Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

AbstractHuman 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders

Summertime transport pathways from different northern hemisphere regions into the Arctic

Trace gases and aerosols play an important role in Arctic chemistry and climate. As most Arctic tracers and aerosols are transported from midlatitude source regions, long-range transport into the Arctic is one of the key factors to understand the current and future states of Arctic climate. While previous studies have investigated the airmass fraction and transit time distribution in the Arctic, the actual transport pathways and their underlying dynamics and efficiencies are yet to be understood. In this study, we implement a large ensemble of idealized tagged pulse passive tracers in the Whole Atmosphere Community Climate Model version 5 to identify and analyze summertime transport pathways from different Northern Hemisphere surface regions into the Arctic. Three different transport pathways are identified as those associated with fast, intermediate and slow time scales. Midlatitude tracers can be transported into the Arctic in the troposphere via the fast transport pathway (∼8 days), which moves tracers northward from the source region mainly through transient eddies. For the intermediate transport pathway, which happens on 1–3 weeks’ time scales, midlatitude tracers are first zonally transported by the jet stream, and then advected northward into the Arctic over Alaska and northern North Atlantic. Tropical and subtropical tracers are transported into the Arctic lower stratosphere via the slow transport pathway (1–3 months), as the tracers are lifted upward into the tropical and subtropical lower stratosphere, and then transported into the Arctic following the isentropic surfaces

Research progress on the role of macrophages in acne and regulation by natural plant products

Acne vulgaris is one of the most common skin diseases. The current understanding of acne primarily revolves around inflammatory responses, sebum metabolism disorders, aberrant hormone and receptor expression, colonization by Cutibacterium acnes, and abnormal keratinization of follicular sebaceous glands. Although the precise mechanism of action remains incompletely understood, it is plausible that macrophages exert an influence on these pathological features. Macrophages, as a constituent of the human innate immune system, typically manifest distinct phenotypes across various diseases. It has been observed that the polarization of macrophages toward the M1 phenotype plays a pivotal role in the pathogenesis of acne. In recent years, extensive research on acne has revealed an increasing number of natural remedies exhibiting therapeutic efficacy through the modulation of macrophage polarization. This review investigates the role of cutaneous macrophages, elucidates their potential significance in the pathogenesis of acne, a prevalent chronic inflammatory skin disorder, and explores the therapeutic mechanisms of natural plant products targeting macrophages. Despite these insights, the precise role of macrophages in the pathogenesis of acne remains poorly elucidated. Subsequent investigations in this domain will further illuminate the pathogenesis of acne and potentially offer guidance for identifying novel therapeutic targets for this condition

Innovación pedagógica en el aula: una propuesta de aprendizaje basado en proyectos

[ES] El presente trabajo tiene como objetivo el desarrollo de una propuesta didáctica sobre formación para el empleo en el aprendizaje por proyectos que desemboque en un producto útil para la enseñanza-aprendizaje de Español Lengua Extranjera. Se basa en dar respuesta a los intereses del alumnado acerca de la búsqueda de prácticas en empresas tras finalizar el máster en Lenguas y Tecnología. Por consiguiente, pretende satisfacer una necesidad. Para conseguirlo, se fundamenta en un aprendizaje basado en la investigación-acción y adopta una metodología mixta de recogida de datos, los cuantitativos y los cualitativos. Los resultados obtenidos ponen de manifiesto la conveniencia del proyecto desarrollado, evalúan el proyecto final, el blog, plantean mejoras y evidencian las competencias transversales trabajadas.[EN] The aim of this work is to develop a didactic proposal on training for employment in project-based learning that will result in a useful product for the teaching-learning of Spanish as a foreign language. It is based on responding to the interests of the students regarding the search for internships in companies after completing the master in Languages and Technology. Therefore, it aims to satisfy a need. To achieve this, it is based on action-research-based learning and adopts a mixed methodology of data collection, both quantitative and qualitative. The results obtained show the suitability of the project developed, evaluate the final project, the blog, propose improvements and highlight transversal competences worked on.[CA] El present treball té com a objectiu el desenvolupament d'una proposta didàctica sobre formació per a l'ocupació en l'aprenentatge per projectes que desemboque en un producte útil per a l'ensenyament-aprenentatge d'Espanyol Llengua Estrangera. Es basa a donar resposta als interessos de l'alumnat sobre la cerca de pràctiques en empreses després de finalitzar el màster en Llengües i Tecnologia. Per consegüent, pretén satisfer una necessitat. Per a aconseguir-ho, es basa en un aprenentatge basat en la investigació-acció i adopta una metodologia mixta de recollida de dades, els quantitatius i els qualitatius. Els resultats obtinguts posen de manifest la conveniència del projecte desenvolupat, avaluen el projecte final, el blog, plantegen millores i evidencien les competències transversals treballades.Zheng, M. (2020). Innovación pedagógica en el aula: una propuesta de aprendizaje basado en proyectos. Universitat Politècnica de València. http://hdl.handle.net/10251/158891TFG

