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1.
Immunity ; 55(9): 1732-1746.e5, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-35961317

RESUMO

Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4+ and CD8+ T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4+ T cells and robust expansions of oligoclonal effector-memory CD45RA+ CD8+ T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Linfócitos T CD8-Positivos , COVID-19/prevenção & controle , Humanos , Imunidade Humoral , RNA Mensageiro/genética , Síndrome , Vacinação , Proteínas do Envelope Viral
2.
HIV Med ; 25(6): 692-699, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38350653

RESUMO

OBJECTIVES: In countries with access to early antiretroviral treatment (ART), opportunistic infections caused by cytomegalovirus (CMV) in people living with HIV (PLWH) are becoming increasingly rare. As potential complications are severe, it is critical to remain aware of this important diagnosis. However, clinical characteristics and prognosis of CMV infection in PLWH in the era of modern ART have not been well described. METHODS: Here, we compiled the clinical presentation, management and outcome of CMV infection in PLWH treated at the infectious diseases clinic of Karolinska University Hospital during 2010-2020. RESULTS: We identified 51 cases of active CMV infection, based on detection of CMV-DNA, mainly diagnosed in patients with CD4 T-cell count <200 cells/µL (86%). Median time from HIV diagnosis to detection of CMV infection was 16 days. In 20 cases (39%), CMV infection was symptomatic with retinitis identified as a manifestation in 70% of cases. Symptomatic CMV infection was treated for 73 (20-313) days upon diagnosis, mostly using valganciclovir. One-year mortality was 22% and was associated with longer time to ART initiation from HIV diagnosis and with comorbidities, but not with CMV-DNA levels or CD4 count. Immune reconstitution was not significantly compromised in patients with symptomatic CMV, although CD4/8 ratio tended to be lower in patients with systemic CMV infection. CONCLUSIONS: Retinitis remains the most common manifestation of symptomatic CMV infection in PLWH. Recognizing CMV infection is important, especially in the management of 'late presenters'. Adequate duration of antiviral therapy and appropriate follow-up must be ensured to avoid complications.


Assuntos
Antivirais , Infecções por Citomegalovirus , Infecções por HIV , Hospitais Universitários , Humanos , Masculino , Feminino , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/complicações , Adulto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Pessoa de Meia-Idade , Suécia/epidemiologia , Contagem de Linfócito CD4 , Antivirais/uso terapêutico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Resultado do Tratamento , Citomegalovirus/isolamento & purificação , Valganciclovir/uso terapêutico
3.
Liver Int ; 44(1): 228-240, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37904316

RESUMO

BACKGROUND AND AIMS: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden. METHODS: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression. RESULTS: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6). CONCLUSION: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis.


Assuntos
Coinfecção , Infecções por HIV , Hepatite B , Hepatite D , Humanos , Antígenos de Superfície da Hepatite B , Hepatite B/complicações , Suécia/epidemiologia , Coinfecção/epidemiologia , Hepatite D/epidemiologia , Hepatite D/complicações , Vírus Delta da Hepatite/genética , Infecções por HIV/complicações , Hepatite Crônica/complicações , RNA , Vírus da Hepatite B/genética
4.
Perspect Biol Med ; 67(1): 1-21, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38662060

RESUMO

According to the mainstream bioethical stance, death constitutes the termination of an organism. This essay argues that such an understanding of death is inappropriate in the usual context of determining death, since it also has a social bearing. There are two reasons to justify this argument. First, the mainstream bioethical definition generates an organismal superposition challenge, according to which a given patient in a single physiological state might be both alive and dead, like Schrödinger's cat. Therefore, there is no clear answer as to whether organ retrieval from a brain-dead patient is an act of killing or not. Second, when combined with the dead donor rule, the mainstream position in the definition of death might lead to ethically unacceptable verdicts, since there is a discrepancy between terminating an organism and depriving someone of moral status.


