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BACKGROUND: Intravenous immune globulin (IVIG) for the treatment of dermatomyositis has not been extensively evaluated. METHODS: We conducted a randomized, placebo-controlled trial involving patients with active dermatomyositis. The patients were assigned in a 1:1 ratio to receive IVIG at a dose of 2.0 g per kilogram of body weight or placebo every 4 weeks for 16 weeks. The patients who received placebo and those without confirmed clinical deterioration while receiving IVIG could enter an open-label extension phase for another 24 weeks. The primary end point was a response, defined as a Total Improvement Score (TIS) of at least 20 (indicating at least minimal improvement) at week 16 and no confirmed deterioration up to week 16. The TIS is a weighted composite score reflecting the change in a core set of six measures of myositis activity over time; scores range from 0 to 100, with higher scores indicating greater improvement. Key secondary end points included at least moderate improvement (TIS ≥40) and major improvement (TIS ≥60), and change in score on the Cutaneous Dermatomyositis Disease Area and Severity Index. RESULTS: A total of 95 patients underwent randomization: 47 patients were assigned to the IVIG group, and 48 to the placebo group. At 16 weeks, 79% of the patients in the IVIG group (37 of 47) and 44% of those in the placebo group (21 of 48) had a TIS of at least 20 (difference, 35 percentage points; 95% confidence interval, 17 to 53; P<0.001). The results with respect to the secondary end points, including at least moderate improvement and major improvement, were generally in the same direction as the results of the primary end-point analysis, except for the change in creatine kinase level (an individual core measure of the TIS), which did not differ meaningfully between the two groups. Over 40 weeks, 282 treatment-related adverse events occurred in the IVIG group, including headache (in 42% of patients), pyrexia (in 19%), and nausea (in 16%). A total of 9 serious adverse events that were considered to be related to IVIG occurred, including 6 thromboembolic events. CONCLUSIONS: In this 16-week trial involving adults with dermatomyositis, the percentage of patients with a response of at least minimal improvement based on a composite score of disease activity was significantly greater among those who received IVIG than among those who received placebo. IVIG was associated with adverse events, including thromboembolism. (Funded by Octapharma Pharmazeutika; ProDERM ClinicalTrials.gov number, NCT02728752.).
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Dermatomiosite , Imunoglobulinas Intravenosas , Adulto , Creatina Quinase/análise , Dermatomiosite/tratamento farmacológico , Dermatomiosite/terapia , Método Duplo-Cego , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/uso terapêuticoRESUMO
This manuscript details a comprehensive investigation into the synthesis, structural characterization, thermal stability, and optical properties of nickel-containing hybrid perovskites, namely CH3NH3NiCl3, CsNiCl3, and CH3NH3NiBrCl2. The focal point of this study is to unravel the intricate crystal structures, thermal behaviors, and optical characteristics of these materials, thereby elucidating their potential application in energy conversion and storage technologies. X-ray powder diffraction measurements confirm that CH3NH3NiCl3 adopts a crystal structure within the Cmcm space group, while CsNiCl3 is organized in the P63/mmc space group, as reported previously. Such structural diversity underscores the complex nature of these perovskites and their potential for tailored applications. Thermal analysis further reveals the stability of CH3NH3NiCl3 and CH3NH3NiBrCl2, which begin to decompose at 260 °C and 295 °C, respectively. The optical absorption properties of these perovskites studied by UV-VIS-NIR spectroscopy revealed the bands characteristic of Ni2+ ions in an octahedral environment. Notably, these absorption bands exhibit subtle shifts upon bromide substitution, suggesting that optical properties can be finely tuned through halide modification. Such tunability is paramount for the design and development of materials with specific optical requirements. By offering a detailed examination of these properties, the study lays the groundwork for future advancements in material science, particularly in the development of innovative materials for sustainable energy technologies.
