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Identification of an exosomal miRNA-mRNA regulatory network contributing to methotrexate efficacy.
No full textOBJECTIVE
Methotrexate (MTX) is an economic and effective medicine treatment for psoriasis. Extracellular vesicle (EV) miRNA biomarkers related to its efficiency have been identified in various diseases. Whether certain miRNA profiles are associated with psoriasis treatment is unknown. In order to determine specific miRNA biomarkers for MTX effectiveness prediction and the severity of psoriasis, our study looked at the variations in circulating EV miRNA profiles before and after MTX therapy.
METHODS
Plasma EV isolation and next-generation sequencing were performed to identify differentially expressed EV miRNAs between GRs (n = 14) and NRs (n = 6). Univariate and multiple linear regression analyses were performed to evaluate the correlation between PASI scores and miRNA expression levels.
RESULTS
15 miRNAs out of a total profile of 443 miRNAs were substantially different between GRs and NRs at baseline, 4 of them (miR-199a-5p, miR-195-5p, miR-196a-5p, and miR-1246) have the potential to distinguish between GRs and NRs [area under the curve (AUC) ≥ 0.70, all P < 0.05]. KEGG pathway analyses revealed differentially expressed miRNAs to potentially target immune-related pathways. SIRT1 was discovered to be a target of miR-199a-5p and involved in MAPK signaling pathway. MiR-191-5p and miR-21-5p expression levels have been discovered to positively correlate with PASI scores[P < 0.05].
CONCLUSION
This pilot investigation found that miR-199a-5p, miR-195-5p, miR-196a-5p, and miR-1246 might be prospective biomarkers to predict the efficacy of MTX, and that miR-191-5p and miR-21-5p were correlated with psoriasis severity. Five of them previously reported to be involved in MAPK signaling pathway, indicating a potential role of MTX in delaying the progression of psoriatic inflammation
Optimal antibiotics duration following surgical management of septic olecranon bursitis: a 12-year retrospective analysis.
Get PDFIntroduction: The absence of a standardized postoperative antibiotic treatment approach for patients with surgically treated septic bursitis results in disparate practices. Methods: We retrospectively reviewed charts of adult patients with surgically treated septic olecranon bursitis at Mayo Clinic sites between 1 January 2000 and 20 August 2022, focusing on their clinical presentation, diagnostics, management, postoperative antibiotic use, and outcomes. Results: A total of 91 surgically treated patients were identified during the study period. Staphylococcus aureus was the most common pathogen (64 %). Following surgery, 92 % (84 of 91 patients) received systemic antibiotics. Excluding initial presentations of bacteremia or osteomyelitis (), the median duration of postoperative antibiotics was 21 d (interquartile range, IQR: 14-29). Postoperative complications were observed in 23 % (21 of 91) of patients, while cure was achieved in 87 % (79 of 91). Active smokers had 4.53 times greater odds of clinical failure compared with nonsmokers (95 % confidence interval, 95 % CI: 1.04-20.50; ). The highest odds of clinical failure were noted in cases without postoperative antibiotic administration (odds ratio, OR: 7.4). Conversely, each additional day of antibiotic treatment, up to 21 d, was associated with a progressive decrease in the odds of clinical failure (OR: 1 at 21 d). Conclusion: The optimal duration of antibiotics postoperatively in this study was 21 d, which was associated with a 7.4-fold reduction in the odds clinical failure compared with cases without postoperative antibiotics. Further validation through a randomized controlled trial is needed
Exploring the lung-gut direction of the gut-lung axis in patients with ARDS.
