Identification and validation of supervariants reveal novel loci associated with human white matter microstructure.

As an essential part of the central nervous system, white matter coordinates communications between different brain regions and is related to a wide range of neurodegenerative and neuropsychiatric disorders. Previous genome-wide association studies (GWASs) have uncovered loci associated with white matter microstructure. However, GWASs suffer from limited reproducibility and difficulties in detecting multi-single-nucleotide polymorphism (multi-SNP) and epistatic effects. In this study, we adopt the concept of supervariants, a combination of alleles in multiple loci, to account for potential multi-SNP effects. We perform supervariant identification and validation to identify loci associated with 22 white matter fractional anisotropy phenotypes derived from diffusion tensor imaging. To increase reproducibility, we use United Kingdom (UK) Biobank White British (n = 30,842) data for discovery and internal validation, and UK Biobank White but non-British (n = 1927) data, Europeans from the Adolescent Brain Cognitive Development study (n = 4399) data, and Europeans from the Human Connectome Project (n = 319) data for external validation. We identify 23 novel loci on the discovery set that have not been reported in the previous GWASs on white matter microstructure. Among them, three supervariants on genomic regions 5q35.1, 8p21.2, and 19q13.32 have P-values lower than 0.05 in the meta-analysis of the three independent validation data sets. These supervariants contain genetic variants located in genes that have been related to brain structures, cognitive functions, and neuropsychiatric diseases. Our findings provide a better understanding of the genetic architecture underlying white matter microstructure.

Biochemical and genetic dissection of the RNA-binding surface of the FinO domain of Escherichia coli ProQ.

RNA-binding proteins play important roles in bacterial gene regulation through interactions with both coding and noncoding RNAs. ProQ is a FinO-domain protein that binds a large set of RNAs in Escherichia coli, though the details of how ProQ binds these RNAs remain unclear. In this study, we used a combination of in vivo and in vitro binding assays to confirm key structural features of E. coli ProQ's FinO domain and explore its mechanism of RNA interactions. Using a bacterial three-hybrid assay, we performed forward genetic screens to confirm the importance of the concave face of ProQ in RNA binding. Using gel shift assays, we directly probed the contributions of ten amino acids on ProQ binding to seven RNA targets. Certain residues (R58, Y70, and R80) were found to be essential for binding of all seven RNAs, while substitutions of other residues (K54 and R62) caused more moderate binding defects. Interestingly, substitutions of two amino acids (K35, R69), which are evolutionarily variable but adjacent to conserved residues, showed varied effects on the binding of different RNAs; these may arise from the differing sequence context around each RNA's terminator hairpin. Together, this work confirms many of the essential RNA-binding residues in ProQ initially identified in vivo and supports a model in which residues on the conserved concave face of the FinO domain such as R58, Y70, and R80 form the main RNA-binding site of E. coli ProQ, while additional contacts contribute to the binding of certain RNAs.

Deep learning identified genetic variants for COVID-19-related mortality among 28,097 affected cases in UK Biobank.

Analysis of host genetic components provides insights into the susceptibility and response to viral infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). To reveal genetic determinants of susceptibility to COVID-19 related mortality, we train a deep learning model to identify groups of genetic variants and their interactions that contribute to the COVID-19 related mortality risk using the UK Biobank data (28,097 affected cases and 1656 deaths). We refer to such groups of variants as super variants. We identify 15 super variants with various levels of significance as susceptibility loci for COVID-19 mortality. Specifically, we identify a super variant (odds ratio [OR] = 1.594, p = 5.47 × 10-9 ) on Chromosome 7 that consists of the minor allele of rs76398985, rs6943608, rs2052130, 7:150989011_CT_C, rs118033050, and rs12540488. We also discover a super variant (OR = 1.353, p = 2.87 × 10-8 ) on Chromosome 5 that contains rs12517344, rs72733036, rs190052994, rs34723029, rs72734818, 5:9305797_GTA_G, and rs180899355.

