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1.
J Med Chem ; 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35704802

RESUMO

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.

2.
Gels ; 8(5)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35621572

RESUMO

Alpha-crystallin protein performs structural and chaperone functions in the lens and comprises alphaA and alphaB subunits at a molar ratio of 3:1. The highly complex alpha-crystallin structure challenges structural biologists because of its large dynamic quaternary structure (300-1000 kDa). Camel lens alpha-crystallin is a poorly characterized molecular chaperone, and the alphaB subunit possesses a novel extension at the N-terminal domain. We purified camel lens alpha-crystallin using size exclusion chromatography, and the purity was analyzed by gradient (4-12%) sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Alpha-crystallin was equilibrated in the pH range of 1.0 to 7.5. Subsequently, thermal stress (20-94 °C) was applied to the alpha-crystallin samples, and changes in the conformation and stability were recorded by dynamic multimode spectroscopy and intrinsic and extrinsic fluorescence spectroscopic methods. Camel lens alpha-crystallin formed a random coil-like structure without losing its native-like beta-sheeted structure under two conditions: >50 °C at pH 7.5 and all temperatures at pH 2.0. The calculated enthalpy of denaturation, as determined by dynamic multimode spectroscopy at pH 7.5, 4.0, 2.0, and 1.0 revealed that alpha-crystallin never completely denatures under acidic conditions or thermal denaturation. Alpha-crystallin undergoes a single, reversible thermal transition at pH 7.5. The thermodynamic data (unfolding enthalpy and heat capacity change) and chaperone activities indicated that alpha-crystallin does not completely unfold above the thermal transition. Camels adapted to live in hot desert climates naturally exhibit the abovementioned unique features.

3.
Bioorg Med Chem ; 67: 116833, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35605346

RESUMO

Allosteric integrase inhibitors (ALLINIs) of HIV-1 may hold promise as a novel mechanism for HIV therapeutics and cure. Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of ALLINIs provided a series of potent compounds with differentiated 5/6 fused ring systems. Notably, inhibitors containing the 1,2,4-triazolopyridine and imidazopyridine core exhibited single digit nM antiviral potency and low to moderate clearance after intravenous (IV) dosing in rat pharmacokinetic (PK) studies. The 1,2,4-triazolopyridines showed a higher oral exposure when compared to the imidazopyridines. Further modifications to the C5 substituent of the 1,2,4-triazolopyridines resulted in a new lead compound, which had improved rat IV/PO PK compared to the former lead compound GSK3739936, while maintaining antiviral potency. Structure-activity relationships (SAR) and rat pharmacokinetic profiles of this series are discussed.


Assuntos
Fármacos Anti-HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Regulação Alostérica , Animais , Fármacos Anti-HIV/farmacologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , HIV-1/metabolismo , Ratos
4.
J Nat Prod ; 85(5): 1419-1427, 2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35465663

RESUMO

Chemical investigation of the marine hydroid Dentitheca habereri led to the identification of eight new diacylated zoanthoxanthin alkaloids, named dentithecamides A-H (1-8), along with three previously reported analogues, zoamides B-D (9-11). The structures of compounds 1-11 were elucidated by spectroscopic and spectrometric analyses, including IR, HRESIMS, and NMR experiments, and by comparison with literature data. Compounds 1-11 are the first zoanthoxanthin alkaloids to be reported from a hydroid. Dentithecamides A (1) and B (2) along with zoamides B-D (9-11), which all share a conformationally mobile cycloheptadiene core, inhibited PAX3-FOXO1 regulated transcriptional activity and thus provided a structural framework for the potential development of more potent PAX3-FOXO1 inhibitors.


