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1.
J Clin Lipidol ; 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39256087

RESUMO

This National Lipid Association (NLA) Expert Clinical Consensus provides an overview of the physiologic and clinical considerations regarding the role of apolipoprotein B (apoB) measurement to guide clinical care based on the available scientific evidence and expert opinion. ApoB represents the total concentration of atherogenic lipoprotein particles in the circulation and more accurately reflects the atherogenic burden of lipoproteins when compared to low-density lipoprotein cholesterol (LDL-C). ApoB is a validated clinical measurement that augments the information found in a standard lipoprotein lipid panel; therefore, there is clinical value in using apoB in conjunction with a standard lipoprotein lipid profile when assessing risk and managing lipid-lowering therapy (LLT). ApoB has been shown to be superior to LDL-C in risk assessment both before and during treatment with LLT. In individuals, there can be discordance between levels of LDL-C and apoB, as well as LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C), despite high levels of population-wide correlation. When there is discordance between LDL-C and apoB, or LDL-C and non-HDL-C, atherosclerotic cardiovascular disease risk generally aligns better with apoB or non-HDL-C. Additionally, apoB can be used in tandem with standard lipoprotein lipid measurements to diagnose distinct lipoprotein phenotypes. ApoB testing can inform clinical prognosis and care, as well as enable family cascade screening, when an inherited lipoprotein syndrome is identified. The NLA and other organizations will continue to educate clinicians about the role of apoB measurement in improving clinical risk assessment and dyslipidemia management. An urgent need exists to improve access and reimbursement for apoB testing.

2.
J Am Coll Cardiol ; 84(11): 994-1006, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39232634

RESUMO

BACKGROUND: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations. OBJECTIVES: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial. METHODS: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations. RESULTS: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82). CONCLUSIONS: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).


Assuntos
Síndrome Coronariana Aguda , Anticorpos Monoclonais Humanizados , Triglicerídeos , Humanos , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Triglicerídeos/sangue , Pessoa de Meia-Idade , Idoso , Método Duplo-Cego , Resultado do Tratamento , Inibidores de PCSK9/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle
3.
Biochimie ; 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39033971

RESUMO

Protein aggregation is undesirable for cells due to its possible toxicity, and is also undesirable in biotechnology and pharmaceuticals. Polyamines are known to be capable of both suppressing and stimulating protein aggregation. In the present work polyamines (spermidine, putrescine) have been shown to alter the pathway of α-lactalbumin aggregation induced by dithiothreitol, leading to the formation of larger protein particles during the initial stages of aggregation and promoting the later stage of sticking of aggregates. According to the aggregation kinetics data, polyamines accelerate protein aggregation in a concentration-dependent manner, with a maximum at 50 mM spermidine and 100 mM putrescine. With a further increase in polyamines concentration the effect of aggregation acceleration decreased, thus, the modulation of the aggregation rate by polyamines was shown. A comparison of the aggregation kinetics and hydrodynamic radii growth data registered by dynamic light scattering with the data obtained by asymmetric flow field-flow fractionation and analytical ultracentrifugation allowed us to describe the early stages of aggregation and formation of initial α-lactalbumin clusters. Our results provide a deeper insight into the mechanism of amorphous aggregation of α-lactalbumin and polyamines action on protein aggregation and protein-protein interaction in general.

