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PloS One 2024Bicuspid aortic valves (BAV) are frequently associated with ascending aortic aneurysms. The etiology is incompletely understood, but genetic factors, in addition to flow...
BACKGROUND
Bicuspid aortic valves (BAV) are frequently associated with ascending aortic aneurysms. The etiology is incompletely understood, but genetic factors, in addition to flow perturbations, are likely involved. Since loss of contractility and elaboration of extracellular matrix in the vessel wall are features of BAV-associated aortopathy, phenotypic modulation of smooth muscle cells (SMCs) may play a role.
METHODS
Ascending aortic tissue was collected intra-operatively from 25 individuals with normal (i.e., tricuspid) aortic valves (TAV) and from 25 individuals with BAVs. For both TAV and BAV, 10 patients had non-dilated (ND) and 15 patients had dilated (D) aortas. SMCs were isolated and cultured from a subset of patients from each group. Aortic tissue and SMCs were fluorescently immunolabeled for SMC phenotypic markers (i.e., alpha-smooth muscle actin (ASMA, contractile), vimentin (synthetic) and p16INK4a and p21Cip1 (senescence). SMCs were also analyzed for replicative senescence in culture.
RESULTS
In normal-sized and dilated BAV aortas, SMCs switched from the contractile state to either synthetic or senescent phenotypes, as observed by loss of ASMA (ND: P = 0.001, D: P = 0.002) and associated increases in vimentin (ND: P = 0.03, D: P = 0.004) or p16/p21 (ND: P = 0.03, D: P<0.0001) compared to TAV. Dilatation of the aorta exacerbated SMC phenotypic switching in both BAV and TAV aortas (all P<0.05). In SMCs cultured from normal and dilated aortas, those isolated from BAV reached replicative senescence faster than those from TAV aortas (all P = 0.02). Furthermore, there was a stark inverse correlation between ASMA and cell passage number in BAV SMCs (ND: P = 0.0006, D: P = 0.01), but not in TAV SMCs (ND: P = 0.93, D: P = 0.20).
CONCLUSIONS
The findings of this study provide direct evidence from cell culture studies implying that SMCs switch from the contractile state to either synthetic or senescent phenotypes in the non-dilated BAV aorta. In cultured SMCs from both non-dilated and dilated aortas, we found that this process may precede dilatation and accompany aneurysm development in BAV. Our findings suggest that therapeutically targeting SMC phenotypic modulation in BAV patients may be a viable option to prevent or delay ascending aortic aneurysm formation.
Topics: Humans; Aortic Valve; Bicuspid Aortic Valve Disease; Myocytes, Smooth Muscle; Heart Valve Diseases; Aorta; Male; Middle Aged; Phenotype; Female; Dilatation, Pathologic; Adult; Cellular Senescence; Cells, Cultured; Aged; Actins; Aortic Aneurysm; Vimentin
PubMed: 38954721
DOI: 10.1371/journal.pone.0306515 -
PLoS Biology Jul 2024The prevalence of antibiotic-resistant pathogens has become a major threat to public health, requiring swift initiatives for discovering new strategies to control...
The prevalence of antibiotic-resistant pathogens has become a major threat to public health, requiring swift initiatives for discovering new strategies to control bacterial infections. Hence, antibiotic stewardship and rapid diagnostics, but also the development, and prudent use, of novel effective antimicrobial agents are paramount. Ideally, these agents should be less likely to select for resistance in pathogens than currently available conventional antimicrobials. The usage of antimicrobial peptides (AMPs), key components of the innate immune response, and combination therapies, have been proposed as strategies to diminish the emergence of resistance. Herein, we investigated whether newly developed random antimicrobial peptide mixtures (RPMs) can significantly reduce the risk of resistance evolution in vitro to that of single sequence AMPs, using the ESKAPE pathogen Pseudomonas aeruginosa (P. aeruginosa) as a model gram-negative bacterium. Infections of this pathogen are difficult to treat due the inherent resistance to many drug classes, enhanced by the capacity to form biofilms. P. aeruginosa was experimentally evolved in the presence of AMPs or RPMs, subsequentially assessing the extent of resistance evolution and cross-resistance/collateral sensitivity between treatments. Furthermore, the fitness costs of resistance on bacterial growth were studied and whole-genome sequencing used to investigate which mutations could be candidates for causing resistant phenotypes. Lastly, changes in the pharmacodynamics of the evolved bacterial strains were examined. Our findings suggest that using RPMs bears a much lower risk of resistance evolution compared to AMPs and mostly prevents cross-resistance development to other treatments, while maintaining (or even improving) drug sensitivity. This strengthens the case for using random cocktails of AMPs in favour of single AMPs, against which resistance evolved in vitro, providing an alternative to classic antibiotics worth pursuing.