Rotenone encapsulated in pH-responsive alginate-based microspheres reduces toxicity to zebrafish.

Rotenone is a botanical pesticide and has long been used for control of insect pests and also as a natural piscicide for management of fish populations in many countries. Field application for pest control, however, often encounters the movement of rotenone into surface water due to spray drift or surface runoff after rainfall, which could potentially result in water pollution and unexpected death of fishes. To minimize its effect on freshwater and the problem of fish dying, one solution was to encapsulate rotenone in specific microspheres, limiting its release and reducing its toxicity since rotenone can be quickly degraded under sunlight. In this study, pH-responsive alginate-based microspheres were synthesized to encapsulating rotenone, which were designated as rotenone beads. The rotenone beads, along with alginate beads (devoid of rotenone) were characterized and evaluated for their responses to pH and effects on zebrafish. Results showed that the microspheres had high loading efficiency (4.41%, w/w) for rotenone, and rotenone beads well responded to solution pH levels. The cumulative release rates of rotenone from the beads were 27.91%, 42.72%, and 90.24% at pH 5.5, 7.0, and 9.0, respectively. Under acidic conditions, the rotenone release rate was lower due to hydrogen bonding. On the contrary, rotenone became more quickly released at the high pH due to intermolecular repulsion. The toxicity of rotenone beads to zebrafish and fish embryos at a pH of 5.5 was reduced by 2- and 4-fold than chemical rotenone. Since pH levels in most freshwater lakes, ponds, and streams vary from 6 to 8, rotenone release from the beads in such freshwater could be limited. Thus, the synthesized rotenone beads could be relatively safely used for pest control with limited effects on freshwater fishers.

(n, m) Distribution of Single-Walled Carbon Nanotubes Grown from a Non-Magnetic Palladium Catalyst.

Non-magnetic metal nanoparticles have been previously applied for the growth of single-walled carbon nanotubes (SWNTs). However, the activation mechanisms of non-magnetic metal catalysts and chirality distribution of synthesized SWNTs remain unclear. In this work, the activation mechanisms of non-magnetic metal palladium (Pd) particles supported by the magnesia carrier and thermodynamic stabilities of nucleated SWNTs with different (n, m) are evaluated by theoretical simulations. The electronic metal-support interaction between Pd and magnesia upshifts the d-band center of Pd, which promotes the chemisorption and dissociation of carbon precursor molecules on the Pd surface, making the activation of magnesia-supported non-magnetic Pd catalysts for SWNT growth possible. To verify the theoretical results, a porous magnesia supported Pd catalyst is developed for the bulk synthesis of SWNTs by chemical vapor deposition. The chirality distribution of Pd-grown SWNTs is understood by operating both Pd-SWNT interfacial formation energy and SWNT growth kinetics. This work not only helps to gain new insights into the activation of catalysts for growing SWNTs, but also extends the use of non-magnetic metal catalysts for bulk synthesis of SWNTs.

The Accelerated Progression of Atherosclerosis Correlates with Decreased miR-33a and miR-21 and Increased miR-122 and miR-3064-5p in Circulation and the Liver of ApoE-/- Mice with Streptozocin (STZ)-Induced Type 2 Diabetes.

