Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study.

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Effect of Moxibustion on Inflammatory Cytokines for Low Back Pain: A Systematic Review, Meta-Analysis and Meta-Regression.

Background and Objective: Moxibustion is effective for low back pain (LBP), and inflammatory cytokines may play an important role in the mechanism of moxibustion treatment. The purpose of this meta-analysis was to explore the mechanism of moxibustion in LBP in terms of inflammatory cytokines. Methods: We searched China National Knowledge Infrastructure, Wanfang database, Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Embase, PubMed, and Web of Science to identify eligible randomized controlled trials (RCTs). There was no restriction on the publication date. Results: Thirty RCTs measuring interleukin (IL-) 1, IL-1ß, IL-6, IL-12, IL-17, IL-23, and tumor necrosis factor (TNF-) α were included in this meta-analysis. Compared to controls: single moxibustion could effectively decrease levels IL-6 and IL-23 (SMD, -0.71, 95% CI: -1.25 to -0.17, p = 0.01; SMD, -1.61, 95% CI: -2.20 to -1.03, p < 0.01, respectively); combined moxibustion had significant effects on IL-1, IL-1ß, IL-6, IL-12, IL-17, and TNF-α (p < 0.05). Overall, for LBP, single or combined moxibustion could effectively down-regulate levels of pro-inflammatory cytokines (p = 0.007 and p < 0.00001, respectively). For safety of moxibustion, the incidence rate of side effects was similar to that of controls (RD, -0.01, 95% CI: -0.02 to 0.01, p = 0.59). Sensitivity analysis showed that the pooled estimates were robust, and publication bias analysis showed there was a significant small study effect (Egger's test p = 0.0000). High statistical heterogeneity existed between included RCTs, meta-regression showed there was no potential factor explaining the source of heterogeneity. Conclusion: For LBP, moxibustion can effectively decrease levels of IL-1, IL-1ß, IL-6, IL-12, IL-17, IL-23, and TNF-α to achieve analgesia. Because the side effects of moxibustion are transient, it is relatively safe for clinical use. However, based on high heterogeneity in this meta-analysis, rigorously designed RCTs are required to further confirm the results in this review.

Evaluation of bi-directional causal association between periodontal disease and erectile dysfunction: a two-sample Mendelian randomization study.

BACKGROUND: The association between periodontal disease (PD) and erectile dysfunction (ED) has been well-documented in observational studies. However, observational studies are vulnerable to reverse causality and confounding factors, making the inference of causal-effect relationships challenging. Contrary to the current belief, Mendelian randomization (MR) can be applied to comprehensively assess the bi-directional causal effects between PD and ED. METHODS: A two-sample MR analysis was performed using pooled statistics from genome-wide association studies involving European populations with PD (12,289 patients with PD and 22,326 controls) and ED (6,175 patients with clinically diagnosed ED and 217,630 controls). In this MR analysis, three methods--the inverse-variance weighted (IVW) average, weighted median, and MR-Egger regression methods--were used to evaluate the causal relationships between PD and ED. RESULTS: According to the IVW analysis results, genetically predicted PD did not have a causal effect on ED (odds ratio 1.07, 95% confidence interval 0.96-1.20, p = 0.22). Furthermore, there was no clear indication of a significant causal effect of ED on PD in the reverse MR analysis (odds ratio 0.98, 95% confidence interval 0.90-1.08, p = 0.74). The results of the MR-Egger regression and weighted median methods were consistent with those of the IVW method. Based on the sensitivity analysis results, a major bias from genetic pleiotropy was unlikely to distort the causal estimates. CONCLUSION: The present study does not support a causal effect between PD and ED. CLINICAL RELEVANCE: From the perspective of genetics, PD does not appear to be a risk factor for the development of ED.

