Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI.

Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapy targeting LMCG represented a promising strategy for the treatment of AMI.

Sintilimab-Induced Myocarditis in a Patient with Gastric Cancer: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) have emerged as a powerful and efficacious therapeutic approach for many cancer patients. Sintilimab is a fully human IgG4 monoclonal antibody that binds with programmed cell death receptor-1 (PD-1) to block its interaction with ligands, thereby enhancing the antitumor effects of T cells. However, ICIs may induce immune-related adverse events (irAEs) in various systems and organs, with fulminant myocarditis being the most severe one. We report the case of a 45-year-old female with gastric cancer who developed chest pain two weeks after chemotherapy with sintilimab; she was diagnosed with immune-associated fulminant myocarditis and experienced an Adams-Stokes syndrome attack in the hospital. Eventually, she was discharged after being treated with methylprednisolone, immunoglobulin, and an IABP.

Bayesian Cramér-Rao Lower Bounds for Prediction and Smoothing of Nonlinear TASD Systems.

The performance evaluation of state estimators for nonlinear regular systems, in which the current measurement only depends on the current state directly, has been widely studied using the Bayesian Cramér-Rao lower bound (BCRLB). However, in practice, the measurements of many nonlinear systems are two-adjacent-states dependent (TASD) directly, i.e., the current measurement depends on the current state as well as the most recent previous state directly. In this paper, we first develop the recursive BCRLBs for the prediction and smoothing of nonlinear systems with TASD measurements. A comparison between the recursive BCRLBs for TASD systems and nonlinear regular systems is provided. Then, the recursive BCRLBs for the prediction and smoothing of two special types of TASD systems, in which the original measurement noises are autocorrelated or cross-correlated with the process noises at one time step apart, are presented, respectively. Illustrative examples in radar target tracking show the effectiveness of the proposed recursive BCRLBs for the prediction and smoothing of TASD systems.

Novel long non-coding RNA lncAMPC downregulates PTEN via miR-214 to promote nasopharyngeal carcinoma progression.

Long non-coding RNAs (lncRNAs) are a type of non-coding RNAs with transcript lengths exceeding 200 nt. lncRNAs suppress or promote cancer mainly by regulating gene expression. The aim of this study was to explore the role of lncRNAs activated in metastatic PCa (lncAMPC) in nasopharyngeal carcinoma (NPC). Total RNAs were isolated from NPC and adjacent non-tumor tissues from 60 NPC patients and subjected to RT-qPCR to analyze differential expression of lncAMPC and miR-214. The roles of lncAMPC and miR-214 in regulating PTEN expression were analyzed using RT-qPCR and Western blot. Cell proliferation was analyzed using the BrdU assay. The results showed that lncAMPC was overexpressed in NPC tissues and was localized in both nuclei and cytoplasms of NPC cells. MiR-214 was positively correlated with lncAMPC. LncAMPC overexpression upregulated miR-214 and indirectly downregulated PTEN via miR-214. BrdU incorporation assay showed that lncAMPC and miR-214 overexpression increased cell proliferation. PTEN overexpression completely reversed the promoting effects of lncAMPC and miR-214 overexpression on cell proliferation. Therefore, lncAMPC might downregulate PTEN via miR-214 to increase NPC cell proliferation.

Causes of PM2.5 pollution in an air pollution transport channel city of northern China.

To develop effective mitigation policies, a comprehensive understanding of the evolution of the chemical composition, formation mechanisms, and the contribution of sources at different pollution levels is required. PM2.5 samples were collected for 1 year from August 2016 to August 2017 at an urban site in Zibo, then chemical compositions were analyzed. Secondary inorganic aerosols (SNA), anthropogenic minerals (MIN), and organic matter (OM) were the most abundant components of PM2.5, but only the mass fraction of SNA increased as the pollution evolved, implying that PM2.5 pollution was caused by the formation of secondary aerosols, especially nitrate. A more intense secondary transformation was found in the heating season (from November 15, 2016, to March 14, 2017), and a faster secondary conversion of nitrate than sulfate was discovered as the pollution level increased. The formation of sulfate was dominated by heterogeneous reactions. High relative humidity (RH) in polluted periods accelerated the formation of sulfate, and high temperature in the non-heating season also promoted the formation of sulfate. Zibo city was under ammonium-rich conditions during polluted periods in both seasons; therefore, nitrate was mainly formed through homogeneous reactions. The liquid water content increased significantly as the pollution levels increased when the RH was above 80%, indicating that the hygroscopic growth of aerosol aggravated the PM2.5 pollution. Source apportionment showed that PM2.5 was mainly from secondary aerosol formation, road dust, coal combustion, and vehicle emissions, contributing 36.6%, 16.5%, 14.7%, and 13.1% of PM2.5 mass, respectively. The contribution of secondary aerosol formation increased remarkably with the deterioration of air quality, especially in the heating season.

