Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 133
Filtrar
1.
Science ; 367(6476): 374, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974240
2.
Cell Rep ; 30(1): 112-123.e4, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31914379

RESUMO

Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31786678

RESUMO

Understanding how bone adapts to mechanical stimuli is fundamental for optimising treatments against musculoskeletal diseases in preclinical studies, but the contribution of physiological loading to bone adaptation in mouse tibia has not been quantified so far. In this study, a novel mechanistic model to predict bone adaptation based on physiological loading was developed and its outputs were compared with longitudinal scans of the mouse tibia. Bone remodelling was driven by the mechanical stimuli estimated from micro-FEA models constructed from micro-CT scans of C57BL/6 female mice (N = 5) from weeks 14 and 20 of age, to predict bone changes in week 16 or 22. Parametric analysis was conducted to evaluate the sensitivity of the models to subject-specific or averaged parameters, parameters from week 14 or week 20, and to strain energy density (SED) or maximum principal strain (εmaxprinc). The results at week 20 showed no significant difference in bone densitometric properties between experimental and predicted images across the tibia for both stimuli, and 59% and 47% of the predicted voxels matched with the experimental sites in apposition and resorption, respectively. The model was able to reproduce regions of bone apposition in both periosteal and endosteal surfaces (70% and 40% for SED and εmaxprinc, respectively), but it under-predicted the experimental sites of resorption by over 85%. This study shows for the first time the potential of a subject-specific mechanoregulation algorithm to predict bone changes in a mouse model under physiological loading. Nevertheless, the weak predictions of resorption suggest that a combined stimulus or biological stimuli should be accounted for in the model.

4.
Front Immunol ; 10: 2755, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849952

RESUMO

Behçet's disease (BD) is an immune-mediated vasculitis related to imbalances between the innate and adaptive immune response. Infectious agents or environmental factors may trigger the disease in genetically predisposed individuals. HLA-B51 is the genetic factor stronger associated with the disease, although the bases of this association remain elusive. NK cells have also been implicated in the etiopathogenesis of BD. A family of NK receptors, Killer-cell Immunoglobulin-like Receptor (KIR), with a very complex organization, is very important in the education and control of the NK cells by the union to their ligands, most of them, HLA class I molecules. This study aimed to investigate the contribution of certain KIR functional polymorphisms to the susceptibility to BD. A total of 466 BD patients and 444 healthy individuals were genotyped in HLA class I (A, B, and C). The set of KIR genes and the functional variants of KIR3DL1/DS1 and KIR2DS4 were also determined. Frequency of KIR3DL1*004 was lower in patients than in controls (0.15 vs. 0.20, P = 0.005, Pc = 0.015; OR = 0.70; 95% CI 0.54-0.90) in both B51 positive and negative individuals. KIR3DL1*004, which encodes a misfolded protein, is included in a common telomeric haplotype with only one functional KIR gene, KIR3DL2. Both, KIR3DL1 and KIR3DL2 sense pathogen-associated molecular patterns but they have different capacities to eliminate them. The education of the NK cells depending on the HLA, the balance of KIR3DL1/KIR3DL2 licensed NK cells and the different capacities of these receptors to eliminate pathogens could be involved in the etiopathogenesis of BD.

5.
Eur J Hum Genet ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527859

RESUMO

Palliative care may be an opportunity to discuss cancer family history and familial cancer risks with patients' relatives. It may also represent the last opportunity to collect, from dying patients, clinical data and biospecimens that will inform cancer risk assessment and prevention in their surviving relatives. This study aims to explore the perspectives of cancer patients' relatives about cancer heritability, addressing cancer family history, and performing genetic testing in palliative care settings. Thirteen first-degree relatives of cancer patients who died in palliative care participated in the study. Two focus groups were conducted and transcribed verbatim. Two independent coders conducted a thematic content analysis. The themes included: (1) Knowledge of cancer heritability; (2) Experiences and expectations regarding cancer family history discussions, and (3) Views on genetic testing in palliative care patients and DNA biobanking. Participants seemed aware that cancer family history is a potential risk factor for developing the disease. They considered the palliative care period an inappropriate moment to discuss cancer heritability. They also did not consider palliative care providers as appropriate resources to consult for such matters as they are not specialized in this field. Participants welcomed DNA biobanking and genetic testing conducted at the palliative care patients' request. Cancer occurrence within families raises concerns among relatives about cancer heritability, but the palliative care period is not considered the most appropriate moment to address this issue. However, discussions about the risk to cancer patients' relatives might need to be considered on a case-by-case basis.

