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Cardiac amyloidosis (CA) involves the abnormal deposition and accumulation of amyloid proteins in the heart muscle. A hallmark of disease progression is declining heart function, which can lead to structural irregularities, arrhythmias, and ultimately heart failure. Atrial fibrillation (AF) is the most common arrhythmia that presents in CA patients, and this arrhythmia is significant because it can moderately increase the risk of patients developing intracardiac thrombi, thereby putting them at risk for thromboembolic events. The management of this complication entails the use of anticoagulants like vitamin K antagonists and direct oral anticoagulants to reduce the risk of thrombus formation. This article seeks to review AF in CA and the use of anticoagulation therapy for the management and reduction of thromboembolic risk. The major conclusions of this review are centered around the need for safe administration of anticoagulant therapy to CA patients, regardless of their CHA2DS2-VASc risk score. This review highlights the importance of taking a multidisciplinary or collaborative approach to CA treatment to ensure that all aspects of this multifaceted disease can be properly managed while minimizing adverse events like bleeding risk and drug-drug interactions.
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To unravel why computational design fails in creating viable enzymes, while directed evolution (DE) succeeds, our research delves into the laboratory evolution of protoglobin. DE has adapted this protein to efficiently catalyze carbene transfer reactions. We show that the previously proposed enhanced substrate access and binding alone cannot account for increased yields during DE. The 3D electric field in the entire active site is tracked through protein dynamics, clustered using the affinity propagation algorithm, and subjected to principal component analysis. This analysis reveals notable changes in the electric field with DE, where distinct field topologies influence transition state energetics and mechanism. A chemically meaningful field component emerges and takes the lead during DE and facilitates crossing the barrier to carbene transfer. Our findings underscore intrinsic electric field dynamic's influence on enzyme function, the ability of the field to switch mechanisms within the same protein, and the crucial role of the field in enzyme design.
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Reaction barriers are key to our understanding of chemical reactivity and catalysis. Certain reactions are so seminal in chemistry that countless variants, with or without catalysts, have been studied, and their barriers have been computed or measured experimentally. This wealth of data represents a perfect opportunity to leverage machine learning models, which could quickly predict barriers without explicit calculations or measurement. Here, we show that the topological descriptors of the quantum mechanical charge density in the reactant state constitute a set that is both rigorous and continuous and can be used effectively for the prediction of reaction barrier energies to a high degree of accuracy. We demonstrate this on the Diels-Alder reaction, highly important in biology and medicinal chemistry, and as such, studied extensively. This reaction exhibits a range of barriers as large as 270 kJ/mol. While we trained our single-objective supervised (labeled) regression algorithms on simpler Diels-Alder reactions in solution, they predict reaction barriers also in significantly more complicated contexts, such a Diels-Alder reaction catalyzed by an artificial enzyme and its evolved variants, in agreement with experimental changes in kcat. We expect this tool to apply broadly to a variety of reactions in solution or in the presence of a catalyst, for screening and circumventing heavily involved computations or experiments.
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Dengue and Zika are two mosquito-borne diseases of great impact on public health around the world in tropical and subtropical countries. DENV and ZIKV belong to the Flaviviridae family and the Flavivirus genus. Currently, there are no effective therapeutic agents to treat or prevent these pathologies. The main objective of this work was to evaluate potential inhibitors from active compounds obtained from Marcetia taxifolia by performing inverse molecular docking on ZIKV-NS3-helicase and ZIKV-NS5-RNA polymerase as targets. This computational strategy is based on renormalizing the binding scores of the compounds to these two proteins, allowing a direct comparison of the results across the proteins. The crystallographic structures of the ZIKV-NS3-helicase and ZIKV-NS5-RNA-polymerase proteins share a great similarity with DENV homologous proteins. The P-loop active site of the crystallographic structure of ZIKV-NS3-helicase presents a high percentage of homology with the four dengue serotypes. It was found that most ligands of the active compounds (5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (5DP); 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5HH); myricetin-3-O-rhamnoside (M3OR)) from Marcetia taxifolia had a better affinity for ZIKV-NS3-helicase than for ZIKV-NS5-RNA polymerase, as indicated by the negative multiple active site correction (MASC) score, except for M3RG that showed a higher affinity for ZIKV-NS5-RNA polymerase. On the other hand, the AutoDock Vina scores showed that M3OR had the highest score value (-9.60 kcal/mol) and the highest normalized score (1.13) against ZIKV-NS3-helicase. These results in silico demonstrated that the nonstructural proteins NS3-helicase and NS5-RNA polymerase, which share similar molecular structures between the selected viruses, could become therapeutic targets for some bioactive compounds derived from Marcetia taxifolia.