4.
Pflugers Arch ; 476(10): 1571-1585, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39042141

RESUMO

Advanced glycation endproducts (AGEs) contribute to cellular damage of various pathologies, including kidney diseases. Acute kidney injury (AKI) represents a syndrome seldom characterized by a single, distinct pathophysiological cause. Rhabdomyolysis-induced acute kidney injury (RIAKI) constitutes roughly 15% of AKI cases, yet its underlying pathophysiology remains poorly understood. Using a murine model of RIAKI induced by muscular glycerol injection, we observed elevated levels of AGEs and the AGE receptor galectin-3 (LGALS3) in the kidney. Immunofluorescence localized LGALS3 to distal nephron segments. According to transcriptomic profiling via next-generation sequencing, RIAKI led to profound changes in kidney metabolism, oxidative stress, and inflammation. Cellular stress was evident in both proximal and distal tubules, as shown by kidney injury markers KIM-1 and NGAL. However, only proximal tubules exhibited overt damage and apoptosis, as detected by routine morphology, active Caspase-3, and TUNEL assay, respectively. In vitro, distal convoluted tubule (DCT) cells challenged with AGEs underwent apoptosis, which was markedly enhanced by Lgals3 siRNA treatment. Thus, in RIAKI, the upregulation of LGALS3 may protect the distal nephron from AGE-mediated damage, while proximal tubules lacking LGALS3 stay at risk. Thus, stimulating LGALS3 in the proximal nephron, if achievable, may attenuate RIAKI.


Assuntos
Injúria Renal Aguda , Apoptose , Galectina 3 , Túbulos Renais Distais , Rabdomiólise , Animais , Masculino , Camundongos , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Galectina 3/metabolismo , Galectina 3/genética , Produtos Finais de Glicação Avançada/metabolismo , Túbulos Renais Distais/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Rabdomiólise/metabolismo , Rabdomiólise/complicações
5.
J Clin Lipidol ; 18(4): e548-e561, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38960812

RESUMO

BACKGROUND: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). OBJECTIVE: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. METHODS: This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. RESULTS: Women were older, had higher baseline low-density lipoprotein cholesterol (LDL-C) levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes. CONCLUSIONS: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).


Assuntos
Síndrome Coronariana Aguda , Anticorpos Monoclonais Humanizados , Lipoproteína(a) , Humanos , Masculino , Feminino , Lipoproteína(a)/sangue , Síndrome Coronariana Aguda/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Fatores Sexuais , LDL-Colesterol/sangue , Inibidores de PCSK9 , Caracteres Sexuais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle
6.
Nanoscale ; 16(28): 13663-13676, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-38963335

RESUMO

Carbon materials have paramount importance in various fields of materials science, from electronic devices to industrial catalysts. The properties of these materials are strongly related to the distribution of defects-irregularities in electron density on their surfaces. Different materials have various distributions and quantities of these defects, which can be imaged using a procedure that involves depositing palladium nanoparticles. The resulting scanning electron microscopy (SEM) images can be characterized by a key descriptor-the ordering of nanoparticle positions. This work presents a highly interpretable machine learning approach for distinguishing between materials with ordered and disordered arrangements of defects marked by nanoparticle attachment. The influence of the degree of ordering was experimentally evaluated on the example of catalysis via chemical reactions involving carbon-carbon bond formation. This represents an important step toward automated analysis of SEM images in materials science.

8.
Chem Commun (Camb) ; 60(62): 8099-8102, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38993133

RESUMO

Electrochemical hydrocarboxylation of enol acetates with CO2 is developed. The disclosed process provides ß-acetoxycarboxylic acids in 25-66% yields, in contrast to the electrolysis of ketones, silyl enol ethers and vinyl tosylates with CO2, which leads mainly to alcohols.

9.
Trends Cell Biol ; 34(9): 700-702, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38897887

RESUMO

Embryonic and adult stem cells enable development and regeneration. Embryonic cells, like adult stem cells, can enter dormancy as part of their lifecycle. Recent evidence suggests that this cellular transition to dormancy requires active rewiring of metabolism. The dormancy-induced metabolic switches in embryonic and adult stem cells are explored here.


