Time delays between physiological signals in interpreting the body's responses to intermittent hypoxia in obstructive sleep apnea.

Objective.Intermittent hypoxia, the primary pathology of obstructive sleep apnea (OSA), causes cardiovascular responses resulting in changes in hemodynamic parameters such as stroke volume (SV), blood pressure (BP), and heart rate (HR). However, previous studies have produced very different conclusions, such as suggesting that SV increases or decreases during apnea. A key reason for drawing contrary conclusions from similar measurements may be due to ignoring the time delay in acquiring response signals. By analyzing the signals collected during hypoxia, we aim to establish criteria for determining the delay time between the onset of apnea and the onset of physiological parameter response.Approach.We monitored oxygen saturation (SpO2), transcutaneous oxygen pressure (TcPO2), and hemodynamic parameters SV, HR, and BP, during sleep in 66 patients with different OSA severity to observe body's response to hypoxia and determine the delay time of above parameters. Data were analyzed using the Kruskal-Wallis test, Quade test, and Spearman test.Main results.We found that simultaneous acquisition of various parameters inevitably involved varying degrees of response delay (7.12-25.60 s). The delay time of hemodynamic parameters was significantly shorter than that of SpO2and TcPO2(p< 0.01). OSA severity affected the response delay of SpO2, TcPO2, SV, mean BP, and HR (p< 0.05). SV delay time was negatively correlated with the apnea-hypopnea index (r= -0.4831,p< 0.0001).Significance.The real body response should be determined after removing the effect of delay time, which is the key to solve the problem of drawing contradictory conclusions from similar studies. The methods and important findings presented in this study provide key information for revealing the true response of the cardiovascular system during hypoxia, indicating the importance of proper signal analysis for correctly interpreting the cardiovascular hemodynamic response phenomena and exploring their physiological and pathophysiological mechanisms.

A Novel Method to Classify the Responses of Genioglossus to Negative Pressure in OSA Patients.

OBJECTIVE: This study aims to develop a novel method to classify different genioglossus (GG) responses to upper airway (UA) negative pressure in obstructive sleep apnea (OSA) patients. STUDY DESIGN: A single-center, prospective, cohort study. SETTING: Sleep Medical Center. METHODS: Patients with OSA underwent drug-induced sleep endoscopy with synchronous genioglossus electromyography (ggEMG) and UA pressure monitoring. In spontaneous obstructive apnea events, the value of epiglottis negative pressure at the end of inspiration (Pepi ) and corresponding peak phasic ggEMG were recorded as pairing data for linear regression analysis to classify GG response modes: peak phasic ggEMG-Pepi linear mode (P < .05) were classified as group 1; others (P ≥ .05) were classified as group 2. Using nasopharyngeal tube (NPT) to reopen the palatopharyngeal cavity for comparing the improvement between the OSA patients with different GG response modes. RESULTS: Sixty subjects were analyzed for GG response modes: 22 patients were in group 1 (r2 = 0.233-0.867), and 38 patients were in group 2. The proportion of partial (63.16% vs 59.09%) or complete (36.84% vs 22.73%) collapse rate of the tongue base in group 2 was significantly higher (χ2 = 7.823, P = .020). The improvement of the apnea-hypopnea index after NPT placement in group 2 was significantly lower than in group 1 (59.09% vs 31.58%, χ2 = 4.339, P = .037). CONCLUSION: This novel method is advantageous for distinguishing OSA patients with different GG response abilities to UA negative pressure, whose GG responses conforming to peak phasic ggEMG-Pepi linear mode might be more suitable for palatopharyngeal surgery.

Parental Exposure to Environmentally Relevant Concentrations of Bisphenol-A Bis(diphenyl phosphate) Impairs Vascular Development in Offspring through DNA/RNA Methylation-Dependent Transmission.