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In this study, a systematic investigation of MoS2 nanostructure growth on a SiO2 substrate was conducted using a two-stage process. Initially, a thin layer of Mo was grown through sputtering, followed by a sulfurization process employing the CVD technique. This two-stage process enables the control of diverse nanostructure formations of both MoS2 and MoO3 on SiO2 substrates, as well as the formation of bulk-like grain structures. Subsequently, the addition of reduced graphene oxide (rGO) was examined, resulting in MoS2/rGO(n), where graphene is uniformly deposited on the surface, exposing a higher number of active sites at the edges and consequently enhancing electroactivity in the HER. The influence of the synthesis time on the treated MoS2 and also MoS2/rGO(n) samples is evident in their excellent electrocatalytic performance with a low overpotential.
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This article describes the development of a nickel-catalyzed regio- and diastereoselective formal [3+2] cycloaddition between N-substituted indoles and donor-acceptor cyclopropanes to synthesize cyclopenta[b]indoles. Optimized reaction conditions provide the desired nitrogen-containing cycloadducts in up to 93% yield and dr 8.6:1 with complete regioselectivity. The substrate scope showed high tolerance to various substituted indoles and cyclopropanes, resulting in the synthesis of six new cyclopenta[b]indoles and the isolation of five derivatives previously reported in the literature. In addition, a mechanistic proposal for the reaction was studied through online reaction monitoring by ESI-MS, allowing for the identification of the reactive intermediates in the Ni(II) catalyzed process. X-ray crystallography confirmed the structure and relative endo stereochemistry of the products. This method enables the fast and efficient construction of fused indolines from readily accessible starting materials.
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The physis, or growth plate, is the primary structure responsible for longitudinal growth of the long bones. Diffusion tensor imaging (DTI) is a technique that depicts the anisotropic motion of water molecules, or diffusion. When diffusion is limited by cellular membranes, information on tissue microstructure can be acquired. Tractography, the visual display of the direction and magnitude of water diffusion, provides qualitative visualization of complex cellular architecture as well as quantitative diffusion metrics that appear to indirectly reflect physeal activity. In the growing bones, DTI depicts the columns of cartilage and new bone in the physeal-metaphyseal complex. In this "How I do It", we will highlight the value of DTI as a clinical tool by presenting DTI tractography of the physeal-metaphyseal complex of children and adolescents during normal growth, illustrating variation in qualitative and quantitative tractography metrics with age and skeletal location. In addition, we will present tractography from patients with physeal dysfunction caused by growth hormone deficiency and physeal injury due to trauma, chemotherapy, and radiation therapy. Furthermore, we will delineate our process, or "DTI pipeline," from image acquisition to data interpretation.
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Imagem de Tensor de Difusão , Lâmina de Crescimento , Criança , Adolescente , Humanos , Imagem de Tensor de Difusão/métodos , Lâmina de Crescimento/diagnóstico por imagem , Osso e Ossos , Anisotropia , ÁguaRESUMO
[Eu(3DPIQC)3] (where DPIQC = 3-(diphenyl phosphoryl)-1-isoquinolinecarboxylate), a luminescent europium complex with antenna ligands, has been carefully embedded within a polyvinyl butyral (PVB) matrix and the resulting material was used to prepare films used as luminescent down-shifting layers (LDSLs) for crystalline Si-based solar cells. The films were characterized using photoluminescence spectroscopy, atomic force spectroscopy (AFM), UV-Vis spectroscopy, and fluorescence microscopy. The AFM analysis shows films with low surface roughness, while fluorescence microscopy revealed that the Eu complex embedded in PVB assumed a spheroidal configuration, a morphology especially beneficial for optical applications. The so-obtained LDSLs were utilized as energy converters in c-Si solar cells to enhance the utilization of high-energy photons, thereby improving their overall efficiency. The determination of photovoltaic parameters carried out before and after the deposition of the LDSLs on the c-Si cells confirms a positive effect on the efficiency of the cell. The Jsc increases from 121.6 mA/cm2 to 124.9 mA/cm2, and the open circuit voltage (Voc) is found to be unrelated to the complex concentration in the films. The fill factor (FF) remains constant with the Eu concentration. The EQE curves indicate an enhancement in the performance of the photovoltaic cells within the UV region of the spectrum for all coated devices. Electrochemical impedance spectroscopy (EIS) was also carried out in order to analyze the effect of the Eu complex in the charge transfer process of the devices.