Assuntos
Alcaloides , Imidazóis , Alcaloides/química
5.
Int J Biol Macromol ; 209(Pt A): 984-990, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35452699

RESUMO

MERS-CoV main protease (Mpro) is essential for the maturation of the coronavirus; therefore, considered a potential drug target. Detailed conformational information is essential to developing antiviral therapeutics. However, the conformation of MERS-CoV Mpro under different conditions is poorly characterized. In this study, MERS-CoV Mpro was recombinantly produced in E.coli and characterized its structural stability with respect to changes in pH and temperatures. The intrinsic and extrinsic fluorescence measurements revealed that MERS-CoV Mpro tertiary structure was exposed to the polar environment due to the unfolding of the tertiary structure. However, the secondary structure of MERS-CoV Mpro was gained at low pH because of charge-charge repulsion. Furthermore, differential scanning fluorometry studies of Mpro showed a single thermal transition at all pHs except at pH 2.0; no transitions were observed. The data from the spectroscopic studies suggest that the MERS-CoV Mpro forms a molten globule-like state at pH 2.0. Insilico studies showed that the covid-19 Mpro shows 96.08% and 50.65% similarity to that of SARS-CoV Mpro and MERS-CoV Mpro, respectively. This study provides a basic understanding of the thermodynamic and structural properties of MERS-CoV Mpro.


Assuntos
Proteases 3C de Coronavírus , Coronavírus da Síndrome Respiratória do Oriente Médio , Proteases 3C de Coronavírus/genética , Proteases 3C de Coronavírus/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/enzimologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Conformação Proteica , Proteínas Recombinantes
6.
Sensors (Basel) ; 22(5)2022 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35270898

RESUMO

To address the problem of automatically detecting and removing the mask without user interaction, we present a GAN-based automatic approach for face de-occlusion, called Automatic Mask Generation Network for Face De-occlusion Using Stacked Generative Adversarial Networks (AFD-StackGAN). In this approach, we decompose the problem into two primary stages (i.e., Stage-I Network and Stage-II Network) and employ a separate GAN in both stages. Stage-I Network (Binary Mask Generation Network) automatically creates a binary mask for the masked region in the input images (occluded images). Then, Stage-II Network (Face De-occlusion Network) removes the mask object and synthesizes the damaged region with fine details while retaining the restored face's appearance and structural consistency. Furthermore, we create a paired synthetic face-occluded dataset using the publicly available CelebA face images to train the proposed model. AFD-StackGAN is evaluated using real-world test images gathered from the Internet. Our extensive experimental results confirm the robustness and efficiency of the proposed model in removing complex mask objects from facial images compared to the previous image manipulation approaches. Additionally, we provide ablation studies for performance comparison between the user-defined mask and auto-defined mask and demonstrate the benefits of refiner networks in the generation process.


Assuntos
Processamento de Imagem Assistida por Computador , Redes Neurais de Computação , Face/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos
7.
Materials (Basel) ; 15(5)2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35269163

RESUMO

Membrane fouling is a major hindrance to widespread wastewater treatment applications. This study optimizes operating parameters in membrane rotating biological contactors (MRBC) for maximized membrane fouling through Response Surface Methodology (RSM) and an Artificial Neural Network (ANN). MRBC is an integrated system, embracing membrane filtration and conventional rotating biological contactor in one individual bioreactor. The filtration performance was optimized by exploiting the three parameters of disk rotational speed, membrane-to-disk gap, and organic loading rate. The results showed that both the RSM and ANN models were in good agreement with the experimental data and the modelled equation. The overall R2 value was 0.9982 for the proposed network using ANN, higher than the RSM value (0.9762). The RSM model demonstrated the optimum operating parameter values of a 44 rpm disk rotational speed, a 1.07 membrane-to-disk gap, and a 10.2 g COD/m2 d organic loading rate. The optimization of process parameters can eliminate unnecessary steps and automate steps in the process to save time, reduce errors and avoid duplicate work. This work demonstrates the effective use of statistical modeling to enhance MRBC system performance to obtain a sustainable and energy-efficient treatment process to prevent human health and the environment.

8.
J Med Chem ; 65(6): 4949-4971, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35235334

RESUMO

Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of 29.


