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1.
EMBO J ; 40(20): e107966, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34520050

RESUMO

Phosphatidylcholine (PC) is an abundant membrane lipid component in most eukaryotes, including yeast, and has been assigned multiple functions in addition to acting as building block of the lipid bilayer. Here, by isolating S. cerevisiae suppressor mutants that exhibit robust growth in the absence of PC, we show that PC essentiality is subject to cellular evolvability in yeast. The requirement for PC is suppressed by monosomy of chromosome XV or by a point mutation in the ACC1 gene encoding acetyl-CoA carboxylase. Although these two genetic adaptations rewire lipid biosynthesis in different ways, both decrease Acc1 activity, thereby reducing average acyl chain length. Consistently, soraphen A, a specific inhibitor of Acc1, rescues a yeast mutant with deficient PC synthesis. In the aneuploid suppressor, feedback inhibition of Acc1 through acyl-CoA produced by fatty acid synthase (FAS) results from upregulation of lipid synthesis. The results show that budding yeast regulates acyl chain length by fine-tuning the activities of Acc1 and FAS and indicate that PC evolved by benefitting the maintenance of membrane fluidity.


Assuntos
Acetil-CoA Carboxilase/genética , Ácido Graxo Sintases/genética , Bicamadas Lipídicas/metabolismo , Lipídeos de Membrana/metabolismo , Fosfatidilcolinas/deficiência , Saccharomyces cerevisiae/metabolismo , Acetil-CoA Carboxilase/metabolismo , Cromossomos Fúngicos , Ácido Graxo Sintases/metabolismo , Retroalimentação Fisiológica , Regulação Fúngica da Expressão Gênica , Bicamadas Lipídicas/química , Metabolismo dos Lipídeos/genética , Fluidez de Membrana , Lipídeos de Membrana/química , Mutação Puntual , Saccharomyces cerevisiae/genética
2.
Mol Cell Proteomics ; 22(6): 100562, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37142056

RESUMO

Modern mass spectrometers routinely allow deep proteome coverage in a single experiment. These methods are typically operated at nanoflow and microflow regimes, but they often lack throughput and chromatographic robustness, which is critical for large-scale studies. In this context, we have developed, optimized, and benchmarked LC-MS methods combining the robustness and throughput of analytical flow chromatography with the added sensitivity provided by the Zeno trap across a wide range of cynomolgus monkey and human matrices of interest for toxicological studies and clinical biomarker discovery. Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectra (SWATH) data-independent acquisition (DIA) experiments with Zeno trap activated (Zeno SWATH DIA) provided a clear advantage over conventional SWATH DIA in all sample types tested with improved sensitivity, quantitative robustness, and signal linearity as well as increased protein coverage by up to 9-fold. Using a 10-min gradient chromatography, up to 3300 proteins were identified in tissues at 2 µg peptide load. Importantly, the performance gains with Zeno SWATH translated into better biological pathway representation and improved the ability to identify dysregulated proteins and pathways associated with two metabolic diseases in human plasma. Finally, we demonstrate that this method is highly stable over time with the acquisition of reliable data over the injection of 1000+ samples (14.2 days of uninterrupted acquisition) without the need for human intervention or normalization. Altogether, Zeno SWATH DIA methodology allows fast, sensitive, and robust proteomic workflows using analytical flow and is amenable to large-scale studies.


Assuntos
Proteômica , Espectrometria de Massas em Tandem , Animais , Humanos , Espectrometria de Massas em Tandem/métodos , Macaca fascicularis , Proteômica/métodos , Software , Cromatografia Líquida/métodos , Proteoma
3.
Phys Rev Lett ; 132(9): 098101, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38489655

RESUMO

Understanding nanoscale mechanisms responsible for the recently discovered ferroelectric nematics can be helped by direct visualization of self-assembly of strongly polar molecules. Here, we report on scanning tunneling microscopy studies of monomolecular layers of a ferroelectric nematic liquid crystal on a reconstructed Au(111) surface. The monolayers are obtained by deposition from a solution at ambient conditions. The adsorbed ferroelectric nematic molecules self-assemble into regular rows with tilted orientation, resembling a layered structure of a smectic C. Remarkably, each molecular dipole in this architecture is oriented along the same direction giving rise to polar ferroelectric ordering.