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A method for the synthesis of rafoxanide 6, a halogenated salicylanilide used as an efficient anthelmintic in sheep and cattle, is presented. Rafoxanide 6 was synthesized in only three steps from readily available 4-chlorophenol with 74% overall yield. The synthesis has two key stages: the first was salicylic acid iodination, adding iodine in the presence of hydrogen peroxide, which allowed obtaining a 95% yield. The second key stage was the reaction of 3,5-diiodosalicylic acid 5 with aminoether 4, where salicylic acid chloride was formed in situ with PCl3 achieving 82% yield. Chemical characterization of both intermediates and final product was achieved through physical and spectroscopic (IR, NMR and MS) techniques. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-023-02846-9.
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Alzheimer's disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT4 receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT4 receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures' field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R2training = 0.821, and for the test set R2test = 0.667, while for Gaussian-field QSAR the training and the test were R2training = 0.898 and R2test = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of Q2LOO = 0.804 and Q2LOO = 0.886 for force- and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT4 partial agonists with potential biological activity (pEC50 8.209-9.417 for force-field QSAR and 9.111-9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT4 partial agonists.
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Relação Quantitativa Estrutura-Atividade , Receptores 5-HT4 de Serotonina/efeitos dos fármacos , Receptores 5-HT4 de Serotonina/metabolismo , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Agonistas do Receptor 5-HT4 de Serotonina/química , Antagonistas do Receptor 5-HT4 de Serotonina/química , Relação Estrutura-AtividadeRESUMO
A number of new substituted morpholinopyrimidines were prepared utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. One of the disubstituted pyrimidines was converted into two trisubstituted compounds which were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor ZSTK474, and were found to be 1.5â»3-times more potent. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by prostate-specific antigen, and it did not prevent inhibition of AKT phosphorylation and hence the inhibition of PI3K by the modified inhibitor.
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Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Humanos , Isomerismo , Leucina/química , Peptídeos/química , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/químicaRESUMO
A number of new trisubstituted triazine phosphatidylinositol 3-kinase (PI3K) inhibitors were prepared via a three-step procedure utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. All were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor, ZSTK474. The most active inhibitors prepared here were 2â»4 times more potent than ZSTK474. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by a prostate-specific antigen, and it did not prevent inhibition of protein kinase B (Akt) phosphorylation, and hence, the inhibition of PI3K by the modified inhibitor.
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Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Triazinas/síntese química , Linhagem Celular Tumoral , Humanos , Leucina/química , Masculino , Fosforilação/efeitos dos fármacos , Antígeno Prostático Específico/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triazinas/química , Triazinas/farmacologiaRESUMO
Genetic exchange by hybridization or admixture can make an important contribution to evolution, and introgression of favourable alleles can facilitate adaptation to new environments. A small number of honeybees (Apis mellifera) with African ancestry were introduced to Brazil ~60 years ago, which dispersed and hybridized with existing managed populations of European origin, quickly spreading across much of the Americas in an example of a massive biological invasion. Here, we analyse whole-genome sequences of 32 Africanized honeybees sampled from throughout Brazil to study the effect of this process on genome diversity. By comparison with ancestral populations from Europe and Africa, we infer that these samples have 84% African ancestry, with the remainder from western European populations. However, this proportion varies across the genome and we identify signals of positive selection in regions with high European ancestry proportions. These observations are largely driven by one large gene-rich 1.4-Mbp segment on chromosome 11 where European haplotypes are present at a significantly elevated frequency and likely confer an adaptive advantage in the Africanized honeybee population. This region has previously been implicated in reproductive traits and foraging behaviour in worker bees. Finally, by analysing the distribution of ancestry tract lengths in the context of the known time of the admixture event, we are able to infer an average generation time of 2.0 years. Our analysis highlights the processes by which populations of mixed genetic ancestry form and adapt to new environments.
