Efficient identification of trait-associated loss-of-function variants in the UK Biobank cohort by exome-sequencing based genotype imputation.

The large-scale open access whole-exome sequencing (WES) data of the UK Biobank ~200,000 participants is accelerating a new wave of genetic association studies aiming to identify rare and functional loss-of-function (LoF) variants associated with complex traits and diseases. We proposed to merge the WES genotypes and the genome-wide genotyping (GWAS) genotypes of 167,000 UKB homogeneous European participants into a combined reference panel, and then to impute 241,911 UKB homogeneous European participants who had the GWAS genotypes only. We then used the imputed data to replicate association identified in the discovery WES sample. The average imputation accuracy measure r2 is modest to high for LoF variants at all minor allele frequency intervals: 0.942 at MAF interval (0.01, 0.5), 0.807 at (1.0 × 10-3 , 0.01), 0.805 at (1.0 × 10-4 , 1.0 × 10-3 ), 0.664 at (1.0 × 10-5 , 1.0 × 10-4 ) and 0.410 at (0, 1.0 × 10-5 ). As applications, we studied associations of LoF variants with estimated heel BMD and four lipid traits. In addition to replicating dozens of previously reported genes, we also identified three novel associations, two genes PLIN1 and ANGPTL3 for high-density-lipoprotein cholesterol and one gene PDE3B for triglycerides. Our results highlighted the strength of WES based genotype imputation as well as provided useful imputed data within the UKB cohort.

LncRNA TUG1 exhibits pro-fibrosis activity in hypertrophic scar through TAK1/YAP/TAZ pathway via miR-27b-3p.

Hypertrophic Scar (HS) is a complicated fibrotic disease. In addition, its pathogenesis is still to be further explored. Long non-coding RNAs (lncRNAs) have been proved to be participated in multiple diseases, including HS. However, the role of lncRNA TUG1 in HS remains unclear. The expression level of RNA and protein in cells were detected by q-PCR and western blot, respectively. MTT assay was performed to test the cell proliferation. Cell migration was detected by transwell assay. Cell apoptosis was measured by flow cytometry. Dual luciferase report assay and RNA pull down were used to verify the relationship between TUG1, miR-27b-3p and TAK1.TUG1 and TAK1 were upregulated in HS, while miR-27b-3p was downregulated. Knockdown of TUG1 significantly suppressed the proliferation and migration and induced the apoptosis of HS fibroblasts (HSF). In addition, silencing of TUG1 notably inhibited the extracellular matrix (ECM) biosynthesis in HSF. Overexpression of miR-27b-3p has the same effect on HS as that of TUG1 knockdown. Meanwhile, TUG1 could sponge miR-27b-3p, and TAK1 was the direct target of miR-27b-3p. Furthermore, knockdown of TUG1 significantly suppressed the fibrosis in HS via miR-27b-3p/TAK1/YAP/TAZ axis mediation. LncRNA TUG1 promotes the fibrosis in HS via sponging miR-27b-3p and then activates TAK1/YAP/TAZ pathway, which may serve as a potential target for treatment of HS.

Proton pump inhibitor in upper gastrointestinal fecal microbiota transplant: A systematic review and analysis.

BACKGROUND AND AIMS: Fecal microbiota transplantation (FMT) is used in recurrent Clostridioides difficile infections. However, protocols are facility dependent, and one variable is whether pre-procedural proton pump inhibitors (PPIs) are given. In theory, PPIs reduce acidity and protect the transplanted microbiome for the most potent dose. We conducted a systematic review to study the effect of PPIs on FMT delivered by upper gastrointestinal (GI) routes. METHODS: We searched Pubmed/Medline, Cochrane Library, Embase, Scopus, and Web of Science through December 16, 2018 using variations of keywords "fecal microbiota transplant" and "Clostridium difficile infection." Two authors independently reviewed 4210 results and found 11 qualifying studies with data on upper GI FMT, use of PPIs, and the rate of treatment failure at follow-up. RESULTS: Of 233 included patients, treatment failure occurred in 20.6% of those with use of PPIs versus 22.6% in the group without (relative risk 0.91; confidence interval 0.56-1.50). Limitations include the lack of studies directly comparing outcomes based on use of PPIs and inability to control for possible confounders such as chronic PPI use, amount of stool transplanted, and pre-FMT antibiotics. CONCLUSIONS: We did not find evidence supporting a clinically significant benefit from routine use of PPIs in FMT protocol. It is possible that the theoretical benefit from improved survival of transplanted microbiota is offset by negative effects on the microbiome. We suggest that routine use of PPIs in upper GI FMT be reconsidered. Further investigation is needed to optimize protocols for safety and efficacy.

Highly efficient utilization of light and charge separation over a hematite photoanode achieved through a noncontact photonic crystal film for photoelectrochemical water splitting.