Assuntos
Morte Encefálica , Morte , Humanos , Morte Encefálica/diagnóstico , Obtenção de Tecidos e Órgãos/ética
5.
Am J Bioeth ; : 1-12, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39018166

RESUMO

Much of the debate over the definition and criteria for determining our death has focused on disagreement over the correct biological account of death, i.e., what it means for any organism to die. In this paper, we argue that this exclusive focus on the biology of death is misguided, because it ignores ethical and social factors that bear on the acceptability of criteria for determining our death. We propose that attention shift from strictly biological considerations to ethical and social considerations that bear on the determination of what we call "civil death." We argue for acceptance of a neurological criterion for determining death on grounds that it is the most reasonable way to synthesize biological, ethical, and social considerations about our death..

6.
Infection ; 51(1): 261-263, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35482208

RESUMO

PROPOSE: Pregnancy is a risk factor for severe COVID-19. Treatment with monoclonal antibodies has been shown to decrease the risk of progression to severe COVID-19, but there are few reports on treating pregnant women. Here, we describe the clinical outcome of seven hospitalized pregnant women treated with the casirivimab-imdevimab. METHODS/RESULTS: Seven unvaccinated pregnant patients hospitalized due to COVID-19 met the monoclonal antibodies treatment criteria applied at our center. After consultations with obstetricians, the decisions to administer casirivimab-imdevimab to halt the progression of COVID-19 were made by two senior infectious diseases specialists. No patient experienced an adverse drug reaction, and only one patient progressed to severe disease. Two patients had a cesarian section performed during hospitalization, both with delivery of healthy babies. Three patients gave birth to healthy babies at a later time point, while two pregnancies are ongoing. CONCLUSION: The hospitalized pregnant patients who received monoclonal antibodies due to COVID-19 had favorable outcomes, but further research is recommended to fully assess safety and efficacy of monoclonal antibody treatment in pregnancy.


Assuntos
Anticorpos Monoclonais , COVID-19 , Gravidez , Humanos , Feminino , Anticorpos Monoclonais/efeitos adversos , Anticorpos Neutralizantes , Cesárea
7.
Mol Cell Proteomics ; 20: 100159, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34619366

RESUMO

Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multiomics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 reproduction and their association with disease severity. We used multiomics platforms (targeted and untargeted proteomics and untargeted metabolomics) on patient samples and cell-line models along with immune phenotyping of metabolite transporters in patient blood cells to understand viral-induced metabolic modulations. We also modulated key metabolic pathways that were identified using multiomics data to regulate the viral reproduction in vitro. Coronavirus disease 2019 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of carbohydrate transporter, glucose transporter 1, in CD8+ T cells, intermediate and nonclassical monocytes, and amino acid transporter, xCT, in classical, intermediate, and nonclassical monocytes. In in vitro lung epithelial cell (Calu-3) infection model, we found that glycolysis and glutaminolysis are essential for virus replication, and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that severe acute respiratory syndrome coronavirus-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.


Assuntos
Proteínas Sanguíneas/metabolismo , COVID-19/etiologia , SARS-CoV-2/fisiologia , Adulto , Idoso , Sistema y+ de Transporte de Aminoácidos/sangue , Aminoácidos/sangue , Biomarcadores/sangue , Proteínas Sanguíneas/análise , COVID-19/metabolismo , COVID-19/virologia , Carboidratos/sangue , Estudos de Casos e Controles , Transportador de Glucose Tipo 1/sangue , Hospitalização , Humanos , Imunofenotipagem , Manose/sangue , Lectina de Ligação a Manose/sangue , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Replicação Viral
8.
J Med Philos ; 48(5): 504-518, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37134311

RESUMO

The mainstream concept of death-the biological one-identifies death with the cessation of an organism. In this article, I challenge the mainstream position, showing that there is no single well-established concept of an organism and no universal concept of death in biological terms. Moreover, some of the biological views on death, if applied in the context of bedside decisions, might imply unacceptable consequences. I argue the moral concept of death-one similar to that of Robert Veatch-overcomes such difficulties. The moral view identifies death with the irreversible cessation of a patient's moral status, that is, a state when she can no longer be harmed or wronged. The death of a patient takes place when she is no longer capable of regaining her consciousness. In this regard, the proposal elaborated herein resembles that of Veatch yet differs from Veatch's original project since it is universal. In essence, it is applicable in the case of other living beings such as animals and plants, provided that they have some moral status.