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Adaptação Fisiológica/genética , Abelhas/genética , Hibridização Genética , África , Animais , Brasil , Europa (Continente) , Genoma de Inseto , HaplótiposRESUMO
Individuals involved in a social interaction exhibit different behavioral traits that, in combination, form the individual's behavioral responses. Selectively bred strains of silver foxes (Vulpes vulpes) demonstrate markedly different behaviors in their response to humans. To identify the genetic basis of these behavioral differences we constructed a large F2 population including 537 individuals by cross-breeding tame and aggressive fox strains. 98 fox behavioral traits were recorded during social interaction with a human experimenter in a standard four-step test. Patterns of fox behaviors during the test were evaluated using principal component (PC) analysis. Genetic mapping identified eight unique significant and suggestive QTL. Mapping results for the PC phenotypes from different test steps showed little overlap suggesting that different QTL are involved in regulation of behaviors exhibited in different behavioral contexts. Many individual behavioral traits mapped to the same genomic regions as PC phenotypes. This provides additional information about specific behaviors regulated by these loci. Further, three pairs of epistatic loci were also identified for PC phenotypes suggesting more complex genetic architecture of the behavioral differences between the two strains than what has previously been observed.
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Comportamento Animal , Raposas/genética , Comportamento Social , Animais , Mapeamento Cromossômico , Cromossomos de Mamíferos/genética , Epistasia Genética , Feminino , Masculino , Fenótipo , Análise de Componente Principal , Locos de Características Quantitativas/genética , Característica Quantitativa HerdávelRESUMO
Quantitative genetics traces its roots back through more than a century of theory, largely formed in the absence of directly observable genotype data, and has remained essentially unchanged for decades. By contrast, molecular genetics arose from direct observations and is currently undergoing rapid changes, making the amount of available data ever greater. Thus, the two disciplines are disparate both in their origins and their current states, yet they address the same fundamental question: how does the genotype affect the phenotype? The rapidly accumulating genomic data necessitate sophisticated analysis, but many of the current tools are adaptations of methods designed during the early days of quantitative genetics. We argue here that the present analysis paradigm in quantitative genetics is at its limits in regards to unraveling complex traits and it is necessary to re-evaluate the direction that genetic research is taking for the field to realize its full potential.
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Genética , Alelos , Epigênese Genética , Epistasia Genética , Evolução Molecular , Heterogeneidade Genética , Estudo de Associação Genômica Ampla , Modelos TeóricosRESUMO
A practical synthesis of (-)-englerinâ A was accomplished in 17â steps and 11 % global yield from commercially available achiral precursors. The key step consists of a platinum-catalyzed [4C+3C] allenediene cycloaddition that directly delivers the trans-fused guaiane skeleton with complete diastereoselectivity. The high enantioselectivity (99 %â ee) stems from an asymmetric ruthenium-catalyzed transfer hydrogenation of a readily assembled diene-ynone. The synthesis also features a highly stereoselective oxygenation, and a late-stage cuprate alkylation that enables the preparation of previously inaccessible structural analogues.
