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This study focuses on the assessment of the mechanical effect produced by Morton's extension as an orthopedic intervention in patients with bilateral foot pronation posture, through a variation in hindfoot and forefoot prone-supinator forces during the stance phase of gait. A quasi-experimental and transversal research was designed comparing three conditions: barefoot (A); wearing footwear with a 3 mm EVA flat insole (B); and wearing a 3 mm EVA flat insole with a 3 mm thick Morton's extension (C), with respect to the force or time relational to the maximum time of supination or pronation of the subtalar joint (STJ) using a Bertec force plate. Morton's extension did not show significant differences in the moment during the gait phase in which the maximum pronation force of the STJ is produced, nor in the magnitude of the force, although it decreased. The maximum force of supination increased significantly and was advanced in time. The use of Morton's extension seems to decrease the maximum force of pronation and increase supination of the subtalar joint. As such, it could be used to improve the biomechanical effects of foot orthoses to control excessive pronation.
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Articulação Talocalcânea , Humanos , Projetos Piloto , Pronação , Pé , Marcha , Fenômenos BiomecânicosRESUMO
A population of neutrophils recruited into cystic fibrosis (CF) airways is associated with proteolytic lung damage, exhibiting high expression of primary granule exocytosis marker CD63 and reduced phagocytic receptor CD16. Causative factors for this population are unknown, limiting intervention. Here we present a laboratory model to characterize responses of differentiated airway epithelium and neutrophils following respiratory infection. Pediatric primary airway epithelial cells were cultured at the air-liquid interface, challenged individually or in combination with rhinovirus (RV) and Pseudomonas aeruginosa, then apically washed with medical saline to sample epithelial infection milieus. Cytokine multiplex analysis revealed epithelial antiviral signals, including IP-10 and RANTES, increased with exclusive RV infection but were diminished if P. aeruginosa was also present. Proinflammatory signals interleukin-1α and ß were dominant in P. aeruginosa infection milieus. Infection washes were also applied to a published model of neutrophil transmigration into the airways. Neutrophils migrating into bacterial and viral-bacterial co-infection milieus exhibited the in vivo CF phenotype of increased CD63 expression and reduced CD16 expression, while neutrophils migrating into milieus of RV-infected or uninfected cultures did not. Individually, bacterial products lipopolysaccharide and N-formylmethionyl-leucyl-phenylalanine and isolated cytokine signals only partially activated this phenotype, suggesting that additional soluble factors in the infection microenvironment trigger primary granule release. Findings identify P. aeruginosa as a trigger of acute airway inflammation and neutrophil primary granule exocytosis, underscoring potential roles of airway microbes in prompting this neutrophil subset. Further studies are required to characterize microbes implicated in primary granule release, and identify potential therapeutic targets.
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Fibrose Cística , Infecções por Pseudomonas , Citocinas/metabolismo , Exocitose , Humanos , Neutrófilos/metabolismo , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/fisiologiaRESUMO
Grapevine (Vitis vinifera L.) displays wide plasticity to climate; however, the physiology of dormancy along a seasonal continuum is poorly understood. Here we investigated the apparent disconnect between dormancy and the underlying respiratory physiology and transcriptome of grapevine buds, from bud set in summer to bud burst in spring. The establishment of dormancy in summer was pronounced and reproducible; however, this was coupled with little or no change in physiology, indicated by respiration, hydration, and tissue oxygen tension. The release of dormancy was biphasic; the depth of dormancy declined substantially by mid-autumn, while the subsequent decline towards spring was moderate. Observed changes in physiology failed to explain the first phase of dormancy decline, in particular. Transcriptome data contrasting development from summer through to spring also indicated that dormancy was poorly reflected by metabolic quiescence during summer and autumn. Gene Ontology and enrichment data revealed the prevailing influence of abscisic acid (ABA)-related gene expression during the transition from summer to autumn, and promoter motif analysis suggested that photoperiod may play an important role in regulating ABA functions during the establishment of dormancy. Transcriptomic data from later transitions reinforced the importance of oxidation and hypoxia as physiological cues to regulate the maintenance of quiescence and resumption of growth. Collectively these data reveal a novel disconnect between growth and metabolic quiescence in grapevine following bud set, which requires further experimentation to explain the phenology and dormancy relationships.