Bisphenol-A bis(diphenyl phosphate) (BDP) has been increasingly detected in indoor environmental and human samples. Little is known about its developmental toxicity, particularly the intergenerational effects of parental exposure. In this study, adult zebrafish were exposed to BDP at 30-30,000 ng/L for 28 days, with results showing that exposure did not cause a transfer of BDP or its metabolites to offspring. Vascular morphometric profiling revealed that parental exposure to BDP at 30 and 300 ng/L exerted significant effects on the vascular development of offspring, encompassing diverse alterations in multiple types of blood vessels. N6-Methyladenosine (m6A) methylated RNA immunoprecipitation sequencing of larvae in the 300 ng/L group revealed 378 hypomethylated and 350 hypermethylated m6A peaks that were identified in mRNA transcripts of genes crucial for vascular development, including the Notch/Vegf signaling pathway. Concomitant changes in 5 methylcytosine (m5C) DNA methylation and gene expression of m6A modulators (alkbh5, kiaa1429, and ythdf1) were observed in both parental gonads and offspring exposed to BDP. These results reveal that parental exposure to low concentrations of BDP caused offspring vascular disorders by interfering with DNA and RNA methylation, uncovering a unique DNA-RNA modification pattern in the intergenerational transmission of BDP's developmental toxicity.

CircGNB1 facilitates the malignant phenotype of GSCs by regulating miR-515-5p/miR-582-3p-XPR1 axis.

Glioma is the most common and aggressive primary malignant brain tumor. Circular RNAs (circRNAs) and RNA-binding proteins (RBPs) have been verified to mediate diverse biological behaviors in various human cancers. Therefore, the aim of this study was to explore a novel circRNA termed circGNB1 and elucidate relative molecular mechanism in functional phenotypes, which might be a potential prognostic biomarker and therapeutic approach for glioma. CircGNB1 was upregulated in glioma and closely associated with the low poor prognosis. Functional assays demonstrated that circGNB1 overexpression promoted glioma stem cells (GSCs) viability proliferation, invasion, and neurosphere formation. Mechanistically, circGNB1 upregulated the expression of oncogene XPR1 via sponging miR-515-5p and miR-582-3p. The following experiments proved XPR1 could promote the malignant phenotype of GSCs via upregulating IL6 expression and activating JAK2/STAT3 signaling. Moreover, the RNA binding protein IGF2BP3 could bind to and maintain the stability of circGNB1, thus promoting the effects of circGNB1 on GSCs. Our study reveals that circGNB1 plays a crucial role in promoting tumorigenesis and malignant progression in glioma, which provides a promising cancer biomarker.

Effectiveness and safety of (adeno) tonsillectomy for pediatric obstructive sleep apnea in different age groups: A systematic review and meta-analysis.

This meta-analysis aimed to assess the effectiveness and safety of (adeno)tonsillectomy (AT) for uncomplicated pediatric obstructive sleep apnea (OSA) across different age groups. Four electronic databases were searched until April 2022, and 93 studies (9087 participants) were selected, including before-after studies, cohort studies, and randomized controlled trials. It has been suggested that age, disease severity, and length of follow-up are associated with surgical effects. Compared with older children (>7 years), patients receiving AT surgery before the age of 7 exhibited a significantly greater release of disease severity, as well as a greater decrease in hypoxemic burden, improvement in sleep quality, and better cardiovascular function. Cognitive/behavioral performance also improved after AT, although it was more related to the length of follow-up than the age at surgery. Notably, the surgical complication rate was considerably higher in patients younger than 3 years old. Overall, we suggest that the age of 3-7 years might be optimal for AT in polysomnography-diagnosed uncomplicated OSA to maximize potential benefits for both disease and comorbidities and balance the risks of surgery.

The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-ß pathway.

