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1.
Opt Express ; 32(2): 2460-2472, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38297775

RESUMO

We explore the synchronization of chaotic microresonator frequency combs, emphasizing the modulation instability state, which is known for its inherent chaotic behaviors. Our study confirms that the synchronization of two such combs is feasible by injecting the output from the lead microresonator into the next microresonator's input. We also identify the optimal parameters for this synchronization. Remarkably, even partial injection from the leader is sufficient for synchronization, paving the way for versatile future system configurations. Such systems could simultaneously utilize distinct spectral components for synchronization and transmission. This work advances our understanding of chaotic microresonator combs, showing them to be pivotal elements in next-generation optical communication systems.

2.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34480005

RESUMO

The development of high-performance photoacoustic (PA) probes that can monitor disease biomarkers in deep tissue has the potential to replace invasive medical procedures such as a biopsy. However, such probes must be optimized for in vivo performance and exhibit an exceptional safety profile. In this study, we have developed PACu-1, a PA probe designed for biopsy-free assessment (BFA) of hepatic Cu via photoacoustic imaging. PACu-1 features a Cu(I)-responsive trigger appended to an aza-BODIPY dye platform that has been optimized for ratiometric sensing. Owing to its excellent performance, we were able to detect basal levels of Cu in healthy wild-type mice as well as elevated Cu in a Wilson's disease model and in a liver metastasis model. To showcase the potential impact of PACu-1 for BFA, we conducted two blind studies in which we were able to successfully identify Wilson's disease animals from healthy control mice in each instance.


Assuntos
Cobre/metabolismo , Degeneração Hepatolenticular/metabolismo , Neoplasias Hepáticas/secundário , Técnicas Fotoacústicas/instrumentação , Animais , Biópsia , Modelos Animais de Doenças , Degeneração Hepatolenticular/patologia , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Tecidual
3.
Br J Haematol ; 200(2): 187-196, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36210485

RESUMO

Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell-free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele-specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r = 0.8; p < 0.001). CXCR4 C1013G was analysed in MYD88-mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r = 0.9; p < 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88-mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular-based risk classification.


Assuntos
Ácidos Nucleicos Livres , Linfoma de Células B , Gamopatia Monoclonal de Significância Indeterminada , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Gamopatia Monoclonal de Significância Indeterminada/genética , Fator 88 de Diferenciação Mieloide/genética , Prognóstico , Mutação , Reação em Cadeia da Polimerase , Ácidos Nucleicos Livres/genética , Imunoglobulina M/genética , Receptores CXCR4/genética
4.
Anal Chem ; 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36608324

RESUMO

Nonionic surfactants are often used as general reagents for cell lysis enabling protein extraction, stabilization, and purification under nondenaturing conditions for downstream analysis in structural biology. However, the presence of surfactants in the sample matrix often has a deleterious effect on electrospray ionization (ESI)-mass spectrometry (MS) analysis of proteins and complexes. Here, we report a nonionic, cleavable surfactant, n-decyl-disulfide-ß-D-maltoside (DSSM), for top-down proteomics. DSSM was designed to mimic the properties of one of the most common surfactants used in structural biology, n-dodecyl-ß-D-maltoside (DDM), but contains a disulfide bond that allows for facile cleavage and surfactant removal before or during MS analysis. We have shown that DSSM is compatible with direct electrospray ionization (ESI)-MS analysis and reversed-phase liquid chromatography (RPLC)-MS analysis of proteins and protein complexes. We have demonstrated that DSSM can facilitate top-down proteomic characterization of membrane proteins such as a model ion channel protein and a G protein-coupled receptor as well as endogenous proteins from cell lysates for the determination of sequence variations and posttranslational modifications (PTMs). Conceivably, DSSM could serve as a general replacement for DDM in proteomic experiments and structural biology studies.