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Leptin is one of the main adipokines secreted in breast tissue. Leptin promotes epithelial-mesenchymal transition (EMT), cell migration and invasion in epithelial breast cells, leading to tumor progression. Although, the molecular mechanisms that underlie these events are not fully understood, the activation of different signaling pathways appears to be essential. In this sense, the effects of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, are not completely described. Therefore, we investigated the involvement of these kinases using an in vitro model for leptin-induced EMT process in the non-tumorigenic MCF10A cell line. To this end, MCF10A cells were stimulated with leptin, and Src and FAK activation was assessed. Specific events occurring during EMT were also evaluated in the presence or absence of the kinases' chemical inhibitors PP2 and PF-573228. For instance, we tested the expression and subcellular localization of the EMT-related transcription factors Twist and ß-catenin, by western blot and immunofluorescence. We also evaluated the secretion and activation of matrix metalloproteases (MMP-2 and MMP-9) by gelatin zymography. Invasiveness properties of leptin-stimulated cells were determined by invadopodia formation assays, and by the Transwell chamber method. Our results showed that leptin promotes EMT through Src and FAK activation, which leads to the secretion and activation of MMP-2 and MMP-9, invadopodia formation and cell invasion in MCF10A cells. In conclusion, our data suggest that leptin promotes an increase in the expression levels of Twist and ß-catenin, the secretion of MMP-2, MMP-9, the invadopodia formation and invasion in MCF10A cells in a Src and FAK-dependent manner.
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Mama/patología , Leptina/farmacología , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Regulación hacia Arriba , beta Catenina/metabolismo , Mama/citología , Mama/efectos de los fármacos , Mama/metabolismo , Línea Celular , Movimiento Celular , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Transición Epitelial-Mesenquimal , Femenino , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Pirimidinas/farmacología , Quinolonas/farmacología , Transducción de Señal/efectos de los fármacos , Sulfonas/farmacología , Familia-src Quinasas/metabolismoRESUMEN
Cerebral palsy describes a group of movement and posture disorders that cause activity limitation, and are attributable to nonprogressive disorders that occur in the fetal or infant brain. The growth of these children should not be compared with those of the healthy population. We studied 452 children, 186 female and 266 male. We compared the results in 2 growth charts, Centers for Disease Control and Prevention (CDC) and cerebral palsy, and the results were statistically significant ( P = .00001). With the CDC charts, 40.71% of the patients were below the 5th percentile and only 5.5% of them when we used the charts for cerebral palsy patients. The Mexican cerebral palsy patients were similar to US cerebral palsy patients when we compared height ( P = .4075) and body mass index (BMI) ( P = .4075). Only the weight was found to be different ( P = .00001). All the correlation indexes were negative: Eating and Drinking Ability Classification System (EDACS)-BMI (rho = -0.4798) ( P = .00001), Communication Function Classification System (CFCS)-BMI (rho = -0.4353) ( P = .00001), and Gross Motor Function Classification System (GMFCS)-BMI (rho = -0.3584) ( P = .00001). The growth charts of the healthy pediatric population tend to overestimate the underweight. We propose to use cerebral palsy charts as a reference in our patients. It is possible to determine a functional profile (communication, gross motor function and safety, and feed efficiency) for the cerebral palsy population based on their BMI.
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Parálisis Cerebral/epidemiología , Gráficos de Crecimiento , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Masculino , México/epidemiología , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
Poison frogs acquire chemical defenses from the environment for protection against potential predators. These defensive chemicals are lipophilic alkaloids that are sequestered by poison frogs from dietary arthropods and stored in skin glands. Despite decades of research focusing on identifying poison frog alkaloids, we know relatively little about how environmental variation and subsequent arthropod availability impacts alkaloid loads in poison frogs. We investigated how seasonal environmental variation influences poison frog chemical profiles through changes in the diet of the Climbing Mantella (Mantella laevigata). We collected M. laevigata females on the Nosy Mangabe island reserve in Madagascar during the wet and dry seasons and tested the hypothesis that seasonal differences in rainfall is associated with changes in diet composition and skin alkaloid profiles of M. laevigata. The arthropod diet of each frog was characterized into five groups (i.e. ants, termites, mites, insect larvae, or 'other') using visual identification and cytochrome oxidase 1 DNA barcoding. We found that frog diet differed between the wet and dry seasons, where frogs had a more diverse diet in the wet season and consumed a higher percentage of ants in the dry season. To determine if seasonality was associated with variation in frog defensive chemical composition, we used gas chromatography / mass spectrometry to quantify alkaloids from individual skin samples. Although the assortment of identified alkaloids was similar across seasons, we detected significant differences in the abundance of certain alkaloids, which we hypothesize reflects seasonal variation in the diet of M. laevigata. We suggest that these variations could originate from seasonal changes in either arthropod leaf litter composition or changes in frog behavioral patterns. Although additional studies are needed to understand the consequences of long-term environmental shifts, this work suggests that alkaloid profiles are relatively robust against short-term environmental perturbations.