Assuntos
Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Regulação Alostérica , Animais , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/fisiologia , Ratos
9.
Case Rep Orthop ; 2022: 9365719, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35127191

RESUMO

Intradural mature teratomas are spinal tumors containing all the germinal layers and rarely present in adulthood. This study describes an unusual case of intradural mature teratoma in a 19-year-old male who presented with persistent lower limb pain and difficulty in micturition. The magnetic resonance imaging (MRI) scan showed heterogeneously enhancing intramedullary mass in the L3-L4 vertebral region and was associated with tethering of the spinal cord. Scalloping of the posterior aspect of vertebral body and narrowing of the pedicles were present. Subtotal excision of the tumor was done because of its adherence to the conus. Attempt to completely excise such adherent intramedullary tumors can lead to permanent neurological deficits. The tissue was sent for histopathological examination which showed tissue from all the three germinal layers confirming the diagnosis. The patient showed improvement of symptoms following the surgery. This study also compared the literature of similar cases and the treatments available for this disease.

10.
Polymers (Basel) ; 14(3)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35160385

RESUMO

Protein aggregation is of two types: (i) amorphous and (ii) amyloid fibril. Several extrinsic factors (temperature, pH, and small ligands) stimulate protein aggregation in vitro. In this study, we have examined the role of sunset yellow (SY) on the ß-lactoglobulin (BLG) aggregation at pH 2.0. We have used spectroscopic (turbidity, Rayleigh light scattering (RLS), far-UV CD) and microscopic (transmission electron microscopy [TEM]) techniques to describe the effects of SY on BLG aggregation. Our results showed that BLG aggregation is dependent on SY concentrations. Very low concentrations (0.0-0.07 mM) of SY were unable to induce aggregation, while SY in the concentrations range of 0.1-5.0 mM induces aggregation in BLG. The kinetics of SY-stimulated aggregation is very fast and monomeric form of BLG directly converted into polymeric aggregates. The kinetics results also showed SY-induced BLG aggregation disappeared in the presence of NaCl. The far-UV CD and TEM results indicated the amorphous nature of SY-induced BLG aggregates. We believe that our results clearly suggest that SY dye effectively stimulates BLG aggregation.

11.
Sensors (Basel) ; 22(4)2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35214282

RESUMO

Recent technological developments, such as the Internet of Things (IoT), artificial intelligence, edge, and cloud computing, have paved the way in transforming traditional healthcare systems into smart healthcare (SHC) systems. SHC escalates healthcare management with increased efficiency, convenience, and personalization, via use of wearable devices and connectivity, to access information with rapid responses. Wearable devices are equipped with multiple sensors to identify a person's movements. The unlabeled data acquired from these sensors are directly trained in the cloud servers, which require vast memory and high computational costs. To overcome this limitation in SHC, we propose a federated learning-based person movement identification (FL-PMI). The deep reinforcement learning (DRL) framework is leveraged in FL-PMI for auto-labeling the unlabeled data. The data are then trained using federated learning (FL), in which the edge servers allow the parameters alone to pass on the cloud, rather than passing vast amounts of sensor data. Finally, the bidirectional long short-term memory (BiLSTM) in FL-PMI classifies the data for various processes associated with the SHC. The simulation results proved the efficiency of FL-PMI, with 99.67% accuracy scores, minimized memory usage and computational costs, and reduced transmission data by 36.73%.


Assuntos
Internet das Coisas , Dispositivos Eletrônicos Vestíveis , Inteligência Artificial , Computação em Nuvem , Atenção à Saúde , Humanos
12.
Artigo em Inglês | MEDLINE | ID: mdl-34187809

RESUMO

The change in cell state from normal to malignant is driven fundamentally by oncogenic mutations in cooperation with epigenetic alterations of chromatin. These alterations in chromatin can be a consequence of environmental stressors or germline and/or somatic mutations that directly alter the structure of chromatin machinery proteins, their levels, or their regulatory function. These changes can result in an inability of the cell to differentiate along a predefined lineage path, or drive a hyperactive, highly proliferative state with addiction to high levels of transcriptional output. We discuss how these genetic alterations hijack the chromatin machinery for the oncogenic process to reveal unique vulnerabilities and novel targets for cancer therapy.