Genetic Predisposition to Periodontitis and Risk of Migraine: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: Previous observational studies have associated periodontitis (PD) with migraine; however, the results are inconclusive and the causality of the association between PD and migraine remains unclear. This two-sample Mendelian randomization (MR) study was performed to explore the bi-directional causal relationship between PD and migraine. METHODS: To investigate the relationship between PD (17,353 cases; 28,210 controls) and migraine (1072 cases; 360,122 controls), we used genetic tools from the largest available genome-wide association study of European descent. Inverse variance-weighted (IVW) and a series of sensitivity analyses were used to explore the association between migraine and PD. We performed an MR study using seven SNPs (single nucleotide polymorphisms) as instrumental variables for PD to investigate the causal relationship between migraine and PD. RESULTS: We found no significant causal relationship between PD and migraine (odds ratio, OR = 1.000; 95% confidence interval, CI = 0.99-1.00; p = 0.65). Similarly, no evidence supported a causal relationship between migraine and PD (OR = 0.07; CI = 2.04 × 10-9-2.65 × 106; p = 0.77). A sensitivity analysis revealed that no potential polymorphic effect (p = 0.356) and heterogeneity (p = 0.652) exists for the variants used in constructing the genetic instrument. CONCLUSIONS: Based on the results of our MR study, there is no causal relationship between PD and migraines or migraines and PD.

Efficacy and safety of electroacupuncture combined with medication for rheumatoid arthritis: A systematic review and meta-analysis.

Objective: The aim of this study was to evaluate the effect of electroacupuncture (EA) combined with medication on clinical efficacy, pain scores (Visual Analogue Scale, [VAS]), Disease Activity Score in 28 joints (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and adverse events in treating patients with rheumatoid arthritis (RA). Methods: A systematic search of PubMed, the Cochrane Library, Web of Science, Embase, SinoMed, China National Knowledge Infrastructure, Wanfang, and VIP until December 12, 2021 was used to identify randomized controlled trials (RCTs) on the EA treatment of RA. Study selection and data extraction were performed critically and independently by two reviewers. Cochrane criteria for risk of bias was used to evaluate the methodological quality of the trials. The Grading of Recommendations Assessment, Development, and Evaluation Methodology (GRADE) was applied to assess the quality of evidence from quantitative analysis. Results: Seventeen RCTs, including 1317 patients, satisfied the inclusion criteria. Compared with the control group, EA combined with medication had a superior effect on clinical efficacy (RR = 1.25 [95% CI = 1.18 to 1.33], P < 0.00001), VAS score (MD = -1.34 [95% CI = -1.90 to -0.78], P < 0.00001), DAS28 (MD = -0.76 [95% CI = -1.08 to -0.44], P < 0.00001), CRP level (SMD = -1.46 [95% CI = -2.19 to -0.74], P < 0.0001), and ESR (MD = -7.74 [95% CI = -13.77 to -1.72], P = 0.01). Compared with the control group, the meta-analysis showed no significant changes in adverse events in the EA group (RR = 1.08 [95% CI = 0.51 to 2.25], P = 0.85). The evidence level of the results from the 17 studies was very low to moderate. Conclusions: EA combined with medication showed a superior effect than Western medicine alone in clinical efficacy, VAS, DAS28, CRP, and ESR. The clinical safety of EA warrants further investigation in experimental studies.

The prognostic value of fear-avoidance beliefs on postoperative pain and dysfunction for lumbar degenerative disk disease: a meta-analysis.

The study aimed to explore the prognostic value of fear-avoidance beliefs (FABs) on postoperative pain and back-specific function for patients with lumbar degenerative disk disease (LDDD). FABs have been proven to be a predictorof pain and disability for patients with low back pain. However, whether FABs are a predictor of surgical outcomes for LDDD is a matter of debate. PubMed, Cochrane library, EMBASE, and EBSCO were searched for eligible cohort studies or secondary analyses of randomized controlled trials. Fixed-effect meta-analysis models were used to estimate odds ratios (OR) because of absent or low heterogeneity ( I ² < 50%). Subgroup analyses were conducted according to different follow-up durations. Forest plots were used for graphical representation. Six studies with a total of 829 participants were included in the meta-analyses. Risk of bias was high for three studies and moderate for the other three studies. For patients with LDDD, meta-analyses showed that FABs were a predictor of postoperative pain intensity [OR 2.88; 95% confidence interval (CI), 2.76-3.00] and back-specific function (OR 3.13; 95% CI, 3.02-3.24). Patients with FABs are less likely to report improvement in pain (OR 2.56; 95% CI, 1.73-3.86) and function (OR 2.81; 95% CI, 2.57-3.07). In conclusion, FABs were a predictor of postoperative pain and back-specific function for patients with LDDD. This prognostic value is sustained for a long period after surgery (>12 months). Clinicians are advised to initiate targeted interventions for patients with FABs at different stages after surgery. Due to the limited number and low quality of included studies, the results of this meta-analysis should be interpreted with caution.