Atherosclerosis is a major risk factor for type 2 diabetes (T2D) mortality. We aim to investigate the changes in miR-21, miR-122, miR-33a and miR-3064-5p in circulation and the liver of ApoE-/- mice with streptozocin (STZ)-induced T2D. Twenty 5-week-old male ApoE-/- mice were randomly assigned to the control (n = 10) and T2D group (n = 10) and intraperitoneally injected with a citrate buffer and streptozotocin (STZ) (40 mg/kg BW) once a day for three consecutive days. The successfully STZ-induced T2D mice (n = 5) and control mice (n = 5) were then fed with a high-fat diet (HFD) for 34 weeks. Compared to the control mice, ApoE-/- mice with STZ-induced T2D had slower (p < 0.05) growth, increased (p < 0.05) total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), decreased (p < 0.05) high-density lipoprotein cholesterol (HDL-C) in serum, reduced (p < 0.05) TC and sterol regulatory element-binding protein-2 (Srebp-2), elevated (p < 0.05) ATP-binding-cassette-transporter-A1 (Abca1) in the liver, aggravated (p < 0.05) atherosclerotic lesions in the aorta, downregulated (p < 0.05) miR-21 and miR-33a, and upregulated (p < 0.05) miR-122 and miR-3064-5p in serum and the liver. In addition, the aortic lesions showed a positive correlation with miR-122 (r = 1.000, p = 0.001) and a negative correlation with miR-21 (r = −1.000, p = 0.001) in ApoE-/- mice with T2D. In conclusion, T2D-accelerated atherosclerosis correlates with a reduction in miR-21 and miR-33a and an elevation in miR-122 and miR-3064-5p in circulation and the liver of ApoE-/- mice.

Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogeneous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors. METHODS: In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations. RESULTS: We find 8 super variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV-2. CONCLUSIONS: Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.

Sonication-Free Dispersion of Single-Walled Carbon Nanotubes for High-Sorption-Capacity Aerogel Fabrication.

Homogenously dispersing single-walled carbon nanotubes (SWNTs) in solvents has been one critical step towards exploiting their exceptional properties in high-performance components. However, the solubility of SWNTs is severely limited by the inert tube surfaces and strong tube-tube van der Waals attractions. Starting with carbon nanotubides, i.e., negatively charged SWNTs reduced by alkali metals, we herein propose a sonication-free approach to prepare an aqueous dispersion of SWNTs. The approach combines the spontaneous dissolution of nanotubides in polar aprotic solvents with polyvinylpyrrolidone wrapping and dialysis in deionized H2O, which results in well-dispersed, neutralized SWNTs. The gelation of concentrated SWNT dispersion leads to the formation of hydrogels, which is subsequently transformed into SWNT aerogels through lyophilization. The prepared SWNT aerogels exhibit high-mass-sorption capacities for organic solvent absorption, paving the way towards harvesting the extraordinary properties of SWNTs.

Supervariants identification for breast cancer.

In genome-wide association studies, signals associated with rare variants and interactions between genes are hard to detect even when the sample size is in tens of thousands. To overcome these problems, we examine the concept of supervariant. Like the classic concept of the gene, a supervariant is a combination of alleles in multiple loci, but the contributing loci can be anywhere in the genome. We hypothesize that supervariants are easy to detect and the aggregated signals are more stable in their associations with the disease than that from a single nucleoid polymorphism. Using the UK Biobank databases, we develop a ranking and aggregation method for identifying supervariants. Specifically, we examine 9,377 breast cancer cases with 46,861 controls matched by sex and age. In our simulations, the use of supervariants outperforms single-nucleotide polymorphism-based association method in detecting rare variants and signals with interactive structure. In real data analysis, we identify supervariants on Chromosomes 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 16, and 22 which cover previously reported loci that have associations with breast or other cancers, and several novel loci on Chromosomes 2, 5, 9, and 12. These findings demonstrate the validity of supervariants and its potential of discovering replicable and novel results for complex disease.

Super-variants identification for brain connectivity.

Identifying genetic biomarkers for brain connectivity helps us understand genetic effects on brain function. The unique and important challenge in detecting associations between brain connectivity and genetic variants is that the phenotype is a matrix rather than a scalar. We study a new concept of super-variant for genetic association detection. Similar to but different from the classic concept of gene, a super-variant is a combination of alleles in multiple loci but contributing loci can be anywhere in the genome. We hypothesize that the super-variants are easier to detect and more reliable to reproduce in their associations with brain connectivity. By applying a novel ranking and aggregation method to the UK Biobank databases, we discovered and verified several replicable super-variants. Specifically, we investigate a discovery set with 16,421 subjects and a verification set with 2,882 subjects, where they are formed according to release date, and the verification set is used to validate the genetic associations from the discovery phase. We identified 12 replicable super-variants on Chromosomes 1, 3, 7, 8, 9, 10, 12, 15, 16, 18, and 19. These verified super-variants contain single nucleotide polymorphisms that locate in 14 genes which have been reported to have association with brain structure and function, and/or neurodevelopmental and neurodegenerative disorders in the literature. We also identified novel loci in genes RSPO2 and TMEM74 which may be upregulated in brain issues. These findings demonstrate the validity of the super-variants and its capability of unifying existing results as well as discovering novel and replicable results.

