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Sleep disordered breathing (SDB) is a frequent comorbidity in cardiac disease patients. Nevertheless, the prevalence and relationship between SDB and severe primary mitral regurgitation (PMR) has not been well investigated to date. Methods: A cohort of 121 patients with significant PMR undergoing mitral valve surgery were prospectively enrolled and received a cardiorespiratory single night polygraphy screening using ApneaLink before surgery. Eighty-two of them underwent a follow-up examination including a follow-up single-night sleep study 3 months after surgery. Results: The mean age of patients was 65.3 ± 12.0 years. Sixty patients (49.6%) were female. The mean EuroSCORE II was 2.5 ± 2.4%. Initially, 91 (75.2%) patients presented with SDB, among whom 50.4% (46 patients, 38.0% of total cohort) were classified as moderate to severe. These patients tended to require significantly longer postoperative intensive care and mechanical ventilation. Among the 82 patients who completed follow-up exams, mitral valve surgery led to a significant reduction in relevant SDB (20.7%). The apnea-hypopnea index (from 11/h [4;18] to 4/h [3;14] (p = 0.04)), the oxygenation-desaturation index (from 8/h [3;18] to 5/h [3;12] (p = 0.008)) as well as the saturation time below 90% (from 32 min [13;86] to 18 min [5;36] (p = 0.005)), were all shown to be improved significantly. Conclusion: The prevalence of SDB is very high in patients with severe primary mitral regurgitation and may contribute to postoperative complications and prolonged intensive care. A significantly reduced but still high prevalence of SDB was observed 3 months after mitral valve surgery, highlighting the bidirectional relationship between SDB and heart failure.
Microplastics (MPs) are ubiquitous and persistent pollutants, and have been detected in a wide variety of media, from soils to aquatic systems. MPs, consisting primarily of polyethylene, polypropylene, and polyacrylamide polymers, have recently been found in 12% of samples of honey collected in Ecuador. Recently, MPs have also been identified in honey bees collected from apiaries in Copenhagen, Denmark, as well as nearby semiurban and rural areas. Given these documented exposures, assessment of their effects is critical for understanding the risks of MP exposure to honey bees. Exposure to polystyrene (PS)-MPs decreased diversity of the honey bee gut microbiota, followed by changes in gene expression related to oxidative damage, detoxification, and immunity. As a result, the aim of this perspective was to investigate whether wide-spread prevalence of MPs might have unintended negative effects on health and fitness of honey bees, as well as to draw the scientific community’s attention to the possible risks of MPs to the fitness of honey bees. Several research questions must be answered before MPs can be considered a potential threat to bees.
Drug interactions are a well-known cause of adverse drug events, and drug interaction databases can help the clinician to recognize and avoid such interactions and their adverse events. However, not every interaction leads to an adverse drug event. This is because the clinical relevance of drug–drug interactions also depends on the genetic profile of the patient. If inhibitors or inducers of drug metabolising enzymes (e.g., CYP and UGT) are added to the drug therapy, phenoconcversion can occur. This leads to a genetic phenotype that mismatches the observable phenotype. Drug–drug–gene and drug–gene–gene interactions influence the toxicity and/or ineffectivness of the drug therapy. To date, there have been limited published studies on the impact of genetic variations on drug–drug interactions. This review discusses the current evidence of drug–drug–gene interactions, as well as drug–gene–gene interactions. Phenoconversion is explained, the and methods to calculate the phenotypes are described. Clinical recommendations are given regarding the integratation of the PGx results in the assessment of the relevance of drug interactions in the future.
This paper investigates how French signals prominence in prosody in the post-verbal domain of sentences with two objects or two adjuncts that vary in information status and prosodic length. The information status of particular interest here is dual focus, defined as the presence of two foci in a mono-clausal sentence, but other information states are investigated as well. The controlled production experiment we report on allows for a detailed examination of prosodic prominence. High boundary tones at the end of non-final prosodic phrases are pervasive, as has been documented in many studies before the present one. An important but less documented result is the variation in different prosodic curs, in particular in the number and position of high tones, as well as the particular scaling relationship between them, providing a powerful tool for the expression of (dual) focus. We also report on a perception experiment with our data, showing a clear tendency for French listeners to select the intended context question, recognizing dual focus better than other information states. Overall, this article provides elements of answers as to why French prosody is so difficult to pin down, and why contradictory results and analyses have been proposed for this language.
Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.
Determining how the elevation of the Northern Andes has evolved over time is of paramount importance for understanding the response of the Northern Andes to deformational and geodynamic processes and its role as an orographic barrier for atmospheric vapor transport over geologic time. However, a fundamental requirement when using stable isotope data for paleoaltimetry reconstructions is knowledge about the present-day changes of δ18O and δD with elevation (isotopic lapse rate). This study defines the present-day river isotopic lapse rate near the Equator (∼3°S) based on analysis of δ18O and δD of surface waters collected from streams across the Western Cordillera and the Inter-Andean depression in Southern Ecuador. The results for the two domains show a decrease of δ18O with elevation which fits a linear regression with a slope of −0.18‰/100 m (R2 = 0.73, n = 83). However, we establish a present-day lapse rate of −0.15‰/100 m for δ18O (R2 = 0.88, n = 19) and -1.4‰/100 m for δD (R2 = 0.93, n = 19) from water samples collected along the west facing slopes of the Western Ecuadorian Cordillera which is mainly subject to moisture transport from the Pacific. We argue that this empirical relationship, consistent with those obtained in different tropical areas of the world, can inform stable isotope paleoaltimetry reconstructions in tropical latitudes.
