The relationship between obstructive sleep apnea and osteoarthritis: evidence from an observational and Mendelian randomization study

ObjectivesObstructive sleep apnea (OSA) and osteoarthritis (OA) are common comorbidities that significantly impact individuals’ quality of life. However, the relationship between OSA and OA remains unclear. This study aims to explore the connection between OSA and OA and evaluate causality using Mendelian randomization (MR).MethodsA total of 12,454 participants from the National Health and Nutrition Examination Survey (2009–2012) were included. OSA participants were identified based on self-reported interviews. The association between OA and OSA was assessed through multivariable logistic regression analysis. A two-sample MR was employed to investigate the relationship between OSA and OA, specifically hip OA and knee OA, utilizing the inverse variance-weighted (IVW) approach.ResultsBased on the observational study, individuals with OSA exhibited a higher risk of OA (OR = 1.67, 95% CI = 1.40–1.98). IVW demonstrated that the risk of OA (OR = 1.13, 95% CI: 1.05–1.21, p = 0.001), hip OA (OR = 1.11, 95% CI: 1.04–1.18, p = 0.002), and knee OA (OR = 1.08, 95% CI: 1.02–1.14, p = 0.005) was significantly associated with OSA. Reverse MR analyses indicated no effect of OA on OSA. Additionally, body mass index (BMI) was found to mediate 36.9% (95% CI, 4.64–73.2%, p = 0.026) of the OSA effects on OA risk.ConclusionThe cross-sectional observational analysis unveiled noteworthy associations between OSA and OA. Meanwhile, findings from the MR study provide support for a causal role

Using multi-tissue transcriptome-wide association study to identify candidate susceptibility genes for respiratory infectious diseases

Objective: We explore the candidate susceptibility genes for influenza A virus (IAV), measles, rubella, and mumps and their underlying biological mechanisms.Methods: We downloaded the genome-wide association study summary data of four virus-specific immunoglobulin G (IgG) level data sets (anti-IAV IgG, anti-measles IgG, anti-rubella IgG, and anti-mumps virus IgG levels) and integrated them with reference models of three potential tissues from the Genotype-Tissue Expression (GTEx) project, namely, whole blood, lung, and transformed fibroblast cells, to identify genes whose expression is predicted to be associated with IAV, measles, mumps, and rubella.Results: We identified 19 significant genes (ULK4, AC010132.11, SURF1, NIPAL2, TRAP1, TAF1C, AC000078.5, RP4-639F20.1, RMDN2, ATP1B3, SRSF12, RP11-477D19.2, TFB1M, XXyac-YX65C7_A.2, TAF1C, PCGF2, and BNIP1) associated with IAV at a Bonferroni-corrected threshold of p < 0.05; 14 significant genes (SOAT1, COLGALT2, AC021860.1, HCG11, METTL21B, MRPL10, GSTM4, PAQR6, RP11-617D20.1, SNX8, METTL21B, ANKRD27, CBWD2, and TSFM) associated with measles at a Bonferroni-corrected threshold of p < 0.05; 15 significant genes (MTOR, LAMC1, TRIM38, U91328.21, POLR2J, SCRN2, Smpd4, UBN1, CNTROB, SCRN2, HOXB-AS1, SLC14A1, AC007566.10, AC093668.2, and CPD) associated with mumps at a Bonferroni-corrected threshold of p < 0.05; and 13 significant genes (JAGN1, RRP12, RP11-452K12.7, CASP7, AP3S2, IL17RC, FAM86HP, AMACR, RRP12, PPP2R1B, C11orf1, DLAT, and TMEM117) associated with rubella at a Bonferroni-corrected threshold of p < 0.05.Conclusions: We have identified several candidate genes for IAV, measles, mumps, and rubella in multiple tissues. Our research may further our understanding of the pathogenesis of infectious respiratory diseases

Functional studies on Vps74p, a novel protein sorting regulator in sacchromyces[sic] cerevisiae