4.
Nucleic Acids Res ; 50(D1): D11-D19, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34850134

RESUMO

The European Bioinformatics Institute (EMBL-EBI) maintains a comprehensive range of freely available and up-to-date molecular data resources, which includes over 40 resources covering every major data type in the life sciences. This year's service update for EMBL-EBI includes new resources, PGS Catalog and AlphaFold DB, and updates on existing resources, including the COVID-19 Data Platform, trRosetta and RoseTTAfold models introduced in Pfam and InterPro, and the launch of Genome Integrations with Function and Sequence by UniProt and Ensembl. Furthermore, we highlight projects through which EMBL-EBI has contributed to the development of community-driven data standards and guidelines, including the Recommended Metadata for Biological Images (REMBI), and the BioModels Reproducibility Scorecard. Training is one of EMBL-EBI's core missions and a key component of the provision of bioinformatics services to users: this year's update includes many of the improvements that have been developed to EMBL-EBI's online training offering.


Assuntos
Biologia Computacional/educação , Biologia Computacional/métodos , Bases de Dados Factuais , Academias e Institutos , Inteligência Artificial , COVID-19 , Bases de Dados Factuais/economia , Bases de Dados Factuais/estatística & dados numéricos , Bases de Dados de Produtos Farmacêuticos , Bases de Dados de Proteínas , Europa (Continente) , Genoma Humano , Humanos , Armazenamento e Recuperação da Informação , RNA não Traduzido/genética , SARS-CoV-2/genética
5.
Food Microbiol ; 121: 104520, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38637082

RESUMO

Sequence-based analysis of fermented foods and beverages' microbiomes offers insights into their impact on taste and consumer health. High-throughput metagenomics provide detailed taxonomic and functional community profiling, but bacterial and yeast genome reconstruction and mobile genetic elements tracking are to be improved. We established a pipeline for exploring fermented foods microbiomes using metagenomics coupled with chromosome conformation capture (Hi-C metagenomics). The approach was applied to analyze a collection of spontaneously fermented beers and ciders (n = 12). The Hi-C reads were used to reconstruct the metagenome-assembled genomes (MAGs) of bacteria and yeasts facilitating subsequent comparative genomic analysis, assembly scaffolding and exploration of "plasmid-bacteria" links. For a subset of beverages, yeasts were isolated and characterized phenotypically. The reconstructed Hi-C MAGs primarily belonged to the Lactobacillaceae family in beers, along with Acetobacteraceae and Enterobacteriaceae in ciders, exhibiting improved quality compared to conventional metagenomic MAGs. Comparative genomic analysis of Lactobacillaceae Hi-C MAGs revealed clustering by niche and suggested genetic determinants of survival and probiotic potential. For Pediococcus damnosus, Hi-C-based networks of contigs enabled linking bacteria with plasmids. Analyzing phylogeny and accessory genes in the context of known reference genomes offered insights into the niche specialization of beer lactobacilli. The subspecies-level diversity of cider Tatumella spp. was disentangled using a Hi-C-based graph. We obtained highly complete yeast Hi-C MAGs primarily represented by Brettanomyces and Saccharomyces, with Hi-C-facilitated chromosome-level genome assembly for the former. Utilizing Hi-C metagenomics to unravel the genomic content of individual species can provide a deeper understanding of the ecological interactions within the food microbiome, aid in bioprospecting beneficial microorganisms, improving quality control and improving innovative fermented products.