6.
Chemphyschem ; 20(22): 3045-3055, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31342615

RESUMO

In the present work, the Pt(111) surface was disordered by controlling the density of {110}- and {100}-type defects. The cyclic voltammogram (CV) of a disordered surface in acid media consists of three contributions within the hydrogen adsorption/desorption region: one from the well-ordered Pt(111) symmetry and the other two transformed from the {111}-symmetry with contributions of {110}- and {100}-type surface defects. The ethanol oxidation reaction (EOR) was studied on these disordered surfaces. Electrochemical studies were performed in 0.1 M HClO4 +0.1 M ethanol using cyclic voltammetry and chronoamperometry. Changes in current densities associated to the specific potentials at which each oxidation peak appears suggest that different surface domains of disordered platinum oxidize ethanol independently. Additionally, as the surface-defect density increases, the EOR is catalysed better. This tendency is directly observed from the CV parameters because the onset and peak potentials are shifted to less positive values and accompanied by increases in the oxidation-peak current on disordered surfaces. Similarly, the CO oxidation striping confirmed this same tendency. Chronoamperometric experiments showed two opposite behaviors at short oxidation times (0.1 s). The EOR was quickly catalyzed on the most disordered surface, Pt(111)-16, and was then rapidly deactivated. These results provide fundamental information on the EOR, which contributes to the atomic-level understanding of real catalysts.

7.
Plant Cell Environ ; 42(9): 2696-2714, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31152467

RESUMO

Cadmium treatment induces transient peroxisome proliferation in Arabidopsis leaves. To determine whether this process is regulated by pexophagy and to identify the mechanisms involved, we analysed time course-dependent changes in ATG8, an autophagy marker, and the accumulation of peroxisomal marker PEX14a. After 3 hr of Cd exposure, the transcript levels of ATG8h, ATG8c, a, and i were slightly up-regulated and then returned to normal. ATG8 protein levels also increased after 3 hr of Cd treatment, although an opposite pattern was observed in PEX14. Arabidopsis lines expressing GFP-ATG8a and CFP-SKL enabled us to demonstrate the presence of pexophagic processes in leaves. The Cd-dependent induction of pexophagy was demonstrated by the accumulation of peroxisomes in autophagy gene (ATG)-related Arabidopsis knockout mutants atg5 and atg7. We show that ATG8a colocalizes with catalase and NBR1 in the electron-dense peroxisomal core, thus suggesting that NBR1 may be an autophagic receptor for peroxisomes, with catalase being possibly involved in targeting pexophagy. Protein carbonylation and peroxisomal redox state suggest that protein oxidation may trigger pexophagy. Cathepsine B, legumain, and caspase 6 may also be involved in the regulation of pexophagy. Our results suggest that pexophagy could be an important step in rapid cell responses to cadmium.

8.
J Exp Bot ; 70(16): 4251-4265, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31087094

RESUMO

Two cysteine metabolism-related molecules, hydrogen sulfide and hydrogen cyanide, which are considered toxic, have now been considered as signaling molecules. Hydrogen sulfide is produced in chloroplasts through the activity of sulfite reductase and in the cytosol and mitochondria by the action of sulfide-generating enzymes, and regulates/affects essential plant processes such as plant adaptation, development, photosynthesis, autophagy, and stomatal movement, where interplay with other signaling molecules occurs. The mechanism of action of sulfide, which modifies protein cysteine thiols to form persulfides, is related to its chemical features. This post-translational modification, called persulfidation, could play a protective role for thiols against oxidative damage. Hydrogen cyanide is produced during the biosynthesis of ethylene and camalexin in non-cyanogenic plants, and is detoxified by the action of sulfur-related enzymes. Cyanide functions include the breaking of seed dormancy, modifying the plant responses to biotic stress, and inhibition of root hair elongation. The mode of action of cyanide is under investigation, although it has recently been demonstrated to perform post-translational modification of protein cysteine thiols to form thiocyanate, a process called S-cyanylation. Therefore, the signaling roles of sulfide and most probably of cyanide are performed through the modification of specific cysteine residues, altering protein functions.