Development of rapid low temperature assistant modified QuEChERS method for simultaneous determination of 107 pesticides and relevant metabolites in animal lipid.

A modified QuEChERS LC-MS/MS method was developed for 107 pesticides analysis in animal lipids such as pork lard, mutton tallow, chicken oil and butter. The challenges for high fat matrices clean up were studied in details by optimizing dispersive purification adsorbents coupled with rapid low temperature assistant methods. The method validation was carried out using pork lard and further appplied to other matrices by testing their recoveries. Good linearities were obtained with correlation coefficients greater than 0.99. Sensitive LOQs ranged from 5.0-50.0 µg kg-1. Both inter-day and intra-day precisions were lower than 20% indicating the good precision and accuracy of this method. The method applied to four animal lipids with 93%∼100% of analytes revealed satisfactory recoveries (ranged from 70% to 120%) and RSD (≤20%) at 10 µg kg-1and 50 µg kg-1 spiking levels respectively related to the matrix.

Classification of Visual Field Abnormalities in Highly Myopic Eyes without Pathologic Change.

PURPOSE: To develop a classification system of visual field (VF) abnormalities in highly myopic eyes with and without glaucoma. DESIGN: Secondary analysis of VF data from a longitudinal cohort study. PARTICIPANTS: One thousand eight hundred ninety-three VF tests from 1302 eyes (825 individuals). METHODS: All participants underwent VF testing (Humphrey 24-2 Swedish interactive threshold algorithm standard program; Carl Zeiss Meditec) and detailed ophthalmic examination. A comprehensive set of VF defect patterns was defined via observation of the 1893 VF reports, literature review, and consensus meetings. The classification system comprised 4 major types of VF patterns, including normal type, glaucoma-like defects (paracentral defect, nasal step, partial arcuate defect, arcuate defect), high myopia-related defects (enlarged blind spot, vertical step, partial peripheral rim, nonspecific defect), and combined defects (nasal step with enlarged blind spot). A subset (n = 1000) of the VFs was used to evaluate the interobserver and intraobserver agreement and weighted κ values of the classification system by 2 trained readers. The prevalence of various VF patterns and their associated factors were determined. MAIN OUTCOME MEASURES: The classification of VF in highly myopic eyes and its associated risk factors. RESULTS: We found that normal type, glaucoma-like defects, high myopia-related defects, and combined defects accounted for 74.1%, 10.8%, 15.0%, and 0.1% of all unique VF tests, respectively. The interobserver and intraobserver agreements were > 89%, and the corresponding κ values were 0.86 or more between readers. Both glaucoma-like and high myopia-related VF defects were associated with older age (odds ratios [ORs], 1.07 [95% confidence interval (CI), 1.04-1.10; P < 0.001] and 1.06 [95% CI, 1.04-1.10; P < 0.001]) and longer axial length (ORs, 1.65 [95% CI, 1.32-2.07; P < 0.001] and 1.37 [95% CI, 1.11-1.68; P = 0.003]). Longer axial length showed a stronger effect on the prevalence of glaucoma-like VF defects than on the prevalence of high myopia-related VF defects (P = 0.036). CONCLUSIONS: We propose a new and reproducible classification system of VF abnormalities for nonpathologic high myopia. Applying a comprehensive classification system will facilitate communication and comparison of findings among studies.

Psychological stress induces moderate pathology in the ganglion cell layer in mice.