Assuntos
Status Moral , Princípios Morais , Animais , Feminino , Humanos
9.
Entropy (Basel) ; 25(3)2023 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-36981415

RESUMO

The paper is dedicated to modeling electricity spot prices and pricing forward contracts on energy markets. The underlying dynamics of electricity spot prices is governed by a stochastic mean reverting diffusion with jumps having mixed-exponential distribution. Application of financial mathematics and stochastic methods enabled the derivation of the analytical formula for the forward contract's price in a crisp case. Since the model parameters' incertitude is considered, their fuzzy counterparts are introduced. Utilization of fuzzy arithmetic enabled deriving an analytical expression for the futures price and proposing a modified method for decision-making under uncertainty. Finally, numerical examples are analyzed to illustrate our pricing approach and the proposed financial decision-making method.

10.
Mol Med ; 28(1): 54, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35562666

RESUMO

Mucosa-associated invariant T (MAIT) cells are unconventional T cells with innate-like capacity to rapidly respond to microbial infection via MR1-restricted antigen recognition. Emerging evidence indicate that they can also act as rapid sensors of viral infection via innate cytokine activation. However, their possible role in the immune response to mRNA vaccination is unknown. Here, we evaluated the involvement of MAIT cells in individuals vaccinated with the BNT162b2 mRNA SARS-CoV-2 vaccine. MAIT cell levels, phenotype and function in circulation were preserved and unperturbed through day 35 post-vaccination in healthy donor (HD) vaccinees, as well as people living with HIV (PLWH) or with primary immunodeficiency (PID). Unexpectedly, pre-vaccination and post-vaccination levels of MAIT cells correlated positively with the magnitude of the SARS-CoV-2 spike protein-specific CD4 T cell and antibody responses in the HD vaccinees. This pattern was largely preserved in the PID group, but less so in the PLWH group. Furthermore, in the HD vaccinees levels of MAIT cell activation and cytolytic potential correlated negatively to the adaptive antigen-specific immune responses. These findings indicate an unexpected association between MAIT cell compartment characteristics and the immune response magnitude to the BNT162b2 mRNA vaccine.


Assuntos
COVID-19 , Células T Invariantes Associadas à Mucosa , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Imunidade Humoral , RNA Mensageiro/genética , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vacinas Sintéticas , Vacinas de mRNA
11.
Mol Med ; 28(1): 20, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35135470

RESUMO

Adaptive immune responses have been studied extensively in the course of mRNA vaccination against COVID-19. Considerably fewer studies have assessed the effects on innate immune cells. Here, we characterized NK cells in healthy individuals and immunocompromised patients in the course of an anti-SARS-CoV-2 BNT162b2 mRNA prospective, open-label clinical vaccine trial. See trial registration description in notes. Results revealed preserved NK cell numbers, frequencies, subsets, phenotypes, and function as assessed through consecutive peripheral blood samplings at 0, 10, 21, and 35 days following vaccination. A positive correlation was observed between the frequency of NKG2C+ NK cells at baseline (Day 0) and anti-SARS-CoV-2 Ab titers following BNT162b2 mRNA vaccination at Day 35. The present results provide basic insights in regards to NK cells in the context of mRNA vaccination, and have relevance for future mRNA-based vaccinations against COVID-19, other viral infections, and cancer.Trial registration: The current study is based on clinical material from the COVAXID open-label, non-randomized prospective clinical trial registered at EudraCT and clinicaltrials.gov (no. 2021-000175-37). Description: https://clinicaltrials.gov/ct2/show/NCT04780659?term=2021-000175-37&draw=2&rank=1 .