5.
Langmuir ; 39(4): 1465-1473, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36638323

RESUMO

We report the synthesis and characterization of a new family of maltose-derived nonionic surfactants that contain a photocleavable azo-sulfide linker (mAzo). The self-assembly properties of these surfactants were investigated using surface tension measurements to determine the critical micelle concentration (CMC), dynamic light scattering (DLS) to reveal the hydrodynamic radius of their self-assemblies, and transmission electron microscopy (TEM) to elucidate the micelle morphology. Ultraviolet-visible (UV-visible) spectroscopy confirmed the rapid photodegradation of these surfactants, but surface tension measurements of the surfactant solutions before and after degradation showed unusual degradation products. The photodegradation process was further studied using online liquid chromatography coupled with mass spectrometry (LC-MS),which revealed that these surfactants can form another photo-stable surfactant post-degradation. Finally, traditionally challenging proteins from heart tissue were solubilized using the mAzo surfactants to demonstrate their potential in biological applications.

6.
Bull Environ Contam Toxicol ; 110(5): 89, 2023 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-37140760

RESUMO

In the present study, livers, kidneys and adipose tissue of Yellow-legged Gull (Larus michahellis) were collected. Samples were used to determine relationships between heavy metals/metalloids in liver and kidneys (Hg, Cd, Pb, Se and As) or persistent organic pollutants in adipose tissue (7 PCBs and 11 organochlorine pesticides) with biomarkers of oxidative stress (CAT, GPx, GR, GSH, GST, MDA) analysed in both internal organs. Three possible influencing variables have been studied: age, sex and sampling area. As a result, statistically significant differences (P < 0.05, P < 0.01) were only found according to the sampling area, with differences among the three studied areas found in both organs. Significant positive correlations (P < 0.01) were found in liver (Hg vs. GST; Se vs. MDA) and in kidney (As vs. GR; As vs. GPx; PCB52 vs. CAT; PCB138 vs. CAT). The scarcity in correlations suggests that the levels of pollutants found in animals were not high enough to trigger an effect at the oxidative level.


Assuntos
Charadriiformes , Hidrocarbonetos Clorados , Mercúrio , Metais Pesados , Animais , Monitoramento Ambiental , Metais Pesados/análise , Hidrocarbonetos Clorados/análise , Mercúrio/análise
7.
Br J Haematol ; 196(3): 649-659, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34622447

RESUMO

The prognostic landscape of multiple myeloma (MM) has evolved significantly over the last few decades. There are, however, few data measuring such improvement in real-world patients. This study aimed to investigate trends in survival improvement over 45 years, and the associated clinical factors, in an unselected population of patients with MM. Between 1970 and 2015, 1 161 MM patients were included. Patients were classified into three calendar periods (1970-1984, 1985-1999, and 2000-2015), according to the treatment received; polychemotherapy, autologous stem cell transplantation, and novel drugs respectively. We analysed relative survival (RS) to accurately evaluate MM-related death rates after excluding the mortality expected in the general population. RS at five years increased from 27% in 1970-1984 to 38% and 56% in the next two calendar periods respectively. The improvement to survival was greater in the younger population, but it was also observed in elderly patients and those with poor performance status and more advanced disease. Although myeloma is still a non-curable disease, encouraging results have been observed in the last decades. Progress is expected to continue with the use of new generations of anti-myeloma drugs, and will, hopefully, be documented in real-world patients by the appropriate population-based studies.


Assuntos
Mieloma Múltiplo/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Feminino , História do Século XX , História do Século XXI , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/história , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Gradação de Tumores , Estadiamento de Neoplasias
8.
Chemistry ; 28(13): e202104574, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35061302