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Dormência de Plantas , Vitis , Ácido Abscísico/metabolismo , Regulação da Expressão Gênica de Plantas , Fotoperíodo , Dormência de Plantas/genética , Estações do Ano , Vitis/metabolismoRESUMO
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.
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Predisposição Genética para Doença , Inflamação/genética , Esclerose Múltipla/genética , Transcriptoma/genética , Adulto , Códon sem Sentido , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Exoma/genética , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Bainha de Mielina/genética , Bainha de Mielina/patologia , Degeneração Neural/genética , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Sequenciamento do Exoma , Adulto JovemRESUMO
MAIN CONCLUSION: Genome-wide identification, together with gene expression patterns and promoter region analysis of FYVE and PHOX proteins in Physcomitrella patens, emphasized their importance in regulating mainly developmental processes in P. patens. Phosphatidylinositol 3-phosphate (PtdIns3P) is a signaling phospholipid, which regulates several aspects of plant growth and development, as well as responses to biotic and abiotic stresses. The mechanistic insights underlying PtdIns3P mode of action, specifically through effector proteins have been partially explored in plants, with main focus on Arabidopsis thaliana. In this study, we searched for genes coding for PtdIns3P-binding proteins such as FYVE and PHOX domain-containing sequences from different photosynthetic organisms to gather evolutionary insights on these phosphoinositide binding domains, followed by an in silico characterization of the FYVE and PHOX gene families in the moss Physcomitrella patens. Phylogenetic analysis showed that PpFYVE proteins can be grouped in 7 subclasses, with an additional subclass whose FYVE domain was lost during evolution to higher plants. On the other hand, PpPHOX proteins are classified into 5 subclasses. Expression analyses based on RNAseq data together with the analysis of cis-acting regulatory elements and transcription factor (TF) binding sites in promoter regions suggest the importance of these proteins in regulating stress responses but mainly developmental processes in P. patens. The results provide valuable information and robust candidate genes for future functional analysis aiming to further explore the role of this signaling pathway mainly during growth and development of tip growing cells and during the transition from 2 to 3D growth. These studies would identify ancestral regulatory players undertaken during plant evolution.
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Bryopsida/genética , Evolução Molecular , Proteínas de Plantas/genética , Cromossomos de Plantas/genética , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Genes de Plantas , Anotação de Sequência Molecular , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas/genética , Domínios Proteicos , Estresse Fisiológico/genéticaRESUMO
Endolysins are bacteriophage-encoded peptidoglycan hydrolases that specifically degrade the bacterial cell wall at the end of the phage lytic cycle. They feature a distinct modular architecture, consisting of enzymatically active domains (EADs) and cell wall-binding domains (CBDs). Structural analysis of the complete enzymes or individual domains is required for better understanding the mechanisms of peptidoglycan degradation and provides guidelines for the rational design of chimeric enzymes. We here report the crystal structure of the EAD of PlyP40, a member of the GH-25 family of glycosyl hydrolases, and the first muramidase reported for Listeria phages. Site-directed mutagenesis confirmed key amino acids (Glu98 and Trp10) involved in catalysis and substrate stabilization. In addition, we found that PlyP40 contains two heterogeneous CBD modules with homology to SH3 and LysM domains. Truncation analysis revealed that both domains are required for full activity but contribute to cell wall recognition and lysis differently. Replacement of CBDP40 with a corresponding domain from a different Listeria phage endolysin yielded an enzyme with a significant shift in pH optimum. Finally, domain swapping between PlyP40 and the streptococcal endolysin Cpl-1 produced an intergeneric chimera with activity against Listeria cells, indicating that structural similarity of individual domains determines enzyme function.