Pollution Assessment of Potentially Toxic Elements (PTEs) in Soils around the Yanzhuang Gold Mine Tailings Pond, Pinggu County, Beijing, China.

The accumulation of tailings from gold mining and smelting may result in PTE pollution. We investigated PTE contamination from a large amalgamated gold mine tailings pond in Pinggu County, Beijing. In November 2017, 30 soil samples were collected around the tailings pond. The concentrations and pollution degree of PTEs in the samples and the sources of Sb, As, Cd, Cu, Pb, Zn and Hg were analyzed. The average concentration of these elements in soil samples near the tailings pond (16.24, 28.29, 0.99, 171.04, 263.25, 99.73, 0.72 mg/kg, respectively) were higher than their corresponding standard values and background values of the study area. The geoaccumulation index showed that the pollution degree of As, Pb and Hg was moderate, while Sb and Cu present non-pollution to moderate pollution. The average EF values of the elements were Sb (38.31), As (4.23), Cd (0.71), Cu (3.68), Pb (21.24), Zn (0.82) and Hg (5.29), respectively. The environmental risk assessment developed throughout the PERI method indicated that Sb, As, Hg and Pb were the main pollutants in the study area. The three quantitative risk indicators (RI, Igeo and EF) were positively correlated, and all of them indicated that PTEs had significant pollution to the local area. Thus, Sb, As, Pb, Cu, and Hg pollution should be highly concerning. Multivariate statistical analysis shows that the pollution of PTEs was mainly caused by the accumulation of tailings ponds after gold mining and smelting. The research result is of great significance for the prevention and control of soil pollution of PTEs near the tailings pond.

Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy.

Background: Mutations in the TTN gene are the most common causes of dilated cardiomyopathy (DCM). The clinical significance of TTN gene variants remains inadequately understood. Methods: Whole-exome sequencing and phenotypic characterisation were performed, and patients were followed up for a median of 44 months. Results: We analyzed the association of the TTN variants with the clinical outcomes in a prospective study of 1,041 patients with sporadic DCM. TTN truncating variants (tTTN) were detected in 120 (11.5%) patients as compared with 2.4/10,000 East Asian populations in the Genome Aggregation Database (GnomAD; p < 0.0001). Pathogenic TTN missense variants were also enriched in DCM as compared with the GnomAD populations (27.6 vs. 5.9%, p < 0.0001). DCM patients with tTTN had a lower left ventricular ejection fraction (28.89 ± 8.72 vs. 31.81 ± 9.97, p = 0.002) and a lower frequency of the left bundle branch block (3.3 vs. 11.3%, p = 0.011) than those without or with mutations in other known causal genes (OCG). However, tTTN were not associated with the composite primary endpoint of cardiac death and heart transplantation during the follow-up period [adjusted hazard ratio (HR): 0.912; 95% confidence interval: 0.464-1.793; p = 0.790]. There was also no sex-dependent effect. Concomitant tTTN and pathogenic variants in OCG were present in only eight DCM patients and did not affect the outcome. Conclusion: The phenotype of DCM caused by tTTN, major causes of sporadic DCM, is not distinctly different from those caused by other causal genes for DCM.

Dietary Intake of N-3 and N-6 Polyunsaturated Fatty Acids and Risk of Cancer: Meta-Analysis of Data from 32 Studies.

BACKGROUND: Large epidemiological studies have yielded conflicting results regarding the relationship between polyunsaturated fatty acids (PUFAs) and cancers. Here, we performed a meta-analysis to examine the link between dietary intake of n-3 and n-6 PUFAs and cancer risk. MATERIALS AND METHODS: We performed a search on PubMed, EMBASE, and the Cochrane Library. Studies that reported adjusted relative risk (RR) estimates with 95% confidence intervals (CI) for the associations of interest were included. RESULTS: Thirty-two studies involving 1,445,732 participants were included. Colorectal, breast and prostate cancer had been analyzed in our study. Specifically, for colorectal cancer, total n-3 PUFAs, marine n-3 PUFAs, α-linolenic acids (ALA) and n-6 PUFAs were not associated with the risk of it (RR 1.04, 95%CI 0.85-1.28; RR 0.99, 95%CI 0.89-1.09; RR 1.05, 95%CI 0.93-1.19; RR 1.02, 95%CI 0.94-1.11, respectively). For breast cancer, only marine n-3 PUFAs, but not total n-3 PUFAs, ALA, and n-6 PUFAs, was associated with a lower risk of it (RR 0.70, 95%CI 0.55-0.91). For prostate cancer, ALA and n-6 PUFAs also have no association with the risk of it. CONCLUSIONS: Most subtypes of PUFAs are probably not related to cancers. However, additional high-quality trials are warranted to corroborate the findings of this meta-analysis.