Purpose: Primary open-angle glaucoma (POAG) is a condition with unclear pathogenesis. Researchers have observed an increased incidence of young Chinese POAG patients who manifest significant psychological stress while their intraocular pressure (IOP) is normal or close to normal; we hypothesize that psychological stress may play a causal role in initiating POAG. Methods: Twenty-four male C57BL/6 mice were included and divided randomly into two groups. A chronic unpredictable mild stress (CUMS) mouse model was established to evaluate the effect of psychological stress on glaucoma-related retinal pathologies. Body weight and IOP were recorded weekly. At 5 weeks after the CUMS procedure, a behavior test, serum corticosterone level, retinal nerve fiber layer (RNFL) thickness, retinal ganglion cell (RGC) number and neurotrophic factor expression were evaluated and compared between the CUMS group and the control group. Results: CUMS exposure induced depression-like behaviors, lighter body weight, and increased serum corticosterone levels in mice. RNFL thinning and neural cell loss in the ganglion cell layer (GCL) were observed in CUMS mice without significant IOP elevation. Decreased mRNA expression and protein levels of neurotropic factors in retinas of CUMS mice were observed, especially brain-derived neurotrophic factor (BDNF). Conclusions: The CUMS mouse model demonstrated that psychological stress induced glaucoma-like changes in the retinas of CUMS mice. The mechanism by which psychological stress induces retina defects may be due to a reduced expression of retinal neurotropic factors. Thus, we conclude that psychological stress is causally associated with POAG.

Longitudinal Macular Retinal and Choroidal Microvasculature Changes in High Myopia.

Purpose: The purpose of this study was to determine the longitudinal changes in macular retinal and choroidal microvasculature in normal healthy and highly myopic eyes. Methods: Seventy-one eyes, including 32 eyes with high myopia and 39 healthy control eyes, followed for at least 12 months and examined using optical coherence tomography angiography imaging in at least 3 visits, were included in this study. Fovea-centered 6 × 6 mm scans were performed to measure capillary density (CD) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC). The rates of CD changes in both groups were estimated using a linear mixed model. Results: Over a mean 14-month follow-up period, highly myopic eyes exhibited a faster rate of whole image CD (wiCD) loss (-1.44%/year vs. -0.11%/year, P = 0.001) and CD loss in the outer ring of the DCP (-1.67%/year vs. -0.14%/year, P < 0.001) than healthy eyes. In multivariate regression analysis, baseline axial length (AL) was negatively correlated with the rate of wiCD loss (estimate = -0.27, 95% confidence interval [CI] = -0.48 to -0.06, P = 0.012) and CD loss in the outer ring (estimate = -0.33, 95% CI = -0.56 to -0.11, P = 0.005), of the DCP. The CD reduction rates in the SCP and CC were comparable in both groups (all P values > 0.05). Conclusions: The rate of CD loss in the DCP is significantly faster in highly myopic eyes than in healthy eyes and is related to baseline AL. The CD in the outer ring reduces faster in eyes with longer baseline AL.

Phosphine-Catalyzed Annulations Based on [3+3] and [3+2] Trapping of Ketene Intermediates with Thioamides.

With the aim of developing novel annulations via ketene intermediates, allenyl imide and alkynoates bearing good leaving groups are used for their function in a tandem conjugate addition-elimination reaction (SN2' type) promoted by nucleophilic phosphine catalysts. By utilizing thioamides as 1S,3N-bis-nucleophiles, [3+3] and [3+2] annulations have been established to allow rapid access to 1,3-thiazin-4-ones and 5-alkenyl thiazolones in high yields, respectively. Furthermore, the possible reaction mechanisms are proposed on the basis of deuterium labeling experiments and density functional theory calculations.

Endoplasmic reticulum stress is involved in retinal injury induced by repeated transient spikes of intraocular pressure.

Clinically, a large proportion of glaucoma patients undergo repeated intraocular pressure (IOP) spike (Spike IOP) attacks during their sleep, which may facilitate retinopathy. In this study, we established a mouse model of repeated transient Spike IOP to investigate the direct damage to the retina following Spike IOP attacks, and elucidated the underlying molecular mechanism. We analyzed the changes in the number of retinal ganglion cells (RGCs) via immunofluorescence. Thereafter, we detected retinal cell apoptosis via terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining, and performed RNA sequencing (RNA-seq) to reveal the underlying molecular mechanism. Finally, we validated the expression of key molecules in the endoplasmic reticulum (ER) stress pathway using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. Results revealed a time-dependent RGC loss in Spike IOP, evidenced by a reduction in the number of Brn3a-positive RGCs in experimental eyes following a 7-d continuous treatment with Spike IOP. In addition, TUNEL staining indicated that apoptosis of retinal cells started in the outer nuclear layer (ONL), and then spread to the ganglion cell layer (GCL) with time. RNA-seq analysis revealed that ER stress might be involved in Spike IOP-induced retinal injury. This result was corroborated by western blot, which revealed upregulation of ER stress-related proteins including binding immunoglobulin protein/glucose-regulated protein 78 (BiP/GRP78), phosphorylated inositol-requiring enzyme 1 (p-IRE1), unspliced X-box-binding protein 1 (XBP1-u), spliced X-box-binding protein 1 (XBP1-s), phosphorylated c-Jun N-terminal kinase (p-JNK), C/EBP-homologous protein (CHOP), and B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax). These findings indicate that repeated IOP transients are detrimental to the retina, while ER stress plays an important role in retinal cell apoptosis in this situation. Notably, repeated Spike IOP among glaucoma patients is a crucial factor for progressive retinopathy.