Assuntos
Células-Tronco Embrionárias , Animais , Humanos , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Adultas/metabolismo , Células-Tronco Adultas/citologia
10.
Adv Ther ; 41(8): 3183-3195, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38904899

RESUMO

INTRODUCTION: Perimenopause is a time of transition in a woman's life that links her reproductive years to the cessation of ovulation, or menopause. For many women, this time is characterized by a variety of physiological and lifestyle changes, including increasing irregularity in menstrual bleeding, frequency and severity of vasomotor symptoms, etc. Therapies evaluated specifically for the perimenopausal women are very limited. This study aimed to evaluate the effectiveness and safety of Amberen® (a succinate-based non-hormonal supplement) combined with a Smart B® (vitamin B) complex in women with typical (without complications) mild to moderate climacteric syndrome during perimenopause. METHODS: Women up to 50 years of age, in perimenopause, with vasomotor and psychosomatic symptoms of the climacteric syndrome were enrolled for the study. The trial was randomized, double-blinded, placebo-controlled, comparative, and prospective. RESULTS: A total of 106 participants were enrolled in the trial and, per protocol, 105 completed the trial. We observed statistically significant improvements in most of the Greene Climacteric Scale symptoms, State-Trait Anxiety Inventory (STAI), Hospital Anxiety and Depression Scale (HADS), and Well-being, Activity, and Mood (WAM) scores. The intervention was well tolerated with few adverse effects reported to be mild and transient. CONCLUSION: The use of this dietary supplement is safe and eliminates or improves vasomotor and psychosomatic symptoms of climacteric symptoms in perimenopausal women: it improves sleep and cognitive abilities, lowers depression and anxiety, improves mood and well-being, and positively affects quality of life. GOV IDENTIFIER: NCT03897738.


Assuntos
Suplementos Nutricionais , Perimenopausa , Humanos , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Complexo Vitamínico B/uso terapêutico , Depressão , Estudos Prospectivos , Ansiedade , Qualidade de Vida , Resultado do Tratamento , Adulto , Fogachos/tratamento farmacológico , Síndrome
11.
Nanoscale ; 16(26): 12424-12430, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38887059

RESUMO

Existing methods for the mass detection of viruses are limited to the registration of small amounts of a viral genome or specific protein markers. In spite of high sensitivity, the applied methods cannot distinguish between virulent viral particles and non-infectious viral particle debris. We report an approach to solve this long-standing challenge using the SARS-CoV-2 virus as an example. We show that wide-field optical microscopy with the state-of-the-art mesoscopic fluorescent labels, formed by a core-shell plasmonic nanoparticle with fluorescent dye molecules in the core-shell that are strongly coupled to the plasmonic nanoparticle, not only rapidly, i.e. in less than 20 minutes after sampling, detects SARS-CoV-2 virions directly in a patient sample without a pre-concentration step, but can also distinguish between infectious and non-infectious virus strains by counting the spikes on the lipid envelope of individual viral particles.


Assuntos
COVID-19 , Corantes Fluorescentes , SARS-CoV-2 , Vírion , SARS-CoV-2/isolamento & purificação , Vírion/isolamento & purificação , Vírion/química , Humanos , COVID-19/virologia , COVID-19/diagnóstico , Corantes Fluorescentes/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Nanopartículas Metálicas/química , Microscopia de Fluorescência/métodos
12.
Viruses ; 16(6)2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38932227

RESUMO

The HIV envelope glycoprotein (Env) is a trimeric protein that facilitates viral binding and fusion with target cells. As the sole viral protein on the HIV surface, Env is important both for immune responses to HIV and in vaccine designs. Targeting Env in clinical applications is challenging due to its heavy glycosylation, high genetic variability, conformational camouflage, and its low abundance on virions. Thus, there is a critical need to better understand this protein. Flow virometry (FV) is a useful methodology for phenotyping the virion surface in a high-throughput, single virion manner. To demonstrate the utility of FV to characterize Env, we stained HIV virions with a panel of 85 monoclonal antibodies targeting different regions of Env. A broad range of antibodies yielded robust staining of Env, with V3 antibodies showing the highest quantitative staining. A subset of antibodies tested in parallel on viruses produced in CD4+ T cell lines, HEK293T cells, and primary cells showed that the cellular model of virus production can impact Env detection. Finally, in addition to being able to highlight Env heterogeneity on virions, we show FV can sensitively detect differences in Env conformation when soluble CD4 is added to virions before staining.