Assuntos
Vacina BNT162/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Hospedeiro Imunocomprometido/imunologia , Células Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Vacina BNT162/administração & dosagem , COVID-19/epidemiologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Feminino , Citometria de Fluxo , Humanos , Células Matadoras Naturais/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Pandemias/prevenção & controle , SARS-CoV-2/fisiologia , Vacinação/métodos , Vacinação/estatística & dados numéricos , Adulto Jovem
12.
J Virol ; 95(18): e0047921, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34232744

RESUMO

HIV-1 elite controllers (EC) are a rare group among HIV-1-infected individuals who can naturally control viral replication for a prolonged period. Due to their heterogeneous nature, no universal mechanism could be attributed to the EC status; instead, several host and viral factors have been discussed as playing a role. In this study, we investigated the fecal metabolome and microbiome in a Swedish cohort of EC (n = 14), treatment-naive viremic progressors (VP; n = 16), and HIV-negative individuals (HC; n = 12). Fecal untargeted metabolomics was performed by four ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Molecular docking and biochemical microscale thermophoresis (MST) were used to describe the peptide-metabolite interactions. Single-cycle infectivity assays were performed in TZM-Bl cell lines using CCR5- and CXCR4-tropic HIV-1 strains. The microbiome analysis was performed using 16S rRNA sequencing. Th effects of metabolites on bacterial species viability were determined using several clinical isolates. We observed an enrichment of dipeptides in EC compared to VP and HC (adjusted P < 0.05). In silico analysis by molecular docking, in vitro biochemical assays, and ex vivo infection assays identified anti-HIV-1 properties for two dipeptides (WG and VQ) that could bind to the HIV-1 gp120, of which WG was more potent. The microbiome analysis identified enrichment of the genus Prevotella in EC, and these dipeptides supported bacterial growth of the genus Prevotella in vitro. The enrichments of the dipeptides and higher abundance of Prevotella have a distinct mechanism of elite control status in HIV-1 infection that influences host metabolism. IMPORTANCE HIV-1 elite controllers (EC) are a rare group among HIV-1-infected individuals who can naturally control viral replication for a prolonged period. Due to their heterogeneous nature, no universal mechanism could be attributed to the EC status; instead, several host and viral factors have been discussed as playing a role. In this study, we investigated the fecal metabolome and microbiome in a Swedish cohort of EC, treatment-naive viremic progressors (VP), and HIV-negative individuals (HC). We observed an enrichment of dipeptides in EC compared to the other two study groups. In silico and in vitro analyses identified anti-HIV-1 properties for two dipeptides that could bind to the HIV-1 gp120 and act as an HIV-1 antagonist. Furthermore, these dipeptides supported bacterial growth of the genus Prevotella in vitro that was enriched in EC, which influences host metabolism. Thus, increased levels of both dipeptides and Prevotella could provide beneficial effects for EC.


Assuntos
Infecções por Bacteroidaceae/microbiologia , Dipeptídeos/farmacologia , Fezes/microbiologia , Infecções por HIV/prevenção & controle , HIV-1/fisiologia , Metaboloma , Prevotella/patogenicidade , Adulto , Infecções por Bacteroidaceae/tratamento farmacológico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , Estudos de Coortes , Fezes/química , Feminino , Perfilação da Expressão Gênica , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Fenótipo , Replicação Viral
13.
Molecules ; 27(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35684391