Fatty acid and polyketide synthases (FASs and PKSs) synthesize physiologically and pharmaceutically important products by condensation of acyl building blocks. The transacylation reaction catalyzed by acyl transferases (ATs) is responsible for the selection of acyl-CoA esters for further processing by FASs and PKSs. In this study, the AT domains of different multidomain (type I) PKS systems are kinetically described in their substrate selectivity, AT−Acyl carrier protein (ACP) domain-domain interaction and enzymatic kinetic properties. We observe that the ATs of modular PKSs, intricate protein complexes occurring in bacteria and responsible for the biosynthesis of bioactive polyketides, are significantly slower than ATs of mammalian FASs, reflecting the respective purpose of the biosynthetic pathways within the organism and their metabolic context. We further perform a mutational study on the kinetics of the AT−ACP interaction in the modular PKS 6-deoxyerythronolide B synthase (DEBS) and find a high plasticity in enzyme properties, which we explain by a high plasticity in AT−ACP recognition. Our study enlarges the understanding of ATs in its molecular properties and is similarly a call for thorough AT-centered PKS engineering strategies.
Aims: In primary central nervous system tumours, epithelial-to-mesenchymal transition (EMT) gene expression is associated with increased malignancy. However, it has also been shown that EMT factors in gliomas are almost exclusively expressed by glioma vessel-associated pericytes (GA-Peris). In this study, we aimed to identify the mechanism of EMT in GA-Peris and its impact on angiogenic processes.
Methods; In glioma patients, vascular density and the expression of the pericytic markers platelet derived growth factor receptor (PDGFR)-β and smooth muscle actin (αSMA) were examined in relation to the expression of the EMT transcription factor SLUG and were correlated with survival of patients with glioblastoma (GBM). Functional mechanisms of SLUG regulation and the effects on primary human brain vascular pericytes (HBVP) were studied in vitro by measuring proliferation, cell motility and growth characteristics.
Results: The number of PDGFR-β- and αSMA-positive pericytes did not change with increased malignancy nor showed an association with the survival of GBM patients. However, SLUG-expressing pericytes displayed considerable morphological changes in GBM-associated vessels, and TGF-β induced SLUG upregulation led to enhanced proliferation, motility and altered growth patterns in HBVP. Downregulation of SLUG or addition of a TGF-β antagonising antibody abolished these effects.
Conclusions: We provide evidence that in GA-Peris, elevated SLUG expression is mediated by TGF-β, a cytokine secreted by most glioma cells, indicating that the latter actively modulate neovascularisation not only by modulating endothelial cells, but also by influencing pericytes. This process might be responsible for the formation of an unstructured tumour vasculature as well as for the breakdown of the blood–brain barrier in GBM.
Climatic niches describe the climatic conditions in which species can persist. Shifts in climatic niches have been observed to coincide with major climatic change, suggesting that species adapt to new conditions. We test the relationship between rates of climatic niche evolution and paleoclimatic conditions through time for 65 Old-World flycatcher species (Aves: Muscicapidae). We combine niche quantification for all species with dated phylogenies to infer past changes in the rates of niche evolution for temperature and precipitation niches. Paleoclimatic conditions were inferred independently using two datasets: a paleoelevation reconstruction and the mammal fossil record. We find changes in climatic niches through time, but no or weak support for a relationship between niche evolution rates and rates of paleoclimatic change for both temperature and precipitation niche and for both reconstruction methods. In contrast, the inferred relationship between climatic conditions and niche evolution rates depends on paleoclimatic reconstruction method: rates of temperature niche evolution are significantly negatively related to absolute temperatures inferred using the paleoelevation model but not those reconstructed from the fossil record. We suggest that paleoclimatic change might be a weak driver of climatic niche evolution in birds and highlight the need for greater integration of different paleoclimate reconstructions.
The factors that vary the aroma of Tuber magnatum fruiting bodies are poorly understood. The study determined the headspace aroma composition, sensory aroma profiles, maturity and bacterial communities from T. magnatum originating from Italy, Croatia, Hungary, and Serbia, and tested if truffle aroma is dependent on provenance and if fruiting body volatiles are explained by maturity and/or bacterial communities.
Headspace volatile profiles were determined using gas chromatography–mass spectrometry–olfactometry (GC-MS-O) and aroma of fruiting body extracts were sensorially assessed. Fruiting body maturity was estimated through spore melanisation. Bacterial community was determined using 16S rRNA amplicon sequencing.
Main odour active compounds were present in all truffles but varied in concentration. Aroma of truffle extracts were sensorially discriminated by sites. However, volatile profiles of individual fruiting bodies varied more within sites than across geographic area, while maturity level did not play a role. Bacterial communities varied highly and were partially explained by provenance. A few rare bacterial operational taxonomical units associated with a select few nonodour active volatile compounds.
Specificities of the aroma of T. magnatum truffles are more likely to be linked to individual properties than provenance. Some constituents of bacteria may provide biomarkers of provenance and be linked to nonodour active volatiles.