Topics: Pseudomonas aeruginosa; Anti-Bacterial Agents; Antimicrobial Peptides; Microbial Sensitivity Tests; Drug Resistance, Bacterial; Biofilms; Pseudomonas Infections
PubMed: 38954678
DOI: 10.1371/journal.pbio.3002692 -
Urogynecology (Philadelphia, Pa.) Jun 2024Interstitial cystitis/bladder pain syndrome (IC/BPS) is a highly prevalent condition with incompletely understood pathophysiology, especially in relation to the systemic...
IMPORTANCE
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a highly prevalent condition with incompletely understood pathophysiology, especially in relation to the systemic symptoms experienced. The role of autonomic nervous system dysfunction in IC/BPS remains poorly understood.
OBJECTIVE
The purpose of this study was to assess the relationship between autonomic symptom severity and clinical characteristics of patients with IC/BPS.
STUDY DESIGN
This is a retrospective cohort study of 122 IC/BPS patients who completed the Composite Autonomic Symptoms Score (COMPASS-31) questionnaire. Data were collected on anesthetic bladder capacity (BC), Hunner lesion (HL) status, results for validated IC/BPS symptom questionnaires (O'Leary Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index (ICSI/ICPI) and the Pelvic Pain and Urgency/Frequency (PUF) scale), and comorbid nonurologic associated syndromes. Using the first quartile of COMPASS-31 scores as the cutoff, we compared patients within the first quartile (low symptom load; n = 30), to the remainder of the patients (high symptom load; n = 92).
RESULTS
Patients scoring ≥20.36 were significantly less likely to be HL positive (10.9% vs 26.7%; P = 0.043) and had a significantly higher BC (823.10 ± 396.07 vs 635.00 ± 335.06; P = 0.027), higher scores on the PUF questionnaire (23.80 ± 4.98 vs; 19.61 ± 5.22 P < 0.001), and a higher number of nonurologic associated syndromes (5.65 ± 2.90 vs 2.60 ± 1.89; P < 0.001).
CONCLUSIONS
Patients with IC/BPS experience widespread symptoms associated with autonomic nervous system dysfunction. A higher symptom load strongly correlates with a nonbladder-centric phenotype. These findings provide further evidence that total body nervous system dysfunction is present in patients with nonbladder centric IC/BPS.
PubMed: 38954605
DOI: 10.1097/SPV.0000000000001536 -
Journal of Experimental Botany Jul 2024Linear mixed models (LMMs) are a commonly used method for genome-wide association studies (GWAS) that aim to detect associations between genetic markers and phenotypic...
Linear mixed models (LMMs) are a commonly used method for genome-wide association studies (GWAS) that aim to detect associations between genetic markers and phenotypic measurements in a population of individuals while accounting for population structure and cryptic relatedness. In a standard GWAS, hundreds of thousands to millions of statistical tests are performed, requiring control for multiple hypothesis testing. Typically, static corrections that penalize the number of tests performed are used to control for the family-wise error rate, which is the probability of making at least one false positive. However, it has been shown that in practice this threshold is too conservative for normally distributed phenotypes and not stringent enough for non-normally distributed phenotypes. Therefore, permutation-based LMM approaches have recently been proposed to provide a more realistic threshold that takes phenotypic distributions into account. In this work, we will discuss the advantages of permutation-based GWAS approaches, including new simulations and results from a re-analysis of all publicly available Arabidopsis thaliana phenotypes from the AraPheno database.