RESUMO

Hydroxyl radical (•OH) scavenging and the regeneration of Fe2+ may inhibit or enhance peroxidative damage induced by a Fenton system, respectively. Plant polyphenols reveal the afore-mentioned activities, and their cumulative net effect may determine anti- or pro-oxidant actions. We investigated the influence of 17 phenolics on ultra-weak photon emission (UPE) from a modified Fenton system (92.6 µmol/L Fe2+, 185.2 µmol/L EGTA (ethylene glycol-bis(ß-aminoethyl-ether)-N,N,N',N,-tetraacetic acid) and 2.6 mmol/L H2O2 pH = 7.4). A total of 8 compounds inhibited (antioxidant effect), and 5 enhanced (pro-oxidant effect) UPE at all studied concentrations (5 to 50 µmol/L). A total of 4 compounds altered their activity from pro- to antioxidant (or vice versa) along with increasing concentrations. A total of 3 the most active of those (ferulic acid, chlorogenic acid and cyanidin 3-O-glucoside; mean UPE enhancement by 63%, 5% and 445% at 5 µmol/L; mean UPE inhibition by 28%, 94% and 24% at 50 µmol/L, respectively) contained catechol or methoxyphenol structures that are associated with effective •OH scavenging and Fe2+ regeneration. Most likely, these structures can determine the bidirectional, concentration-dependent activity of some phenolics under stable in vitro conditions. This is because the concentrations of the studied compounds are close to those occurring in human fluids, and this phenomenon should be considered in the case of dietary supplementation with isolated phenolics.


Assuntos
Peróxido de Hidrogênio , Polifenóis , Antioxidantes/química , Antioxidantes/farmacologia , Ácido Egtázico , Humanos , Peróxido de Hidrogênio/química , Fenóis/química , Fenóis/farmacologia , Polifenóis/farmacologia , Espécies Reativas de Oxigênio
14.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915907

RESUMO

Ascorbic acid (AA) has antioxidant properties. However, in the presence of Fe2+/Fe3+ ions and H2O2, it may behave as a pro-oxidant by accelerating and enhancing the formation of hydroxyl radicals (•OH). Therefore, in this study we evaluated the effect of AA at concentrations of 1 to 200 µmol/L on •OH-induced light emission (at a pH of 7.4 and temperature of 37 °C) from 92.6 µmol/L Fe2+-185.2 µmol/L EGTA (ethylene glycol-bis (ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid)-2.6 mmol/L H2O2, and 92.6 µmol/L Fe3+-185.2 µmol/L EGTA-2.6 mmol/L H2O2 systems. Dehydroascorbic acid (DHAA) at the same range of concentrations served as the reference compound. Light emission was measured with multitube luminometer (AutoLumat Plus LB 953) for 120 s after automatic injection of H2O2. AA at concentrations of 1 to 50 µmol/L and of 1 to 75 µmol/L completely inhibited light emission from Fe2+-EGTA-H2O2 and Fe3+-EGTA-H2O2, respectively. Concentrations of 100 and 200 µmol/L did not affect chemiluminescence of Fe3+-EGTA-H2O2 but tended to increase light emission from Fe2+-EGTA-H2O2. DHAA at concentrations of 1 to 100 µmol/L had no effect on chemiluminescence of both systems. These results indicate that AA at physiological concentrations exhibits strong antioxidant activity in the presence of chelated iron and H2O2.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Ácido Ascórbico/química , Ácido Ascórbico/farmacologia , Ácido Egtázico/química , Compostos Férricos/química , Compostos Ferrosos/química , Peróxido de Hidrogênio/química , Radical Hidroxila/efeitos adversos , Radical Hidroxila/antagonistas & inibidores , Radical Hidroxila/química , Luminescência , Medições Luminescentes
15.
PLoS Pathog ; 14(4): e1006973, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29652923

RESUMO

CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine ß-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and ß-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of ß-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and eomesodermin (Eomes). This effector population is predominately found in peripheral blood and is limited in LNs regardless of HIV infection or treatment status. As a result, CD4+ T cells generally lack effector functions in LNs, including cytolytic capacity and IFNγ and ß-chemokine expression, even in HIV elite controllers and during acute/early HIV infection. While we do find the presence of degranulating CD4+ T cells in LNs, these cells do not bear functional or transcriptional effector T cell properties and are inherently poor to form stable immunological synapses compared to their peripheral blood counterparts. We demonstrate that CD4+ T cell cytolytic function, phenotype, and programming in the peripheral blood is dissociated from those characteristics found in lymphoid tissues. Together, these data challenge our current models based on blood and suggest spatially and temporally dissociated mechanisms of viral control in lymphoid tissues.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Vigilância Imunológica , Linfonodos/imunologia , Tecido Linfoide/imunologia , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , Infecções por HIV/virologia , Humanos , Linfonodos/virologia , Tecido Linfoide/virologia , Carga Viral
16.
Sensors (Basel) ; 20(23)2020 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-33260393