A Novel Gain-of-Function KCND3 Variant Associated with Brugada Syndrome.

Brugada syndrome (BrS) is a known cause of sudden cardiac death (SCD) characterized by abnormal electrocardiograms and fatal arrhythmias. The variants in KCND3 encoding the KV4.3 potassium-channel (the α-subunit of the Ito) have seldom been reported in BrS. This study aimed to identify novel KCND3 variants associated with BrS and elucidate BrS pathogenesis. High-depth targeted sequencing was performed and the electrophysiological properties of the variants were detected by whole-cell patch-clamp methods in a cultured-cell expressing system. The transcriptional levels of KV4.3 in different genotypes were studied by real-time PCR. Western blot was used to assess channel protein expression. A novel KCND3heterozygous variant, c.1292G>A (Arg431His, R431H), was found in the proband. Whole-cell patch-clamp results revealed a gain-of-function phenotype in the variant, with peak Ito current density increased and faster recovery from inactivation. The expression of mutant Kv4.3 membrane protein increased and the cytoplasmic protein decreased, demonstrating that the membrane/cytoplasm ratio was significantly different. In conclusion, a novel KCND3 heterozygous variant was associated with BrS. The increased Ito current explained the critical role of KCND3 in the pathogenesis of BrS. Genetic screening for KCND3 could be useful for understanding the pathogenesis of BrS and providing effective risk stratification in the clinic.

Whole-exome sequencing identifies a de novo PDE3A variant causing autosomal dominant hypertension with brachydactyly type E syndrome: a case report.

BACKGROUND: Autosomal dominant hypertension with brachydactyly type E syndrome caused by pathogenic variants in the PDE3A gene was first reported in 2015. To date, there are only a few reports of this kind of syndrome. Other patients still lack a genetic diagnosis. CASE PRESENTATION: Whole-exome sequencing was performed in an 18-year-old female proband with a clinical diagnosis of hypertension with brachydactyly syndrome. Quantitative real-time PCR was used to identify pathogenic copy number variations (CNVs). After bioinformatics analysis and healthy control database filtering, we revealed a heterozygous missense PDE3A variant (c.1346G > A, p.Gly449Asp). The variant was absent in the ExAC database and located in a highly evolutionarily conserved cluster of reported PDE3A pathogenic variants. Importantly, this variant was predicted to affect protein function by both SIFT (score = 0) and PolyPhen-2 (score = 1). After Sanger sequencing, the variant was determined to be absent in the healthy parents of the proband as well as 800 ethnically and geographically matched healthy controls. CONCLUSION: We present a report linking a de novo PDE3A variant to autosomal dominant hypertension with brachydactyly type E syndrome.

Distal myopathy induced arrhythmogenic right ventricular cardiomyopathy in a pedigree carrying novel DSG2 null variant.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disease predominantly caused by variants in desmosome genes. Variants in human Desmoglein-2 (DSG2) gene can cause ARVC with incomplete penetrance. However, it remains unknown whether ARVC would penetrate by distal myopathy. METHODS: We performed targeted next-generation sequencing using a cardiomyopathy/ionchannelopathy panel in a Chinese ARVC pedigree. Plasmids of DSG2 were constructed, and pathogenicity of the DSG2 variant was investigated by real-time PCR, western blots, Immunofluorescence, and electron microscope. RESULTS: We identified a novel nonsense variant in DSG2 (c.710T > A, p.Leu237Ter) and a reported pathogenic missense variant of distal myopathy in MYH7 (c. 1322C > T, p.Thr441Met) in the proband of an ARVC pedigree. The functional analyses suggested that the nonsense variant could affect the expression and cell location of DSG2, and the number and shape of desmosomes were affected as well, indicating that the variant was implicated in the pathogenesis of ARVC. We found only patients carrying the distal myopathy pathogenic variant would manifested early-onset severe ARVC phenotype, which suggested that MYH7-p.Thr441Met variant could induced the onset of ARVC in the DSG2-p.Leu237Ter variant carriers. CONCLUSIONS: Our study identified a novel null variant in DSG2 gene (c.710T > A, p.Leu237Ter) in an ARVC pedigree with incomplete penetrance. Only patients who carried a distal myopathy associated variant in MYH7 (c. 1322C > T, p.Thr441Met) would induce the onset of ARVC with early-onset and severe symptoms.