Myelin regulatory factor deficiency is associated with the retinal photoreceptor defects in mice.

Previously, we reported the myelin regulatory factor (MYRF) as a candidate gene for nanophthalmos. We have also produced Myrf knockdown (Myrf+/-) mouse strain to investigate the cellular and molecular phenotypes of reduced MYRF expression in the retina. Myrf+/- mouse strain was generated using the CRISPR/Cas9 system. Optomotor response system, electroretinogram (ERG), spectral-domain optical coherence tomography (SD-OCT), histology, and immunohistochemistry were performed to evaluate retinal spatial vision, electrophysiological function, retinal thickness, and pathological changes in cone or rod photoreceptors, respectively. RNA sequencing (RNA-seq) was performed to investigate the underlying molecular mechanism linking Myrf deficiency with photoreceptor defects. The genotype and phenotype of CRISPR/Cas9-induced Myrf+/- mice and their offspring were comprehensively investigated. Photoreceptor defects were detected in the retinas of Myrf+/- mice. Visual acuity and ERG responses were decreased in Myrf+/- mice compared with the control mice (Myrf+/+). The loss of cone and rod neurons was proportional to the decreased outer nuclear layer (ONL) thickness. Moreover, RNA-seq revealed that phototransduction and estrogen signaling pathways played important roles in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Myrf+/- mouse strain provides a good model to investigate the function of the MYRF gene. Photoreceptor defects with impaired functions of spatial vision and retinal electrophysiology indicate an important role played by MYRF in retinal development. Alterations in phototransduction and estrogen signaling pathways play important roles in linking Myrf deficiency with retinal photoreceptor defects.

Anterior vitrectomy, phacoemulsification cataract extraction and irido-zonulo-hyaloid-vitrectomy in protracted acute angle closure crisis.

PURPOSE: To describe a modified surgical approach with anterior vitrectomy, phacoemulsification (phaco) cataract extraction and irido-zonulo-hyaloid-vitrectomy (IZHV) in protracted acute angle closure crisis (AACC). PATIENTS AND METHODS: Non-comparative, retrospective case series including 21 eyes in 19 consecutive cases of protracted AACC, which persists for at least 7 days despite maximal medical and laser therapies, were included in this study. All patients underwent a modified surgical procedure with anterior vitrectomy, phaco cataract extraction, IOL implantation, goniosynechialysis (GSL) and IZHV, using modest phaco dynamic parameters with intraocular pressure (IOP) set at 30 mmHg through the procedure using Centurion® Vision System equipped with active fluidics while the anterior vitrectomy was set at 4000 or 5000 rpm. IOP and anterior chamber space were maintained through the procedure using ophthalmic viscosurgical device (OVD) injected through paracentesis whenever the Phaco or I/A probe was withdrawn from within the anterior chamber. Medical history, visual acuity (VA), IOP and anterior and posterior segment findings were recorded and compared before and after surgical treatment. RESULTS: The average age of all patients was 60.05 years old, while the average period of persistent AACC was 20.05 days. Preoperatively, the average IOP of all included eyes was 44.40 ± 8.42 mmHg despite maximal topical and systemic anti-glaucoma medications and/or laser surgeries, while the average VA was 1.46 ± 0.88 (log MAR). Postoperatively, IOP was well controlled in all patients with an average IOP at 12.06 ± 3.07 mmHg without any anti-glaucoma medications at follow-ups, which was decreased significantly from that in preoperative measurements (P < 0.001). Visual acuity was improved significantly at final follow-up with an average postoperative VA at 0.74 ± 0.77 (log MAR, P < 0.001). Anterior segment inflammation was surprisingly mild with no or minimal inflammatory cells or exudates. Anterior segment configuration was resolved in all the cases. There was no recurrent IOP spike, anterior chamber shallowing or severe complications during an average follow-up of 5.38 months (ranging from 3 to 6 months). CONCLUSIONS: Protracted AACC is a complex situation while a modified surgical strategy of anterior vitrectomy, phaco cataract extraction and IZHV provides a safe and efficient solution.