RESUMO

Strong push-pull interactions between electron donor, diaminoazobenzene (azo), and an electron acceptor, perylenediimide (PDI), entities in the newly synthesized A-D-A type triads (A=electron acceptor and D=electron donor) and the corresponding A-D dyads are shown to reveal wide-band absorption covering the entire visible spectrum. Electrochemical studies revealed the facile reduction of PDI and relatively easier oxidation of diaminoazobenzene in the dyads and triads. Charge transfer reversal using fluorescence-spectroelectrochemistry wherein the PDI fluorescence recovery upon one-electron oxidation, deterring the charge-transfer interactions, was possible to accomplish. The charge transfer state density difference and the frontier orbitals from the DFT calculations established the electron-deficient PDI to be an electron acceptor and diaminoazobenzene to be an electron donor resulting in energetically closely positioned PDIδ- -Azoδ+ -PDIδ- quadrupolar charge-transfer states in the case of triads and Azoδ+ -PDIδ- dipolar charge-transfer states in the case of dyads. Subsequent femtosecond transient absorption spectral studies unequivocally proved the occurrence of excited-state charge transfer in these dyads and triads in benzonitrile wherein the calculated forward charge transfer rate constants, kf , were limited to instrument response factor, meaning >1012  s-1 revealing the occurrence of ultrafast photo-events. The charge recombination rate constant, kr , was found to depend on the type of donor-acceptor conjugates, that is, it was possible to establish faster kr in the case of triads (∼1011  s-1 ) compared to dyads (∼1010  s-1 ). Modulating both ground and excited-state properties of PDI with the help of strong quadrupolar and dipolar charge transfer and witnessing ultrafast charge transfer events in the studied triads and dyads is borne out from the present study.

9.
BMC Pulm Med ; 22(1): 273, 2022 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-35842603

RESUMO

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) remains one of the leading causes of morbidity and mortality worldwide, and its epidemiology in Latin America and the Caribbean is not well described. The aim of this study was to evaluate the prevalence and incidence of COPD in Latin America and the Caribbean. METHODS: We searched systematically in Web of Science (WoS)/Core Collection, WoS/MEDLINE, WoS/Scielo, Scopus, PubMed, and Embase from 2010 to 2021. Studies assessing the prevalence and incidence of COPD according to the GOLD classification were included. The overall prevalence of COPD was calculated as a function of the general population using a random-effects model. RESULTS: 20 studies (19 cross-sectional and 1 cohort) met the inclusion criteria. The prevalence of COPD in the general population older than 35 years was 8.9%. The prevalence in men was 13.7% and in women 6.7%. The prevalence in smokers and ex-smokers was 24.3%. The incidence in the general population of COPD according to one study was 3.4% at 9 years of follow-up. CONCLUSIONS: COPD is prevalent in Latin America, especially in men and in smokers and ex-smokers. Further prevalence and incidence studies in the general population are needed, as well as health policies and strategies to address the disease.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Região do Caribe/epidemiologia , Estudos Transversais , Feminino , Humanos , Incidência , América Latina/epidemiologia , Masculino , Prevalência , Doença Pulmonar Obstrutiva Crônica/epidemiologia
10.
Clin Adv Hematol Oncol ; 20(8): 506-515, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36125957

RESUMO

The development of high-throughput technologies has allowed us to characterize the molecular landscape of hematologic neoplasms and identify somatic mutations. As a result, we can now use these technologies to screen for and diagnose neoplastic disease, model risk factors for progression, make treatment decisions, track response to treatment, and design clinical trials. Waldenström macroglobulinemia (WM), which is a lymphoplasmacytic lymphoma, serves as a good example of how genomic data collected at the bench can be applied at the bedside. MYD88 L265P and CXCR4 nonsense and frameshift mutations are the most common recurrent variants observed in patients who have WM, with detection rates of 90% and 40%, respectively. Knowing about these mutations has made it possible to develop agents that target the underlying signaling pathways. In this review, we describe the various treatment strategies for WM and detail the genotype of the malignant WM cell.