Glioma is the most aggressive and common malignant neoplasms in human brain tumors. Numerous studies have showed that glioma stem cells (GSCs)drive the malignant progression of gliomas. Recent studies have revealed that circRNAs can maintain stemness and promote malignant progression of glioma stem cells. We used bioinformatics analysis to identify circRNAs and potential RNA-binding proteins (RBPs) in glioma. qRT-PCR, western blotting, RNA FISH, RNA pull-down, RNA immunoprecipitation assay, ChIP, immunohistochemistry, and immunofluorescence methods were used to quantified the expression of circNCAPG, U2AF65, RREB1 and TGF-ß1, and the underlying mechanisms between them. MTS, EDU, neurosphere formation, limiting dilution neurosphere formation and transwell assays examined the proliferation and invasive capability of GSCs, respectively. We identified a novel circRNA named circNCAPG was overexpressed and indicated the poor prognosis in glioma patients. Upregulating circNCAPG promoted the malignant progression of GSCs. RNA binding protein U2AF65 could stabilize circNCAPG by direct binding. Mechanically, circNCAPG interacted with and stabilized RREB1, as well as stimulated RREB1 nuclear translocation to activate TGF-ß1 signaling pathway. Furthermore, RREB1 transcriptionally upregulated U2AF65 expression to improve the stability of circNCAPG in GSCs, which established a feedback loop involving U2AF65, circNCAPG and RREB1. Since circRNA is more stable than mRNA and can execute its function continuously, targeting circNCAPG in glioma may be a novel promising therapeutic.

UPF1/circRPPH1/ATF3 feedback loop promotes the malignant phenotype and stemness of GSCs.

Glioblastoma multiforme (GBM) is the most lethal type of craniocerebral gliomas. Glioma stem cells (GSCs) are fundamental reasons for the malignancy and recurrence of GBM. Revealing the critical mechanism within GSCs' self-renewal ability is essential. Our study found a novel circular RNA (circRPPH1) that was up-regulated in GSCs and correlated with poor survival. The effect of circRPPH1 on the malignant phenotype and self-renewal of GSCs was detected in vitro and in vivo. Mechanistically, UPF1 can bind to circRPPH1 and maintain its stability. Therefore, more existing circRPPH1 can interact with transcription factor ATF3 to further transcribe UPF1 and Nestin expression. It formed a feedback loop to keep a stable stream for stemness biomarker Nestin to strengthen tumorigenesis of GSCs continually. Besides, ATF3 can activate the TGF-ß signaling to drive GSCs for tumorigenesis. Knocking down the expression of circRPPH1 significantly inhibited the proliferation and clonogenicity of GSCs both in vitro and in vivo. The overexpression of circRPPH1 enhanced the self-renewal of GSCs. Our findings suggest that UPF1/circRPPH1/ATF3 maintains the potential self-renewal of GSCs through interacting with RNA-binding protein and activating the TGF-ß signal pathway. Breaking the feedback loop against self-renewing GSCs may represent a novel therapeutic target in GBM treatment.

Electroencephalography Theta/Beta Ratio Decreases in Patients with Severe Obstructive Sleep Apnea.

Purpose: Accumulating evidence suggests that theta/beta ratio (TBR), an electroencephalographic (EEG) frequency band parameter, might serve as an objective marker of executive cognitive control in healthy adults. Obstructive sleep apnea (OSA) has a detrimental impact on patients' behavior and cognitive performance while whether TBR is different in OSA population has not been reported. This study aimed to explore the difference in relative EEG spectral power and TBR during sleep between patients with severe OSA and non-OSA groups. Patients and Methods: 142 participants with in-laboratory nocturnal PSG recording were included, among which 100 participants suffered severe OSA (apnea hypopnea index, AHI > 30 events/hour; OSA group) and 42 participants had no OSA (AHI ≤ 5 events/h; control group). The fast Fourier transformation was used to compute the EEG power spectrum for total sleep duration within contiguous 30-second epochs of sleep. The demographic and polysomnographic characteristics, relative EEG spectral power and TBR of the two groups were compared. Results: It was found that the beta band power during NREM sleep and total sleep was significantly higher in the OSA group than controls (p < 0.001, p = 0.012, respectively), and the theta band power during NREM sleep and total sleep was significantly lower in the OSA group than controls (p = 0.019, p = 0.014, respectively). TBR during NREM sleep, REM sleep and total sleep was significantly lower in the OSA group compared to the control group (p < 0.001 for NREM sleep and total sleep, p = 0.015 for REM sleep). TBR was negatively correlated with AHI during NREM sleep (r=-0.324, p < 0.001) and total sleep (r=-0. 312, p < 0.001). Conclusion: TBR was significantly decreased in severe OSA patients compared to the controls, which was attributed to both increased beta power and decreased theta power. TBR may be a stable EEG-biomarker of OSA patients, which may accurately and reliably identify phenotype of patients.