Get PDFAcute respiratory distress syndrome (ARDS) represents a life-threatening inflammatory reaction marked by refractory hypoxaemia and pulmonary oedema. Despite advancements in treatment perspectives, ARDS still carries a high mortality rate, often due to systemic inflammatory responses leading to multiple organ dysfunction syndrome (MODS). Indeed, the deterioration and associated mortality in patients with acute lung injury (LI)/ARDS is believed to originate alongside respiratory failure mainly from the involvement of extrapulmonary organs, a consequence of the complex interaction between initial inflammatory cascades related to the primary event and ongoing mechanical ventilation-induced injury resulting in multiple organ failure (MOF) and potentially death. Even though recent research has increasingly highlighted the role of the gastrointestinal tract in this process, the pathophysiology of gut dysfunction in patients with ARDS remains mainly underexplored. This review aims to elucidate the complex interplay between lung and gut in patients with LI/ARDS. We will examine various factors, including systemic inflammation, epithelial barrier dysfunction, the effects of mechanical ventilation (MV), hypercapnia, and gut dysbiosis. Understanding these factors and their interaction may provide valuable insights into the pathophysiology of ARDS and potential therapeutic strategies to improve patient outcomes
Comparisons of interglacial vegetation responses to climate variability between the Massif Central, France, and the Balkan Peninsula since 423 ka
Get PDFPalynological long sequences offer a unique possibility to study the effect of pronounced climate change on vegetation dynamics over several glacial-interglacial cycles. Such long sequences are rare, especially outside of the Mediterranean realm. Additionally, they often lack robust chronologies, which are a precondition for com- parisons across records and proxies. In this study we present a refined chronology of the Velay pollen sequence (0–423 ka) from south-central France by tuning it to the recently published Lake Ohrid pollen sequence from the southern Balkans, which itself has a vegetation-independent, numerical chronology. Furthermore, we use ordi- nation techniques in combination with independent palaeo-temperature proxies and seasonality as explanatory variables for both sites. This allows us to infer climatic responses of interglacial vegetation over a broad ecological gradient, i.e., from a cool-temperate to a submediterranean site. Our analysis shows that temperature is a significant determinant for interglacial vegetation composition at both sites but explains slightly more variance at cool-temperate Velay compared to submediterranean Lake Ohrid, where precessional-driven mois- ture availability might have had a greater influence. Temperate oceanic taxa such as Abies and Taxus were most affected by comparably cool or warm interglacials at Velay, whereas at Lake Ohrid, the same accounts for Mediterranean taxa such as Quercus ilex, Q. cerris, or Ostrya/Carpinus orientalis. Responses of single taxa and vegetation groups to seasonality changes over the last five interglacials suggest that species-specific niche preferences have remained stable since 423 ka. Additionally, we suggest that unless a future climate exceeds the MIS 5e anomaly of c. +1.3 ◦C (if compared to the Holocene), evergreen Mediterranean taxa such as Quercus ilex will not expand into temperate biomes north of the Alps. However, even temperature rises below +1.3 ◦C will cause a restructuring of the current vegetation in both areas
No Initial Elevation on Personality Self-Reports in an Online Convenience Sample
Get PDFResearch shows that people’s self-reports may be biased by an initial elevation phenomenon in which ratings are higher the first time that people take a survey as compared to the second and subsequent times. Apart from the fact that this phenomenon exists, and that it might bias ratings for negative subjective experiences more strongly than positive ones, little else is known. In the present study, we examined whether the initial elevation phenomenon occurs for commonly used trait measures, such as ratings on personality inventories and life satisfaction. We hypothesized that the initial elevation phenomenon may be associated with the (un)desirability of the content of the self-report items such that scores for undesirable facets would show initial elevation and scores for desirable facets would show the reverse. We tested this in an online convenience sample (N = 3,329) using 5 facets of a personality inventory and a single item measure of life satisfaction. Our hypotheses were not supported. Our findings suggest that at least for online convenience samples, ratings on personality inventories and life satisfaction are not strongly impacted by initial elevation
AmiA and AliA peptide ligands, found in Klebsiella pneumoniae, are imported into pneumococci and alter the transcriptome
