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Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.
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Insuficiência Cardíaca , Animais , Camundongos , Ratos , Cardiomegalia , Proteínas de Ligação a DNA/metabolismo , Insuficiência Cardíaca/metabolismo , Mitocôndrias/metabolismo , Proteínas Musculares/genética , Miócitos Cardíacos/metabolismo , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/farmacologia , RNA Mensageiro/metabolismo , RNA Mensageiro/farmacologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/farmacologiaRESUMO
The aim of this study is to explore the possible pharmacological effects of fruit waste that may have a key role in converting the fruit waste into pharmaceutical agents. Citrus limetta (Rutaceae) is an important commercial citrus fruit crops used by juice processing industries. C. limetta peels are perishable waste material, which creates a big challenge in juice processing industries. Initial pharmaco-chemical profile of peels' extracts revealed that the ethanol extract (ClPs) has promising anti-inflammatory activity and rich in hesperidin content. In vivo experimental pharmacology profile of ClPs against arthritis and related complications revealed that oral administration of ClPs significantly reduced the arthritis score and arthritis index in elbow and knee joints against collagen-induced arthritis (CIA) in rats. Biochemical parameters include pro-inflammatory cytokines (TNF-α, IL-6, and IL-17A), and C-RP level in blood serum of CIA rats further confirmed the anti-arthritic profile of ClPs. Further individual experiments related to arthritis-related complications in experimental animals demonstrated the analgesic, anti-inflammatory, and antipyretic potential of ClPs in dose-dependent manner. The result of this study suggests the suitability of ClPs as a drug-like candidate for further investigation toward the management of arthritis and related complications.
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Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Citrus/química , Hesperidina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Citocinas/sangue , Etanol/química , Feminino , Frutas , Masculino , Camundongos , Extratos Vegetais/farmacologia , RatosRESUMO
Over 100 genetically distinct causal known loci for hereditary ataxia phenotype poses a challenge for diagnostic work-up for ataxia patients in a clinically relevant time and precision. In the present study using next-generation sequencing, we have investigated pathogenic variants in early-onset cerebellar ataxia cases using whole exome sequencing in singleton/family-designed and targeted gene-panel sequencing. A total of 98 index patients were clinically and genetically (whole exome sequencing (WES) in 16 patients and targeted gene panel of 41 ataxia causing genes in 82 patients) evaluated. Four families underwent WES in family based design. Overall, we have identified 24 variants comprising 20 pathogenic and four likely-pathogenic both rare/novel, variations in 21 early onset cerebellar ataxia patients. Among the identified variations, SACS (n = 7) and SETX (n = 6) were frequent, while ATM (n = 2), TTPA (n = 2) and other rare loci were observed. We have prioritized novel pathogenic variants in RARS2 and FA2H loci through family based design in two out of four families.
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Sequenciamento do Exoma , Genes Recessivos , Variação Genética , Degenerações Espinocerebelares/genética , Adulto , Sequência de Bases , Família , Loci Gênicos , Predisposição Genética para Doença , Humanos , Mutação/genéticaRESUMO
Transforming growth factor-ß1 (TGF-ß1) is a multifunctional pro-inflammatory cytokine involved in inflammation and pathogenesis of cerebrovascular disease. As per our knowledge, there is no published study investigating the association between variations within the TGF-ß1 gene polymorphisms and risk of intracerebral hemorrhage (ICH). The aim of this study was to investigate the association of the TGF-ß1 gene (C509T, G800A and T869C) polymorphisms, and their haplotypes with the risk of ICH in North Indian population. 100 ICH patients and 100 age- and sex-matched controls were studied. Genotyping was performed using SNaPshot method. Conditional logistic regression analysis was used to calculate the strength of association between TGF-ß1 gene polymorphisms and risk of ICH. Hypertension, diabetes, dyslipidemia, low socioeconomic status, smoking, physical activity were found to be associated with the risk of ICH. The distribution of C509T, G800A and T869C genotypes was consistent with Hardy-Weinberg Equilibrium (HWE) in the ICH and control group. Adjusted conditional logistic regression analysis showed an independent association of TGF-ß1 G800A (OR 9.07; 95% CI 2.3-35.6; P = 0.002) and T869C (OR 5.1; 95 % CI 1.9-13.2; P = 0.001) with the risk of ICH under dominant model. Haplotype analysis showed that C509-G800-C869 and C509-A800-C869 haplotypes were significantly associated with the increased risk of ICH. C509T and T869C were in strong linkage disequilibrium (D' = 0.53, r(2) = 0.23). Our results suggest that TGF-ß1 (G800A, T869C) gene polymorphisms and their haplotypes are significantly associated with the risk of ICH in North Indian population. Further prospective studies with large sample size are required for independent validation. Our findings could be helpful in identifying individuals at increased risk for developing ICH.