Active eavesdropping detection: a novel physical layer security in wireless IoT

Abstract Considering the variety of Internet of Things (IoT) device types and access methods, it remains necessary to address the security challenges we currently encounter. Physical layer security (PLS) can offer streamlined security solutions for the next generation of IoT networks. Presently, we are witnessing the application of intelligent technologies including machine learning (ML) and artificial intelligence (AI) for precise prevention or detection of security breaches. Active eavesdropping detection is a physical layer security-based method that can differentiate wireless signals between wireless devices through feature classification. However, the operation of numerous IoT devices operate in environments characterized by low signal-to-noise ratios (SNR), and active eavesdropping attack detection during communication is rarely studied. We assume that the wireless system comprising an access point (AP), K authorized users and a proactive eavesdropper (E), following the framework of transforming wireless signals at AP into organized datasets that this article proposes a BP neural network model based on deep learning as a classifier to distinguish eavesdropping and non-eavesdropping attack signals. By conducting experiments under SNRs, the numerical results show that the proposed model has stronger robustness and detection accuracy can significantly improve the up to 19.58% compared with the reference approach, which show the superiority of our proposed method

Optimal ordering policy for platelets: Data-driven method vs model-driven method

Platelets, one of the most significant materials in treating leukemia, have a limited shelf life of approximately five days. Because platelets cannot be manufactured and can only be centrifuged from whole or donated blood directly, an accurate ordering policy is necessary for the efficient use of this limited blood resource. Given this motivation, the present study examines an ordering policy for platelets to minimize the expected shortage and overage. Rather than using the two-step model-driven method that first fits a demand distribution and then optimizes the order quantity, we solve the issue using an integrated data-driven method. Specifically, the data-driven method works directly with demand data and does not rely on the assumption of demand distribution. Consequently, we derive theoretical insights into the optimal solutions. Through a comparative analysis, we find that the data-driven method has a mean anchoring effect, and the amounts of shortage and overage reduced by this method are greater than those reduced by the model-driven method. Finally, we present an extended model with the service level requirement and conclude that the order decided by the data-driven method can precisely satisfy the service level requirement; however, the order decided by the model-driven method may be either higher or lower than the service level requirement and can lead to a higher cost

Modelling guided waves in anisotropic plates using the Legendre polynomial method

A numerical method to compute phase dispersion curve in unidirectional laminate is described. The basic feature of the proposed method is the expansion of fields quantities in single layer on different polynomial bases. The Legendre polynomial method avoid to solve the transcendental dispersion equation of guided wave. Guided waves that have very close propagation constants are calculated with great accuracy. Numerical solution of dispersion relation are calculated for guided waves propagation in orthotropic unidirectional fiber composites. The validation of the polynomial approach is depicted by a comparison between the associated solution and those obtained using Transfer matrix method