Get PDFKlebsiella pneumoniae releases the peptides AKTIKITQTR and FNEMQPIVDRQ, which bind the pneumococcal proteins AmiA and AliA respectively, two substrate-binding proteins of the ABC transporter Ami-AliA/AliB oligopeptide permease. Exposure to these peptides alters pneumococcal phenotypes such as growth. Using a mutant in which a permease domain of the transporter was disrupted, by growth analysis and epifluorescence microscopy, we confirmed peptide uptake via the Ami permease and intracellular location in the pneumococcus. By RNA-sequencing we found that the peptides modulated expression of genes involved in metabolism, as pathways affected were mostly associated with energy or synthesis and transport of amino acids. Both peptides downregulated expression of genes involved in branched chain amino acid metabolism and the Ami permease; and upregulated fatty acid biosynthesis genes but differed in their regulation of genes involved in purine and pyrimidine biosynthesis. The transcriptomic changes are consistent with growth suppression by peptide treatment. The peptides inhibited growth of pneumococcal isolates of serotypes 3, 8, 9N, 12F and 19A, currently prevalent in Switzerland, and caused no detectable toxic effect to primary human airway epithelial cells. We conclude that pneumococci take up K. pneumoniae peptides from the environment via binding and transport through the Ami permease. This changes gene expression resulting in altered phenotypes, particularly reduced growth
Limited home state measures in the WTO Investment Facilitation for Development Agreement: a missed opportunity or a starting point?
No full textThis article explores how the Investment Facilitation for Development Agreement (IFDA), recently made public at the World Trade Organization’s 13th ministerial conference, could be used as a starting point to include additional home state measures to facilitate outward investment in other international investment agreements or national regulations
Fluorescence lifetime imaging and phasor analysis of intracellular porphyrinic photosensitizers applied with different polymeric formulations.
Get PDFThe fluorescence lifetime of a porphyrinic photosensitizer (PS) is an important parameter to assess the aggregation state of the PS even in complex biological environments. Aggregation-induced quenching of the PS can significantly reduce the yield of singlet oxygen generation and thus its efficiency as a medical drug in photodynamic therapy (PDT) of diseased tissues. Hydrophobicity and the tendency to form aggregates pose challenges on the development of efficient PSs and often require carrier systems. A systematic study was performed to probe the impact of PS structure and encapsulation into polymeric carriers on the fluorescence lifetime in solution and in the intracellular environment. Five different porphyrinic PSs including chlorin e6 (Ce6) derivatives and tetrakis(m-hydroxyphenyl)-porphyrin and -chlorin were studied in free form and combined with polyvinylpyrrolidone (PVP) or micelles composed of triblock-copolymers or Cremophor. Following incubation of HeLa cells with these systems, fluorescence lifetime imaging combined with phasor analysis and image segmentation was applied to study the lifetime distribution in the intracellular surrounding. The data suggest that for free PSs, the structure-dependent cell uptake pathways determine their state and emission lifetimes. PS localization in the plasma membrane yielded mostly monomers with long fluorescence lifetimes whereas the endocytic pathway with subsequent lysosomal deposition adds a short-lived component for hydrophilic anionic PSs. Prolonged incubation times led to increasing contributions from short-lived components that derive from aggregates mainly localized in the cytoplasm. Encapsulation of PSs into polymeric carriers led to monomerization and mostly fluorescence emission decays with long fluorescence lifetimes in solution. However, the efficiency depended on the binding strength that was most pronounced for PVP. In the cellular environment, PVP was able to maintain monomeric long-lived species over prolonged incubation times. This was most pronounced for Ce6 derivatives with a logP value around 4.5. Micellar encapsulation led to faster release of the PSs resulting in multiple components with long and short fluorescence lifetimes. The hydrophilic hardly aggregating PS exhibited a mostly stable invariant lifetime distribution over time with both carriers. The presented data are expected to contribute to optimized PDT treatment protocols and improved PS-carrier design for preventing intracellular fluorescence quenching. In conclusion, amphiphilic and concurrent hydrophobic PSs with high membrane affinity as well as strong binding to the carrier have best prospects to maintain their photophysical properties in vivo and serve thus as efficient photodynamic diagnosis and PDT drugs
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