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Small (Weinheim An Der Bergstrasse,... Jul 2024Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of...
Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal-organic-framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1-to-M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy.
PubMed: 38953313
DOI: 10.1002/smll.202402141 -
Molecular Ecology Jul 2024When facing challenges, vertebrates activate a hormonal stress response that can dramatically alter behaviour and physiology. Although this response can be costly,...
When facing challenges, vertebrates activate a hormonal stress response that can dramatically alter behaviour and physiology. Although this response can be costly, conceptual models suggest that it can also recalibrate the stress response system, priming more effective responses to future challenges. Little is known about whether this process occurs in wild animals, particularly in adulthood, and if so, how information about prior experience with stressors is encoded. One potential mechanism is hormonally mediated changes in DNA methylation. We simulated the spikes in corticosterone that accompany a stress response using non-invasive dosing in tree swallows (Tachycineta bicolor) and monitored the phenotypic effects 1 year later. In a subset of individuals, we characterized DNA methylation using reduced representation bisulfite sequencing shortly after treatment and a year later. The year after treatment, experimental females had stronger negative feedback and initiated breeding earlier-traits that are associated with stress resilience and reproductive performance in our population-and higher baseline corticosterone. We also found that natural variation in corticosterone predicted patterns of DNA methylation. Finally, corticosterone treatment influenced methylation on short (1-2 weeks) and long (1 year) time scales; however, these changes did not have clear links to functional regulation of the stress response. Taken together, our results are consistent with corticosterone-induced priming of future stress resilience and support DNA methylation as a potential mechanism, but more work is needed to demonstrate functional consequences. Uncovering the mechanisms linking experience with the response to future challenges has implications for understanding the drivers of stress resilience.
PubMed: 38953311
DOI: 10.1111/mec.17456 -
Autophagy Jul 2024Macroautophagy, simply referred to below as autophagy, is an intracellular degradation system that is highly conserved in eukaryotes. Since the processes involved in...
Macroautophagy, simply referred to below as autophagy, is an intracellular degradation system that is highly conserved in eukaryotes. Since the processes involved in autophagy are accompanied by membrane dynamics, RAB small GTPases, key regulators of membrane trafficking, are generally thought to regulate the membrane dynamics of autophagy. Although more than half of the mammalian RABs have been reported to be involved in canonical and selective autophagy, no consensus has been reached in regard to the role of RABs in mammalian autophagy. Here, we comprehensively analyzed a -knockout (KO) library of MDCK cells to reevaluate the requirement for each RAB isoform in basal and starvation-induced autophagy. The results revealed clear alteration of the MAP1LC3/LC3-II level in only four -KO cells (-KO, -KO, -KO, and -KO cells) and identified RAB14 as a new regulator of autophagy, specifically at the autophagosome maturation step. The autophagy-defective phenotype of two of these -KO cells, -KO and -KO cells, was very mild, but double KO of and caused a severer autophagy-defective phenotype (greater LC3 accumulation than in single-KO cells, indicating an overlapping role of RAB2 and RAB14 during autophagosome maturation. We also found that RAB14 is phylogenetically similar to RAB2 and that it possesses the same properties as RAB2, i.e. autophagosome localization and interaction with the HOPS subunits VPS39 and VPS41. Our findings suggest that RAB2 and RAB14 overlappingly regulate the autophagosome maturation step through recruitment of the HOPS complex to the autophagosome.
PubMed: 38953305
DOI: 10.1080/15548627.2024.2374699 -
The Journal of Antimicrobial... Jul 2024Antimicrobials can select for antimicrobial-resistant bacteria. After treatment the active compound is excreted through urine and faeces. As some antimicrobials are...
OBJECTIVES
Antimicrobials can select for antimicrobial-resistant bacteria. After treatment the active compound is excreted through urine and faeces. As some antimicrobials are chemically stable, recirculation of subinhibitory concentrations of antimicrobials may occur due to coprophagic behaviour of animals such as chickens.
METHODS
The persistence of three antimicrobials over time and their potential effects on antimicrobial resistance were determined in four groups of broilers. Groups were left untreated (control) or were treated with amoxicillin (unstable), doxycycline or enrofloxacin (stable). Antimicrobials were extracted from the faecal samples and were measured by LC-MS/MS. We determined the resistome genotypically using shotgun metagenomics and phenotypically by using Escherichia coli as indicator microorganism.