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Bacteriófagos/enzimologia , Listeria monocytogenes/virologia , N-Acetil-Muramil-L-Alanina Amidase/química , N-Acetil-Muramil-L-Alanina Amidase/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo , Motivos de Aminoácidos , Bacteriófagos/química , Bacteriófagos/genética , Catálise , Domínio Catalítico , Parede Celular/metabolismo , Parede Celular/virologia , Concentração de Íons de Hidrogênio , Listeria monocytogenes/metabolismo , N-Acetil-Muramil-L-Alanina Amidase/genética , Peptidoglicano/metabolismo , Ligação Proteica , Proteínas Virais/genéticaAssuntos
Doenças do Gato , Corpos Estranhos , Intubação Intratraqueal , Gatos , Animais , Corpos Estranhos/veterinária , Corpos Estranhos/cirurgia , Intubação Intratraqueal/veterinária , Intubação Intratraqueal/efeitos adversos , Doenças do Gato/cirurgia , Brônquios , Doença Iatrogênica/veterinária , Masculino , FemininoRESUMO
Subcutaneous (SAT) and visceral (VAT) adipose tissues stores excess energy as triglycerides and synthesize adiponectin to prevent ectopic lipid accumulation and lipotoxicity. During obesity, an impairment in the capacity of SAT to store triglycerides and synthesize adiponectin is associated with increased free fatty acids (FFA) release, leading to VAT hypertrophy and hepatic and skeletal muscle lipotoxicity. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may be involved in SAT dysfunction during obesity. The objectives of this study were to assess UPR activation and adiponectin synthesis in: 1) SAT and VAT from mice exposed to acute pharmacologic or chronic obesity-induced ER stress and in 2) cultured mice primary mature adipocytes or adipocytes differentiated in vitro from SAT and VAT exposed to tunicamycin or thapsigargin. Mice fed a high-fat diet developed obesity, increased FFA and lower circulating adiponectin in association with lower adiponectin synthesis and increased UPR markers in SAT. Mice subjected to acute ER stress by pioglitazone administration and a low-dose tunicamycin injection presented a maladaptive UPR activation in SAT along with reduced adiponectin synthesis and secretion and increased lipolysis with respect to VAT, associated with lipid accumulation in skeletal muscle and liver. Primary adipocytes and adipocytes differentiated from SAT exposed to pharmacologic ER stress also developed maladaptive UPR, along with reduced adiponectin synthesis and increased lipolysis with respect to those from VAT. Our results indicate that compared to VAT, SAT is more susceptible to ER stress, leading to increased lipolysis and reduced adiponectin synthesis and secretion.
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Adipócitos/patologia , Adiponectina/metabolismo , Estresse do Retículo Endoplasmático , Obesidade/fisiopatologia , Gordura Subcutânea/patologia , Adipócitos/metabolismo , Animais , Feminino , Lipólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gordura Subcutânea/metabolismoRESUMO
Dormant or quiescent buds of woody perennials are often dense and in the case of grapevine (Vitis vinifera L.) have a low tissue oxygen status. The precise timing of the decision to resume growth is difficult to predict, but once committed, the increase in tissue oxygen status is rapid and developmentally regulated. Here, we show that more than a third of the grapevine homologues of widely conserved hypoxia-responsive genes and nearly a fifth of all grapevine genes possessing a plant hypoxia-responsive promoter element were differentially regulated during bud burst, in apparent harmony with resumption of meristem identity and cell-cycle gene regulation. We then investigated the molecular and biochemical properties of the grapevine ERF-VII homologues, which in other species are oxygen labile and function in transcriptional regulation of hypoxia-responsive genes. Each of the 3 VvERF-VIIs were substrates for oxygen-dependent proteolysis in vitro, as a function of the N-terminal cysteine. Collectively, these data support an important developmental function of oxygen-dependent signalling in determining the timing and effective coordination bud burst in grapevine. In addition, novel regulators, including GASA-, TCP-, MYB3R-, PLT-, and WUS-like transcription factors, were identified as hallmarks of the orderly and functional resumption of growth following quiescence in buds.