Modelling guided waves in anisotropic plates using the Legendre polynomial method

A numerical method to compute phase dispersion curve in unidirectional laminate is described. The basic feature of the proposed method is the expansion of fields quantities in single layer on different polynomial bases. The Legendre polynomial method avoid to solve the transcendental dispersion equation of guided wave. Guided waves that have very close propagation constants are calculated with great accuracy. Numerical solution of dispersion relation are calculated for guided waves propagation in orthotropic unidirectional fiber composites. The validation of the polynomial approach is depicted by a comparison between the associated solution and those obtained using Transfer matrix method

Beyond the lockdowns: satellite observations of aerosol optical depth through 2020, the first year of the COVID-19 pandemic

Anticipated future reductions in aerosol emissions are expected to accelerate warming and substantially change precipitation characteristics. Therefore, it is vital to identify the existing patterns and possible future pathways of anthropogenic aerosol reductions. The COVID-19 pandemic prompted abrupt, global declines in transportation and industrial activities, providing opportunities to study the aerosol effects of pandemic-driven emissions changes. Here, measurements of aerosol optical depth (AOD) from two satellite instruments were used to characterize aerosol burdens throughout 2020 in four Northern Hemisphere source regions (Eastern & Central China, the United States, India, and Europe). In most regions, record-low measures of AOD persisted beyond the earliest ‘lockdown’ periods of the pandemic. Record-low values were most concentrated during the boreal spring and summer months, when 56% to 72% of sampled months showed record-low AOD values for their respective regions. However, in India and Eastern & Central China, the COVID-19 AOD signature was eclipsed by sources of natural variability (dust) and a multi-year trend, respectively. In the United States and Europe, a likely COVID-19 signal peaks in the summer of 2020, contributing as much as −.01 to −.03 AOD units to observed anomalies

Exonic Splicing Enhancer-Dependent Selection of the Bovine Papillomavirus Type 1 Nucleotide 3225 3′ Splice Site Can Be Rescued in a Cell Lacking Splicing Factor ASF/SF2 through Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway

Bovine papillomavirus type 1 (BPV-1) late pre-mRNAs are spliced in keratinocytes in a differentiation-specific manner: the late leader 5′ splice site alternatively splices to a proximal 3′ splice site (at nucleotide 3225) to express L2 or to a distal 3′ splice site (at nucleotide 3605) to express L1. Two exonic splicing enhancers, each containing two ASF/SF2 (alternative splicing factor/splicing factor 2) binding sites, are located between the two 3′ splice sites and have been identified as regulating alternative 3′ splice site usage. The present report demonstrates for the first time that ASF/SF2 is required under physiological conditions for the expression of BPV-1 late RNAs and for selection of the proximal 3′ splice site for BPV-1 RNA splicing in DT40-ASF cells, a genetically engineered chicken B-cell line that expresses only human ASF/SF2 controlled by a tetracycline-repressible promoter. Depletion of ASF/SF2 from the cells by tetracycline greatly decreased viral RNA expression and RNA splicing at the proximal 3′ splice site while increasing use of the distal 3′ splice site in the remaining viral RNAs. Activation of cells lacking ASF/SF2 through anti-immunoglobulin M-B-cell receptor cross-linking rescued viral RNA expression and splicing at the proximal 3′ splice site and enhanced Akt phosphorylation and expression of the phosphorylated serine/arginine-rich (SR) proteins SRp30s (especially SC35) and SRp40. Treatment with wortmannin, a specific phosphatidylinositol 3-kinase/Akt kinase inhibitor, completely blocked the activation-induced activities. ASF/SF2 thus plays an important role in viral RNA expression and splicing at the proximal 3′ splice site, but activation-rescued viral RNA expression and splicing in ASF/SF2-depleted cells is mediated through the phosphatidylinositol 3-kinase/Akt pathway and is associated with the enhanced expression of other SR proteins