Assuntos
Cromatina , Neoplasias , Epigênese Genética , Humanos , Mutação , Neoplasias/genética , Neoplasias/patologia
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 267(Pt 1): 120494, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34689006

RESUMO

The anionic surfactant sodium dodecyl sulfate (SDS) is homologous to the cellular membrane lipids, and is known to stimulate amyloid fibrillation in several proteins. However, the mechanism by which SDS influences aggregation and structural changes in succinylated protein has not been determined. In this study, we observed the effects of variable SDS concentrations on succinyl-ConA aggregation at pH 3.5 and proposed a possible mechanism of SDS-induced succinyl-ConA aggregation. We used several biophysical techniques to identify the changes caused by SDS. Our results suggest that SDS stimulates succinyl-ConA aggregation in a concentration-dependent manner. From turbidity measurements, it was evident that a very low concentration (<0.1 mM) of SDS did not induce succinyl-ConA aggregation and proteins remained soluble. However, aggregations were observed at 0.1-2.5 mM SDS, which then dissipated at SDS concentrations above 2.5 mM. Far-UV CD results suggest that the ß-sheet secondary structure of succinyl-ConA transformed into the cross-ß-sheet structure in the presence of aggregating SDS concentrations. Notably, at SDS concentrations above 2.5 mM, the succinyl-ConA ß-sheet transformed into an α-helical structure. The SDS-induced succinyl-ConA amyloid-like aggregates were confirmed by transmission electron microscopy (TEM). We propose that SDS modulates amyloid fibrillation in succinyl-ConA due to electrostatic and hydrophobic interactions and succinylation affects SDS-induced succinyl-ConA aggregation.


Assuntos
Amiloide , Agregados Proteicos , Concanavalina A , Concentração de Íons de Hidrogênio , Dodecilsulfato de Sódio
14.
Chemosphere ; 287(Pt 4): 132331, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34607113

RESUMO

This study reported Fe doped zinc oxide (Fe-ZnO) synthesis to degrade chlorpyrifos (CPY), a highly toxic organophosphate pesticide and important sources of agricultural wastes. Fourier transform infrared, X-ray diffraction, scanning electron microscope, and energy-dispersive X-ray spectroscopic analyses showed successful formation of the Fe-ZnO with highly crystalline and amorphous nature. Water collected from agricultural wastes were treated with Fe-ZnO and the results showed 67% degradation of CPY by Fe-ZnO versus 39% by ZnO at 140 min treatment time. Detail mechanism involving reactive oxygen species production from solar light activated Fe-ZnO and their role in degradation of CPY was assessed. Use of H2O2, peroxydisulfate (S2O82-) and peroxymonosulfate (HSO5-) with Fe-ZnO under solar irradiation promoted removal of CPY. The peroxides yielded hydroxyl (OH) and sulfate radical () under solar irradiation mediated by Fe-ZnO. Effects of several parameters including concentration of pollutant and oxidants, pH, co-existing ions, and presence of natural organic matter on CPY degradation were studied. Among peroxides, HSO5- revealed to provide better performance. The prepared Fe-ZnO showed high reusability and greater mineralization of CPY. The GC-MS analysis showed degradation of CPY resulted into several transformation products (TPs). Toxicity analysis of CPY as well as its TPs was performed and the formation of non-toxic acetate imply greater capability of the treatment technology.