Assuntos
HIV-1 , Vírion , Produtos do Gene env do Vírus da Imunodeficiência Humana , Humanos , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , HIV-1/genética , HIV-1/fisiologia , HIV-1/imunologia , Vírion/metabolismo , Células HEK293 , Anticorpos Anti-HIV/imunologia , Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/virologia
13.
Plast Reconstr Surg ; 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38857415

RESUMO

BACKGROUND: Color match of a reconstructed breast with the surrounding area is of importance for the overall aesthetic result. The objective of our study was to quantify the degree of color match achieved with different autologous breast reconstructions and to analyze the changes in color over time by analyzing digital photographs. METHODS: 193 patients that underwent a delayed autologous breast reconstruction (DIEP, PAP, LAP, LD) were included. Standardized pictures from 242 flaps at 3 months and 9-12 months postoperative were analyzed and the L*a*b* values and delta E2000 (dE) values were determined to qualify the color match. The Kruskal-Wallis and Wilcoxon rank-sum tests were used for statistical analysis. RESULTS: Initially, DIEP flaps had a significant lower dE value compared to LD (p=0.012) and PAP flaps (p < 0.001) when compared with the natural breast. PAP flaps showed a significant decrease after 9-12 months (p=0.003). Perception of color match was in all flaps comparable. Compared to the cleavage, at late follow-up, DIEP flaps had a significant higher dE value compared to LD (p=0.017) and PAP flaps (p < 0.001). PAP flaps presented a significant decrease of dE after 9-12 months (p =0.031). Abdominal skin presented no better skin color match in patients with PAP, LD, and LAP flaps. CONCLUSIONS: All analyzed flaps have a comparable color match with the surrounding tissue as well as with the contralateral breast about one year after surgery. The color of PAP flaps changes more, which leads to an improvement at a later follow-up.

14.
Nat Struct Mol Biol ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783076

RESUMO

Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus in a dormant state called diapause, which can be induced in vitro through mTOR inhibition. Cellular strategies that safeguard original cell identity within the silent genomic landscape of dormancy are not known. Here we show that the protection of cis-regulatory elements from silencing is key to maintaining pluripotency in the dormant state. We reveal a TET-transcription factor axis, in which TET-mediated DNA demethylation and recruitment of methylation-sensitive transcription factor TFE3 drive transcriptionally inert chromatin adaptations during dormancy transition. Perturbation of TET activity compromises pluripotency and survival of mouse embryos under dormancy, whereas its enhancement improves survival rates. Our results reveal an essential mechanism for propagating the cellular identity of dormant cells, with implications for regeneration and disease.

15.
Gene ; 921: 148520, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-38702020

RESUMO

A phylogenetic analysis of transcription factors of the Sox-Tcf/Lef-Mata (STM) family of the HMG-B superfamily was carried out in order to clarify the evolutionary roots of the Wnt signaling pathway in unicellular organisms. The data set for analysis included protein sequences of metazoans, fungi, unicellular opisthokonts, apusomonads and amoebozoans. The topology of the phylogenetic tree suggests that STM-related proteins arose in the common ancestor of Opisthokonta and Amoebozoa, two of amoebozoan STM proteins are sister-related to opisthokont ones and the three known lineages of STM transcription factors (STM family in narrow sence) are found in Opisthokonta only. Of these, the holozoan Sox protein branch is the result of either the first or second branching, that originated in the common ancestor of Opisthokonta. The lineage containing Tcf/Lef proteins (holozoan) and the lineage containing Mata proteins (holomycotan) are sister. They derived either at the time of the Holozoa and Holomycota divergence or originate from two paralogs of the common ancestor of Opisthokonta, which arose after the separation of the Sox lineage. Interaction with Armadillo-like proteins may be an original feature of the STM protein family and existed in the unicellular ancestors of multicellular animals; a connection is possible between the presence of Mata-related proteins in Aphelidium protococcorum and specific genome feature of this species.