Glioblastoma-associated microglia-derived exosomal circKIF18A promotes angiogenesis by targeting FOXC2.

Glioblastoma multiforme (GBM) is the most lethal primary tumor with active neovascularization in the central nervous system. Studying the novel molecular mechanisms of GBM angiogenesis is very important. The glioblastoma-associated microglia (GAM) M2 polarization was constructed, and microglia-derived exosomes (MDEs) were isolated to co-culture with human brain microvessel endothelial cells (hBMECs). CircRNA sequence and molecular biological experiments were used to detect the expression levels and regulation functions among circKIF18A, FOXC2, ITGB3, CXCR4, DLL4 and the PI3K/AKT signaling. The functional effects of silencing or overexpression of these molecules were evaluated in hBMECs viability, invasion, and tube formation in vitro and tumorigenicity in vivo. M2 microglia polarization is positively correlated with microvessels' density in GBM patients. M2 GAM can promote the angiogenesis of GBM via transporting exosomal circKIF18A into hBMECs. Mechanistically, circKIF18A can bind to, maintain the stability and nuclear translocation of FOXC2 in hBMECs. Furtherly, as a transcription factor, FOXC2 can directly bind to the promoter of ITGB3, CXCR4, and DLL4 and upregulate their expressions. Besides, FOXC2 can also activate the PI3K/AKT signaling and promote the angiogenesis of GBM. Our study identified a novel molecular mechanism for M2 GAM-derived exosomal circKIF18A participating in GBM angiogenesis via targeting FOXC2. This may provide a novel treatment target to improve the outcomes for anti-angiogenic therapies in GBM.

Conformational changes of a phosphatidylcholine flippase in lipid membranes.

Type 4 P-type ATPases (P4-ATPases) actively and selectively translocate phospholipids across membrane bilayers. Driven by ATP hydrolysis, P4-ATPases undergo conformational changes during lipid flipping. It is unclear how the active flipping states of P4-ATPases are regulated in the lipid membranes, especially for phosphatidylcholine (PC)-flipping P4-ATPases whose substrate, PC, is a substantial component of membranes. Here, we report the cryoelectron microscopy structures of a yeast PC-flipping P4-ATPase, Dnf1, in lipid environments. In native yeast lipids, Dnf1 adopts a conformation in which the lipid flipping pathway is disrupted. Only when the lipid composition is changed can Dnf1 be captured in the active conformations that enable lipid flipping. These results suggest that, in the native membrane, Dnf1 may stay in an idle conformation that is unable to support the trans-membrane movement of lipids. Dnf1 may have altered conformational preferences in membranes with different lipid compositions.

The significance of better utilization of patients' preoperative information in predicting outcomes of velopharyngeal surgery: a prospective cohort study.