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Electrically conductive biomaterials and nanomaterials have demonstrated great potential in the development of functional and mature cardiac tissues. In particular, gold nanomaterials have emerged as promising candidates due to their biocompatibility and ease of fabrication for cardiac tissue engineering utilizing rat- or stem cell-derived cardiomyocytes (CMs). However, despite significant advancements, it is still not clear whether the enhancement in cardiac tissue function is primarily due to the electroconductivity features of gold nanoparticles or the structural changes of the scaffold resulting from the addition of these nanoparticles. To address this question, we developed nanoengineered hydrogel scaffolds comprising gelatin methacrylate (GelMA) embedded with either electrically conductive gold nanorods (GNRs) or nonconductive silica nanoparticles (SNPs). This enabled us to simultaneously assess the roles of electrically conductive and nonconductive nanomaterials in the functionality and fate of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Our studies revealed that both GNR- and SNP-incorporated hydrogel scaffolds exhibited excellent biocompatibility and similar cardiac cell attachment. Although the expression of sarcomere alpha-actinin did not significantly differ among the conditions, a more organized sarcomere structure was observed within the GNR-embedded hydrogels compared to the nonconductive nanoengineered scaffolds. Furthermore, electrical coupling was notably improved in GNR-embedded scaffolds, as evidenced by the synchronous calcium flux and enhanced calcium transient intensity. While we did not observe a significant difference in the gene expression profile of human cardiac tissues formed on the conductive GNR- and nonconductive SNP-incorporated hydrogels, we noticed marginal improvements in the expression of some calcium and structural genes in the nanomaterial-embedded hydrogel groups as compared to the control condition. Given that the cardiac tissues formed atop the nonconductive SNP-based scaffolds (used as the control for conductivity) also displayed similar levels of gene expression as compared to the conductive hydrogels, it suggests that the electrical conductivity of nanomaterials (i.e., GNRs) may not be the sole factor influencing the function and fate of hiPSC-derived cardiac tissues when cells are cultured atop the scaffolds. Overall, our findings provide additional insights into the role of electrically conductive gold nanoparticles in regulating the functionalities of hiPSC-CMs.
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Nanopartículas Metálicas , Engenharia Tecidual , Humanos , Ratos , Animais , Engenharia Tecidual/métodos , Ouro , Dióxido de Silício , Hidrogéis/química , Cálcio/metabolismo , Células-TroncoRESUMO
To assess the impact of a deep learning (DL) denoising reconstruction algorithm applied to identical patient scans acquired with two different voxel dimensions, representing distinct spatial resolutions, this IRB-approved prospective study was conducted at a tertiary pediatric center in compliance with the Health Insurance Portability and Accountability Act. A General Electric Signa Premier unit (GE Medical Systems, Milwaukee, WI) was employed to acquire two DTI (diffusion tensor imaging) sequences of the left knee on each child at 3T: an in-plane 2.0 × 2.0 mm2 with section thickness of 3.0 mm and a 2 mm3 isovolumetric voxel; neither had an intersection gap. For image acquisition, a multi-band DTI with a fat-suppressed single-shot spin-echo echo-planar sequence (20 non-collinear directions; b-values of 0 and 600 s/mm2) was utilized. The MR vendor-provided a commercially available DL model which was applied with 75% noise reduction settings to the same subject DTI sequences at different spatial resolutions. We compared DTI tract metrics from both DL-reconstructed scans and non-denoised scans for the femur and tibia at each spatial resolution. Differences were evaluated using Wilcoxon-signed ranked test and Bland-Altman plots. When comparing DL versus non-denoised diffusion metrics in femur and tibia using the 2 mm × 2 mm × 3 mm voxel dimension, there were no significant differences between tract count (p = 0.1, p = 0.14) tract volume (p = 0.1, p = 0.29) or tibial tract length (p = 0.16); femur tract length exhibited a significant difference (p < 0.01). All diffusion metrics (tract count, volume, length, and fractional anisotropy (FA)) derived from the DL-reconstructed scans, were significantly different from the non-denoised scan DTI metrics in both the femur and tibial physes using the 2 mm3 voxel size (p < 0.001). DL reconstruction resulted in a significant decrease in femorotibial FA for both voxel dimensions (p < 0.01). Leveraging denoising algorithms could address the drawbacks of lower signal-to-noise ratios (SNRs) associated with smaller voxel volumes and capitalize on their better spatial resolutions, allowing for more accurate quantification of diffusion metrics.