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Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fator de Crescimento Transformador beta1/genética , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Técnicas de Genotipagem , Haplótipos , Humanos , Índia/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genéticaRESUMO
BACKGROUND: Coats plus syndrome is an autosomal recessive, pleiotropic, multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is caused by compound heterozygous mutations in the CTC1 gene. CASE PRESENTATION: We encountered a case of an eight-year old boy from an Indian family with manifestations of Coats plus syndrome along with an unusual occurrence of dextrocardia and situs inversus. Targeted resequencing of the CTC1 gene as well as whole exome sequencing (WES) were conducted in this family to identify the causal variations. The identified candidate variations were screened in ethnicity matched healthy controls. The effect of CTC1 variation on telomere length was assessed using Southern blot. A novel homozygous missense mutation c.1451A > C (p.H484P) in exon 9 of the CTC1 gene and a rare 3'UTR known dbSNP variation (c.*556 T > C) in HES7 were identified as the plausible candidates associated with this complex phenotype of Coats plus and dextrocardia. This CTC1 variation was absent in the controls and we also observed a reduced telomere length in the affected individual's DNA, suggesting its likely pathogenic nature. The reported p.H484P mutation is located in the N-terminal 700 amino acid regionthat is important for the binding of CTC1 to ssDNA through its two OB domains. WES data also showed a rare homozygous missense variation in the TEK gene in the affected individual. Both HES7 and TEK are targets of the Notch signaling pathway. CONCLUSIONS: This is the first report of a genetically confirmed case of Coats plus syndrome from India. By means of WES, the genetic variations in this family with unique and rare complex phenotype could be traced effectively. We speculate the important role of Notch signaling in this complex phenotypic presentation of Coats plus syndrome and dextrocardia. The present finding will be useful for genetic diagnosis and carrier detection in the family and for other patients with similar disease manifestations.
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Ataxia/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias Encefálicas/genética , Calcinose/genética , Cistos do Sistema Nervoso Central/genética , Dextrocardia/complicações , Exoma/genética , Leucoencefalopatias/genética , Espasticidade Muscular/genética , Mutação de Sentido Incorreto , Doenças Retinianas/genética , Convulsões/genética , Análise de Sequência de DNA , Proteínas de Ligação a Telômeros/genética , Animais , Ataxia/complicações , Ataxia/patologia , Sequência de Bases , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Calcinose/complicações , Calcinose/patologia , Cistos do Sistema Nervoso Central/complicações , Cistos do Sistema Nervoso Central/patologia , Criança , Genômica , Homozigoto , Humanos , Índia , Leucoencefalopatias/complicações , Leucoencefalopatias/patologia , Masculino , Espasticidade Muscular/complicações , Espasticidade Muscular/patologia , Linhagem , Fenótipo , Receptores Notch/metabolismo , Doenças Retinianas/complicações , Doenças Retinianas/patologia , Convulsões/complicações , Convulsões/patologia , Transdução de Sinais , Telômero/genéticaRESUMO
To investigate the variation in the radiation stability of ceria with microstructure under the electronic excitation regime, ceria samples sintered under different conditions were irradiated with high energy 100 MeV Ag ions. The ceria nanopowders were synthesized and sintered at 800 °C (S800), 1000 °C (S1000) and 1300 °C (S1300), respectively. The samples with widely varying grain size, densities and microstructure were obtained. The pristine and irradiated samples were studied by X-ray diffraction (XRD), Scanning electron microscopy (SEM), Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). None of the samples amorphized up to the highest fluence of 1 × 10(14) ions per cm(2) employed in this study. XRD and Raman studies showed that the sample with lowest grain size suffered maximum damage while the sample with largest grain size was most stable and showed little change in crystallinity. Raman spectroscopy indicated the enhanced formation of Ce(3+) and related defects in the sample with larger grain size after irradiation. The most intriguing result was the absence of Ce(3+)-related defects in the sample with lowest grain size which actually showed maximum damage upon irradiation. The XPS studies on S800 and S1300 provided concrete evidence for the presence of Ce(3+) and oxygen ion vacancies in S1300. The grain boundaries and grain size dependent stability have been discussed.