Assuntos
Saccharomyces cerevisiae , Saccharomyces , Saccharomyces cerevisiae/genética , Cerveja/microbiologia , Bactérias/genética , Plasmídeos , Saccharomyces/genética , Metagenoma , Metagenômica , Enterobacteriaceae/genética
6.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33692123

RESUMO

The hippocampus's dorsal and ventral parts are involved in different operative circuits, the functions of which vary in time during the night and day cycle. These functions are altered in epilepsy. Since energy production is tailored to function, we hypothesized that energy production would be space- and time-dependent in the hippocampus and that such an organizing principle would be modified in epilepsy. Using metabolic imaging and metabolite sensing ex vivo, we show that the ventral hippocampus favors aerobic glycolysis over oxidative phosphorylation as compared to the dorsal part in the morning in control mice. In the afternoon, aerobic glycolysis is decreased and oxidative phosphorylation increased. In the dorsal hippocampus, the metabolic activity varies less between these two times but is weaker than in the ventral. Thus, the energy metabolism is different along the dorsoventral axis and changes as a function of time in control mice. In an experimental model of epilepsy, we find a large alteration of such spatiotemporal organization. In addition to a general hypometabolic state, the dorsoventral difference disappears in the morning, when seizure probability is low. In the afternoon, when seizure probability is high, the aerobic glycolysis is enhanced in both parts, the increase being stronger in the ventral area. We suggest that energy metabolism is tailored to the functions performed by brain networks, which vary over time. In pathological conditions, the alterations of these general rules may contribute to network dysfunctions.


Assuntos
Epilepsia/metabolismo , Hipocampo/metabolismo , Animais , Estudos de Casos e Controles , Ritmo Circadiano , Modelos Animais de Doenças , Metabolismo Energético , Epilepsia/fisiopatologia , Glicólise , Hipocampo/fisiopatologia , Masculino , Camundongos , Fosforilação Oxidativa , Probabilidade , Convulsões/metabolismo
7.
Wiad Lek ; 77(3): 608-612, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691808

RESUMO

A case report of Jarisch-Herxheimer (JHR) reaction on a 10th day of Leptospirosis caused by Leptospira Pomona. JHR occurs as a complication of an antibiotic treatment of various spirochetes and may lead to respiratory distress syndrome, renal failure, hepatic insufficiency, and multiple organ failure. This case represents a skin and cardio-vascular form of JHR with no lung involvement. The patient was treated with benzylpenicillin and low dexamethasone doses for 5th day of the disease with a shift to ceftriaxone and high doses of methylprednisolone. The fastest diagnosis of a sporadic zoonotic disease, early start of antibiotic therapy, and adequate doses of corticosteroids are key to the successful treatment of leptospirosis.


Assuntos
Antibacterianos , Leptospirose , Humanos , Masculino , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Ceftriaxona/uso terapêutico , Ceftriaxona/efeitos adversos , Dexametasona/uso terapêutico , Dexametasona/efeitos adversos , Leptospira/isolamento & purificação , Leptospirose/tratamento farmacológico , Leptospirose/complicações , Metilprednisolona/uso terapêutico , Metilprednisolona/administração & dosagem , Idoso
8.
Brief Bioinform ; 22(2): 642-663, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33147627

RESUMO

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causes the infectious disease COVID-19. The biology of coronaviruses has been studied for many years. However, bioinformatics tools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection, understanding and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to get insight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for the routine detection of SARS-CoV-2 infection, the reliable analysis of sequencing data, the tracking of the COVID-19 pandemic and evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets and development of therapeutic strategies. For each tool, we briefly describe its use case and how it advances research specifically for SARS-CoV-2. All tools are free to use and available online, either through web applications or public code repositories. Contact:evbc@unj-jena.de.