Assuntos
Linfoma de Células B , Macroglobulinemia de Waldenstrom , Humanos , Linfoma de Células B/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/uso terapêutico , Transdução de Sinais , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética
11.
Int J Mol Sci ; 23(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216346

RESUMO

Absent in melanoma 2 (AIM2) is a cytosolic dsDNA sensor that has been broadly studied for its role in inflammasome assembly. However, little is known about the function of AIM2 in adaptive immune cells. The purpose of this study was to investigate whether AIM2 has a cell-intrinsic role in CD4+ T cell differentiation or function. We found that AIM2 is expressed in both human and mouse CD4+ T cells and that its expression is affected by T cell receptor (TCR) activation. Naïve CD4+ T cells from AIM2-deficient (Aim2-/-) mice showed higher ability to maintain forkhead box P3 (FOXP3) expression in vitro, while their capacity to differentiate into T helper (Th)1, Th2 or Th17 cells remained unaltered. Transcriptional profiling by RNA sequencing showed that AIM2 might affect regulatory T cell (Treg) stability not by controlling the expression of Treg signature genes, but through the regulation of the cell's metabolism. In addition, in a T cell transfer model of colitis, Aim2-/--naïve T cells induced less severe body weight loss and displayed a higher ability to differentiate into FOXP3+ cells in vivo. In conclusion, we show that AIM2 function is not confined to innate immune cells but is also important in CD4+ T cells. Our data identify AIM2 as a regulator of FOXP3+ Treg cell differentiation and as a potential intervention target for restoring T cell homeostasis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto , Animais , Diferenciação Celular/fisiologia , Colite/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Inflamassomos/metabolismo , Ativação Linfocitária/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th17/metabolismo
12.
Curr Genet ; 67(2): 267-281, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33159551

RESUMO

Controlling chromatin state constitutes a major regulatory step in gene expression regulation across eukaryotes. While global cellular features or processes are naturally impacted by chromatin state alterations, little is known about how chromatin regulatory genes interact in networks to dictate downstream phenotypes. Using the activity of the canonical galactose network in yeast as a model, here, we measured the impact of the disruption of key chromatin regulatory genes on downstream gene expression, genetic noise and fitness. Using Trichostatin A and nicotinamide, we characterized how drug-based modulation of global histone deacetylase activity affected these phenotypes. Performing epistasis analysis, we discovered phenotype-specific genetic interaction networks of chromatin regulators. Our work provides comprehensive insights into how the galactose network activity is affected by protein interaction networks formed by chromatin regulators.


Assuntos
Cromatina/genética , Epistasia Genética , Galactoquinase/genética , Histona Desacetilases/genética , Proteínas de Saccharomyces cerevisiae/genética , Cromatina/efeitos dos fármacos , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Genes Reguladores/genética , Ácidos Hidroxâmicos/farmacologia , Niacinamida/farmacologia , Saccharomyces cerevisiae/genética
13.
Chemistry ; 27(60): 14996-15005, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34405918

RESUMO

Photoinduced charge transfer and separation events in a newly synthesized azobenzene-bridged perylenediimide-dimer (PDI-dimer) are demonstrated. Trans-to-cis conversion (∼50 % efficiency) from the initial trans PDI-dimer by 355 nm pulsed laser light, and its reversal, cis-to-trans, process by 435 nm laser light irradiation has been possible to accomplish. Efficient fluorescence quenching in the PDI-dimer, more so for the cis isomer was witnessed, and such quenching increased with increasing solvent polarity. DFT-calculated geometry and electronic structures helped in visualizing the charge transfer in the PDI-dimer in both isomeric forms, and also revealed certain degree of participation of the azobenzene entity in the charge transfer events. Femtosecond transient absorption spectral studies confirmed occurrence of both charge transfer followed by charge separation in the studied PDI-dimer in both trans and cis forms in polar solvents, and the evaluated time constants from Global target analysis revealed accelerated events in the cis PDI-dimer due to proximity effects. The present study offers key insights on the role of the azobenzene bridge, and the dimer geometry in governing the excited state charge transfer and separation in symmetrically linked PDI dimer.