RESULTS
Up to 37 days after treatment, doxycycline and enrofloxacin had concentrations in faeces equal to or higher than the minimal selective concentration (MSC), in contrast to the amoxicillin treatment. The amoxicillin treatment showed a significant difference (P ≤ 0.01 and P ≤ 0.0001) in the genotypic resistance only directly after treatment. On the other hand, the doxycycline treatment showed approximately 52% increase in phenotypic resistance and a significant difference (P ≤ 0.05 and P ≤ 0.0001) in genotypic resistance throughout the trial. Furthermore, enrofloxacin treatment resulted in a complete non-WT E. coli population but the quantity of resistance genes was similar to the control group, likely because resistance is mediated by point mutations.
CONCLUSIONS
Based on our findings, we suggest that persistence of antimicrobials should be taken into consideration in the assessment of priority classification of antimicrobials in livestock.
PubMed: 38953288
DOI: 10.1093/jac/dkae213 -
Development (Cambridge, England) Jul 2024Spermatogonial stem cell (SSC) self-renewal and differentiation provide foundational support for long-term, steady-state spermatogenesis in mammals. Here, we have...
Spermatogonial stem cell (SSC) self-renewal and differentiation provide foundational support for long-term, steady-state spermatogenesis in mammals. Here, we have investigated the essential role of RNA exosome associated DIS3 ribonuclease in maintaining spermatogonial homeostasis and facilitating germ cell differentiation. We have established male germ-cell Dis3 conditional knockout (cKO) mice in which the first and subsequent waves of spermatogenesis are disrupted. This leads to a Sertoli cell-only phenotype and sterility in adult male mice. Bulk RNA-seq documents that Dis3 deficiency partially abolishes RNA degradation and causes significant increases in the abundance of transcripts. This also includes pervasively transcribed PROMoter uPstream Transcripts (PROMPTs), which accumulate robustly in Dis3 cKO testes. In addition, scRNA-seq analysis indicates that Dis3 deficiency in spermatogonia significantly disrupts RNA metabolism and gene expression, and impairs early germline cell development. Overall, we document that exosome-associated DIS3 ribonuclease plays crucial roles in maintaining early male germ cell lineage in mice.
Topics: Animals; Male; Spermatogenesis; Mice; Mice, Knockout; Fertility; Testis; Spermatogonia; Sertoli Cells; Cell Differentiation; Exosome Multienzyme Ribonuclease Complex; Exosomes; RNA Stability; Infertility, Male
PubMed: 38953252
DOI: 10.1242/dev.202579 -
Circulation. Genomic and Precision... Jul 2024Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated...
BACKGROUND
Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model.
METHODS
Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both mutant and WT (wild-type) mice.
RESULTS
A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, knockdown in human cardiac fibroblasts enhanced accelerated cell migration.
CONCLUSIONS
This study identified a rare nonsynonymous variant in the gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.
PubMed: 38953222
DOI: 10.1161/CIRCGEN.124.004614 -
Circulation. Genomic and Precision... Jul 2024Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in . Interpreting the pathogenicity of missense variants...
BACKGROUND
Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in . Interpreting the pathogenicity of missense variants is challenging, and ≈79% of missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.
METHODS
An in vitro -Brugada syndrome automated patch clamp assay was generated and independently studied at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with loss-of-function.
RESULTS
Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak density (=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values yielded 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic.
CONCLUSIONS
This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future -Brugada syndrome variants of uncertain significance.
PubMed: 38953211
DOI: 10.1161/CIRCGEN.124.004569 -
Lung India : Official Organ of Indian... Jul 2024Tobacco smoking is an established risk factor for chronic obstructive pulmonary disease (COPD). Current evidence suggests that non-tobacco-related risk factors vary...
BACKGROUND AND OBJECTIVE
Tobacco smoking is an established risk factor for chronic obstructive pulmonary disease (COPD). Current evidence suggests that non-tobacco-related risk factors vary geographically and are less understood than smoking. This study aims to compare the risk factors, symptoms, and clinical features of smoking (S-COPD) and non-smoking (NS-COPD) in a COPD population.
MATERIALS AND METHODS
In this retrospective cross-sectional study, 489 COPD patients were screened. Data on socio-demographics, smoking and medical history, other risk factors, symptoms, and clinical characteristics including COPD Assessment Test (CAT) score, and Modified Medical Research Council (mMRC) Dyspnea Scale were examined.