Assuntos
COVID-19/prevenção & controle , Biologia Computacional , SARS-CoV-2/isolamento & purificação , Pesquisa Biomédica , COVID-19/epidemiologia , COVID-19/virologia , Genoma Viral , Humanos , Pandemias , SARS-CoV-2/genética
9.
Opt Express ; 31(9): 14286-14298, 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-37157296

RESUMO

The first steps towards the development and characterization of next-generation chirped volume Bragg gratings (CVBGs) by means of fs laser inscription were made. Based on the phase mask inscription technique we realized CVBGs in fused silica with a 3 × 3 mm2 aperture and a length of almost 12 mm with a chirp rate of ∼190 ps/nm around a central wavelength of 1030.5 nm. Strong mechanical stresses induced serious polarization and phase distortions of the radiation. We show a possible approach to solution of this problem. The change in the linear absorption coefficient associated with local modification of fused silica is quite small, enabling utilization of this type of gratings in high average power lasers.

10.
Nucleic Acids Res ; 49(D1): D192-D200, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33211869

RESUMO

Rfam is a database of RNA families where each of the 3444 families is represented by a multiple sequence alignment of known RNA sequences and a covariance model that can be used to search for additional members of the family. Recent developments have involved expert collaborations to improve the quality and coverage of Rfam data, focusing on microRNAs, viral and bacterial RNAs. We have completed the first phase of synchronising microRNA families in Rfam and miRBase, creating 356 new Rfam families and updating 40. We established a procedure for comprehensive annotation of viral RNA families starting with Flavivirus and Coronaviridae RNAs. We have also increased the coverage of bacterial and metagenome-based RNA families from the ZWD database. These developments have enabled a significant growth of the database, with the addition of 759 new families in Rfam 14. To facilitate further community contribution to Rfam, expert users are now able to build and submit new families using the newly developed Rfam Cloud family curation system. New Rfam website features include a new sequence similarity search powered by RNAcentral, as well as search and visualisation of families with pseudoknots. Rfam is freely available at https://rfam.org.


Assuntos
Bases de Dados de Ácidos Nucleicos , Metagenoma , MicroRNAs/genética , RNA Bacteriano/genética , RNA não Traduzido/genética , RNA Viral/genética , Bactérias/genética , Bactérias/metabolismo , Pareamento de Bases , Sequência de Bases , Humanos , Internet , MicroRNAs/classificação , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Conformação de Ácido Nucleico , RNA Bacteriano/classificação , RNA Bacteriano/metabolismo , RNA não Traduzido/classificação , RNA não Traduzido/metabolismo , RNA Viral/classificação , RNA Viral/metabolismo , Alinhamento de Sequência , Análise de Sequência de RNA , Software , Vírus/genética , Vírus/metabolismo
11.
Int J Mol Sci ; 24(14)2023 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-37511000

RESUMO

Aristolochia manshuriensis is a relic liana, which is widely used in traditional Chinese herbal medicine and is endemic to the Manchurian floristic region. Since this plant is rare and slow-growing, alternative sources of its valuable compounds could be explored. Herein, we established hairy root cultures of A. manshuriensis transformed with Agrobacterium rhizogenes root oncogenic loci (rol)B and rolC genes. The accumulation of nitrogenous secondary metabolites significantly improved in transgenic cell cultures. Specifically, the production of magnoflorine reached up to 5.72 mg/g of dry weight, which is 5.8 times higher than the control calli and 1.7 times higher than in wild-growing liana. Simultaneously, the amounts of aristolochic acids I and II, responsible for the toxicity of Aristolochia species, decreased by more than 10 fold. Consequently, the hairy root extracts demonstrated pronounced cytotoxicity against human glioblastoma cells (U-87 MG), cervical cancer cells (HeLa CCL-2), and colon carcinoma (RKO) cells. However, they did not exhibit significant activity against triple-negative breast cancer cells (MDA-MB-231). Our findings suggest that hairy root cultures of A. manshuriensis could be considered for the rational production of valuable A. manshuriensis compounds by the modification of secondary metabolism.