Nanophthalmos-Associated MYRF Gene Mutation Causes Ciliary Zonule Defects in Mice.

Purpose: Patients with nanophthalmos who undergo intraocular surgery often present with abnormal ciliary zonules. In a previous study, we reported mutation in MYRF that is implicated in the pathogenesis of nanophthalmos. The aim of this study was to model the mutation in mice to explore the role of MYRF on zonule structure and its major molecular composition, including FBN1 and FBN2. Methods: Human MYRF nanophthalmos frameshift mutation was generated in mouse using the CRISPR-Cas9 system. PCR and Sanger sequencing were used for genotype analysis of the mice model. Anterior chamber depth (ACD) was measured using hematoxylin and eosin-stained histology samples. Morphologic analysis of ciliary zonules was carried out using silver staining and immunofluorescence. Transcript and protein expression levels of MYRF, FBN1, and FBN2 in ciliary bodies were quantified using quantitative real-time PCR (qRT-PCR) and Western blot. Results: A nanophthalmos frameshift mutation (c.789delC, p.N264fs) of MYRF in mice showed ocular phenotypes similar to those reported in patients with nanophthalmos. ACD was reduced in MYRF mutant mice (MYRFmut/+) compared with that in littermate control mice (MYRF+/+). In addition, the morphology of ciliary zonules showed reduced zonular fiber density and detectable structural dehiscence of zonular fibers. Furthermore, qRT-PCR analysis and Western blot showed a significant decrease in mRNA expression levels of MYRF, FBN1, and FBN2 in MYRFmut/+ mice. Conclusions: Changes in the structure and major molecular composition of ciliary zonules accompanied with shallowing anterior chamber were detected in MYRFmut/+ mice. Therefore, MYRF mutant mice strain is a useful model for exploring pathogenesis of zonulopathy, which is almost elusive for basic researches due to lack of appropriate animal models.

Asymmetric Petasis reaction for the synthesis of chiral α- and ß-butadienyl amines.

The Petasis reaction using (1S,2R)-1-amino-2-indanol as the substrate and an activator to construct α- and ß-butadienyl amines in optically pure forms was realized, which are otherwise difficult to prepare. The reactions feature a metal-free nature, broad substrate scope, complete regioselectivities (γ-selectivity of pinacol homoallenyl- and isoprenylboronates), and high to excellent chirality induction (up to >20 : 1 dr). The favored nucleophilic addition across the Si-face of the imine intermediate was explained using DFT calculations of the six-membered chair-like transition state.

Coinheritance of OLFM2 and SIX6 variants in a Chinese family with juvenile-onset primary open-angle glaucoma: A case report.

BACKGROUND: Juvenile-onset primary open-angle glaucoma (JOAG), characterized by severe elevation of intraocular pressure and optic neuropathy prior to the age of 40, is a rare subtype of primary open-angle glaucoma. Several genetic mutations have been associated with JOAG. CASE SUMMARY: The proband patient was a young male, diagnosed with primary open-angle glaucoma at the age of 27. The patient and his unaffected parents who have been excluded from classic genetic mutations for primary open-angle glaucoma were included to explore for other possible genetic variants through whole genome sequencing and bioinformatics analysis. In this trio, we found two heterozygous variants inherited from the parents in the proband: c.281G>A, p.Arg94His in OLFM2 and c.177C>G, p.Ile59Met in SIX6. Both genetic mutations are predicted through bioinformatics analysis to replace evolutionary conserved amino acids, therefore rendering a pathogenic effect on proteins. In contrast, very low frequencies for these genetic mutations were recorded in most common control databases. CONCLUSION: This is the first report on coinherited mutations of OLFM2 and SIX6 in a JOAG family, which shows the complexity of JOAG inheritance. Large-scale clinical screening and molecular functional investigations on these coinherited mutations are imperative to improve our understanding of the development of JOAG.