RESUMO

Thin-film n-n nanoheterostructures of SnO2/TiO2, highly sensitive to NO2, were obtained in a two-step process: (i) magnetron sputtering, MS followed by (ii) Langmuir-Blodgett, L-B, technique. Thick (200 nm) SnO2 base layers were deposited by MS and subsequently overcoated with a thin and discontinuous TiO2 film by means of L-B. Rutile nanopowder spread over the ethanol/chloroform/water formed a suspension, which was used as a source in L-B method. The morphology, crystallographic and electronic properties of the prepared sensors were studied by scanning electron microscopy, SEM, X-ray diffraction, XRD in glancing incidence geometry, GID, X-ray photoemission spectroscopy, XPS, and uv-vis-nir spectrophotometry, respectively. It was found that amorphous SnO2 films responded to relatively low concentrations of NO2 of about 200 ppb. A change of more than two orders of magnitude in the electrical resistivity upon exposure to NO2 was further enhanced in SnO2/TiO2 n-n nanoheterostructures. The best sensor responses RNO2/R0 were obtained at the lowest operating temperatures of about 120 °C, which is typical for nanomaterials. Response (recovery) times to 400 ppb NO2 were determined as a function of the operating temperature and indicated a significant decrease from 62 (42) s at 123 °C to 12 (19) s at 385 °C A much smaller sensitivity to H2 was observed, which might be advantageous for selective detection of nitrogen oxides. The influence of humidity on the NO2 response was demonstrated to be significantly below 150 °C and systematically decreased upon increase in the operating temperature up to 400 °C.

17.
Molecules ; 25(18)2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32957629

RESUMO

Propolis is a natural bee product with various beneficial biological effects. The health-promoting properties of propolis depend on its chemical composition, particularly the presence of phenolic compounds. The aim of this study was to evaluate the relationship between extraction solvent (acetone 100%, ethanol 70% and 96%) and the antifungal, antioxidant, and cytoprotective activity of the extracts obtained from propolis. Concentrations of flavonoids and phenolic acids in the propolis extracts were determined using ultrahigh-performance liquid chromatography. The antioxidant potential of different extracts was assessed on the basis of 2,2-diphenyl-1-picrylhydrazyl (DPPH·) free-radical-scavenging activity, Fe3+-reducing power, and ferrous ion (Fe2+)-chelating activity assays. The ability of the extracts to protect human red blood cell membranes against free-radical-induced damage and their antifungal activity was also determined. The results showed that the concentration of flavonoids in the propolis extracts was dependent on the solvent used in the extraction process and pinocembrin, chrysin, galangin, and coumaric acid were the most abundant phenols. All extracts exhibited high antioxidant potential and significantly protected human erythrocytes against oxidative damage. On the other hand, the antifungal activity of the propolis extracts depended on the solvent used in extraction and the fungal strains tested. It needs to be stressed that, to the best of our knowledge, there is no study relating the effect of solvent used for extraction of Polish propolis to its phenolic profile, and its antifungal, antioxidant, and cytoprotective activity.


Assuntos
Antifúngicos/química , Antioxidantes/química , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Própole/química , Solventes/química , Acetona/química , Animais , Antifúngicos/farmacologia , Antioxidantes/farmacologia , Abelhas , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Ácidos Cumáricos/química , Avaliação Pré-Clínica de Medicamentos , Eritrócitos/efeitos dos fármacos , Etanol/química , Flavanonas/química , Flavonoides/química , Humanos , Hidroxibenzoatos/química , Extração Líquido-Líquido
18.
Pol Merkur Lekarski ; 48(284): 97-99, 2020 Apr 22.
Artigo em Polonês | MEDLINE | ID: mdl-32352939