Common genetic variants have associations with human cortical brain regions and risk of schizophrenia.

Schizophrenia is a highly heritable mental disorder and is reported to be associated with measurements in cortical regions of the human brain. In this study, we considered genome-wide association studies to uncover genetic effects on cortical regions and prodromal symptoms of schizophrenia. Specifically, area, thickness, and volume of 66 cortical regions derived from magnetic resonance imaging scans of 1,445 children and adolescents from the Philadelphia Neurodevelopmental Cohort were studied. Two common variants were identified as being associated with two prefrontal cortical regions (one significant variant rs11601331 on chromosome 11p11 for right rostral middle frontal gyral area, p = 1.97 × 10 -8 ; one suggestive variant rs2345981 on chromosome 6q11 for left frontal pole gyral volume, p = 2.07 × 10 -7 ), where the significance of rs11601331 was independently replicated on the Pediatric Imaging, Neurocognition, and Genetics study of size 1,239 (p = 9.19 × 10 -3 ). Moreover, genetic effects on schizophrenia were investigated based on a sample of 8,719 subjects. The two identified variants rs11601331 and rs2345981 showed significant association with the longest prodromal symptoms duration (p = 0.048 and p = 0.027, respectively).

Retinal break associated with traumatic lens dislocation or subluxation requiring vitrectomy.

BACKGROUND: Both ectopia lentis and retinal injury are common results of blunt ocular trauma. Here, we investigated the incidence and characteristics of retinal breaks associated with ectopia lentis caused by blunt ocular trauma. METHODS: Patients who underwent pars plana vitrectomy to treat traumatic lens subluxation and dislocation were retrospectively reviewed. The incidence, characteristics, and outcomes of retinal breaks were analyzed. RESULTS: Forty-five eyes from 45 patients were included in the study. Seventeen eyes (37.7%) were complicated by retinal breaks or detachment, but only four (8.9%) were identified pre-operation. Our study revealed that retinal breaks were more frequently located at the superior (72.7%) and peripheral (81.8%) retina. All patients achieved anatomic recovery post-surgery. The eyes with and without retinal breaks did not differ significantly with respect to initial or final visual acuity. The final visual outcomes were independently and significantly associated with visual acuity at presentation (P = 0.001). CONCLUSIONS: Retinal breaks occurred in approximately one-third of patients with traumatic ectopia lentis and were difficult to observe pre-operation. Complete ophthalmic evaluation and timely intervention may help achieve favorable outcomes.

A Retrospective Study Comparing the Effectiveness and Safety of EXOSEAL Vascular Closure Device to Manual Compression in Patients Undergoing Percutaneous Transbrachial Procedures.