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Regulação da Expressão Gênica no Desenvolvimento , Oxigênio/metabolismo , Vitis/fisiologia , Meristema/crescimento & desenvolvimento , Meristema/fisiologia , Dormência de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vitis/crescimento & desenvolvimentoRESUMO
Oreochromis niloticus was used to determine the effects of heavy metals and their concentration in aquatic environments. Its wide distribution, resistance, and economical importance make it a suitable biomonitor. The present study was conducted in the Tenango Dam (Puebla, Mexico) to determine water quality and its impact on O. niloticus, a species that is cultured and commercialized in this area. Five samples were collected over 1 year to evaluate the water's physicochemical parameters (temperature, dissolved oxygen, pH, and hardness) and metal contents (cadmium, chromium, copper, and lead). Metal concentrations, bioconcentration factors, and metallothionein levels were also assessed in O. niloticus livers and muscle tissues. Water and tilapia quality were estimated according to current Mexican guidelines. Results indicated that the water's physicochemical parameters were within acceptable ranges. Metal concentrations, however, suggested that this resource was not suitable for urban use. Moreover, metal levels in fish tissues exceeded the acceptable limits during two periods, rendering it unsuitable for human consumption. The bioconcentration factor indicated that the metals can potentially accumulate in organisms. Furthermore, metallothionein levels in liver and muscle showed a direct correlation with metal concentrations in these tissues. This is the first study to use tilapia as an indicator of contamination in the Tenango Dam, and also the first to describe the presence of metals in this water body.
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Ciclídeos/metabolismo , Monitoramento Ambiental , Metais Pesados/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Cádmio/análise , Cromo/análise , Cobre/análise , Humanos , Metalotioneína/análise , Metais Pesados/análise , México , Músculos/química , Tilápia , Poluentes Químicos da Água/análiseRESUMO
Vitis vinifera berries are sensitive towards infection by the necrotrophic pathogen Botrytis cinerea, leading to important economic losses worldwide. The combined analysis of the transcriptome and metabolome associated with fungal infection has not been performed previously in grapes or in another fleshy fruit. In an attempt to identify the molecular and metabolic mechanisms associated with the infection, peppercorn-sized fruits were infected in the field. Green and veraison berries were collected following infection for microarray analysis complemented with metabolic profiling of primary and other soluble metabolites and of volatile emissions. The results provided evidence of a reprogramming of carbohydrate and lipid metabolisms towards increased synthesis of secondary metabolites involved in plant defence, such as trans-resveratrol and gallic acid. This response was already activated in infected green berries with the putative involvement of jasmonic acid, ethylene, polyamines, and auxins, whereas salicylic acid did not seem to be involved. Genes encoding WRKY transcription factors, pathogenesis-related proteins, glutathione S-transferase, stilbene synthase, and phenylalanine ammonia-lyase were upregulated in infected berries. However, salicylic acid signalling was activated in healthy ripening berries along with the expression of proteins of the NBS-LRR superfamily and protein kinases, suggesting that the pathogen is able to shut down defences existing in healthy ripening berries. Furthermore, this study provided metabolic biomarkers of infection such as azelaic acid, a substance known to prime plant defence responses, arabitol, ribitol, 4-amino butanoic acid, 1-O-methyl- glucopyranoside, and several fatty acids that alone or in combination can be used to monitor Botrytis infection early in the vineyard.