Assuntos
Aristolochia , Humanos , Plantas , Medicina Tradicional Chinesa , China , Raízes de Plantas/metabolismo
12.
Aesthet Surg J ; 43(12): NP1001-NP1009, 2023 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-37439225

RESUMO

BACKGROUND: Tuberous breast is a complex congenital breast anomaly that can be challenging to correct surgically. OBJECTIVES: The authors conducted a systematic review with pooled analysis of data, with the aim of determining the effectiveness and complications related to operative management of the deformity. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were adopted in performing this systematic review. A simplified classification system for tuberous breast deformity was developed to accurately compare data and guide analysis. RESULTS: The review identified 38 studies, reporting a total of 897 patients undergoing tuberous breast surgery. The mean age of patients was 24 years (range 13-53 years). Mean follow-up was 39 months. A combination of tissue rearrangement and implant augmentation was the most common technique (73% of patients) followed by fat transfer alone (9%). Breast implants were employed in 83% of patients. The mean implanted volume per breast was 263 cc. Fat grafting was performed in 13% of patients and mean volume of fat grafted per breast was 185 cc. An overall complication rate of 20% was reported. Subjective assessment of patient satisfaction was 99%, and the mean score on BREAST-Q for satisfaction with clinical outcome was 86.7. Future studies should focus on robust study designs including randomized and cohort studies, use of patient-reported outcome measures, and long-term follow-up. CONCLUSIONS: The surgical techniques to correct tuberous breast deformity are safe, effective, and have a high satisfaction rate. Fat transfer has the capacity to provide promising results in treating tuberous breast deformity.


Assuntos
Doenças Mamárias , Neoplasias da Mama , Mamoplastia , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Feminino , Mamoplastia/efeitos adversos , Mamoplastia/métodos , Resultado do Tratamento , Tecido Adiposo/transplante , Mama/cirurgia , Mama/anormalidades , Doenças Mamárias/cirurgia , Neoplasias da Mama/cirurgia , Estudos Retrospectivos
13.
Wiad Lek ; 76(11): 2401-2405, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38112356

RESUMO

OBJECTIVE: The aim: To improve the results of treatment of hyperactive bladder syndrome in men of working age on the background of barotrauma and stress, as a consequence of combat trauma. PATIENTS AND METHODS: Materials and methods: An analysis of the questionnaire and the results of the clinical examination of 32 patients, injured servicemen and people who were injured in combat zones was carried out. The drug solifenacin succinate was used in the treatment complex, which is a specific antagonist of M3 subtype cholinergic receptors. Its influence allows you to achieve relaxation of the bladder detrusor and reduce the contractility of hyperactive bladder. RESULTS: Results: The main criterion for the effectiveness of the treatment was a decrease in the number of urgent cases, the frequency of urination and manifestations of nocturia by 50% or more, which was considered a positive effect. At the same time, the positive effect was differentiated as follows : an improvement of these parameters by 75% or more from the initial value which is a good result; reduction of symptoms in the range of 50-75% is satisfactory; less than 50% is an unsatisfactory result. A positive effect from the treatment after 8 weeks was observed in 88% of patients, of which 52% had a good result and 36% had a satisfactory result. CONCLUSION: Conclusions: The proposed complex of treatment of hyperactive bladder syndrome as a result of combat trauma against the background of barotrauma with neurological consequences and chronic stress allows to achieve a pronounced clinical effect in the vast majority of male patients of working age. And the diagnostic complex allows you to emphasize aspects of clinical vigilance, both for doctors of a specialized branch and of doctors of a general direction.