RESULTS
Of the total selected 416 COPD patients, 35.34% were NS-COPD while 64.66% were S-COPD. S-COPD was predominant in males, whereas NS-COPD was predominant in females (P < 0.0001). In NS-COPD, biomass fuel exposure was a major risk factor (P < 0.0001), and 61% of subjects had a biomass fuel exposure index of >60. In bivariate and multivariate analyses, no risk factors were correlated with forced expiratory volume in 1 second (FEV1)% predicted, while among clinical features, duration of illness (P = 0.001) was correlated with lower values of FEV1 in the multivariate table of S-COPD. In the multivariate analysis, biomass fuel exposure (P = 0.039) and CAT score (P < 0.0001) were correlated with FEV1(%) in NS-COPD.
CONCLUSION
Biomass fuel exposure is a substantial risk factor for NS-COPD and was correlated with FEV1(%) predicted. In addition, the CAT score correlated with disease severity in patients with NS-COPD. The development of COPD in non-smokers is being recognized as a separate phenotype and it should be managed according to risk factors.
PubMed: 38953187
DOI: 10.4103/lungindia.lungindia_304_23 -
Genome Biology and Evolution Jul 2024Genetic adaptation is the change of a population towards a phenotype that best fits the present ecological conditions in which it inhabits. As environmental conditions...
Genetic adaptation is the change of a population towards a phenotype that best fits the present ecological conditions in which it inhabits. As environmental conditions change, allele frequencies shift, resulting in different populations of the same species possessing genetic variation and divergent phenotypes. Cooperatively breeding common mole-rats (Cryptomys hottentotus hottentotus) inhabit environments along an aridity gradient in South Africa, which provides an opportunity for local genetic adaptations to occur. Using one mitochondrial gene (cytochrome b) and 3,540 SNP loci across the whole genome, we determined the phylogenetic relationship, population structure and genetic diversity of five populations of C. h. hottentotus located along an aridity gradient. Mitochondrial data identified population-specific clades that were less distinct in the two mesic populations, potentially indicating historical or recent gene flow, or the retention of ancestral haplotypes. Arid and semi-arid populations formed a distinct cluster from the non-arid populations. Genetic diversity and gene flow were higher in arid-dwelling individuals, suggesting greater connectivity and interactions between colonies in arid regions in comparison to mesic ones. Using an Aridity Index, we determined that isolation by environment, rather than isolation by geographical distance, best explains the genetic distance between the populations. Further analyses using target loci may determine if there are differing underlying genetic adaptations among populations of C. h. hottentotus. These analyses could help unravel population differences in response to environmental factors within a sub-species of bathyergid mole-rat and determine the adaptive capacity of this small non-migratory subterranean rodent species in response to aridification in the face of climate change.
PubMed: 38953183
DOI: 10.1093/gbe/evae144 -
Journal of Leukocyte Biology Jul 2024Ethnopharmacological treatments have shown beneficial effects in the clinical practice of autoimmune disorders. However, the underlying mechanism of immunomodulatory...
Ethnopharmacological treatments have shown beneficial effects in the clinical practice of autoimmune disorders. However, the underlying mechanism of immunomodulatory effects remains challenging, given the complicate composition of herbal medicines. Here, we developed an immunological approach to interrogate the T helper cell response. Through data mining we hypothesized that Chinese medicine formula, Yu-Ping-Feng (YPF) might be a promising candidate for treating primary Sjögren's syndrome (pSS), a common autoimmune disease manifested by exocrine gland dysfunction. We took advantage of a mouse model of experimental Sjögren's syndrome (ESS) that we previously established for YPF formula treatment. YPF therapy ameliorated the ESS pathology in mice with active disease, showing improved salivary function and decreased serum levels of autoantibodies. Phenotypic analysis suggested that both effector T and B cells were significantly suppressed. Using co-culture assay and adoptive transfer models, we demonstrated that YPF formula directly restrained effector/memory T cell expansion and differentiation into Th17 and T follicular helper (Tfh) cells, the key subsets in ESS pathogenesis. Importantly, we recruited 20 pSS patients and conducted a pilot study of 8-week therapy of YPF formula. YPF treatment effectively improved fatigue symptoms, exocrine gland functions and reduced serum IgG/IgA levels, while effector T and B cell subsets were significantly decreased. There was a trend of reduction on disease activity, but not statistically significant. Together, our findings suggested a novel approach to assess the immunomodulatory effects of YPF formula, which may be favorable for patients with autoimmune disorders.
PubMed: 38953166
DOI: 10.1093/jleuko/qiae155