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Botrytis/fisiologia , Interações Hospedeiro-Patógeno , Metaboloma , Doenças das Plantas/microbiologia , Transcriptoma , Vitis/genética , Aciltransferases/genética , Aciltransferases/metabolismo , Frutas/genética , Frutas/metabolismo , Ácido Gálico/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenilalanina Amônia-Liase/genética , Fenilalanina Amônia-Liase/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Poliaminas/metabolismo , Resveratrol , Estilbenos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vitis/metabolismo , Vitis/microbiologiaRESUMO
Grape and wine production and quality is extremely dependent on the fruit ripening process. Sensory and nutritional characteristics are important aspects for consumers and their development during fruit ripening involves complex hormonal control. In this review, we explored data already published on grape ripening and compared it with the hormonal regulation of ripening of other climacteric and non-climacteric fruits. The roles of abscisic acid, ethylene, and brassinosteroids as promoters of ripening are discussed, as well as the role of auxins, cytokinins, gibberellins, jasmonates, and polyamines as inhibitors of ripening. In particular, the recently described role of polyamine catabolism in grape ripening is discussed, together with its putative interaction with other hormones. Furthermore, other recent examples of cross-talk among the different hormones are presented, revealing a complex interplay of signals during grape development and ripening.
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Frutas/crescimento & desenvolvimento , Reguladores de Crescimento de Plantas/metabolismo , Vitis/crescimento & desenvolvimento , Vinho/classificação , Ácido Abscísico/metabolismo , Brassinosteroides/metabolismo , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas , Metaboloma/fisiologia , Transdução de Sinais/fisiologiaAssuntos
Oxigênio/metabolismo , Folhas de Planta/fisiologia , Brotos de Planta/fisiologia , Vitis/fisiologia , Cloroplastos/fisiologia , Metabolismo Energético , Regulação da Expressão Gênica de Plantas , Luz , Meristema/fisiologia , Brotos de Planta/crescimento & desenvolvimento , Plastídeos/genética , Plastídeos/metabolismo , Transdução de SinaisRESUMO
Introduction: Many survivors of preterm birth (<37 weeks gestation) have lifelong respiratory deficits, the drivers of which remain unknown. Influencers of pathophysiological outcomes are often detectable at the gene level and pinpointing these differences can help guide targeted research and interventions. This study provides the first transcriptomic analysis of primary nasal airway epithelial cells in survivors of preterm birth at approximately 1 year of age. Methods: Nasal airway epithelial brushings were collected, and primary cell cultures established from term (>37 weeks gestation) and very preterm participants (≤32 weeks gestation). Ex vivo RNA was collected from brushings with sufficient cell numbers and in vitro RNA was extracted from cultured cells, with bulk RNA sequencing performed on both the sample types. Differential gene expression was assessed using the limma-trend pipeline and pathway enrichment identified using Reactome and GO analysis. To corroborate gene expression data, cytokine concentrations were measured in cell culture supernatant. Results: Transcriptomic analysis to compare term and preterm cells revealed 2,321 genes differentially expressed in ex vivo samples and 865 genes differentially expressed in cultured basal cell samples. Over one third of differentially expressed genes were related to host immunity, with interferon signalling pathways dominating the pathway enrichment analysis and IRF1 identified as a hub gene. Corroboration of disrupted interferon release showed that concentrations of IFN-α2 were below measurable limits in term samples but elevated in preterm samples [19.4 (76.7) pg/ml/µg protein, p = 0.03]. IFN-γ production was significantly higher in preterm samples [3.3 (1.5) vs. 9.4 (17.7) pg/ml/µg protein; p = 0.01] as was IFN-ß [7.8 (2.5) vs. 13.6 (19.5) pg/ml/µg protein, p = 0.01]. Conclusion: Host immunity may be compromised in the preterm nasal airway epithelium in early life. Altered immune responses may lead to cycles of repeated infections, causing persistent inflammation and tissue damage which can have significant impacts on long-term respiratory function.