Assuntos
Barotrauma , Bexiga Urinária Hiperativa , Humanos , Masculino , Bexiga Urinária , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/etiologia , Succinato de Solifenacina/uso terapêutico , Succinato de Solifenacina/farmacologia , Barotrauma/complicações , Barotrauma/induzido quimicamente , Barotrauma/tratamento farmacológico
14.
Wiad Lek ; 76(11): 2448-2454, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38112363

RESUMO

OBJECTIVE: The aim: To identify clinical and epidemiological features of meningococcal infection on the initial day of a patient's medical consultation, as well as the efficacy of laboratory examinations. PATIENTS AND METHODS: Materials and methods: A retrospective analysis of 76 patients' histories diagnosed with meningococcal disease was carried out. CONCLUSION: Conclusions: Patients in the Transcarpathian region mainly develop an atypical form of meningococcal disease. Only half of all patients diagnosed with meningococcemia had a classical hemorrhagic rash. Generalized forms of meningococcal disease may proceed with normal or subfebrile temperature and without severe leukocytosis. We doubt the use of bacteriological methods of laboratory diagnosis due to their low effectiveness. The most sensitive method of laboratory diagnosis is a microscopic examination of blood smear, and cerebrospinal fluid.


Assuntos
Exantema , Infecções Meningocócicas , Sepse , Criança , Pré-Escolar , Adulto , Adolescente , Humanos , Masculino , Feminino , Lactente , Leucocitose , Estudos Retrospectivos , Infecções Meningocócicas/diagnóstico , Infecções Meningocócicas/epidemiologia , Diagnóstico Precoce
15.
Anal Chem ; 94(43): 14835-14845, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36269894

RESUMO

AZD7442 (tixagevimab [AZD8895]/cilgavimab [AZD1061]) is a monoclonal antibody (mAb) combination in development for the prevention and treatment of coronavirus disease 2019. Traditionally, bioanalysis of mAbs is performed using ligand binding assays (LBAs), which offer sensitivity, robustness, and ease of implementation. However, LBAs frequently require generation of critical reagents that typically take several months. Instead, we developed a highly sensitive (5 ng/mL limit of quantification) method using a hybrid LBA-liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) approach for quantification of the two codosed antibodies in serum and nasal lining fluid (NLF), a rare matrix. The method was optimized by careful selection of multiple reaction monitoring, capture reagents, magnetic beads, chromatographic conditions, evaluations of selectivity, and matrix effect. The final assay used viral spike protein receptor-binding domain as capture reagent and signature proteotypic peptides from the complementarity-determining region of each mAb for detection. In contrast to other methods of similar/superior sensitivity, our approach did not require multidimensional separations and can be operated in an analytical flow regime, ensuring high throughput and robustness required for clinical analysis at scale. The sensitivity of this method significantly exceeds typical sensitivity of ∼100 ng/mL for analytical flow 1D LBA-LC-MS/MS methods for large macromolecules, such as antibodies. Furthermore, infection and vaccination status did not impact method performance, ensuring method robustness and applicability to a broad patient population. This report demonstrated the general applicability of the hybrid LBA-LC-MS/MS approach to platform quantification of antibodies with high sensitivity and reproducibility, with specialized extension to matrices of increasing interest, such as NLF.


Assuntos
COVID-19 , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , SARS-CoV-2 , Reprodutibilidade dos Testes , Anticorpos Monoclonais/análise , Indicadores e Reagentes , Anticorpos Antivirais
16.
Arterioscler Thromb Vasc Biol ; 41(12): 3005-3014, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34706556