Assuntos
Evolução Molecular , Filogenia , Animais , Fungos/genética , Fungos/metabolismo , Proteínas HMGB/genética , Proteínas HMGB/metabolismo , Fatores de Transcrição SOX/genética , Fatores de Transcrição SOX/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Via de Sinalização Wnt
16.
Crit Care Explor ; 6(6): e1093, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38813435

RESUMO

OBJECTIVES: To develop and validate a prediction model for 1-year mortality in patients with a hematologic malignancy acutely admitted to the ICU. DESIGN: A retrospective cohort study. SETTING: Five university hospitals in the Netherlands between 2002 and 2015. PATIENTS: A total of 1097 consecutive patients with a hematologic malignancy were acutely admitted to the ICU for at least 24 h. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We created a 13-variable model from 22 potential predictors. Key predictors included active disease, age, previous hematopoietic stem cell transplantation, mechanical ventilation, lowest platelet count, acute kidney injury, maximum heart rate, and type of malignancy. A bootstrap procedure reduced overfitting and improved the model's generalizability. This involved estimating the optimism in the initial model and shrinking the regression coefficients accordingly in the final model. We assessed performance using internal-external cross-validation by center and compared it with the Acute Physiology and Chronic Health Evaluation II model. Additionally, we evaluated clinical usefulness through decision curve analysis. The overall 1-year mortality rate observed in the study was 62% (95% CI, 59-65). Our 13-variable prediction model demonstrated acceptable calibration and discrimination at internal-external validation across centers (C-statistic 0.70; 95% CI, 0.63-0.77), outperforming the Acute Physiology and Chronic Health Evaluation II model (C-statistic 0.61; 95% CI, 0.57-0.65). Decision curve analysis indicated overall net benefit within a clinically relevant threshold probability range of 60-100% predicted 1-year mortality. CONCLUSIONS: Our newly developed 13-variable prediction model predicts 1-year mortality in hematologic malignancy patients admitted to the ICU more accurately than the Acute Physiology and Chronic Health Evaluation II model. This model may aid in shared decision-making regarding the continuation of ICU care and end-of-life considerations.


Assuntos
Neoplasias Hematológicas , Unidades de Terapia Intensiva , Humanos , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Feminino , Idoso , Países Baixos/epidemiologia , Adulto , APACHE , Estudos de Coortes
17.
Nanoscale Horiz ; 9(6): 1013-1022, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38597212

RESUMO

In recent years, extensive research efforts have been dedicated to the investigation of CdSe/CdS-based quantum-confined nanostructures, driven by their distinctive properties. The morphologies of these nanostructures have been shown to directly affect their properties, an area which has proven to be an important field of study. Herein, we report a new morphology of CdSe/CdS core-shell heterostructures in the form of a 'nanonail' - a modified nanorod-like morphology, in which a distinctive triangular head can be observed at one end of the structure. In-depth studies of this morphology reveal a material with tuneable rod length and width, as well as exceptional photoluminescent properties. Following this, we have demonstrated the ability to induce chiroptical activity via ligand exchange, revealing the important role of the specific morphology, shell thickness and chiral ligand concentration in the effect of ligand induced chirality. In addition, the cellular uptake and cytotoxicity of obtained chiral nanostructures were evaluated on human lung-derived A549 cancer cells, revealing a significant enantioselectivity in biological activity. Finally, analysis on monolayers of the material demonstrate the complete absence of FRET processes. Overall, this CdSe/CdS heterostructure is another tuneable morphology of a very important nanomaterial, one which shows great advantages and a range of potential applications.