9.
Rev Esp Enferm Dig ; 111(7): 530-536, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31140286

RESUMO

BACKGROUND: transit times in the gastric cavity and the small bowel can be easily calculated using capsule endoscopy software. The factors that can influence these times and impact on diagnostic yield have not been completely assessed. AIMS: to analyze the influence of demographic and clinical features on transit times and the impact on diagnostic yield. METHODS: a retrospective, single-center study of examinations between January 2013 and November 2017 was performed. The analyzed features included gender, age, body mass index, diabetes, thyroid disease and indications. The association and correlation between the variables were assessed, as well as the presence of positive and significant findings. RESULTS: six hundred and thirty-one patients were included in the study. Gastric and small bowel transit times were 36.10 ± 48.50 and 251.82 ± 116.42 minutes, respectively. Gastric time was not affected by any of the variables. Small bowel time was longer in males, patients over 60 years of age and diabetics. Prolonged small bowel time, male gender and older age were associated with a higher diagnostic yield. Age over 60 years was the only factor independently associated with positive findings (OR: 1.550 [1.369-1.754]; p: 0.007). CONCLUSIONS: patients over 60 years have a longer small bowel transit time and higher probability of having small bowel lesions. Males and diabetic patients also seem more likely to have longer transit times and higher rates of positive findings.

12.
Biomed Opt Express ; 10(2): 944-960, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30800525

RESUMO

In this proof-of-concept study we combine two optical techniques to enable assessment of structure and composition of human skin in vivo: Pulsed photothermal radiometry (PPTR), which involves measurements of transient dynamics in mid-infrared emission from sample surface after exposure to a light pulse, and diffuse reflectance spectroscopy (DRS) in visible part of the spectrum. The analysis involves simultaneous fitting of measured PPTR signals and DRS with corresponding predictions of a Monte Carlo model of light-tissue interaction. By using a four-layer optical model of skin we obtain a good match between the experimental and model data when scattering properties of the epidermis and dermis are also optimized on an individual basis. The assessed parameter values correlate well with literature data and demonstrate the expected trends in controlled tests involving temporary obstruction of peripheral blood circulation using a pressure cuff, and acute as well as seasonal sun tanning.

13.
Sci Rep ; 9(1): 2777, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808881

RESUMO

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established genetic base. In a previous study, using a next generation sequencing approach, we found many rare variants and some functional polymorphisms in genes related to autoinflammatory syndromes (AID): CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A in our BD cohort. Our strategy did not allow us to establish either number of patients with variants, proportion of individuals accumulating them or relationship with other genetic factors. With the goal to answer these questions, the individual samples were sequenced. Additionally, three functional polymorphisms: NLRP3 p.Gln703Lys, NOD2 p.Arg702Trp and p.Val955Ile were genotyped using TaqMan assays. A total of 98 patients (27.6%) carried at least one rare variant and 13 of them (3.7%) accumulated two or three. Functional regression model analysis suggests epistatic interaction between B51 and MEFV (P = 0.003). A suggestive protective association of the minor allele of NOD2 p.Arg702Trp (P = 0.01) was found in both, B51 positive and negative individuals. Therefore, a high percentage of patients with BD have rare variants in AID genes. Our results suggest that the association of MEFV with BD could be modulated by the HLA molecules; whereas the protective effect of NOD2 p.Arg702Trp would be independent of HLA.

14.
Accid Anal Prev ; 123: 99-106, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30472530

RESUMO

The use of advanced driver assistance systems and the transition towards semi-autonomous vehicles are expected to contribute to a lower frequency of motor accidents and to have a significant impact for the automobile insurance industry, as rating methods must be revised to ensure that risks are correctly measured. Telematics information and usage-based insurance research are analyzed to identify the effect of driving patterns on the risk of accident. This is used as a starting point for addressing risk quantification and safety for vehicles that can control speed. The effect of excess speed on the risk of accidents is estimated with a real telematics data set. Scenarios for a reduction of speed limit violations and the consequent decrease in the expected number of accident claims are shown. If excess speed could be eliminated, then the expected number of accident claims could be reduced to half of its initial value, applying the average conditions of the data used in this study. As a consequence, insurance premiums also diminish.


Assuntos
Acidentes de Trânsito/prevenção & controle , Automação , Condução de Veículo/legislação & jurisprudência , Veículos Automotores/classificação , Acidentes de Trânsito/estatística & dados numéricos , Humanos , Seguro/estatística & dados numéricos , Distribuição de Poisson
15.
Risk Anal ; 39(3): 662-672, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30566751

RESUMO

Most automobile insurance databases contain a large number of policyholders with zero claims. This high frequency of zeros may reflect the fact that some insureds make little use of their vehicle, or that they do not wish to make a claim for small accidents in order to avoid an increase in their premium, but it might also be because of good driving. We analyze information on exposure to risk and driving habits using telematics data from a pay-as-you-drive sample of insureds. We include distance traveled per year as part of an offset in a zero-inflated Poisson model to predict the excess of zeros. We show the existence of a learning effect for large values of distance traveled, so that longer driving should result in higher premiums, but there should be a discount for drivers who accumulate longer distances over time due to the increased proportion of zero claims. We confirm that speed limit violations and driving in urban areas increase the expected number of accident claims. We discuss how telematics information can be used to design better insurance and to improve traffic safety.