BACKGROUND: This study aimed to assess the safety and efficacy of EXOSEAL vascular closure device (EVCD) insertion by comparing its performance with manual compression (MC) in achieving hemostasis at the brachial artery puncture site. METHODS: A retrospective study of brachial artery access by using either MC or EVCD for achieving hemostasis from March 2016 to October 2017 was conducted. Patients with Stanford type B aortic dissection (TBAD) undergoing percutaneous transbrachial procedures were included. Time to hemostasis (TTH) was the primary efficacy end point. Seven-day incidence of major access site-related complications was the primary safety end point. TTH and major and minor complications associated with treatment of these 2 groups were also evaluated. RESULTS: A total of 157 patients with TBAD undergoing percutaneous transbrachial procedures entered the analysis. Of these, 107 patients underwent EVCD insertion and 50 patients underwent MC. The baseline characteristics of the 2 groups were similar. TTH was significantly shorter for EVCD over MC (P < 0.05). The TTH ≥10 min in the MC group was 100.0% (n = 50), but in the EVCD group, it was ≤2 min, 87.9% (n = 107); 2-5 min, 7.5% (n = 107); and ≥10 min, 4.7% (n = 107). The EVCD group had several major complications, while the MC group had none. Two patients (1.9%, n = 107) required vascular repair, one patient (0.6%, n = 107) required blood transfusion, and 1 patient (0.6%, n = 107) developed upper limb numbness and weakness after EVCD deployment. Minor complication such as the occurrence of hematoma (≤5 cm) in the MC group was 4 (8.0%) but was also 4 (3.7%) in the EVCD group, showing statistically significant difference (P = 0.030). The incidence of ecchymosis was 8 (7.5%) in the EVCD group when compared with 13 (26.0%) in the MC group, which showed statistically significant difference (P = 0.001). Other major and minor complications showed no significant differences between these 2 groups. CONCLUSIONS: After invasive procedures by 6F percutaneous access via the brachial artery in preprocedurally fully anticoagulated patients, TTH was significantly reduced in patients who underwent EVCD when compared with patients who underwent MC. MC is a safer and more convenient way to achieve hemostasis but has higher incidence of minor complications.

Outcome of Surgical Treatment for Carotid Body Tumors in Different Shambling Type Without Preoperative Embolization: A Single-Center Retrospective Study.

BACKGROUND: Carotid body tumor (CBT) is the most common head and neck paragangliomas. Surgical resection is the golden standard management for CBT. While preoperative embolization is still controversial, long-term outcomes and perioperative results are still deficient. We, here, presented the outcomes of surgical treatment for CBT without preoperative embolization at our institution. METHODS: In this retrospective study, we collected data from 101 patients who received surgical treatment for CBTs without preoperative embolization from 2011 to 2016. In addition, we attempted to conduct 2 years of follow-up under the guidance of both neurologist and vascular surgeon. Patients' demographics, clinical characteristics, complications, and follow-up results were all analyzed with descriptive statistics. RESULTS: Complete resection of the CBT was achieved in 101 cases (100%). Postoperative adverse events (AEs) mostly observed during hospitalization were as follows: tongue bias (I: 4, 36.4%; II: 8, 19.5%; III: 13, 26.5%), hoarseness (I: 1, 9.1%; II: 4, 9.8%; III: 7, 14.3%), dysphagia (I: 0; II: 2, 4.9%; III: 7, 14.3%), and hematoma (I: 0; II: 0; III: 1, 2.0%). No other serious AEs were observed. The total incidence of AEs in type I patients was 5 (45.5%), 14 (34.1%) in type II, and 28 (57.1%) in type III, and the type III group has significantly higher than the other two groups. At the end of 2 years of follow-up, there were no AEs in type I patients. The number of patients with AEs in type III was greater than that in type II, although there was no significant difference. Based on our findings, 3 most commonly injured cranial nerves (CNs) after surgical resection of CBT were CN XII (hypoglossal nerve, 21.9%), CN X (vagus nerve, 20.3%), and recurrent laryngeal nerve (18.8%). CONCLUSIONS: Surgical management without preoperative embolization for CBT patients is a safe and effective therapeutic approach.

Preparation of sodium alginate-poly (vinyl alcohol) blend beads for base-triggered release of dinotefuran in Spodoptera litera midgut.