Assuntos
Clorpirifos , Óxido de Zinco , Catálise , Clorpirifos/toxicidade , Peróxido de Hidrogênio , Difração de Raios X
15.
Cancers (Basel) ; 13(23)2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34885201

RESUMO

BACKGROUND: A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. METHODS: Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype). RESULTS: Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5% of IDH-wildtype gliomas (p = 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R = -0.46, p = 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. The Antigen Processing and Presentation (APP) score correlated with immune score and was surprisingly higher in NHMP versus HMP samples in IDH-wildtype gliomas, but higher in HMP versus NHMP in IDH-mutant gliomas. CONCLUSION: TMB was inversely correlated with immune score in IDH-wildtype gliomas and showed no correlation in IDH-mutant tumors. APP was correlated with immune score and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a larger glioma cohort are warranted.

16.
Materials (Basel) ; 14(23)2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34885576

RESUMO

The release of phenolic-contaminated treated palm oil mill effluent (TPOME) poses a severe threat to human and environmental health. In this work, manganese-modified black TiO2 (Mn-B-TiO2) was produced for the photodegradation of high concentrations of total phenolic compounds from TPOME. A modified glycerol-assisted technique was used to synthesize visible-light-sensitive black TiO2 nanoparticles (NPs), which were then calcined at 300 °C for 60 min for conversion to anatase crystalline phase. The black TiO2 was further modified with manganese by utilizing a wet impregnation technique. Visible light absorption, charge carrier separation, and electron-hole pair recombination suppression were all improved when the band structure of TiO2 was tuned by producing Ti3+ defect states. As a result of the enhanced optical and electrical characteristics of black TiO2 NPs, phenolic compounds were removed from TPOME at a rate of 48.17%, which is 2.6 times higher than P25 (18%). When Mn was added to black TiO2 NPs, the Ti ion in the TiO2 lattice was replaced by Mn, causing a large redshift of the optical absorption edges and enhanced photodegradation of phenolic compounds from TPOME. The photodegradation efficiency of phenolic compounds by Mn-B-TiO2 improved to 60.12% from 48.17% at 0.3 wt% Mn doping concentration. The removal efficiency of phenolic compounds from TPOME diminished when Mn doping exceeded the optimum threshold (0.3 wt%). According to the findings, Mn-modified black TiO2 NPs are the most effective, as they combine the advantages of both black TiO2 and Mn doping.

17.
Molecules ; 26(24)2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34946628

RESUMO

Janerin is a cytotoxic sesquiterpene lactone that has been isolated and characterized from different species of the Centaurea genus. In this study, janerin was isolated form Centaurothamnus maximus, and its cytotoxic molecular mechanism was studied in THP-1 human leukemic cells. Janerin inhibited the proliferation of THP-1 cells in a dose-dependent manner. Janerin caused the cell cycle arrest at the G2/M phase by decreasing the CDK1/Cyclin-B complex. Subsequently, we found that janerin promoted THP-1 cell death through apoptosis as indicated by flow cytometry. Moreover, apoptosis induction was confirmed by the upregulation of Bax, cleaved PARP-1, and cleaved caspase 3 and the downregulation of an anti-apoptotic Bcl-2 biomarker. In addition, immunoblotting indicated a dose dependent upregulation of P38-MAPK and ERK1/2 phosphorylation during janerin treatment. In conclusion, we have demonstrated for the first time that janerin may be capable of inducing cell cycle arrest and apoptosis through the MAPK pathway, which would be one of the mechanisms underlying its anticancer activity. As a result, janerin has the potential to be used as a therapeutic agent for leukemia.


Assuntos
Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Leucemia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sesquiterpenos , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Células THP-1
18.
BMC Bioinformatics ; 22(1): 588, 2021 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-34895138