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Aurora kinase B (AURK-B) is a serine/threonine kinase protein that plays an essential role in chromosomal separation during the cell cycle event. AURK-B is highly expressed in various types of cancer such as human seminoma, thyroid carcinoma, non-small cell lung carcinoma (NSCLC), oral carcinoma, and gastric cancer. Hence, it is a potential therapeutic target in the treatment of various cancers. The structure of AURK-B in complex with one of its substrate inner centromeric protein (INCENP) is present, but the structural and functional characterization of native AURK-B at different pH environment is still unexplored.This study determines the effect of different pH milieu on the structure and function of AURK-B protein wherein the influence of pH on the protein conformation was probed using Circular dichroism (CD) and fluorescence spectroscopy. The structural studies were further combined with functional activity assay to observe the change in kinase activity at various pH milieu (2.0-11.0). CD and fluorescence spectroscopy experiments dictate that at high acidic conditions (pH 2.0 - 5.0), the secondary and tertiary structures of AURK-B become distorted, leading to diminished activity. The protein, however, was observed to stabilize towards pH 7.0 - 8.0 with minimal structure alteration over the basic pH range (pH 9.0 -11.0). The measured spectroscopic structural features were found to be in-line with obtained experimental kinase activity assays. Further, in-vitro experiments indicate that the enzyme is maximally active at pH 8.0. More ordered conformation and compact structure was observed at this pH (pH 8.0) as compared to other pH values through molecular dynamics simulation studies (MDS). As AURK-B localizes itself in the intracellular compartment, this study may provide a clue about the role of different pH environments in enhancing cancer growth, proliferation, and invasion.
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Carcinoma , Proteínas Serina-Treonina Quinases , Humanos , Aurora Quinase B/metabolismo , Concentração de Íons de Hidrogênio , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
AIM: The main aim/objective of this study was to detect and characterize the Brucella species from patients having complaints of joint pain and also to know the potential causes of human brucellosis. In our study, we focused on joint pain symptoms that may be due to arthralgia or arthritis. Introduction: Brucellosis is a neglected zoonotic disease that affects both humans and animals. In humans, brucellosis begins with chronic illness leading to great financial losses from not being able to work well and continued treatment costs, but few such studies have come from northern India. Joint pain is the common presentation of brucellosis and there are several risk factors associated with brucellosis. METHODS: A total of 200 blood samples were collected from the participants having joints pain from September 2019 to September 2021 at Gandhi Memorial & Associated Hospitals of King George's Medical University, Lucknow, India, and tested by serology for anti-Brucella IgM and IgG enzyme-linked immunosorbent assay (ELISA), molecular tests byreverse transcriptase-polymerase chain reaction (RT-PCR), conventional polymerase chain reaction (PCR), and automated blood culture system. The anti-Brucella IgM and IgG ELISA were performed using the kit from NovaTec Immundiagnostica GmbH (Dietzenbach, Germany). Isolation of DNA was carried out using the QIAamp DNA Mini kit (QIAGEN, Hilden, Germany), and the primers and probes specific for targeted regions (BCSP31 and IS711 gene) in the Brucella genome were procured from Eurofins Scientific SE (Luxembourg, France), and for internal control from CDC. RESULT: The study showed 19 (9.5%) and 23 (11.5%) positive results by anti-Brucella IgM ELISA and anti-Brucella IgG, respectively, and of these, one (0.5%) was positive for both anti-Brucella IgM and anti-Brucella IgG ELISA. Out of 19 anti-Brucella IgM ELISA positive, eight (4%) samples were positive for PCR/RT-PCR and that was negative for anti-Brucella IgG ELISA. All blood culture reports of all patients were negative. Conclusion: Anti-Brucella IgM ELISA was more accurate than anti-Brucella IgG ELISA in detecting human brucellosis. Consumption of animal products (i.e. milk, a dairy product of cow, buffalo, goat, and meat of goat) and contact with animals were the main risk factors that were identified for Brucella disease.