This study investigated the ability of dual crosslinked interpenetrating polymer network (IPN) blend beads (DIN:SA/PVA-beads), composed of sodium alginate (SA) and poly (vinyl alcohol) (PVA), as a base-triggered carrier for the controlled release of dinotefuran (DIN) in Spodoptera litera midgut. The blend beads were characterized for morphology, encapsulation efficiency, swelling degree, and in vitro release of the blend beads were characterized. The results revealed that the double-crosslinked gel beads had a tightly interpenetrating network structure and exhibited a satisfactory embedding effect for DIN. The maximum of the DIN loading capacity was approximately 1.01%, with a high encapsulation efficiency of 83.19%. The triggered release of DIN from the blend beads was studied in deionized water (pH 3.0-11.0) via high-performance liquid chromatography (HPLC); it was found that the release rate was higher in alkaline pH conditions than in acidic and neutral conditions. An in vivo dynamics and degradation study also demonstrated that the excellent release characteristics of DIN:SA/PVA-beads in the midgut of S. litera. This study provides a promising controlled-release form of dinotefuran that is more effective and can be used for the targeted control of pests with alkaline midgut.

Ultrasonographic Features of Lower-Limb Joints in Gout: Which Joints and Clinical Characteristics Would Provide More Information for Diagnosis?

OBJECTIVE: This observational cross-sectional study evaluated the distribution of ultrasound (US) features of lower-limb joints and the risk factors of tophus in gout patients. METHODS: We examined 588 joints including the bilateral knee, ankle, and first metatarsophalangeal (MTP) joints in 98 gout patients by US between March to August in 2017. The distribution of double-contour (DC), tophus, aggregates, synovitis, effusion and erosion in different joint, course, and age groups were investigated by Cochran Q and χ test. The risk factors of tophus were analyzed using logistic regression method. RESULTS: Double-contour was most commonly observed in the knee (p = 0.005). Tophus, aggregates, synovitis, and erosion were mostly detected in the first MTP (p < 0.001, p = 0.01, p = 0.001, p < 0.001, respectively). The prevalence rates of DC, tophus, and erosion in patients with a longer course were significantly higher (p = 0.029, p = 0.002, p < 0.001, respectively). Older patients had more detectable tophus and erosion than younger patients (p = 0.028, p = 0.021). Patients of older age (odds ratio [OR], 3.83; 95% confidence interval [CI], 1.27-11.48), with frequent attacks (OR, 3.80; 95% CI, 1.10-13.15), and with longer course (OR, 6.52; 95% CI, 1.37-30.96) had higher risks of tophus. CONCLUSIONS: Most signs were detected by US in the first MTP, except that DC was most commonly observed in the knees. Patients of older age with frequent attacks and longer course may experience higher risks for tophus. Comprehensive assessment of the lower limbs, particularly the knee and first MTP, can significantly help diagnosis.

[Progress on clinical application of orthodontic-implant combined therapy].

For complex implant cases, simple implantation could not achieve the desired therapeutic effect, and a multidisciplinary approach has become a general trend. Orthodontic treatment before implantation creates favorable conditions for subsequent implantation by increasing restoring three-dimensional space, improving occlusion of patients. It also stimulates the increase of autologous soft and hard tissue while biological potential of periodontal ligament is fully developed. The choice of operation time is vital to keep the level of soft and hard tissue at the implantation site, which improves the curative effect of implantation in terms of function and aesthetics. In this article, the orthodontic-implant combined therapy is briefly reviewed focusing on the three-dimensional space optimization, implant site enhancement by orthodontic extrusion and delayed orthodontic space opening.

Upregulation of miR-330-5p is associated with carotid plaque's stability by targeting Talin-1 in symptomatic carotid stenosis patients.