Amlodipine induces vasodilation via Akt2/Sp1-activated miR-21 in smooth muscle cells.

BACKGROUND AND PURPOSE: The calcium antagonist amlodipine exerts important cardioprotective effects by modulating smooth muscle and endothelial functions. However, the mechanisms underlying these effects are incompletely understood. EXPERIMENTAL APPROACH: Western blotting was used to compare the expression of key genes involved in vascular smooth muscle cell (VSMC) phenotype conversion. Recombinant adeno-associated virus system was used to regulate miRNA expression in rats via tail vein. Bioinformatics was used to predict the transcriptional regulation of miR-21 upstream followed by biochemical validation using quantitative real-time polymerase chain reaction, ChIP-qPCR and EMSA assays. KEY RESULTS: Only the calcium antagonist amlodipine, and no other type of anti-hypertensive drug, induced miR-21 overexpression in plasma and aortic vessels in the animal model. Real-time PCR and luciferase assays showed that amlodipine induced miR-21 overexpression in vascular smooth muscle cells. Western blot and immunofluorescence assays demonstrated that amlodipine activated Akt2, rather than Akt1, followed by activation of transcription factor Sp1, which regulated VSMC phenotype conversion via binding to the miR-21 promoter. Furthermore, bioinformatic analyses and luciferase assays demonstrated that amlodipine activated miR-21 transcription at the -2034/-2027 Sp1-binding site, which was further demonstrated by ChIP-qPCR and EMSA assays. Consistently, small-interfering RNA-mediated knockdown of Akt2 and Sp1 significantly attenuated the effects of amlodipine on miR-21 expression in smooth muscle cells. CONCLUSION AND IMPLICATIONS: These results indicate that amlodipine induces smooth muscle cell differentiation via miR-21, which is regulated by p-Akt2 and Sp1 nuclear translocation, thereby providing a novel target for cardiovascular diseases.

A PLN nonsense variant causes severe dilated cardiomyopathy in a novel autosomal recessive inheritance mode.

BACKGROUND: Pathogenic variants in human phospholamban coding gene (PLN) are known to cause hereditary dilated cardiomyopathy with heart failure in an autosomal dominant mode. METHODS: We performed high-depth targeted next-generation sequencing using a cardiomyopathy-panel containing 80 disease-related genes in 650 unrelated patients with non-ischemic cardiomyopathy to identify potential pathogenic PLN variants. To comprehensively evaluate the genetic cause of the proband and his pedigree, whole-exome sequencing and Sanger sequencing were performed. RESULTS: A novel homozygous nonsense variant (p.Glu2Ter, c.4G>T) in PLN was identified in a 36-year-old male suffering from dilated cardiomyopathy with severe heart failure. No more cardiomyopathy-causing variant or likely pathogenic copy number variation was identified. This variant was not detected in 800 unrelated healthy controls. Furthermore, the variant is not in the Exome Aggregation Consortium or the Genome Aggregation databases. Western blots showed that this variant significantly reduced the expression of phospholamban. Furthermore, in pedigree analysis, we found that all five heterozygous PLN-p.Glu2Ter carriers (including four elder relatives) had normal heart size and cardiac function, which revealed a novel autosomal recessive inheritance mode. CONCLUSIONS: Our study identified a novel pathogenic variant of PLN, and revealed a novel pathogenic inheritance mode of PLN causing dilated cardiomyopathy with heart failure.

Proton pump inhibitors therapy and risk of bone diseases: An update meta-analysis.