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Algoritmos , Aprendizado Profundo , Imagem de Tensor de Difusão , Lâmina de Crescimento , Humanos , Imagem de Tensor de Difusão/métodos , Estudos Prospectivos , Criança , Masculino , Feminino , Lâmina de Crescimento/diagnóstico por imagem , Razão Sinal-Ruído , Processamento de Imagem Assistida por Computador/métodosRESUMO
High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/ß-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestinal tumours when compared with normal intestinal mucosa. Conversely, restoration of Wnt signalling by the zinc induction of wild-type APC resulted in HMGA1 down-regulation in HT-29 cells. Because APC mutations are associated with mobilization of the ß-catenin/TCF-4 transcriptional complex and subsequent activation of downstream oncogenic targets, we analyzed the 5'-flanking sequence of HMGA1 for putative TCF-4 binding elements. We identified two regions that specifically bind the ß-catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the ß-catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/ß-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/ß-catenin/TCF-4 signalling.
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Proteína HMGA1a/metabolismo , Proteína HMGA1b/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Regiões 5' não Traduzidas , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação para Baixo/efeitos dos fármacos , Células HCT116 , Proteína HMGA1a/genética , Proteína HMGA1b/genética , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas , Ligação Proteica , Transdução de Sinais , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Zinco/farmacologia , beta Catenina/genéticaRESUMO
In this work, electrocatalytic changes of Cu(II) triazole complexes (Cu(L)2) resulting from inductive effects were evaluated to fabricate a sensor for hydrogen peroxide (H2O2) determination. Three copper(II) complexes with electronically differentiated ligands were synthesized by slow diffusion method and characterized by X-ray crystallography, Fourier transformed infrared (FTIR), UV-Vis, scanning electron microscopy (SEM) and voltammetry cyclic (CV). Cu(LOMe)2/GC, Cu(LBr)2/GC and Cu(LNO2)2/GC sensors were then prepared. Under optimal conditions (pH = 11), the optimal sensor presented a response at -0.5 V, good linear range of 1-32 µM, reproducibility (1.7%), repeatability (1.2%), LOD of 0.0246 µM (S/N = 5), LOQ of 0.0747 µM (S/N = 5) and selectivity. Additionally, Cu(LNO2)2/GC sensor has been successfully applied in commercial substances, such as mouthwash, milk and tea.
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A novel series of 6-iodo-2-methylquinazolin-4-(3H)-one derivatives, 3a-n, were synthesized and evaluated for their in vitro cytotoxic activity. Compounds 3a, 3b, 3d, 3e, and 3h showed remarkable cytotoxic activity on specific human cancer cell lines when compared to the anti-cancer drug, paclitaxel. Compound 3a was found to be particularly effective on promyelocytic leukaemia HL60 and non-Hodgkin lymphoma U937, with IC50 values of 21 and 30 µM, respectively. Compound 3d showed significant activity against cervical cancer HeLa (IC50 = 10 µM). The compounds 3e and 3h were strongly active against glioblastoma multiform tumour T98G, with IC50 values of 12 and 22 µM, respectively. These five compounds showed an interesting cytotoxic activity on four human cancer cell types of high incidence. The molecular docking results reveal a good correlation between experimental activity and calculated binding affinity on dihydrofolate reductase (DHFR). Docking studies proved 3d as the most potent compound. In addition, the three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis exhibited activities that may indicate the existence of electron-withdrawing and lipophilic groups at the para-position of the phenyl ring and hydrophobic interactions of the quinazolinic ring in the DHFR active site.
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Female biased sex ratios reduce competition between brothers when mating takes place within local patches. Male dispersal prior to mating is another strategy that reduces competition between brothers. One may thus expect these two traits to co-evolve and this is partially met in that sex ratios becomes less female biased as dispersal increases. However, the evolutionary stable degree of dispersal is unaffected by the sex ratio. The analytical models developed to reach these conclusions ignored variance in sex ratios, since this increases the structural complexity of models. For similar reasons finite clutch sizes are also routinely ignored. To overcome these shortfalls, we developed individual based simulations that allowed us to incorporate realistic clutch sizes and binomial variance in sex ratios between patches. We show that under variable sex ratios, males evolve to more readily disperse away from patches with higher sex ratios than lower sex ratios. We show that, while the dispersal rate is insensitive to the sex ratio when sex ratios are precise, it is affected by the number of males with dispersal decreasing as the number of males decreases.