RESUMO

OBJECTIVE: Functional HDL (high-density lipoprotein) particles that facilitate cholesterol efflux may be cardioprotective. EL (endothelial lipase) hydrolyzes phospholipids promoting catabolism of HDL and subsequent renal excretion. MEDI5884 is a selective, humanized, monoclonal, EL-neutralizing antibody. We sought to determine the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of MEDI5884 in patients with stable coronary artery disease. Approach and Results: LEGACY was a phase 2a, double-blind, placebo-controlled, parallel-design trial that randomized 132 patients with stable coronary artery disease receiving high-intensity statin therapy to 3 monthly doses of 1 of 5 dose levels of MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary end point was the safety and tolerability of MEDI5884 through the end of the study (day 151). Additional end points included change in HDL cholesterol and cholesterol efflux from baseline to day 91, hepatic uptake of cholesterol at day 91, changes in various other lipid parameters. The incidence of adverse events was similar between the placebo and MEDI5884 groups. In a dose-dependent manner, MEDI5884 increased HDL cholesterol up to 51.4% (P<0.0001) and global cholesterol efflux up to 26.2% ([95% CI, 14.3-38.0] P<0.0001). MEDI5884 increased HDL particle number up to 14.4%. At the highest dose tested, an increase in LDL (low-density lipoprotein) cholesterol up to 28.7% (P<0.0001) and apoB (apolipoprotein B) up to 13.1% (P=0.04) was observed with MEDI5884. However, at the potential target doses for future studies, there was no meaningful increase in LDL cholesterol or apoB. CONCLUSIONS: Inhibition of EL by MEDI5884 increases the quantity and quality of functional HDL in patients with stable coronary artery disease on high-intensity statin therapy without an adverse safety signal at the likely dose to be used. These data support further clinical investigation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03351738.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Lipase/antagonistas & inibidores , Idoso , Biomarcadores/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipase/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
17.
J Intensive Care Med ; 37(2): 211-221, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33356770

RESUMO

PURPOSE: We evaluated the effects of after-hours/nighttime patient transfers out of the ICU on patient outcomes, by performing a systematic review and meta-analysis (PROSPERO CRD 42017074082). DATA SOURCES: MEDLINE, PubMed, EMBASE, Google Scholar, CINAHL, and the Cochrane Library from 1987-November 2019. Conference abstracts from the Society of Critical Care Medicine, American Thoracic Society, CHEST, Critical Care Canada Forum, and European Society of Intensive Care Medicine from 2011-2019. DATA EXTRACTION: Observational or randomized studies of adult ICU patients were selected if they compared after-hours transfer out of the ICU to daytime transfer on patient outcomes. Case reports, case series, letters, and reviews were excluded. Study year, country, design, co-variates for adjustment, definitions of after-hours, mortality rates, ICU readmission rates, and hospital length of stay (LOS) were extracted. DATA SYNTHESIS: We identified 3,398 studies. Thirty-one observational studies (1,418,924 patients) were selected for the systematic review and meta-analysis. Included studies had varying definitions of after-hours, with the after-hours period starting anytime between 16:00-22:00 and ending between 06:00-09:00. Approximately 16% of transfers occurred after-hours. After-hours transfers were associated with increased in-hospital mortality for both unadjusted (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.30-1.75, I2 = 96%, number of studies [n] = 26, P < 0.001, low certainty) and adjusted (OR 1.32, 95% CI 1.25-1.38, I 2 = 33%, n = 10, P < 0.001, low certainty) data, compared to daytime transfers. They were also associated with increased ICU readmission (pooled unadjusted OR 1.28, 95% CI 1.18-1.38, I2 = 85%, n = 17, P < 0.001, low certainty) and longer hospital LOS (standardized mean difference 0.13, 95% CI 0.09-0.18, I 2 = 93%, n = 9, P < 0.001, low certainty), compared to daytime transfers. CONCLUSIONS: After-hours transfers out of the ICU are associated with increased in-hospital mortality, ICU readmission, and hospital LOS, across many settings. While the certainty of evidence is low, future research is needed to reduce the number and effects of after-hours transfers.