STUDY OBJECTIVES: To compare the efficiency of a TCM scoring system that includes 3 independent predictors obtained by physical examination, computed tomography, and polysomnography with the standard Friedman staging system that includes only physical examination variables for predicting surgical outcomes in patients with obstructive sleep apnea syndrome who undergo velopharyngeal surgery. METHODS: This prospective study was carried out in 265 patients with obstructive sleep apnea syndrome who underwent velopharyngeal surgery. All these patients were re-examined with polysomnography for evaluation of surgical outcomes at least 3 months after surgery. The efficacies in the surgical outcome prediction of 2 systems were calculated and compared. RESULTS: The overall response rate and cure rate was 63.8% (169/265) and 22.3% (59/265), respectively. There were 32 patients with Friedman stage I, with a response rate and cure rate of 81.3% (26/32) and 28.1% (9/32), respectively, and 70 patients with TCM scores of < 14 with a response rate and cure rate of 91.4% (64/70) and 42.9% (30/70), respectively. Friedman stage and TCM grade were the only 2 factors independently predictive of surgical response (P < .05, odds ratio value = 0.642 and 0.382). The receiver operating characteristic curve analysis for surgical response showed that the area under the curve value was 0.600 for Friedman stage, which was significantly lower than that for TCM grade, 0.718 (P = .005). Apnea-hypopnea index and TCM grade were the only 2 factors independently predictive of surgical cure (P < .05, odds ratio value = 0.981 and 0.465). CONCLUSIONS: Compared with the Friedman staging system, the TCM scoring system was more efficient in selecting proper candidates for velopharyngeal surgery. The main reason may be its better utilization of patients' preoperative information, especially the inclusion of physiological factors. CLINICAL TRIAL REGISTRATION: Registry: Chinese Clinical Trials Register; Name: Clinical Phenotypes and Precise Treatment of Adult OSA (Obstructive Sleep Apnea): A Multicenter Study; URL: http://www.ChiCTR.org.cn/showproj.aspx?proj=21189; Identifier: ChiCTR-ONC-17013132. CITATION: Zhang J, Cao X, Yin G, et al. The significance of better utilization of patients' preoperative information in predicting outcomes of velopharyngeal surgery: a prospective cohort study. J Clin Sleep Med. 2022;18(3):843-850.

SLC39A7 promotes malignant behaviors in glioma via the TNF-α-mediated NF-κB signaling pathway.

Purpose: Several studies have indicated that SLC39A7 plays an important role in tumor progression; however, little is known about the function and mechanism of SLC39A7 in glioma. In this study, we aimed to explore the role of SLC39A7 in glioma development. Patients and methods: Bioinformatic analysis was used to predict the role of SLC39A7 in glioma. Cell viability and Edu assays were used to detect the proliferation of glioma cells. A transwell assay was used to measure the invasion and migration of glioma cells. Western blotting, qPCR and ELISA were used to detect the expression of all molecules. Results: SLC39A7 was found to be highly expressed in high-grade glioma patients with a poor prognosis. Our results indicated that SLC39A7 significantly promoted the proliferation, invasion and migration of glioma cells. Furthermore, SLC39A7 promoted tumorigenesis in orthotopic models. We determined that SLC39A7 promotes the malignant behaviors of glioma by activating the TNF-α-mediated NF-κB signaling pathway. Conclusion: Our study revealed that SLC39A7 promotes the proliferation, invasion and migration of glioma cells via the TNF-α-mediated NF-κB signaling pathway, which provides potential targets for glioma therapy.

The SRSF1/circATP5B/miR-185-5p/HOXB5 feedback loop regulates the proliferation of glioma stem cells via the IL6-mediated JAK2/STAT3 signaling pathway.

BACKGROUND: Glioma is the most common and malignant tumor of central nervous system. The tumor initiation, self-renewal, and multi-lineage differentiation abilities of glioma stem cells (GSCs) are responsible for glioma proliferation and recurrence. Although circular RNAs (circRNAs) play vital roles in the progression of glioma, the detailed mechanisms remain unknown. METHODS: qRT-PCR, western blotting, immunohistochemistry, and bioinformatic analysis were performed to detect the expression of circATP5B, miR-185-5p, HOXB5, and SRSF1. Patient-derived GSCs were established, and MTS, EDU, neurosphere formation, and limiting dilution assays were used to detect the proliferation of GSCs. RNA-binding protein immunoprecipitation, RNA pull-down, luciferase reporter assays, and chromatin immunoprecipitation assays were used to detect these molecules' regulation mechanisms. RESULTS: We found circATP5B expression was significantly upregulated in GSCs and promoted the proliferation of GSCs. Mechanistically, circATP5B acted as miR-185-5p sponge to upregulate HOXB5 expression. HOXB5 was overexpressed in glioma and transcriptionally regulated IL6 expression and promoted the proliferation of GSCs via JAK2/STAT3 signaling. Moreover, RNA binding protein SRSF1 could bind to and promote circATP5B expression and regulate the proliferation of GSCs, while HOXB5 also transcriptionally regulated SRSF1 expression. CONCLUSIONS: Our study identified the SRSF1/circATP5B/miR-185-5p/HOXB5 feedback loop in GSCs. This provides an effective biomarker for glioma diagnosis and prognostic evaluation.