14.
Ann Hematol ; 100(12): 2997-3005, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34463804

RESUMO

Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous plasma cell disorder, with a highly variable clinical course. Immunoparesis, defined by total immunoglobulin measurements, has been shown to be an independent risk factor for progression to symptomatic disease. The heavy/light chain (HLC) assay allows precise measurement of the polyclonal immunoglobulin of the same isotype, enabling the evaluation of isotype-matched immunoparesis (IMI). In this study, we prospectively characterized immunoparesis, as determined by HLC measurements, in 53 SMM patients. Severe IMI was present in 51% of patients, while severe IP of uninvolved isotypes (HLC IP) was present in 39%. Most of the patients with severe HLC IP presented with severe IMI, but not the other way around. Isotype specificity of immune suppression was suggested by lower relative values of isotype-matched HLC pairs, both for IgG and IgA SMM. Severe IMI was associated with other risk factors for progression while patients with severe IMI and severe HLC IP showed an even higher risk profile. Both severe IMI and severe IgM HLC IP showed a significantly shorter time to progression. Finally, gene expression analysis demonstrated differences in the bone marrow microenvironment between patients with IMI and IMI plus HLC IP, with an increased expression of genes associated with cytolytic cells. In conclusion, our data supports isotype specificity of early immunoglobulin suppression mechanisms. While suppression of both involved and uninvolved isotypes is associated with risk of progression, the later appears to develop with more advanced disease and could be mediated by different mechanisms.


Assuntos
Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Leves de Imunoglobulina/sangue , Mieloma Múltiplo Latente/sangue , Idoso , Feminino , Seguimentos , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
15.
PLoS Biol ; 16(8): e2005388, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30080861

RESUMO

Cell size scales with ploidy in a great range of eukaryotes, but the underlying mechanisms remain unknown. Using various orthogonal single-cell approaches, we show that cell size increases linearly with centromere (CEN) copy number in budding yeast. This effect is due to a G1 delay mediated by increased degradation of Cln3, the most upstream G1 cyclin acting at Start, and specific centromeric signaling proteins, namely Mad3 and Bub3. Mad3 binds both Cln3 and Cdc4, the adaptor component of the Skp1/Cul1/F-box (SCF) complex that targets Cln3 for degradation, these interactions being essential for the CEN-dosage dependent effects on cell size. Our results reveal a pathway that modulates cell size as a function of CEN number, and we speculate that, in cooperation with other CEN-independent mechanisms, it could assist the cell to attain efficient mass/ploidy ratios.


Assuntos
Processos de Crescimento Celular/fisiologia , Centrômero/fisiologia , Ciclina G1/metabolismo , Proteínas de Ciclo Celular/metabolismo , Divisão Celular , Crescimento Celular , Centrômero/metabolismo , Ciclinas/metabolismo , Fase G1/fisiologia , Regulação Fúngica da Expressão Gênica , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/fisiologia , Proteínas Nucleares/metabolismo , Proteólise , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomycetales/metabolismo , Transdução de Sinais
16.
Neuropediatrics ; 52(3): 192-200, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33657631

RESUMO

OBJECTIVE: The study aimed to describe the cases of neurological disease related to the outbreak of enterovirus (EV) in three regions in Northern Spain during 2016. MATERIALS AND METHODS: Multicenter retrospective observational study. Clinical, radiological, and microbiological data were analyzed from patients younger than 15 years with confirmed EV-associated neurological disease admitted to 10 hospitals of Asturias, Cantabria, and Castile and Leon between January 1 and December 31, 2016. RESULTS: Fifty-five patients were included. Median age was 24 months (interquartile range = 18.5 months). Fifteen patients were classified as aseptic meningitis (27.3%). In total, 37 cases presented brainstem encephalitis (67.3%), 25 of them due to EV-A71 with excellent prognosis (84.6% asymptomatic 2 months following the onset). Three cases of acute flaccid myelitis (5.5%) by EV-D68 were reported and presented persistent paresis 2 months following the onset. Microbiological diagnosis by reverse transcriptase polymerase chain reaction was performed in all cases, finding EV in cerebrospinal fluid in meningitis, but not in brainstem encephalitis and acute flaccid myelitis, where EV was found in respiratory or rectal samples. Step therapy was administrated with intravenous immunoglobulin (IVIG; 32.7%), methylprednisolone (10%), and plasmapheresis (3.6%). Four patients received fluoxetine (7.3%). Twenty patients needed to be admitted to pediatric intensive care unit (36.4%). CONCLUSION: Clinical, microbiological, and radiological diagnosis is essential in outbreaks of EV neurological disease, taking into account that it can be difficult to identify EV-A71 and EV-D68 in CSF, requiring throat or rectal samples. There is not specific treatment to these conditions and the efficacy and understanding of the mechanism of action of immune-modulatory treatment (IVIG, corticosteroids, and plasmapheresis) is limited.