18.
J Virol ; 98(5): e0036324, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38661384

RESUMO

HIV-1 has a broad range of nuanced interactions with the immune system, and the incorporation of cellular proteins by nascent virions continues to redefine our understanding of the virus-host relationship. Proteins located at the sites of viral egress can be selectively incorporated into the HIV-1 envelope, imparting new functions and phenotypes onto virions, and impacting viral spread and disease. Using virion capture assays and western blot, we show that HIV-1 can incorporate the myeloid antigen CD14 into its viral envelope. Virion-incorporated CD14 remained biologically active and able to bind its natural ligand, bacterial lipopolysaccharide (LPS), as demonstrated by flow virometry and immunoprecipitation assays. Using a Toll-like receptor 4 (TLR4) reporter cell line, we also demonstrated that virions with bound LPS can trigger TLR4 signaling to activate transcription factors that regulate inflammatory gene expression. Complementary assays with THP-1 monocytes demonstrated enhanced secretion of inflammatory cytokines like tumor necrosis factor alpha (TNF-α) and the C-C chemokine ligand 5 (CCL5), when exposed to LPS-loaded virus. These data highlight a new type of interplay between HIV-1 and the myeloid cell compartment, a previously well-established cellular contributor to HIV-1 pathogenesis and inflammation. Persistent gut inflammation is a hallmark of chronic HIV-1 infection, and contributing to this effect is the translocation of microbes across the gut epithelium. Our data herein provide proof of principle that virion-incorporated CD14 could be a novel mechanism through which HIV-1 can drive chronic inflammation, facilitated by HIV-1 particles binding bacterial LPS and initiating inflammatory signaling in TLR4-expressing cells.IMPORTANCEHIV-1 establishes a lifelong infection accompanied by numerous immunological changes. Inflammation of the gut epithelia, exacerbated by the loss of mucosal T cells and cytokine dysregulation, persists during HIV-1 infection. Feeding back into this loop of inflammation is the translocation of intestinal microbes across the gut epithelia, resulting in the systemic dissemination of bacterial antigens, like lipopolysaccharide (LPS). Our group previously demonstrated that the LPS receptor, CD14, can be readily incorporated by HIV-1 particles, supporting previous clinical observations of viruses derived from patient plasma. We now show that CD14 can be incorporated by several primary HIV-1 isolates and that this virion-incorporated CD14 can remain functional, enabling HIV-1 to bind to LPS. This subsequently allowed CD14+ virions to transfer LPS to monocytic cells, eliciting pro-inflammatory signaling and cytokine secretion. We posit here that virion-incorporated CD14 is a potential contributor to the dysregulated immune responses present in the setting of HIV-1 infection.


Assuntos
Infecções por HIV , HIV-1 , Receptores de Lipopolissacarídeos , Lipopolissacarídeos , Vírion , Humanos , Quimiocina CCL5/metabolismo , Infecções por HIV/virologia , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV-1/imunologia , HIV-1/fisiologia , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/metabolismo , Monócitos/metabolismo , Monócitos/imunologia , Monócitos/virologia , Transdução de Sinais , Células THP-1 , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vírion/metabolismo
19.
Eur Heart J Cardiovasc Pharmacother ; 10(4): 342-352, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38658193

RESUMO

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.


Assuntos
Anticorpos Monoclonais Humanizados , LDL-Colesterol , Inibidores de PCSK9 , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/uso terapêutico , Biomarcadores/sangue , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/sangue , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/diagnóstico , Pró-Proteína Convertase 9/metabolismo , Pró-Proteína Convertase 9/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Serina Proteinase/efeitos adversos , Inibidores de Serina Proteinase/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
20.
J Nematol ; 56(1): 20240011, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38590711

RESUMO

Metaparasitylenchus hypothenemi is a nematode that naturally parasitizes Hypothenemus hampei in a coffee-producing region in Chiapas, Mexico. This study investigated changes in the attraction of parasitized borers to light. We compared the attraction of adult H. hampei females (parasitized and uninfected) to 14 different light wavelengths (350-670 nm) with a control (570 nm, yellow) under laboratory conditions. The response ranges of non-parasitized and parasitized borers were 370-650 nm and 340-650 nm, respectively. The attraction curve showed a similar shape in both borer groups (parasitized and non-parasitized), but a wide wavelength range (380-590 nm) attracted more parasitized than non-parasitized borers. The maximum response of the uninfected borers occurred at 520 nm (green), while parasitized borers exhibited three response peaks (380 nm, violet; 460 nm, blue; 520 nm, green). Parasitized borers were significantly more attracted to green light (520 nm) than to the control. The altered attraction to light in borers parasitized by M. hypothenemi is discussed from the perspective of possible host manipulation and the natural prevalence of this parasite.

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