BACKGROUND: The aim of this study was to investigate the relationship between Talin-1 and stability of carotid atherosclerosis plaque and also find out the role of miRNA, as an upstream regulator, in regulating the expression level of Talin-1. METHODS: Human carotid plaques were obtained from 20 symptomatic carotid stenosis patients who underwent carotid endarterectomy (CEA) in our hospital between October 2014 and August 2017. Western blot analysis and immunohistochemistry was carried out to detect the distribution and expression level of Talin-1 in each plaque sample. The content of miRNAs in carotid plaque was decected by quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the relative expression levels were calculated by 2-△△Ct method after the (cycle threshold) Ct value (power amplification knee point) was obtained. Dual-luciferase reporter assays were applied to verify the successful transfections. Finally, we compared all the groups with independent-samples t-test and one-way analysis of variance (ANOVA). RESULTS: Talin-1 was significantly downregulated in human unstable carotid plaque samples compared with stable carotid plaques (P < 0.05), and the distribution of Talin-1 was mainly found in the fibrous cap of carotid plaque. The overexpression of miRNA-330-5p was found in unstable carotid plaque, which significantly induced the inhibition of expression level of Talin-1. CONCLUSION: Upregulated miR-330-5p may lead to unstable carotid plaques by targeting Talin-1 in symptomatic carotid stenosis patients. This might be a new target for the treatment of atherosclerotic diseases through future studies.

Interleukin-18.

A prospective observational study was conducted to evaluate the predictive value of interleukin-18 (IL-18) for major adverse cardiovascular events (MACEs) in hemodialysis patients. A total of 85 participants (45 hemodialysis patients and 40 healthy volunteers) with a mean age of 56.3 years were enrolled in this study. Demographic and clinical data were collected. MACE was used as the primary endpoint. Results showed that the hemodialysis patients had higher levels of IL-18 (701.6 ± 88.52 versus 152.0 ± 55.31 pg/mL, P < 0.01) and a high rate of MACE (15.6% versus 2.5%, P < 0.01) compared with healthy controls. Multiple linear regression analysis showed that the serum creatinine and left ventricular ejection fraction were significantly effective factors influencing IL-18 (P < 0.01). Receiver-operating characteristic curve analysis showed that IL-18 levels were better predictors for MACE. The area under the curve of IL-18 was 0.81 (0.70-0.92) (P = 0.004). IL-18 levels provided 87.5% sensitivity and 26% specificity with a threshold value of 534.5 pg/mL. Our findings indicated that hemodialysis patients with high levels of IL-18 had a high incidence rate of MACE. IL-18 is a good predictive marker of MACE in hemodialysis patients.

Knockdown of Angiopoietin-Like Protein 2 Ameliorates Diabetic Nephropathy by Inhibiting TLR4.

BACKGROUND/AIMS: Angiopoietin-like protein 2 (ANGPTL2) was reported to be implicated in the pathogenesis of inflammatory disease. Its role in diabetic nephropathy (DN) remained illdefined. METHODS: qRT-PCR and western blot analysis were performed to detect the expressions of ANGPTL2 or TLR4 in streptozotocin (STZ)-induced DN rats and HG-stimulated podocytes. The renal injury index including 24-h proteinuria, blood glucose level, serum creatinine and blood urea nitrogen were measured in DN rats using corresponding commercial kits. The effect of ANGPTL2 knockdown on the secretion or expression of inflammatory cytokines was detected by ELISA or qRT-PCR analysis. The effect of ANGPTL2 knockdown on extracellular matrix (ECM) accumulation was determined by testing TGF-ß1, Collagen-IV, fibronectin (FN) and PTEN expression via western blot. RESULTS: ANGPTL2 and TLR4 were both highly expressed in DN rats compared with control group. ANGPTL2 knockdown alleviated renal injury in STZ-induced DN rat model. ANGPTL2 knockdown also suppressed inflammatory cytokines (IL-6, TNF-α, MCP-1, IL-1ß) expression and ECM accumulation (TGF-ß1, Collagen-IV, FN, PTEN) in HG-induced podocytes. Moreover, ANGPTL2 knockdown led to a significant decrease of TLR4 expression in both DN rat and cell model. Furthermore, TAK-242 treatment exacerbated the inhibitory effect of ANGPTL2 knockdown on inflammatory cytokines expression and ECM accumulation in HG-induced podocytes. CONCLUSION: ANGPTL2 knockdown ameliorates DN by inhibiting TLR4 expression, an observation contributing to a better understanding of DN pathogenesis.