PubMed: 38954539
DOI: 10.1093/jxb/erae280 -
G3 (Bethesda, Md.) Jul 2024In aquaculture, sterile triploids are commonly used for production as sterility gives them potential gains in growth, yields and quality. However, they cannot be...
In aquaculture, sterile triploids are commonly used for production as sterility gives them potential gains in growth, yields and quality. However, they cannot be reproduced, and DNA parentage assignment to their diploid or tetraploid parents is required to estimate breeding values for triploid phenotypes. No publicly available software has the ability to assign triploids to their parents. Here, we updated the R package APIS to support triploids induced from diploid parents. First, we created new exclusion and likelihood tables that account for the double allelic contribution of the dam and the recombination that can occur during female meiosis. As the effective recombination rate of each marker with the centromere is usually unknown, we set it at 0.5 and found that this value maximises the assignment rate even for markers with high or low recombination rates. The number of markers needed for a high true assignment rate did not strongly depend on the proportion of missing parental genotypes. The assignment power was however affected by the quality of the markers (minor allele frequency, call rate). Altogether, 96 to 192 SNPs were required to have a high parentage assignment rate in a real rainbow trout dataset of 1232 triploid progenies from 288 parents. The likelihood approach was more efficient than exclusion when the power of the marker set was limiting. When more markers were used, exclusion was more advantageous, with sensitivity reaching unity, very low False Discovery Rate (<0.01) and excellent specificity (0.96-0.99). Thus, APIS provides an efficient solution to assign triploids to their diploid parents.
PubMed: 38954534
DOI: 10.1093/g3journal/jkae143 -
Cardiovascular Research Jul 2024
Topics: Humans; Genetic Therapy; Cardiomyopathy, Hypertrophic; Animals; Treatment Outcome; Genetic Vectors; Phenotype; Genetic Predisposition to Disease
PubMed: 38954506
DOI: 10.1093/cvr/cvae107 -
Inflammation primes the murine kidney for recovery by activating AZIN1 adenosine-to-inosine editing.The Journal of Clinical Investigation Jul 2024The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of...
The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of determining the potential for recovery from acute kidney injury following various insults. Here, we report that quantitation of post-transcriptional adenosine-to-inosine (A-to-I) RNA editing offers a distinct genome-wide signature, enabling the delineation of disease trajectories in the kidney. A well-defined murine model of endotoxemia permitted the identification of the origin and extent of A-to-I editing, along with temporally discrete signatures of double-stranded RNA stress and Adenosine Deaminase isoform switching. We found that A-to-I editing of Antizyme Inhibitor 1 (AZIN1), a positive regulator of polyamine biosynthesis, serves as a particularly useful temporal landmark during endotoxemia. Our data indicate that AZIN1 A-to-I editing, triggered by preceding inflammation, primes the kidney and activates endogenous recovery mechanisms. By comparing genetically modified human cell lines and mice locked in either A-to-I edited or uneditable states, we uncovered that AZIN1 A-to-I editing not only enhances polyamine biosynthesis but also engages glycolysis and nicotinamide biosynthesis to drive the recovery phenotype. Our findings implicate that quantifying AZIN1 A-to-I editing could potentially identify individuals who have transitioned to an endogenous recovery phase. This phase would reflect their past inflammation and indicate their potential for future recovery.
PubMed: 38954486
DOI: 10.1172/JCI180117 -
International Journal of Systematic and... Jul 2024Four rod-shaped, non-motile, non-spore-forming, facultative anaerobic, Gram-stain-positive lactic acid bacteria, designated as EB0058, SCR0080, LD0937 and SCR0063, were...