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BACKGROUND: Respiratory viruses significantly impact global morbidity and mortality, causing more disease in humans than any other infectious agent. Beyond pathogens, various viruses and bacteria colonize the respiratory tract without causing disease, potentially influencing respiratory diseases' pathogenesis. Nevertheless, our understanding of respiratory microbiota is limited by technical constraints, predominantly focusing on bacteria and neglecting crucial populations like viruses. Despite recent efforts to improve our understanding of viral diversity in the human body, our knowledge of viral diversity associated with the human respiratory tract remains limited. METHODS: Following a comprehensive search in bibliographic and sequencing data repositories using keyword terms, we retrieved shotgun metagenomic data from public repositories (n = 85). After manual curation, sequencing data files from 43 studies were analyzed using EVEREST (pipEline for Viral assEmbly and chaRactEriSaTion). Complete and high-quality contigs were further assessed for genomic and taxonomic characterization. RESULTS: Viral contigs were obtained from 194 out of the 868 FASTQ files processed through EVEREST. Of the 1842 contigs that were quality assessed, 8% (n = 146) were classified as complete/high-quality genomes. Most of the identified viral contigs were taxonomically classified as bacteriophages, with taxonomic resolution ranging from the superkingdom level down to the species level. Captured contigs were spread across 25 putative families and varied between RNA and DNA viruses, including previously uncharacterized viral genomes. Of note, airway samples also contained virus(es) characteristic of the human gastrointestinal tract, which have not been previously described as part of the lung virome. Additionally, by performing a meta-analysis of the integrated datasets, ecological trends within viral populations linked to human disease states and their biogeographical distribution along the respiratory tract were observed. CONCLUSION: By leveraging publicly available repositories of shotgun metagenomic data, the present study provides new insights into viral genomes associated with specimens from the human respiratory tract across different disease spectra. Further studies are required to validate our findings and evaluate the potential impact of these viral communities on respiratory tract physiology.
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Genoma Viral , Metagenômica , Sistema Respiratório , Viroma , Vírus , Humanos , Metagenômica/métodos , Sistema Respiratório/virologia , Vírus/genética , Vírus/classificação , Vírus/isolamento & purificação , Metagenoma , Simulação por Computador , Filogenia , Biologia Computacional/métodos , Microbiota , Bacteriófagos/genética , Bacteriófagos/classificação , Bacteriófagos/isolamento & purificaçãoRESUMO
BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, often associated with high blood levels of LDL cholesterol (LDL-c). Medications like statins and PCSK9 inhibitors, are used to manage LDL-c levels and reduce ASCVD risk. Recent findings connect the gut microbiota and its metabolites to ASCVD development. We showed that statins modulate the gut microbiota including the production of microbial metabolites involved in the regulation of cholesterol metabolism such as short chain fatty acids (SCFAs) and bile acids (BAs). Whether this pleiotropic effect of statins is associated with their antimicrobial properties or it is secondary to the modulation of cholesterol metabolism in the host is unknown. In this observational study, we evaluated whether alirocumab, a PCSK9 inhibitor administered subcutaneously, alters the stool-associated microbiota and the profiles of SCFAs and BAs. METHODS: We used stool and plasma collected from patients enrolled in a single-sequence study using alirocumab. Microbial DNA was extracted from stool, and the bacterial component of the gut microbiota profiled following an amplicon sequencing strategy targeting the V3-V4 region of the 16S rRNA gene. Bile acids and SCFAs were profiled and quantified in stool and plasma using mass spectrometry. RESULTS: Treatment with alirocumab did not alter bacterial alpha (Shannon index, p = 0.74) or beta diversity (PERMANOVA, p = 0.89) in feces. Similarly, circulating levels of SCFAs (mean difference (95% confidence interval (CI)), 8.12 [-7.15-23.36] µM, p = 0.25) and BAs (mean difference (95% CI), 0.04 [-0.11-0.19] log10(nmol mg-1 feces), p = 0.56) were equivalent regardless of PCSK9 inhibition. Alirocumab therapy was associated with increased concentration of BAs in feces (mean difference (95% CI), 0.20 [0.05-0.34] log10(nmol mg-1 feces), p = 0.01). CONCLUSION: In statin-treated patients, the use of alirocumab to inhibit PCSK9 leads to elevated levels of fecal BAs without altering the bacterial population of the gut microbiota. The association of alirocumab with increased fecal BA concentration suggests an additional mechanism for the cholesterol-lowering effect of PCSK9 inhibition.