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Alcaloides/análisis , Animales Ponzoñosos/fisiología , Anuros/fisiología , Conducta Alimentaria/fisiología , Venenos/análisis , Alcaloides/metabolismo , Animales , Artrópodos , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humedad , Madagascar , Venenos/metabolismo , Conducta Predatoria/fisiología , Estaciones del Año , Piel/química , Piel/metabolismo , TemperaturaRESUMEN
RESUMEN Los materiales que están en contacto con el sistema corporal requieren de la característica primordial que les permita su aceptación e integración en el organismo: la biocompatibilidad. De igual manera, deben exhibir excelentes propiedades mecánicas, tribológicas y topográficas para que su prestación del servicio en el tejido especificado sea el más óptimo, pudiendo esbozar estas características mediante la caracterización de estos materiales a través de técnicas espectroscópicas y microscópicas. En el presente trabajo, una válvula artificial para el corazón fabricada en titanio y recubierta con diamond-like carbon (DLC), material altamente biocompatible, fue sometida a análisis XPS, FTIR y morfológico. En estos se encontró una alta interdifusión del recubrimiento con el sustrato junto con una gran señal de enlaces sp3. Los enlaces terminales CH3 suponen una película poco compacta. La rugosidad del recubrimiento fue baja y adecuada para fines hemocompatibles.
ABSTRACT The materials that are in contact with the body system require the fundamental characteristic that allows their acceptance and integration in the organism, the biocompatibility. Likewise, they must show excellent mechanical, tribological and morphological properties, so that their provision of a service in the specific tissue is the most optimal, being able to sketch such characteristics through the characterization of these materials by spectroscopic and microscopic techniques. In this work, an artificial valve for the heart made of titanium and coated with diamond-like carbon (DLC), highly biocompatible material, was subjected to XPS, FTIR, and morphological analysis. A high interdiffusion of the coating and the substrate was found, together with a large signal of sp3 bonds. The CH3 terminal bonds represent a little compact film. The film roughness of the coating was low and adequate for hemocompatible purposes.
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The objective of this research was to identify and characterize the encoded peptides present in nut storage proteins of Carya illinoinensis. It was found, through in silico prediction, proteomic analysis, and MS spectrometry, that bioactive peptides were mainly found in albumin and glutelin fractions. Glutelin was the major fraction with ~53% of the nut storage proteins containing at least 21 peptides with different putative biological activities, including antihypertensives, antioxidants, immunomodulators, protease inhibitors, and inhibitors of cell cycle progression in cancer cells. Data showed that using 50 µg/mL tryptic digests of enriched peptides obtained from nut glutelins is able to induce up to 19% of apoptosis in both HeLa and CasKi cervical cancer cells. To our knowledge, this is the first report that shows the potential value of the nut-encoded peptides to be considered as adjuvants in cancer therapies.
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Antioxidantes/química , Carya/química , Péptidos/química , Proteínas de Almacenamiento de Semillas/genética , Antioxidantes/aislamiento & purificación , Carya/genética , Glútenes/química , Glútenes/genética , Nueces/química , Nueces/genética , Péptidos/genética , Péptidos/aislamiento & purificación , Inhibidores de Proteasas/química , Inhibidores de Proteasas/aislamiento & purificación , Proteómica , Proteínas de Almacenamiento de Semillas/química , Proteínas de Almacenamiento de Semillas/aislamiento & purificación , Semillas/químicaRESUMEN
El presente caso describe un lactante menor femenino de 9 meses de edad con agenesia pulmonar asociada a persistencia del conducto arterioso y su tratamiento por vía percutánea. Este paciente ingreso a nuestro centro con diagnóstico de neumonía izquierda y luego de ser evaluado se confirmó el diagnóstico de agenesia pulmonar izquierda asociado a persistencia del conducto arterioso y se plantea el cierre percutáneo. En nuestro centro es el primer caso reportado de esta anomalía teniendo una evolución satisfactoria durante cuatro años.
We describe a case pulmonary agenesia associated with a patent ductus arteriosus in infant 9 month old female and its percutaneus treatment. This patient came to our center with a previous diagnosis of left pneumonia and after a complete evaluation, left pulmonary agenesis and Patent Ductus Arteriosus were diagnosed. Due to this particular condition endovascular closure was indicated and complete closure of the defect was achieved shortly after years of follow-up, the patient is cardiovascular asympthomatic.