Assuntos
Cuidados Críticos , Unidades de Terapia Intensiva , Adulto , Mortalidade Hospitalar , Humanos , Tempo de Internação , Transferência de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Arch Toxicol ; 96(9): 2391-2417, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35727353

RESUMO

Ferroptosis is a recently discovered form of regulated cell death, implicated in multiple pathologies. Given that the toxicity elicited by some metals is linked to alterations in iron metabolism and induction of oxidative stress and lipid peroxidation, ferroptosis might be involved in such toxicity. Although direct evidence is insufficient, certain pioneering studies have demonstrated a crosstalk between metal toxicity and ferroptosis. Specifically, the mechanisms underlying metal-induced ferroptosis include induction of ferritinophagy, increased DMT-1 and TfR cellular iron uptake, mitochondrial dysfunction and mitochondrial reactive oxygen species (mitoROS) generation, inhibition of Xc-system and glutathione peroxidase 4 (GPX4) activity, altogether resulting in oxidative stress and lipid peroxidation. In addition, there is direct evidence of the role of ferroptosis in the toxicity of arsenic, cadmium, zinc, manganese, copper, and aluminum exposure. In contrast, findings on the impact of cobalt and nickel on ferroptosis are scant and nearly lacking altogether for mercury and especially lead. Other gaps in the field include limited studies on the role of metal speciation in ferroptosis and the critical cellular targets. Although further detailed studies are required, it seems reasonable to propose even at this early stage that ferroptosis may play a significant role in metal toxicity, and its modulation may be considered as a potential therapeutic tool for the amelioration of metal toxicity.


Assuntos
Ferroptose , Antioxidantes/farmacologia , Ferro/metabolismo , Peroxidação de Lipídeos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
19.
Sensors (Basel) ; 22(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35408291

RESUMO

In this paper, we studied the possibility of increasing the Brillouin frequency shift (BFS) detection accuracy in distributed fibre-optic sensors by the separate and joint use of different algorithms for finding the spectral maximum: Lorentzian curve fitting (LCF, including the Levenberg-Marquardt (LM) method), the backward correlation technique (BWC) and a machine learning algorithm, the generalized linear model (GLM). The study was carried out on real spectra subjected to the subsequent addition of extreme digital noise. The precision and accuracy of the LM and BWC methods were studied by varying the signal-to-noise ratios (SNRs) and by incorporating the GLM method into the processing steps. It was found that the use of methods in sequence gives a gain in the accuracy of determining the sensor temperature from tenths to several degrees Celsius (or MHz in BFS scale), which is manifested for signal-to-noise ratios within 0 to 20 dB. We have found out that the double processing (BWC + GLM) is more effective for positive SNR values (in dB): it gives a gain in BFS measurement precision near 0.4 °C (428 kHz or 9.3 µÎµ); for BWC + GLM, the difference of precisions between single and double processing for SNRs below 2.6 dB is about 1.5 °C (1.6 MHz or 35 µÎµ). In this case, double processing is more effective for all SNRs. The described technique's potential application in structural health monitoring (SHM) of concrete objects and different areas in metrology and sensing were also discussed.


Assuntos
Tecnologia de Fibra Óptica , Ruído , Algoritmos , Razão Sinal-Ruído
20.
Molecules ; 27(5)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35268728

RESUMO

Upon the interaction of the hydrated lanthanide(III) salts found in acetonitrile solution with a tripodal paramagnetic compound, 4,4-dimethyl-2,2-bis(pyridin-2-yl)-1,3-oxazolidine-3-oxyl (Rad), functionalized by two pyridyl groups, three neutral, structurally characterized complexes with diamagnetic polydentate ligands-[Dy(RadH)(hbpm)Cl2], [Yb2(ipapm)2(NO3)4], and [Ce2(ipapm)2(NO3)4(EtOAc)2]-were obtained. These coordination compounds are minor uncolored crystalline products, which were formed in a reaction mixture due to the Rad transformation in a lanthanide coordination sphere, wherein the processes of its simultaneous disproportionation, hydrolysis, and condensation proceed differently than in the absence of Ln ions. The latter fact was confirmed by the formation of the structurally characterized product of the oxazolidine nitroxide transformation during its crystallization in toluene solution. Such a conversion in the presence of 4f elements ions is unique since no similar phenomenon was observed during the synthesis of the 3d-metal complexes with Rad.

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