Evaluation of MYRF as a candidate gene for primary angle closure glaucoma.

PURPOSE: Primary angle-closure glaucoma (PACG) is a leading cause of blindness. Despite tremendous human effort and financial input, no definitive causative gene has been identified either through genome-wide association or Mendelian family studies. In the current study, novel candidate genes for PACG were investigated by studying the variants of nanophthalmos-associated genes. METHODS: A case-control study was conducted that included 45 PACG patients and 12 normal controls with short axial length (AL, less than 23.5 mm but more than 20.5 mm). Whole-exome sequencing (WES) was performed to screen the variants in previously identified nanophthalmos-associated genes, as well as other risk genes. RESULTS: The age range of the 45 PACG patients was 24 to 80 years, with an average AL of 21.87±0.65 mm (range: 20.54-23.45 mm) in the right eye and 21.89±0.64 mm (range 20.60-23.23 mm) in the left eye. Four novel myelin regulatory factor (MYRF) gene missense variants (p.G117S, p.H1057R, p.H230R, and p.R316C) were identified in four out of the 45 enrolled PACG patients, respectively. No MYRF or other nanophthalmos-associated gene variants were detected in the 12 normal controls. CONCLUSIONS: An appropriate approach was adopted to investigate the genetics of PACG through nanophthalmos-associated genes. A genetic variant, MYRF, was identified in four out of 45 PACG patients, which might be a novel candidate gene for PACG.

Elevated intraocular pressure causes cellular and molecular retinal injuries, advocating a more moderate intraocular pressure setting during phacoemulsification surgery.

PURPOSE: To evaluate the cellular and molecular retinal injuries induced by various intraocular pressure (IOP) settings in a mouse model of acute ocular hypertension (AOH), and to advise using a more moderate target IOP during phacoemulsification (phaco) surgery. METHODS: A mouse model of AOH that mimics a transient IOP elevation during phacoemulsification cataract surgery was established. Six groups with various settings of target IOP were included. Retinal tissues were assessed with terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labeling (TUNEL) staining for neuron loss, immunofluorescence with Iba1 for microglia activation, and quantitative real-time polymerase chain reaction analysis with tight junction proteins (claudin-3 and claudin-5) or classic inflammation markers (IL-1ß and eNOS) for impairment of the blood-retinal barrier (BRB) and inflammatory injury. RESULTS: Compared with those in the 45-mmHg IOP group, significantly increased number of neurons loss and increased microglia activation were observed in 90-mmHg IOP group. In addition, the expression of claudin-3 and claudin-5 was significantly decreased, while the expression of IL1-ß and eNOS was up-regulated, indicating impairment of the BRB and inflammatory injury in the retina. Furthermore, these findings of neuron loss, microglia activation, and inflammation in the 90-mmHg groups were exacerbated when an IOP-induced retinal injury was established 5 days earlier, while those in the 45-mmHg groups remained almost unchanged. CONCLUSIONS: In conclusion, these results showed that a relatively commonly used high IOP setting (90 mmHg) could induce significantly more serious retinal injury. An IOP setting around 45 mmHg is relatively safe and might be recommended in phaco surgery, especially in patients with advanced glaucoma, previous acute angle closure crisis, or other diseases with fragile retina and optic nerve.

Catalytic asymmetric aldehyde prenylation and application in the total synthesis of (-)-rosiridol and (-)-bifurcadiol.

Chiral phosphoric acid-catalyzed asymmetric aldehyde prenylation has been established using an α,α-dimethyl allyl boronic ester. The transformation provides expedient access to a wide array of aryl, heteroaryl, aryl-substituted alkenyl and primary and secondary aliphatic homoprenyl alcohols with excellent asymmetric induction. The utility of this asymmetric catalysis strategy has been demonstrated through a short and efficient total synthesis of the two natural products (-)-rosiridol and (-)-bifurcadiol.