Probing of the plasticity of the active site in pinene synthase elucidates its potential evolutionary mechanism.

Terpenes form a class of highly diverse natural products. The diversity of terpenes is created by terpene synthases. During the reaction, carbocation intermediates form and their rearrangement could lead to the formation of various products. Terpene synthases determine the final product profile by controlling the conformation of the intermediate or stabilizing the carbocation. Pinene synthase is a monoterpene synthase catalyzing the cyclization of geranyl pyrophosphate (GPP) to form pinene. Our study suggests that by mutating the aromatic residue F482 to Ala, Val, Ile and Thr, the enzyme can be converted to sabinene synthase, with more than 90% of its total terpene products becoming sabinene, which indicates the aromaticity of this residue is essential for stabilizing the pinyl carbocation. We also identified a mutation S491A that could cause an about 29% increase in the overall activity of the enzyme without altering its produce selectivity. Molecular dynamic simulation indicates this mutation could decrease the flexibility of the enzyme when it forms a complex with the pinyl carbocation. Our study suggests the active pocket of pinene synthase has a certain level of plasticity, making it relatively easy to change the product selectivity or overall activity. This property could have an important implication in the evolution of terpene synthases and thereby terpene diversity, as by changing a few residues an enzyme could synthesize a completely different terpene product in a significant amount, which allows selection to take place.

Short-term postoperative CPAP may improve the outcomes of velopharyngeal surgery for obstructive sleep apnea.

PURPOSE: To evaluate the effects of short-term postoperative continuous positive airway pressure (CPAP) on the outcomes of velopharyngeal surgery for obstructive sleep apnea (OSA). MATERIALS AND METHODS: This study included 119 OSA patients who underwent velopharyngeal surgery. Based on the results of postoperative pulse oximetry, the patients were divided into 3 groups: intervention, control, and observation. Patients with oxygen desaturation index (ODI) > 10 and lowest SpO2 < 90% were randomly assigned to the CPAP intervention group and non-CPAP control. Patients with ODI ≤10 or lowest SpO2 ≥ 90% were assigned to the non-CPAP observation group. Patients in the intervention group completed at least 3 months of CPAP treatment. Postoperative polysomnography data were compared to assess the difference of prognosis between the three groups. RESULTS: Baseline data showed no significant differences between the three groups except the observational group showed a significantly larger tonsil size relative to the intervention and control groups. However, there was no significant difference in terms of tonsil size between the control and intervention groups. The surgical success rate of the intervention group was 80.65%, whereas it was 55.17% in the control group, with significant difference. The success rate of the observation group was 85.71% which was significantly different from that of the control group, but not the intervention group. CONCLUSION: Short-term postoperative CPAP treatment may improve the outcomes of velopharyngeal surgery for OSA in patients who have respiratory events related hypoxia after surgery. Further studies are necessary for the underlying mechanisms.

Five-Year Objective and Subjective Outcomes of Velopharyngeal Surgery for Patients with Obstructive Sleep Apnea.