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BACKGROUND: Brucellosis is a neglected zoonotic disease affecting humans and animals. OBJECTIVES: This study aimed to estimate the seroprevalence of brucellosis in patients with joint pain. METHODS: A total of 200 participants aged from 7 to 86 years were involved in this study. Blood samples were collected from all the participants for two years, from September 2019 to September 2021, and screened for Brucella using anti-brucella IgM ELISA and anti-brucella IgG ELISA antibodies. A questionnaire was used to collect data on socio-demographic characteristics and human brucellosis-related risk factors. RESULTS: Human Brucella seroprevalence was 19 (9.5%) for Brucella IgM ELISA and 23 (11.5%) for Brucella IgG ELISA. The sensitivity for Brucella IgM ELISA and Brucella IgG ELISA was 65.2% and 31.6%, respectively, while the specificity was 44.1% for Brucella IgM ELISA and 77.9% for Brucella IgG ELISA. All blood culture reports of all patients were negative. The principal presentation was the observable symptoms of human brucellosis: fever, headache, chills, myalgia, and Joint pain. CONCLUSION: Risk factors like consumption of raw milk or their products were found to be the most important for Brucella infection, so the awareness or information of risk factors and the modes of transmission is much more important in control and prevention programs. General awareness about clinical symptoms should be increased, which will improve proper diagnosis and will be helpful in early treatment. An ELISA test should be considered for diagnosing brucellosis in both acute and chronic phases.
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The 7-nitro-2'-phenyl-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H)-dicarbonitrile (SIQPI), 2'-(4-cyanophenyl)-7-nitro-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H) dicarbonitrile (SIQPII), and 2'-(4-methoxyphenyl)-7-nitro-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H)-dicarbonitrile (SIQPIII) were used to photocatalyze quinonoid phenolphthalein (QHIn) in aq-ACN-EtOH (mixed solvent) with NaCl and KCl electrolytes. SIQPI, II, and III spiroindenoquinoxaline pyrrolidines (SIQPs) as spiroheterocyclic photocatalysts alone could not reduce QHIn, but with the addition of electrolytes they are reduced via π cationic interactions (PCI). SIQPI, II, and III with NaCl reduced QHIn in 120, 28, and 50 min, unlike in 138, 58, and 63 min with KCl in mixed solvent. SIQPI, II, and III alone have reduced methylene blue (MB) in 120, 45, and 70 min, unlike in 110, 27, and 55 min with graphene oxide (GO), whereas with NaCl and KCl hey are reduced in 82, 36, and 44 min and 89, 43, and 50 min, respectively. SIQPs with GO had reduced MB in less time than the SIQPs alone, and SIQPs with NaCl had reduced QHIn in a shorter time than KCl. The electrolytes have cocatalyzed a reduction of dyes under sunlight (SL). The electrolytes have reduced a quinonoid structure (QS) and dyes by generating negative and positive (e - and h +) holes in a shorter time. SIQPII and magnetic nanoparticles (MNPs) of 58 nm with NaCl photocatalyzed the QHIn in 2880 min. The SIQPs also reduced methyl orange (MO) and brilliant blue R (BBR) at variable temperature (T) and pH range, whereas SIQPs have developed a molecular organic framework (MOF) with transition-metal salts (NiCl2, CrO3, KMnO4, CuSO4, and MnCl2) on photocatalysis.