17.
Semin Cell Dev Biol ; 85: 132-142, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29438807

RESUMO

We address current data, views and puzzles on the emerging topic of regulation of lymphocytes by complement proteins or fragments. Such regulation is believed to take place through complement receptors (CR) and membrane complement regulators (CReg) involved in cell function or protection, respectively, including intracellular signalling. Original observations in B cells clearly support that complement cues through CR improve their performance. Other lymphocytes likely integrate complement-derived signals, as most lymphoid cells constitutively express or regulate CR and CReg upon activation. CR-induced signals, particularly by anaphylatoxins, clearly regulate lymphoid cell function. In contrast, data obtained by CReg crosslinking using antibodies are not always confirmed in human congenital deficiencies or knock-out mice, casting doubts on their physiological relevance. Unsurprisingly, human and mouse complement systems are not completely homologous, adding further complexity to our still fragmentary understanding of complement-lymphocyte interactions.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Linfócitos/metabolismo , Animais , Humanos , Linfócitos/citologia
19.
Expert Rev Clin Immunol ; 14(3): 215-224, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29473763

RESUMO

INTRODUCTION: Musculoskeletal manifestations are well-recognized side effects of treatment with statins. New advances in this field have appeared in recent years. This review focuses on the diagnosis of these conditions and their underlying pathogenesis, in particular immune-mediated necrotizing myopathy. Areas covered: Clinical phenotypes including rhabdomyolysis, myalgia and/or mild hyperCKemia, self-limited toxin statin myopathy, and immune-mediated necrotizing myopathy are herein described. Therapeutic recommendations and a diagnostic algorithm in statin-associated myopathy are also proposed. The etiology and pathogenesis of statin-induced myopathy has mainly focused on the anti-HMGCR antibodies and the responsibility of the immune-mediated necrotizing myopathy is discussed. The fact that patients who have not been exposed to statins may develop statin-associated autoimmune myopathy with anti-HMGCR antibodies is also addressed. The literature search strategy included terms identified by searches of PubMed between 1969 and December 2017. The search terms 'myositis', 'statin-induced autoimmune myopathy', 'immune-mediate necrotizing myopathy', 'statins', 'muscular manifestations', and 'anti-HMGCR antibodies' were used. Expert commentary: Full characterization of the known phenotypes of statin toxicity and the specific role of the anti-HMGCR in those exposed and not exposed (i.e. juvenile forms) to statins and in some types of neoplasms is of paramount relevance.


Assuntos
Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Músculos/patologia , Mialgia/diagnóstico , Miosite/diagnóstico , Algoritmos , Autoanticorpos/metabolismo , Prova Pericial , Humanos , Hidroximetilglutaril-CoA Redutases/imunologia , Mialgia/imunologia , Miosite/imunologia , Necrose
20.
PLoS One ; 13(1): e0190675, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29370213

RESUMO

There is increasing evidence of persistent effects of early life vitamin D exposure on later skeletal health; linking low levels in early life to smaller bone size in childhood as well as increased fracture risk later in adulthood, independently of later vitamin D status. A major determinant of bone mass acquisition across all ages is mechanical loading. We tested the hypothesis in an animal model system that early life vitamin D depletion results in abrogation of the response to mechanical loading, with consequent reduction in bone size, mass and strength during both childhood and adulthood. A murine model was created in which pregnant dams were either vitamin D deficient or replete, and their offspring moved to a vitamin D replete diet at weaning. Tibias of the offspring were mechanically loaded and bone structure, extrinsic strength and growth measured both during growth and after skeletal maturity. Offspring of vitamin D deplete mice demonstrated lower bone mass in the non loaded limb and reduced bone mass accrual in response to loading in both the growing skeleton and after skeletal maturity. Early life vitamin D depletion led to reduced bone strength and altered bone biomechanical properties. These findings suggest early life vitamin D status may, in part, determine the propensity to osteoporosis and fracture that blights later life in many individuals.


Assuntos
Desenvolvimento Ósseo , Osso e Ossos/fisiopatologia , Deficiência de Vitamina D/fisiopatologia , Animais , Densidade Óssea , Feminino , Análise de Elementos Finitos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Estresse Mecânico , Vitamina D/administração & dosagem , Microtomografia por Raio-X
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA