the nanoporous coating but is also probably due to direct mechanical stimulus from the nanostructured topography. The nanoporous silica coatings, particularly those doped with calcium and phosphate, also promote the osteogenic differentiation of hBMSCs with spontaneous mineral nodule formation in basal conditions. The bioactive surface properties exhibited by the nanostructured porous silica coatings make these materials a promising alternative to improve the osseointegration properties of titanium dental implants and could have future impact on the nanoscale design of implant surfaces.
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Diferenciación Celular , Materiales Biocompatibles Revestidos/química , Nanoestructuras/química , Osteoblastos/metabolismo , Osteogénesis , Dióxido de Silicio/química , Titanio/química , Adhesión Celular , Línea Celular Tumoral , Humanos , Osteoblastos/citología , PorosidadRESUMEN
Es conocido que el habitante de la altura tiene una glicemia más baja en comparación con el habitante del nivel del mar. Esta diferencia ha sido establecida teniendo en cuenta los valores basales de glicemia. Sin embargo, se desconoce si esta diferencia permanece durante el día. Por lo tanto, el objetivo principal del estudio fue comparar el perfil del monitoreo continuo de glucosa durante 12 horas. El estudio incluyó 10 varones voluntarios del nivel del mar y 10 varones de la altura (3,250 m). La edad promedio fue 24,4 mas menos 1,8 años y 22,2 mas menos 3,2 años, y el índice de masa corporal, 22,8 mas menos 1,2 y 22,9 mas menos 2,6 kg/m², respectivamente. Los sujetos de la altura mostraron una menor glicemia durante las 12 horas de monitoreo en comparación con los del nivel del mar (52,4 mas menos 6,8 mg/dL y 73,0 mas menos 12,6 mg/dL, respectivamente; P menor que 0,001). Los niveles de triglicéridos fueron mayores en el grupo de altura pero no estadísticamente significativos (123 mas menos 53,9 mg/dL y 80,8 mas menos 27,9 mg/dL, respectivamente; P mayor que 0,05) No hubo diferencias en la sensibilidad a la insulina. En conclusión, los sujetos de la altura tuvieron una menor glicemia al menos durante las 12 h de monitoreo continuo.