Assuntos
Enterovirus Humano D , Infecções por Enterovirus , Mielite , Criança , Surtos de Doenças , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/terapia , Humanos , Lactente , Mielite/complicações , Mielite/epidemiologia , Mielite/terapia , Espanha/epidemiologia
17.
Exp Cell Res ; 394(2): 112163, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32640194

RESUMO

Aging is characterized by the progressive decline of physiology at the cell, tissue and organism level, leading to an increased risk of mortality. Proteotoxic stress, mitochondrial dysfunction and genomic instability are considered major universal drivers of cell aging, and accumulating evidence establishes clear biunivocal relationships among these key hallmarks. In this regard, the finite lifespan of the budding yeast, together with the extensive armamentarium of available analytical tools, has made this single cell eukaryote a key model to study aging at molecular and cellular levels. Here we review the current data that link proteostasis to cell cycle progression in the budding yeast, focusing on senescence as an inherent phenotype displayed by aged cells. Recent advances in high-throughput systems to study yeast mother cells while they replicate are providing crucial information on aging-related processes and their temporal interdependencies at a systems level. In our view, the available data point to the existence of multiple feedback mechanisms among the major causal factors of aging, which would converge into the loss of proteostasis as a nodal driver of cell senescence and death.


Assuntos
Senescência Celular , Replicação do DNA , Proteostase , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Ciclo Celular , Retroalimentação Fisiológica
18.
Clin Exp Pharmacol Physiol ; 48(4): 597-604, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33352621

RESUMO

Digestive inflammatory processes induce motility alterations associated with an increase in reactive oxygen species production, including monochloramine (NH2 Cl). The aim of the study was to characterize the effects of the naturally occurring oxidant monochloramine in the guinea pig gallbladder. We used standard in vitro contractility technique to record guinea pig gallbladder strips contractions. NH2 Cl caused a concentration-dependent contraction which was reduced by inhibition of extracellular Ca2+ influx and tyrosine kinase pathways. The PKC antagonist GF109203X also reduced the response but not after previous tyrosine kinase inhibition, suggesting that PKC is activated by tyrosine kinase activity. The NH2 Cl contractile effect was also reduced by inhibitors of mitogen-activated protein kinase (MAPK), nitric oxide synthase, phospholipase A2 and cyclooxygenase. In addition, NH2 Cl impaired the responses to CCK, tissue depolarization and electrical field stimulation. In conclusion, we present new evidence that monochloramine impairs not only the gallbladder response to CCK but also to membrane depolarization and nervous plexus stimulation, and that tyrosine kinase, PKC, MAPK and NO pathways are involved in the contractile direct effect of monochloramine.


Assuntos
Cloraminas , Vesícula Biliar , Animais , Cobaias , Contração Muscular/efeitos dos fármacos
19.
BMC Public Health ; 21(1): 2109, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789226

