Notes

A comparison involving self-report, thorough observation and also third-party judgments involving cathedral attendance inside a non-urban Fijian Community.
UbiA prenyltransferase domain-containing protein-1 (UBIAD1) synthesizes the vitamin K subtype menaquinone-4 (MK-4). Previous studies in cultured cells (Schumacher et al., 2015) revealed that UBIAD1 also inhibits endoplasmic reticulum (ER)-associated degradation (ERAD) of ubiquitinated HMG CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway that produces cholesterol and essential nonsterol isoprenoids. Gene knockout studies were previously attempted to explore the function of UBIAD1 in mice; however, homozygous germ-line elimination of the Ubiad1 gene caused embryonic lethality. We now report that homozygous deletion of Ubiad1 is produced in knockin mice expressing ubiquitination/ERAD-resistant HMGCR. Thus, embryonic lethality of Ubiad1 deficiency results from depletion of mevalonate-derived products owing to enhanced ERAD of HMGCR rather than from reduced synthesis of MK-4. These findings provide genetic evidence for the significance of UBIAD1 in regulation of cholesterol synthesis and offer the opportunity in future studies for the discovery of new physiological roles of MK-4. © 2020, Jo et al.Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes. © 2020, Jarosz-Griffiths et al.Maintaining the essential functions of mitochondria requires mechanisms to recognize and remove misfolded proteins. However, quality control (QC) pathways for misfolded mitochondrial proteins remain poorly-defined. Here, we establish temperature-sensitive (ts-) peripheral mitochondrial outer membrane (MOM) proteins as novel model QC substrates in Saccharomyces cerevisiae. The ts- proteins sen2-1HAts and sam35-2HAts are degraded from the MOM by the ubiquitin-proteasome system. Ubiquitination of sen2-1HAts is mediated by the ubiquitin ligase (E3) Ubr1, while sam35-2HAts is ubiquitinated primarily by San1. Mitochondria-associated degradation (MAD) of both substrates requires SSA family HSP70s and the HSP40 Sis1, providing the first evidence for chaperone involvement in MAD. In addition to a role for the Cdc48-Npl4-Ufd1 AAA-ATPase complex, Doa1 and a mitochondrial pool of the transmembrane Cdc48 adaptor, Ubx2, are implicated in their degradation. This study reveals a unique QC pathway comprised of a combination of cytosolic and mitochondrial factors that distinguish it from other cellular QC pathways.BACKGROUND As existing data investigating obstructive sleep apnea (OSA) and insulin resistance (IR) are inconsistent, we examine OSA and IR in pediatric obesity clinic. METHODS Children (2-18 years) in obesity clinic (2013-2017), undergoing polysomnography (PSG), anthropometric measurements, and fasting laboratory tests were included. Linear regression assessed OSA- defined by the obstructive apnea hypopnea index (oAHI)- with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Secondary aims assessed oxygen desaturation index (ODI) and age interactions with HOMA-IR. Logistic regression models and receiver operating characteristic (ROC) analysis were performed to investigate optimal oAHI and ODI cutoffs relative to HOMA-IR≥3. RESULTS 80 children; mean age 11.4±4.0 years; 56%female; 46%Caucasian; median BMI 34.6kg/m²(IQR 29.9-40.1), median BMI z-score 2.5(IQR 2.3-2.8);46% oAHI≥5. selleck chemicals llc HOMA-IR was higher in the OSA group (oAHI≥ 5)5 vs. 3.8(p=0.034). After adjustment of sex, race and BMI z-score, oAHI≥5 retained significance with HOMA-IR (p=0.041). HOMA-IR increased in older children (age≥12) when adjusting for waist circumference z-score and waist-height ratio (WHR) (statistical interaction p=0.020; 0.034). ROC showed optimal cut-points of oAHI and ODI for predicting significant IR 4.9[AUC 0.70(95%CI0.57-0.83); sensitivity 0.76, specificity 0.66] and 4.6[AUC 0.68(95%CI 0.55-0.80); sensitivity 0.70, specificity 0.67] respectively. CONCLUSIONS In a clinic-based obese pediatric cohort, OSA is associated with increased IR even after adjusting for confounders including obesity defined by the BMI z-score. Age ≥12 years was associated with AHI relative to IR after adjustment for waist circumference z-score and WHR. Significant IR could be discriminated by oAHI ≥4.9 with moderate sensitivity/specificity. Future studies are needed to verify these findings. © 2020 American Academy of Sleep Medicine.OBJECTIVE Body position during sleep has been related to breathing in adults with obstructive sleep apnea (OSA). While sleep-disordered breathing is common, little information is available on the relation between sleep position and maternal breathing in pregnancy. We examined associations between the supine position, maternal breathing, and perinatal outcomes. METHODS Women with a singleton, uncomplicated pregnancy were recruited and underwent an ambulatory overnight sleep study between 33 to 36 weeks using the Watch-PAT device. Their medical records were also reviewed. RESULTS A total of 148 pregnant women were recruited (mean age 33 ± 4 years, mean BMI 27.6 ± 4.0 kg/m²). They spent around one-half of their sleeping time in a supine position. The group's mean AHI was 3.6 in the supine position, and 2.9, 2.6, and 2.1 for the prone, right, and left positions, respectively. Median AHI and ODI were higher and Spo2 nadir was lower in the supine vs. non-supine position (p less then 0.0001; p less then 0.0001 and p=0.
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