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Introduction: Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, in utero exposures, and respiratory exposures in the first year of life. Methods: The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to 5 years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to 6 weeks, 1, 3, and 5 years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and in utero exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal sampling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses. Discussion: The AERIAL study will provide a comprehensive longitudinal assessment of factors influencing the association between epithelial dysfunction and respiratory morbidity in early life, and hopefully identify novel targets for diagnosis and early intervention.
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BACKGROUND: The presence of a tracheal septum dividing the trachea into two makes intubation one of the main challenges of penguin anaesthesia. Differences in the length and location of the aforementioned tracheal septum have been described in some penguin species. However, to the best of the authors' knowledge, it has not been reported in Humboldt penguins (Spheniscus humboldti). Therefore, one of the aims of this publication is to report the septal position in this Humboldt penguin. Furthermore, this publication describes the anaesthetic protocol and complications encountered and discusses some of the more important features of penguin anaesthesia. It is anticipated that this case report will aid in future procedures requiring anaesthesia of this penguin species. CASE PRESENTATION: A 25-year-old female Humboldt penguin was anaesthetized at the University College Dublin Veterinary Hospital for radiographs and computed tomography (CT) following three weeks of inappetence. After assessing the health status of the penguin from the clinical history and performing a physical examination, an American Society of Anesthesiologists physical status score of II was assigned and a combination of butorphanol 1 mg/kg and midazolam 1 mg/kg was administered intramuscularly to sedate the penguin. Induction of anaesthesia was performed via a face mask using sevoflurane in oxygen. The airway was intubated with a 4.0 mm Cole tube and anaesthesia was maintained with sevoflurane in oxygen during the entire procedure. Anaesthetic monitoring consisted of an electrocardiogram, pulse oximetry, non-invasive blood pressure, capnography, and body temperature. CONCLUSIONS: Tracheal bifurcation was identified as the start of the tracheal septum 4.67 cm from the glottis using CT. Most of the anticipated complications of penguin anaesthesia, such as hyperthermia, hypothermia, regurgitation, hypoventilation, and difficulties in intubation were present in this case. However, no major sequalae occurred following the anaesthetic protocol described.
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Hemochromatosis is a disease characterized by excess iron stores in multiple organs, including the liver, pancreas, skin, and heart. The infiltration of the heart is an important factor in morbidity and mortality. Here we describe the case of a pediatric patient with end-stage heart failure who required a heart transplantation, with no complications. After the surgery, she showed biochemical and clinical improvement, with a positive impact on her quality of life and a prolonged survival.
La hemocromatosis es una enfermedad caracterizada por el excesivo depósito de hierro en múltiples órganos, entre ellos hígado, páncreas, piel y corazón. La infiltración de este último es un importante factor en morbilidad y mortalidad. Presentamos un caso de un paciente pediátrico con insuficiencia cardíaca terminal que ameritó trasplante cardíaco, que resultó sin complicaciones. Posterior a la cirugía, mostró mejoría bioquímica y clínica, lo que influyó positivamente en su calidad de vida y prolongó su supervivencia.
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Transplante de Coração , Hemocromatose , Sobrecarga de Ferro , Humanos , Feminino , Criança , Hemocromatose/complicações , Hemocromatose/diagnóstico , Qualidade de Vida , Sobrecarga de Ferro/complicações , FígadoRESUMO
Introduction: Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, in utero exposures, and respiratory exposures in the first year of life. Methods and Analysis: The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to five years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to six weeks, one, three, and five years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and in utero exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal sampling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses. Ethics and Dissemination: Ethical approval has been obtained from Ramsey Health Care HREC WA-SA (#1908). Results will be disseminated through open-access peer-reviewed manuscripts, conference presentations, and through different media channels to consumers, ORIGINS families, and the wider community.