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The COVID-19 pandemic, caused by SARS-CoV-2, emerges as a global health problem, as the viral genome is evolving rapidly to form several variants. Advancement and progress in the development of effective vaccines and neutralizing monoclonal antibodies are promising to combat viral infections. In the current scenario, several lineages containing "co-mutations" in the receptor-binding domain (RBD) region of the spike (S) protein are imposing new challenges. Co-occurrence of some co-mutations includes delta (L452R/T478K), kappa (L452R/E484Q), and a common mutation in both beta and gamma variants (E484K/N501Y). The effect of co-mutants (L452R/E484Q) on human angiotensin-converting enzyme 2 (hACE2) binding has already been elucidated. Here, for the first time, we investigated the role of these RBD co-mutations (L452R/E484Q) on the binding affinity of mAbs by adopting molecular dynamics (MD) simulation and free-energy binding estimation. The results obtained from our study suggest that the structural and dynamic changes introduced by these co-mutations reduce the binding affinity of the viral S protein to monoclonal antibodies (mAbs). The structural changes imposed by L452R create a charged patch near the interfacial surface that alters the affinity towards mAbs. In E484Q mutation, polar negatively charged E484 helps in the formation of electrostatic interaction, while the neutrally charged Q residue affects the interaction by forming repulsive forces. MD simulations along with molecular mechanics-generalized Born surface area (MMGBSA) studies revealed that the REGN 10933, BD-368-2, and S2M11 complexes have reduced binding affinity towards the double-mutant RBD. This indicates that their mutant (MT) structures have a stronger ability to escape from most antibodies than the wild type (WT). However, EY6A Ab showed higher affinity towards the double MT-RBD complex as compared to the WT. However, no significant effect of the per-residue contribution of double-mutated residues was observed, as this mAb does not interact with the region harboring L452 and E484 residues.
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A new class of 2-anilino-3-cyanobenzo[b]thiophenes (2,3-ACBTs) was studied for its antiangiogenic activity for the first time. One of the 2,3-ACBTs inhibited tubulogenesis in a dose-dependent manner without any toxicity. The 2,3-ACBTs significantly reduced neovascularization in both ex vivo and in vivo angiogenic assays without affecting the proliferation of endothelial cells. Neovascularization was limited through reduced phosphorylation of Akt/Src and depolymerization of f-actin and ß-tubulin filaments, resulting in reduced migration of cells. In addition, the 2,3-ACBT compound disrupted the preformed angiogenic tubules, and docking/competitive binding studies showed that it binds to VEGFR2. Compound 2,3-ACBT had good stability and intramuscular profile, translating in suppressing the tumor angiogenesis induced in a xenograft model. Overall, the present study suggests that 2,3-ACBT arrests angiogenesis by regulating the Akt/Src signaling pathway and deranging cytoskeletal filaments of endothelial cells.
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Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Tiofenos/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Apoptose , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Movimento Celular , Proliferação de Células , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/patologia , Fosforilação , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cribriform appearance of the brain in Canavan disease is a rare finding. The two presented cases broaden the magnetic resonance imaging (MRI) phenotype wherein numerous oval, cystic structures, a few resembling dilated Virchow-Robin (VR) spaces, were noted in the centrum semiovale, periventricular, and lobar white matter producing a cribriform pattern. Besides, discrete round to oval cysts were present at the gray-white matter junctions in the second case, which were larger and appeared morphologically distinct from the VR spaces. These cysts did not elongate in any plane on imaging and were more representative of giant intramyelinic vacuoles. Genetic analysis revealed novel mutations in the aspartoacylase or ASPA gene that possibly accounts for the severe form of Canavan disease, which probably explains the imaging findings. The multicystic appearance of the white matter in Canavan disease is unusual and possibly represents two different histopathological substrates.
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[This corrects the article DOI: 10.1021/acsomega.0c02976.].