RESUMO

Ventricular arrhythmias, including tachycardia and ventricular fibrillation are often a dangerous consequence other co-existing conditions in the phase of their destabilization. Causal and symptomatic treatment diseases such as: ischemic heart disease, cardiac insufficiency, hyperthyroidism, or cancer, can be effectively stabilized without necessity for the implantation of cardioverter-defibrillator (ICD). CASE REPORT: The 62-year-old patient was admitted to the cardiology department after a second episode of unconsciousness last week due to recurrent VT. Despite many diagnostic difficulties, the possibility of effective conservative treatment has been demonstrated.


Assuntos
Desfibriladores Implantáveis , Taquicardia Ventricular , Morte Súbita Cardíaca , Cardioversão Elétrica , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Fibrilação Ventricular
19.
EMBO J ; 34(11): 1589-600, 2015 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-25925385

RESUMO

Stress caused by accumulation of misfolded proteins within the endoplasmic reticulum (ER) elicits a cellular unfolded protein response (UPR) aimed at maintaining protein-folding capacity. PERK, a key upstream component, recognizes ER stress via its luminal sensor/transducer domain, but the molecular events that lead to UPR activation remain unclear. Here, we describe the crystal structures of mammalian PERK luminal domains captured in dimeric state as well as in a novel tetrameric state. Small angle X-ray scattering analysis (SAXS) supports the existence of both crystal structures also in solution. The salient feature of the tetramer interface, a helix swapped between dimers, implies transient association. Moreover, interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Transdução de Sinais/fisiologia , eIF-2 Quinase/química , eIF-2 Quinase/metabolismo , Animais , Células Cultivadas , Cristalografia por Raios X , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Humanos , Camundongos , Camundongos Knockout , Fosforilação/fisiologia , Multimerização Proteica/fisiologia , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Resposta a Proteínas não Dobradas/fisiologia , eIF-2 Quinase/genética
20.
Luminescence ; 34(2): 183-192, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30675979

RESUMO

Oxidative reactions can result in the formation of electronically excited species that undergo radiative decay depending on electronic transition from the excited state to the ground state with subsequent ultra-weak photon emission (UPE). We investigated the UPE from the Fe2+ -EDTA (ethylenediaminetetraacetic acid)-AA (ascorbic acid)-H2 O2 (hydrogen peroxide) system with a multitube luminometer (Peltier-cooled photon counter, spectral range 380-630 nm). The UPE, of 92.6 µmol/L Fe2+ , 185.2 µmol/L EDTA, 472 µmol/L AA, 2.6 mmol/L H2 O2 , reached 1217 ± 118 relative light units during 2 min measurement and was about two times higher (P < 0.001) than the UPE of incomplete systems (Fe2+ -AA-H2 O2 , Fe2+ -EDTA-H2 O2 , AA-H2 O2 ) and medium alone. Substitution of Fe2+ with Cr2+ , Co2+ , Mn2+ or Cu2+ as well as of EDTA with EGTA (ethylene glycol-bis(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid) or citrate powerfully inhibited UPE. Experiments with scavengers of reactive oxygen species (dimethyl sulfoxide, mannitol, sodium azide, superoxide dismutase) revealed the dependence of UPE only on hydroxyl radicals. Dimethyl sulfoxide at the concentration of 0.74 mmol/L inhibited UPE by 79 ± 4%. Plant phenolics (ferulic, chlorogenic and caffec acids) at the concentration of 870 µmol/L strongly enhanced UPE by 5-, 13.9- and 46.8-times (P < 0.001), respectively. It is suggested that augmentation of UPE from Fe2+ -EDTA-AA-H2 O2 system can be applied for detection of these phytochemicals.


Assuntos
Ácido Ascórbico/química , Ácido Edético/química , Compostos Ferrosos/química , Peróxido de Hidrogênio/química , Hidroxibenzoatos/química , Luz , Estrutura Molecular , Plantas/química , Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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