RESUMO

BACKGROUND: Chlorine dioxide has been promoted as an alternative for the prevention and treatment of COVID-19, especially in Peru, despite the lack of evidence to support its efficacy. This study aimed to evaluate the factors associated with chlorine dioxide consumption in the Peruvian population. METHODS: Analytical cross-sectional study. An adult Peruvian population was evaluated where chlorine dioxide consumption was divided into two groups according to the purpose of use: as prevention (individuals without COVID-19 history) and as treatment (individuals with COVID-19 history). The associated factors in each group were evaluated using Poisson regressions with the bootstrapping resampling method. RESULTS: Of 3610 participants included, 3213 reported no history of COVID-19, and 397 had been infected. The prevalence of chlorine dioxide consumption to prevent or treat COVID-19 was 8 and 16%, respectively. Factors either positively or negatively associated with chlorine dioxide consumption for prevention were male sex (aPR: 1.36; 95% CI: 1.09-1.71), being an adult or older adult (aPR: 0.54; 95% CI: 0.35-0.82), having a health sciences student within the family unit (aPR: 1.38; 95% CI: 1.02-1.87), using medical information as the main source of information of COVID-19 (aPR: 0.57; 95% CI: 0.40-0.80), having comorbidities for COVID-19 (aPR: 1.36; 95% CI: 1.01-1.82), considering COVID-19 dangerous and deadly (aPR: 0.57; 95% CI: 0.45-0.74), using medications (aPR: 1.59; 95% CI: 1.25-2.06) and plants to prevent COVID-19 (aPR: 1.69; 95% CI: 1.21-2.36), considering chlorine dioxide ineffective (aPR: 0.18; 95% CI: 0.18-0.24), and being uninformed of its efficacy (aPR: 0.21; 95% CI: 0.16-0.28). In addition, factors associated with chlorine dioxide consumption for treatment were considering COVID-19 dangerous and deadly (aPR: 0.56; 95% CI: 0.33-0.96), considering chlorine dioxide ineffective (aPR: 0.22; 95% CI: 0.12-0.42), and being uninformed of its efficacy (aPR: 0.15; 95% CI: 0.07-0.32). CONCLUSIONS: The prevalence of chlorine dioxide consumption to treat COVID-19 was higher than prevent. It is important to apply information strategies, prioritizing population groups with certain characteristics that are associated with a higher consumption pattern.


Assuntos
COVID-19 , Idoso , Compostos Clorados , Estudos Transversais , Humanos , Masculino , Óxidos , Peru/epidemiologia , SARS-CoV-2
20.
Ecotoxicol Environ Saf ; 227: 112949, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34755633

RESUMO

The current environmental hazard assessment is based on the testing of the pristine substance. However, it cannot be excluded that (nano)pharmaceuticals are excreted into sewage during the use phase followed by entry into wastewater treatment plants (WWTPs). Sorption to sewage sludge or release via effluent can result in modified ecotoxicological effects which possibly can only be detected with a modified test approach. The objective of our study was to investigate a realistic exposure scenario for metallic nanoparticles (NPs) in pharmaceutical products, excreted into effluent, and released into the environment after treatment in WWTPs. The test approach was illustrated by using gold (Au) NPs. Effluent from model WWTPs were investigated in aquatic tests (Daphnia magna, fish cell lines). Sewage sludge was used as a sole food source (Eisenia fetida) or mixed with soil and used as test medium (soil microorganisms, Folsomia candida, Enchytraeus crypticus). To cover the aspect of regulation, the test systems described in OECD-test guidelines (OECD TG 201, 211, 220, 232, 249, 317) were applied. Modifications and additional test approaches were included to meet the needs arising out of the testing of nanomaterials and of the exposure scenarios. The results were assessed regarding the suitability of the test design and the toxicity of Au-NPs. Except for activated sludge as a sole food source for E.fetida, the selected test approach is suitable for the testing of nanomaterials. Additional information can be gained when compared to the common testing of the pristine nanomaterials in the standardized test systems. Effects of Au-NPs were observed in concentrations exceeding the modeled environmental.


Assuntos
Nanopartículas Metálicas , Oligoquetos , Preparações Farmacêuticas/análise , Animais , Linhagem Celular , Daphnia , Ecotoxicologia , Peixes , Nanopartículas Metálicas/análise , Nanopartículas Metálicas/toxicidade , Esgotos , Testes de Toxicidade
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