Four rod-shaped, non-motile, non-spore-forming, facultative anaerobic, Gram-stain-positive lactic acid bacteria, designated as EB0058, SCR0080, LD0937 and SCR0063, were isolated from different corn and grass silage samples. The isolated strains were characterized using a polyphasic approach and EB0058 and SCR0080 were identified as by 16S rRNA gene sequence analysis. Based on whole-genome sequence-based characterization, EB0058 and SCR0080 were separated into a distinct clade from DSM 20178, together with CECT9104 and UD2202, whose genomic sequences are available from NCBI GenBank. The average nucleotide identity (ANI) values within the new subgroup are 99.9 % and the digital DNA-DNA hybridization (dDDH) values are 99.3-99.9 %, respectively. In contrast, comparison of the new subgroup with publicly available genomic sequences of strains, including the type strain DSM 20178, revealed dDDH values of 70.2-72.5 % and ANI values of 96.2-96.6 %. Based on their chemotaxonomic, phenotypic and phylogenetic characteristics, EB0058 and SCR0080 represent a new subspecies of . The name subsp. subsp. nov. is proposed with the type strain EB0058 (=DSM 116376=NCIMB 15474). According to the results of 16S rRNA gene sequencing, LD0937 and SCR0063 are members of the group. The dDDH value between the isolates LD0937 and SCR0063 was 67.6 %, which is below the species threshold of 70 %, clearly showing that these two isolates belong to different species. For both strains, whole genome-sequencing revealed that the closest relatives within the group were DSM 11542 (dDDH 66.5 and 65.9 %) and DSM 20011 (dDDH 64.1 and 64.9 %). Based on the genomic, chemotaxonomic and morphological data obtained in this study, two novel species, sp. nov. and sp. nov. are proposed and the type strains are LD0937 (=DSM 116105=NCIMB 15471) and SCR0063 (=DSM 116297=NCIMB 15473), respectively.
Topics: RNA, Ribosomal, 16S; Phylogeny; Bacterial Typing Techniques; Zea mays; Silage; DNA, Bacterial; Nucleic Acid Hybridization; Sequence Analysis, DNA; Fatty Acids; Poaceae; Base Composition; Whole Genome Sequencing; Lacticaseibacillus
PubMed: 38954457
DOI: 10.1099/ijsem.0.006441 -
Biogerontology Jul 2024The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been... (Review)
Review
The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues. Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8 T and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8 T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors. Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.
PubMed: 38954358
DOI: 10.1007/s10522-024-10114-w -
Probiotics and Antimicrobial Proteins Jul 2024Metabolic syndrome (MetS) is a global epidemic complex and will cause serious metabolic comorbidities without treatment. A prevention strategy for MetS development has...
Effect of Lacticaseibacillus casei LC2W Supplementation on Glucose Metabolism and Gut Microbiota in Subjects at High Risk of Metabolic Syndrome: A Randomized, Double-blinded, Placebo-controlled Clinical Trial.
Metabolic syndrome (MetS) is a global epidemic complex and will cause serious metabolic comorbidities without treatment. A prevention strategy for MetS development has been proposed to modulate gut microbiota by probiotic administration to improve intestinal dysbiosis and benefit the host. Lacticaseibacillus casei LC2W has exhibited positive effects in preventing colitis and anti-hypertension in vivo. However, the effect of L. casei LC2W on subjects at high risk of MetS is unknown. Here, a randomized, double-blinded, placebo-controlled study was conducted on 60 subjects with high risk of MetS, and the hypoglycemic and hypolipidemic activity and possible pathways of L. casei LC2W were inferred from the correlation analysis with gut microbiome composition, function, and clinical phenotypic indicators. The results showed that oral administration of L. casei LC2W could exert significant benefits on weight control, glucose and lipid metabolism, inflammatory and oxidative stress parameters, and SCFA production, as well as modulate the composition of gut microbiota. The relative abundance of Lacticaseibacillus, Bifidobacterium, Dorea, and Blautia was enriched, and their interaction with other gut microbes was strengthened by oral administration of L. casei LC2W, which was beneficial in ameliorating gut inflammation, promoting glucose and lipids degradation pathways, thus alleviated MetS. The present study confirmed the prevention effects of L. casei LC2W towards MetS from aspects of clinical outcomes and microflora modulation, providing an alternative strategy for people at high risk of MetS.Trial registration: The study was proactively registered in ClinicalTrial.gov with the registration number of ChiCTR2000031833 on April 09, 2020.
PubMed: 38954305
DOI: 10.1007/s12602-024-10312-5