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Plant genomes can withstand small- and large-scale duplications, at a far greater success than any other kingdom in the tree of life, resulting in the existence and evolution of gene families, often with over a hundred members! The gene families, in turn, go through subfunctionalization or neofunctionalization, to form protein domains performing unique or grouped functions in context of the original activity. Due to the large number of such cases in the plant kingdom, it has become a routine task for plant biologists to investigate their specific gene family of interest. In this chapter, we provide a simple and standard pipeline for this effort, taking the example of steroidogenic acute regulatory protein (StAR) related lipid transfer (START) domains in rice, as reference. We describe the extraction, processing, and downstream analysis of Oryza sativa var. japonica proteome towards identification and comparative exploration of START domains. This was done by training profile Hidden Markov Models (HMM) of 35 reported START domains in Arabidopsis, which were then used to search potential homologs in rice. Downstream investigations included domain structure analysis, visualization of exon-intron patterns, chromosomal localization of START genes, and phylogenetic studies, followed by identification of cis-regulatory elements and gene regulatory network construction. Additionally, we have also highlighted various alternative tools and techniques that can be used to perform similar analyses, along with salient features.
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Cromossomos de Plantas/genética , Genoma de Planta , Oryza/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Plantas/metabolismo , Proteoma/análise , Sequências Reguladoras de Ácido Nucleico , Amplificação de Genes , Regulação da Expressão Gênica de Plantas , Oryza/genética , Oryza/crescimento & desenvolvimento , Fosfoproteínas/genética , Filogenia , Proteínas de Plantas/genética , Domínios ProteicosRESUMO
Objective: The utility and safety of fixed dexmedetomidine infusion was compared to fixed-dose midazolam bolus among patients undergoing EBUS-TBNA.Methods: In this randomized double-blind study, 197 patients were assigned to receive dexmedetomidine (Group D, 1 µg/kg before, and 0.6 µg/kg/hour during, procedure) or midazolam (Group M, 2 mg before procedure) sedation. The primary outcome was number of rescue midazolam boluses administered to achieve Ramsay Sedation Scale (RSS) score of two or more. We also studied sedation depth during procedure, adverse hemodynamic and hypoxemic events, bronchoscopist and patient satisfaction, and time-to-discharge from recovery room.Results: Rescue midazolam requirement was significantly lesser in 99 Group D (0.9 ± 1.2 boluses) than in 98 Group M (2.0 ± 2.4 boluses), subjects. Mean RSS score was significantly higher in Group D subjects (2.5 ± 0.7 vs. 2.3 ± 0.7). Significantly more subjects in Group D developed hypotension (46 vs. 27) or bradycardia (37 vs. 5), but none required specific intervention. Bronchoscopists reported significantly greater overall procedure satisfaction in Group D subjects.Conclusion: Fixed dexmedetomidine infusion reduced need for rescue sedation during EBUS-TBNA, and allowed slightly faster post-procedure recovery, as compared to fixed-dose midazolam bolus. However, it caused hypotension and bradycardia more frequently.Clinical trial registration: www.clinicaltrials.gov identifier is NCT02713191.
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Dexmedetomidina , Midazolam , Sedação Consciente , Dexmedetomidina/efeitos adversos , Método Duplo-Cego , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Humanos , Hipnóticos e Sedativos/efeitos adversos , Midazolam/efeitos adversosRESUMO
Invasive pulmonary aspergillosis (IPA) is mainly caused by Aspergillus fumigatus and other Aspergillus species. Galactomannan (GM) is a polysaccharide antigen that exists primarily in the cell walls of Aspergillus species. GM may be released into the blood and other body fluids even in the early stages of Aspergillus invasion; therefore, detection of the GM antigen level can be useful in making an early diagnosis of IPA.