AIMS: Large observational studies have yielded conflicting results regarding whether the use of proton pump inhibitors (PPI) increases the risk of bone diseases. Here, we performed a meta-analysis to examine the link between PPI and risk of bone fractures, osteoporosis and bone mineral density (BMD) loss. MATERIALS AND METHODS: We systematically performed a search for published reports on PubMed, EMBASE and the Cochrane Library. We considered articles published in English, and restricted the search to studies on human participants. Studies that reported adjusted Hazard ratio (HR) estimates with 95% confidence intervals (CI) for the associations of interest were included. Data from the articles which can be used to estimate standardized mean difference (SMD) were also obtained and utilized to assess the risk of BMD loss. KEY FINDINGS: Compared with patients not taking PPI, those taking PPI, had the increased risk of developing any-site fractures (HR: 1.30; 95%CI: 1.16 to 1.45), hip fracture (HR:1.22; 95%CI:1.15 to 1.31), spine fracture (HR:1.49; 95%CI:1.31 to 1.68), and osteoporosis (HR:1.23; 95%CI:1.06 to 1.42) based on a random model, but there was no correlation with developing BMD loss in the femoral (SMD: -0.27; 95%CI: -0.62 to 0.09), or in the spine (SMD: -0.06; 95%CI: -0.54 to 0.41). SIGNIFICANCE: Results of this meta-analysis suggest that PPI may moderately increase the risk of any-site, hip, spine fracture. Due to the widespread use of PPI and the impact of fractures on human health, clinicians should carefully evaluate the patient condition before prescribing PPI therapy.

Ranolazine prevents pressure overload-induced cardiac hypertrophy and heart failure by restoring aberrant Na+ and Ca2+ handling.

BACKGROUND: Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca2+ handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca 2+ overload. In this study, we investigated the effects of ranolazine on pressure overload-induced cardiac hypertrophy and heart failure in mice. METHODS AND RESULTS: Inhibition of late sodium current with the selective inhibitor ranolazine suppressed cardiac hypertrophy and fibrosis and improved heart function assessed by echocardiography, hemodynamics, and histological analysis in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC). Ca2+ imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca 2+ release and increased SR Ca 2+ leak. Ranolazine restored aberrant SR Ca 2+ handling induced by pressure overload. Ranolazine also suppressed Na + overload induced in the failing heart, and restored Na + -induced Ca 2+ overload in an sodium-calcium exchanger (NCX)-dependent manner. Ranolazine suppressed the Ca 2+ -dependent calmodulin (CaM)/CaMKII/myocyte enhancer factor-2 (MEF2) and CaM/CaMKII/calcineurin/nuclear factor of activated T-cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER-initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER-initiated cardiomyocyte apoptosis. CONCLUSIONS: Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload-induced cardiac hypertrophy and systolic and diastolic function by restoring Na+ and Ca 2+ handling, inhibiting the downstream hypertrophic pathways and ER stress. Inhibition of late sodium current may provide a new treatment strategy for cardiac hypertrophy and heart failure.

A targeted sequencing approach to find novel pathogenic genes associated with sporadic aortic dissection.

Aortic dissection (AD) is a heterogeneous genetic disease of the aorta with high mortality and poor prognosis. However, only few genetic causes of AD have been explored till date. After conducting a broad literature review focused on identifying potential pathogenic pathways, we designed a panel containing 152 AD-associated genes to conduct massively parallel targeted next-generation sequencing of 702 sporadic aortic dissection patients and 163 matched healthy controls. After validation by Sanger sequencing, we identified 21 definitely pathogenic and 635 likely pathogenic variants in 61.25% (430/702) of patients. In these patients, 34.88% (150/430) harbored more than one variant that was either definitely or likely to be pathogenic. Among the candidate genes, we identified 546 likely pathogenic variants in 47.72% (335/702) of patients. Importantly, we identified 94 loss-of-function (LOF) variants in 45 genes in AD patients, but only five LOF variants in the controls (P=1.34×10-4). With a burden test, we highlighted RNF213 as an important new gene for AD pathogenesis. We also performed transcriptome sequencing of human aorta tissues to evaluate the expression levels of these newly identified genes. Our study has compiled a comprehensive genetic map of sporadic AD in the Han Chinese population. We believe it will facilitate risk predicting and genetic diagnosis of this severe disease in the future.

Absence or mislocalization of DNAH5 is a characteristic marker for motile ciliary abnormality in nasal polyps.