RESUMO

BACKGROUND: Copy number variants (CNVs) are the gain or loss of DNA segments in the genome. Studies have shown that CNVs are linked to various disorders, including autism, intellectual disability, and schizophrenia. Consequently, the interest in studying a possible association of CNVs to specific disease traits is growing. However, due to the specific multi-dimensional characteristics of the CNVs, methods for testing the association between CNVs and the disease-related traits are still underdeveloped. We propose a novel multi-dimensional CNV kernel association test (MCKAT) in this paper. We aim to find significant associations between CNVs and disease-related traits using kernel-based methods. RESULTS: We address the multi-dimensionality in CNV characteristics. We first design a single pair CNV kernel, which contains three sub-kernels to summarize the similarity between two CNVs considering all CNV characteristics. Then, aggregate single pair CNV kernel to the whole chromosome CNV kernel, which summarizes the similarity between CNVs in two or more chromosomes. Finally, the association between the CNVs and disease-related traits is evaluated by comparing the similarity in the trait with kernel-based similarity using a score test in a random effect model. We apply MCKAT on genome-wide CNV datasets to examine the association between CNVs and disease-related traits, which demonstrates the potential usefulness the proposed method has for the CNV association tests. We compare the performance of MCKAT with CKAT, a uni-dimensional kernel method. Based on the results, MCKAT indicates stronger evidence, smaller p-value, in detecting significant associations between CNVs and disease-related traits in both rare and common CNV datasets. CONCLUSION: A multi-dimensional copy number variant kernel association test can detect statistically significant associated CNV regions with any disease-related trait. MCKAT can provide biologists with CNV hot spots at the cytogenetic band level that CNVs on them may have a significant association with disease-related traits. Using MCKAT, biologists can narrow their investigation from the whole genome, including many genes and CNVs, to more specific cytogenetic bands that MCKAT identifies. Furthermore, MCKAT can help biologists detect significantly associated CNVs with disease-related traits across a patient group instead of examining each subject's CNVs case by case.


Assuntos
Variações do Número de Cópias de DNA , Genoma , Estudo de Associação Genômica Ampla , Humanos , Fenótipo
19.
Sci Rep ; 11(1): 22132, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34764312

RESUMO

Nanotechnology is a vast field of science with the most vibrant and conspicuous applications. The green synthesis approach is cost-effective, eco-friendly, and produces the most stable metal-based nanoparticles without the use of toxic chemicals. This study presents the green synthesis of iron nanoparticles (FeNPs). For biosynthesis of FeNPs, Phoenix dactylifera extract was used as a reducing agent and iron sulfate heptahydrate (FeSO4·7H2O) was used as a substrate. FeNPs were characterized by different techniques including UV-Visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), and nano zeta-sizer analysis. The antimicrobial activity of FeNPs synthesized by using an aqueous extract of Phoenix dactylifera was evaluated against Escherichia coli, Bacillus subtilis, Micrococcus leutus, and Klebsiella pneumoniae. A notable color change from yellow to black confirmed the synthesis of FeNPs. The sharp peak at 450 nm UV-Visible spectroscopy confirmed the synthesis of FeNPs. FTIR showed the presence of O-H and C=C stretching due to the presence of phenol and alkene functional groups. The average size of FeNPs was 6092 d.nm. The results of antimicrobial activity showed that FeNPs exhibit different potential against different bacterial strains with a maximum 25 ± 0.360 zone of inhibition against Escherichia coli. Thus, green synthesized FeNPs could be used as potential antimicrobial agents.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Ferro/química , Nanopartículas Metálicas/química , Phoeniceae/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Bactérias/efeitos dos fármacos , Química Verde/métodos , Testes de Sensibilidade Microbiana/métodos , Tamanho da Partícula
20.
Nat Commun ; 12(1): 6924, 2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34836971

RESUMO

Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define the mSWI/SNF functional repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes localize to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes, which is recapitulated by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.


Assuntos
Diferenciação Celular , Proliferação de Células , Desenvolvimento Muscular/fisiologia , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo , Linhagem Celular Tumoral , Criança , Cromatina , DNA Helicases/metabolismo , Epigenômica , Regulação Neoplásica da Expressão Gênica , Humanos , Músculo Esquelético , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fator de Transcrição PAX7 , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Proteômica , Fatores de Transcrição/metabolismo , Ativação Transcricional
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