OBJECTIVE: To assess the long-term effects of velopharyngeal surgery on objective and subjective symptoms in patients with obstructive sleep apnea (OSA). STUDY DESIGN: Prospective cohort study. SETTING: University medical center. SUBJECTS AND METHODS: Eighty-six patients with OSA underwent velopharyngeal surgery, which consisted of revised uvulopalatopharyngoplasty with uvula preservation, with or without concomitant transpalatal advancement pharyngoplasty. The results from polysomnography and the Epworth Sleep Scale after 6 months and 5 years were compared with baseline. Baseline variables were compared between responders and nonresponders. RESULTS: Sixty-three patients were successfully followed up at the end of study. The surgical success rate after 6 months and 5 years was 66.67% (42 of 63) and 60.32% (38 of 63), respectively, with no significant difference (P = .459). The apnea-hypopnea index and Epworth Sleep Scale dramatically decreased from baseline after 6 months and 5 years in responders and nonresponders (P < .001 for all). As compared with nonresponders, the responders exhibited larger tonsil size, higher nocturnal lowest oxygen desaturation, lower CT90 (percentage of time with oxygen saturation <90%), and shorter MH (vertical distance between the lower edge of the mandible and hyoid in the midsagittal plane of computed tomography). Tonsil size and CT90 showed significant predictive value for surgery success (P < .001 for both). CONCLUSION: Velopharyngeal surgery was effective in improving nocturnal respiration and excessive daytime sleepiness in patients with OSA at 6-month and 5-year follow-up. Tonsil size and CT90 could be predictors for surgery responders.

Long-term Efficacy of Uvulopalatopharyngoplasty among Adult Patients with Obstructive Sleep Apnea: A Systematic Review and Meta-analysis.

OBJECTIVES: To evaluate the long-term efficacy and potential predictors of uvulopalatopharyngoplasty (UPPP) among adult patients with obstructive sleep apnea (OSA). DATA SOURCES: A systematic search was conducted through PubMed/Medline, Embase, Web of Science, and the Cochrane Library until December 2018. REVIEW METHODS: Full-text articles were selected that studied adult patients who underwent single-level UPPP or its modification for OSA and had a long-term follow-up (at least 34 months) with objective sleep study results. Studies that had no objective outcomes or performed other surgical procedures for OSA were excluded. RESULTS: Of 2600 studies, 11 were included. Meta-analysis comparing long-term post- and preoperative outcomes showed significant improvements, with an 15.4 event/h (46.1%) decrease of apnea-hypopnea index. Compared with the short-term outcomes (3-12 months), the long-term outcomes were less effective, with apnea-hypopnea index increasing 12.3 events/h (63.8%) and the surgical response decreasing from 67.3% to 44.35%. Subanalysis of individual patient data showed significant correlations of baseline body mass index, lowest arterial oxygen saturation, and proportion of sleep time with oxygen saturation <90% with long-term surgical response. CONCLUSIONS: Despite the surgical efficacy decreasing over time, UPPP and its modification are an effective surgical method for adult OSA in both the short term and the long term after the surgery. Baseline body mass index, lowest arterial oxygen saturation, and proportion of sleep time with oxygen saturation <90% were potentially predictive for long-term surgical response. Case-control studies of the long-term surgical effect of OSA are needed.

Mutational analysis and dynamic simulation of S-limonene synthase reveal the importance of Y573: Insight into the cyclization mechanism in monoterpene synthases.

Monoterpene synthases carry out complex reactions to produce multiple products from a sole substrate, geranyl pyrophosphate (GPP). S-limonene synthase (LS) is a model monoterpene synthase that can be explored to understand the catalytic mechanism of these enzymes. In this study, we have identified an active site tyrosine residue (Y573) is crucial for the enzyme activity and mutational analysis indicates that both the aromatic ring and hydroxyl group are essential for the catalysis. Dynamic simulations found a hydrogen bond between Y573 and D496 and also a significant conformational change in the helical form of the LPP intermediate. Further mutagenesis suggested that this hydrogen bond is essential for catalysis. Sequence analysis suggested Y573 is completely conserved among cyclic monoterpene synthases but variable in acyclic enzymes, indicating this residue may be involved in cyclization. Subsequent studies by using neryl diphosphate (NPP) as the substrate ruled out the possibility that Y573 functions solely at the substrate isomerization step. Therefore, a more complicated role may be played by this residue. We proposed that Y573 may be involved in the earlier steps of the reaction, probably by controlling the conformation of the helical LPP intermediate. Our study provides important insights not only on the catalytic mechanism of LS, but also on the cyclization of monoterpene synthases in general.