OBJECTIVE: Motile cilia impairment is a common condition in patients with chronically inflamed airways, such as is seen in nasal polyps (NPs). The mechanism underlying this pathogenic condition is complex and not fully understood. METHODS: We investigated the presence and localization of dynein axonemal heavy chain 5 (DNAH5) in motile cilia using immunofluorescence staining in paraffin-embedded nasal biopsies from NPs (n = 120) and inferior turbinate mucosa (n = 35) of healthy controls. We also performed single-cell staining on cytospin samples (NP = 5, control = 5). Three patterns of DNAH5 localization are defined, including pattern A (presence throughout the axoneme), pattern B (undetectable in the distal part of the axoneme), and pattern C (completely missing throughout the entire axoneme). We developed a semiquantitative scoring system for which 0 = (pattern A > 70%); 1 = (patterns A + B > 70%); and 2 = (pattern C ≥ 30%) in each high-power field (5 fields per sample). RESULTS: Based on our DNAH5 scoring system, the median (1st and 3rd quartile) score was 0.3 (0.2 and 0.4) for samples from controls, and 1.1 (0.6 and 1.6) for samples from NPs in paraffin specimens (P < 0.001). The DNAH5 score had a significant positive relationship with the Lund-Mackay computed tomography score (r = 0.329, P = 0.005) and was higher in patients with eosinophilic NPs (P = 0.006). For cytospin samples, the mean percentage of patterns A, B, and C were 74%, 14%, and 12% in controls, and 48%, 20%, and 32% in NPs, respectively. CONCLUSION: Our results suggest that the absence or mislocalization of DNAH5 from motile cilia is a common and potentially important pathological phenomenon in chronically inflamed airway epithelium. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E97-E104, 2018.

FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection.

Mutations in FBN1 have been well identified in syndromic aortic dissection (AD) and familial thoracic aortic aneurysms and dissections. However, whether mutations of FBN1 contribute to sporadic non-syndromic AD and the characteristics of mutations remain unknown. Using next-generation-sequencing technology, FBN1 was sequenced in a total of 702 sporadic cases (including 687 of non-syndromic AD and 15 of sporadic Marfan syndrome with aortic event, and 527 normal controls). For the sporadic non-syndromic AD cohort, we found 26 variants in 27 patients (18 with missense, 2 frameshift, 1 initiation codon mutation, 3 nonsense and 3 splice site mutations). The prevalence of variants was significantly high in the sporadic non-syndromic AD cohort (27/687, 3.9%). The patients with FBN1 mutations were younger, suffered from fewer risk factors such as hypertension and smoking, and were less gender partitioned than non-FBN1-mutation AD patients. The mutations were spread along the FBN1 gene in our sporadic non-syndromic AD cohort and mutation locations are not different between non-syndromic and syndromic patients. These results demonstrate that the deleterious mutations in FBN1 largely contribute to pathogenesis of sporadic non-syndromic AD, which expands our knowledge of FBN1 variants and the genetic basis and pathology of AD.

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection.

Aortic dissection (AD) is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases (MMPs)/tissue inhibitors of MMPs (TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens (45 genes), MMPs/TIMPs (27 genes) in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% (64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05% (218/702) sporadic AD patients. In them, 84.86% patients (185/218) carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probably pathogenic loss-of-function (LOF) variants (20 nonsense, 16 frameshift, 14 splice sites, one stop-loss, one initiation codon) in 11.06% (50/452) AD patients, which were absent in 163 controls (P=2.5×10-5). Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2 -/- rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis.

Simple and rapid mercury ion selective electrode based on 1-undecanethiol assembled Au substrate and its recognition mechanism.

A simple and rapid mercury ion selective electrode based on 1-undecanethiol (1-UDT) assembled Au substrate (Au/1-UDT) has been well constructed. 1-UDT was for the purpose of generating self-assembled monolayer on gold surface to recognize Hg2+ in aqueous solution, which had a working concentration range of 1.0×10-8-1.0×10-4molL-1, with a Nernst response slope of 28.83±0.4mV/-pC, a detection limit of 4.5×10-9molL-1, and a good selectivity over the other tested cations. Also, the Au/1-UDT possessed good reproducibility, stability, and short response time. The recovery obtained for the determination of mercury ion in practical tremella samples was in the range of 99.8-103.4%. Combined electrochemical analysis and X-ray photoelectron spectroscopy (XPS) with quantum chemical computation, the probable recognition mechanism of the electrode for selective recognition of Hg2+ has been investigated. The covalent bond formed between mercury and sulfur is stronger than the one between gold and sulfur and thus prevents the adsorption of 1-UDT molecules on the gold surface. The quantum chemical computation with density functional theory further demonstrates that the strong interaction between the mercury atom and the sulfur atom on the gold surface leads to the gold sulfur bond ruptured and the gold mercury metallophilic interaction.