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Antígenos de Fungos/sangue , Líquido da Lavagem Broncoalveolar/microbiologia , Diagnóstico Precoce , Galactose/sangue , Aspergilose Pulmonar Invasiva/sangue , Aspergilose Pulmonar Invasiva/diagnóstico , Mananas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Galactose/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Testes Sorológicos/métodosRESUMO
Spiroindenoquinoxaline pyrrolizidines (SIQPs)-7-nitro-2'-phenyl-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H)-dicarbonitrile (SIQP I), 2'-(4-cyanophenyl)-7-nitro-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H)-dicarbonitrile (SIQP II), and 2'-(4-methoxyphenyl)-7-nitro-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H)-dicarbonitrile (SIQP III)-have been synthesized through a one-pot cascade Knoevenagel condensation reaction in acetonitrile (ACN) with 91, 98, and 87% yields, respectively. Structures are characterized by 1H NMR and 13C NMR spectroscopy, nuclear Overhauser enhancement spectroscopy (NOESY), Fourier transform infrared (FT-IR) and UV-vis spectroscopy, thermogravimetric analysis (TGA), high-resolution mass spectroscopy (HRTEM), fluorescence and Raman spectroscopy, and energy-dispersive analysis by X-ray (EDX) spectroscopy. SIQPs in ACN photocatalyzed methylene blue (MB) but not phenolphthalein (HIn). SIQPs distinguished the quaternary atoms and dipoles of the fluorescent dye (MB) contrary to the quinonoid HIn structure. In sunlight, SIQPs without electricity input acted as a photonic sensor to detect fluorescent dyes in waste effluents of textile, paper, dyes, and other industries. Activation energy (E a), enthalpy (ΔH), entropy (ΔS), and Gibbs free energy (ΔG) calculated from UV-vis absorption spectra show photocatalytic reduction (PCR) activities in the order SIQP II > III > I. The N-atom of pyrrolizidine and -NO2 of nitro-indenoquinoxaline (NIQ) induced the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) electrodynamics to enable the SIQPs to catalyze biochemical activities.
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In this study, composite two-dimensional (2D) materials consisting of graphene (Gr) and tungsten disulfide (WS2) were coalesced with gold nanoparticles (AuNPs) through a self-assembly process to boost the conductivity of the resulting graphene-tungsten disulfide-gold nanoparticles (Gr-WS2-AuNPs) nanointerface structure. Structural and morphological characterization of the nanohybrid structure reveals crystalline thin flakelike agglomerates. Electrochemical characterization reveals an excellent electron transfer process for all the modified electrodes at the interface. The Gr/WS2/AuNPs/HRP/GCE modified bioelectrode exhibited a rapid electrobiocatalytic response in detecting H2O2 and a linear response from 0.40 to 23 mM, while 11.07 µA/mM/cm2 is the sensitivity value. This shows that the fabricated Gr/WS2/AuNPs/HRP interface structure is an excellent material for future developments in electrochemical biosensing and bioelectronics applications. The interactions, geometry, and energetic and electronic properties of H2O2 adsorption onto Gr/WS2/Au using the density functional theory (DFT) method have also been investigated along with the Grimme's DFT-D3 dispersion method. Different adsorption modes of the H2O2 molecule onto the Gr/WS2/Au surface were considered. In almost all the cases, the adsorption was found to be energetically favorable and chemisorbed, with energies ranging from -2.198 to -3.782 eV. It was found that the W 5d, S 3p, and Au 6s orbitals play a vital role in the adsorption process. The H2O2 adsorption on Gr/WS2/Au remarkably decreases its work function, thereby increasing the field electron emission from the H2O2 molecule to Gr/WS2/Au.
RESUMO
Aberrant re-entry of neurons into cell cycle appears to be an early event in Alzheimer's disease (AD) and targeting this dysregulation may have therapeutic potential. We have examined whether cell cycle dysregulation in AD can be detected using patient and control derived B-lymphocytes. Cell cycle analysis using flow cytometry demonstrated that cell cycle dysregulation occurs in AD lymphocytes, with a significant difference in the distribution of cells in G0/G1, S and G2/M phases of cell cycle as compared to control lymphocytes. Using global gene expression analysis by RNA sequencing and cell cycle analysis, we examined the role of Retinoic Acid (RA), a candidate molecule predicted to be of therapeutic potential in cell cycle dysregulation associated with AD. CCND1, CCNE2, E2F transcription factors which are known to be dysregulated in AD were among the 32 genes that showed differential expression in response to RA treatment thus suggesting a protective role of RA. However, the cell cycle analysis demonstrated that RA did not reverse the cellular phenotype in AD lymphocytes. This suggests that though RA might have a protective role by influencing the expression of cell cycle genes, it might not be able to arrest abnormal re-entry into cell cycle.