Deletion of the VPS74 (V̲acuolar P̲rotein S̲orting 74) gene in yeast Sacchromyces cerevisiae results in a modest defect in carboxypeptidase Y (CPY) sorting. I found that null mutants of VPS74 were sensitive to Calcofluor white, indicating that the cell walls of these cells were defective. Consistent with this, processing of the GPI-anchored protein Gas1p, which is required for proper cell wall assembly and morphogenesis, was altered in vps74Δ cells. I have established that the defects of cell wall integrity and Gas1p processing observed in vps74Δ cells are attributable to the mislocalization and rapid degradation of a subset of Golgi mannosyltransferases, and in particular, Kre2p. Using a yeast two hybrid assay, I have demonstrated that Vps74p interacts with the cytoplasmic tail of Kre2p and that the FLS amino acid sequence in Kre2p is required to mediate this binding. Mammalian homologues of Vps74p, GMx33α/GPP34 and GMx33β/GPP34R, can complement the Gas1p processing and Calcofluor white sensitivity defects of vps74Δ cells to varying degrees indicating that some of Vps74p’s activities are evolutionarily conserved.My findings suggest that Vps74p functions as a protein sorting receptor mediating the retrieval and hence steady-state distribution of a subset of Golgi mannosyltransferases.To further investigate the function of VPS74, I performed a synthetic lethal screen. From this screen I identified three mutants that showed synthetic lethal interactions with cells lacking the VPS74 gene. The mutations responsible for the synthetic lethal phenotypes all mapped to a single locus - YIL039W (GPS1, G̲as1 P̲rotein S̲orting 1) an uncharacterized, non-essential yeast gene. Null, or temperature-sensitive mutations in GPS1, cause a transport delay of the GPI-anchored protein Gas1p from the endoplasmic reticulum, which suggests a role for Gps1p in ER-to-Golgi traffic. Gps1p contains a presumptive calcineurin-like phosphoesterase domain in its C-terminus and I attempted to identify candidate substrates for Gps1p by looking for dosage suppressors of the temperature-sensitive growth defect of vps74Δgps1ts cells. One such suppressor, termed DCR2 (d̲osage c̲ell cycle r̲egulator 2) also contains a calcineurin-like phosphoesterase domain, which suggests that Gps1p and Dcr2p belong to the same calcineurin-like phosphoesterase protein family. Consistent with this, cells that lack both DCR2 and GPS1 are inviable. I have established that Gps1p and Dcr2p are integral membrane proteins that localize to the ER / Golgi, and that the presumptive catalytic domains of these proteins are located in the lumen of these organelles.Characterization of the gps1-1 temperature-sensitive allele in both vps74Δ and dcr2Δ genetic backgrounds revealed a defect in cell polarity; cells show abnormal actin cytoskeleton organization, depolarized chitin deposition and fail to respond to alpha factor. In addition, I have determined that vps74Δgps1ts cells show a temperature-dependent remedial osmo-resistance phenotype under conditions that induce high osmotic stress.</p

Localization of Golgi-resident Glycosyltransferases

For many glycosyltransferases, the information that instructs Golgi localization is located within a relatively short sequence of amino acids in the N-termini of these proteins comprising: the cytoplasmic tail, the transmembrane spanning region, and the stem region (CTS). Also, one enzyme may be more reliant on a particular region in the CTS for its localization than another. The predominance of these integral membrane proteins in the Golgi has seen these enzymes become central players in the development of membrane trafficking models of transport within this organelle. It is now understood that the means by which the characteristic distributions of glycosyltransferases arise within the subcompartments of the Golgi is inextricably linked to the mechanisms that cells employ to direct the flow of proteins and lipids within this organelle

A Conserved N-terminal Arginine-Motif in GOLPH3-Family Proteins Mediates Binding to Coatomer

Vps74p, a member of the GOLPH3 protein family, binds directly to coatomer and the cytoplasmic tails of a subset of Golgi-resident glycosyltransferases to mediate their Golgi retention. We identify a cluster of arginine residues at the N-terminal end of GOLPH3 proteins that are necessary and sufficient to mediate coatomer binding. While loss of coatomer binding renders Vps74p non-functional for glycosyltransferase retention, the Golgi membrane-binding capabilities of the mutant protein are not significantly reduced. We establish that the oligomerization status and phosphatidylinositol-4-phosphate-binding properties of Vps74p largely account for the membrane-binding capacity of the protein and identify an Arf1pVps74p interaction as a potential contributing factor in Vps74p Golgi membrane association

Remodeling-defective GPI-anchored proteins on the plasma membrane activate the spindle assembly checkpoint

Newly synthesized glycosylphosphatidylinositol-anchored proteins (GPI-APs) undergo extensive remodeling prior to transport to the plasma membrane. GPI-AP remodeling events serve as quality assurance signatures, and complete remodeling of the anchor functions as a transport warrant. Using a genetic approach in yeast cells, we establish that one remodeling event, the removal of ethanolamine-phosphate from mannose 2 via Ted1p (yPGAP5), is essential for cell viability in the absence of the Golgi-localized putative phosphodiesterase Dcr2p. While GPI-APs in which mannose 2 has not been remodeled in dcr2 ted1-deficient cells can still be delivered to the plasma membrane, their presence elicits a unique stress response. Stress is sensed by Mid2p, a constituent of the cell wall integrity pathway, whereupon signal promulgation culminates in activation of the spindle assembly checkpoint. Our results are consistent with a model in which cellular stress response and chromosome segregation checkpoint pathways are functionally interconnected. © 2021 The Author(s

Determination of Blast Vibration Safety Criteria for Buried Polyethylene Pipelines Adjacent to Blast Areas, Using Vibration Velocity and Strain Data

In order to ensure the safe operation of buried polyethylene pipelines adjacent to blasting excavations, controlling the effects of blasting vibration loads on the pipelines is a key concern. Model tests on buried polyethylene pipelines under blasting loads were designed and implemented, the vibration velocity and dynamic strain response of the pipelines were obtained using a TC-4850 blast vibrometer and a UT-3408 dynamic strain tester, and the distribution characteristics of blast vibration velocity and dynamic strain were analyzed based on the experimental data. The results show that the blast load has the greatest effect on the circumferential strain of the polyethylene pipe, and the dynamic strain response is greatest at the section of the pipe nearest to the blast source. Pipe peak vibration velocity (PPVV), ground peak particle velocity (GPPV), and the peak dynamic strain of the pipe were highly positively correlated, which verifies the feasibility of using GPPV to characterize pipeline vibration and strain level. According to the failure criteria and relevant codes, combined with the analysis of experimental results, the safety threshold of additional circumferential stress on the pipeline is 1.52 MPa, and the safety control vibration speed of the ground surface is 21.6 cm/s