The trade-off problem between light absorption and charge collection under lower band-bending (bias) is extremely difficult to resolve in water splitting on photoelectrodes. Although the use of metallic back-reflectors, antireflection coatings, and textured substrates and light absorbers enable the improvement of light utilization efficiency, these methods still suffer from high cost and complex fabrication process, especially, incompetent separation of photogenerated carriers. Here taking the hematite (α-Fe2O3) photoanode as a model, we report that a noncontact photonic crystal (PC) film composed of silica nanoparticles and ethoxylated trimethylolpropane triacrylate (ETPTA) resin can significantly enhance the photoelectrochemical (PEC) activity of the photoelectrode. Specifically, more than 250 mV cathodic shift in the onset potential and 4 times larger photocurrent at 1.0 V versus a reversible hydrogen electrode (RHE) were achieved over the α-Fe2O3-PC photoanode hybrid system, compared with the pristine α-Fe2O3 photoanode. Our work showed that a PC film not only boosted light absorption of the α-Fe2O3 layer but also improved its charge transfer efficiency under light illumination. These new findings of the synergistic effect will open a new avenue to design high-performance solar energy conversion devices.

Wide dynamic range measurement of blood flow in vivo using laser speckle contrast imaging.

Significance: Laser speckle contrast imaging (LSCI) is a real-time wide-field technique that is applied to visualize blood flow in biomedical applications. However, there is currently a lack of relevant research to demonstrate that it can measure velocities over a wide dynamic range (WDR), which is critical for monitoring much higher and more pulsatile blood flow in larger size myocardial vessels, such as the coronary artery bypass graft, and visualizing the spatio-temporal evolution of myocardial blood flow perfusion in cardiac surgery. Aim: We aim to demonstrate that the LSCI technique enables measuring velocities over a WDR from phantom experiments to animal experiments. In addition, LSCI is preliminarily applied to imaging myocardial blood flow distribution in vivo on rabbits. Approach: Phantom and animal experiments are performed to verify that the LSCI method has the ability to measure blood velocities over a wide range. Our method is also validated by transit time flow measurement, which is the gold standard for blood flow measurement in cardiac surgery. Results: Our method is demonstrated to measure the blood flow over a wide range from 0.2 to 635 mm/s. To validate the phantom results, the varying blood flow rate from 0 to 320 mm/s is detected in the rat carotid artery. Additionally, our technique also obtains blood flow maps of different myocardial vessels, such as superficial large/small veins, veins surrounded by fat, and myocardial deeper arteriole. Conclusions: Our study has the potential to visualize the spatio-temporal evolution of myocardial perfusion in coronary artery bypass grafting, which would be of great benefit for future research in the life sciences and clinical medicine.

Early tirofiban versus heparin for bridging dual antiplatelet therapy in patients undergoing coronary endarterectomy combined with coronary artery bypass grafting: a multicenter randomized controlled trial protocol (the THACE-CABG trial).

BACKGROUND: For complete revascularization, patients with diffuse coronary artery disease should have a coronary endarterectomy and a coronary artery bypass graft (CE-CABG). Sadly, CE can lead to a lack of endothelium, which raises the risk of thrombotic events. Even though daily dual antiplatelet therapies (DAPT) have been shown to reduce thrombotic events, the risk of perioperative thrombotic events is high during the high-risk period after CE-CABG, and there is no consistent protocol to bridge DAPT. This trial aims to compare safety and efficacy between tirofiban and heparin as DAPT bridging strategies after CE-CABG. METHODS: In phase I, 266 patients undergoing CE-CABG will be randomly assigned to tirofiban and heparin treatment groups to compare the two treatments in terms of the primary safety endpoint, chest tube drainage in the first 24 h. If the phase I trial shows tirofiban non-inferiority, phase II will commence, in which an additional 464 patients will be randomly assigned. All 730 patients will be studied to compare major cardiovascular and cerebrovascular events (MACCEs) between the groups in the first 30 days after surgery. DISCUSSION: Given the possible benefits of tirofiban administration after CE-CABG, this trial has the potential to advance the field of adult coronary heart surgery. TRIAL REGISTRATION: chictr.org.cn, ChiCTR2200055697. Registered 6 January 2022. https://www.chictr.org.cn/com/25/showproj.aspx?proj=149451 . Current version: 20,220,620.

Trends and hotspots in familial hypercholesterolemia: A bibliometric systematic review from 2002 to 2022.

BACKGROUND: We visually assessed the research hotspots of familial hypercholesterolemia (FH) using bibliometrics and knowledge mapping in light of the research state and development trend of FH. METHODS: We employed bibliometric tools, such as CiteSpace and the alluvial generator, to illustrate the scientific accomplishments on FH by extracting pertinent literature on FH from the Web of Science Core Collection database from January 1, 2002, to December 31, 2022. RESULTS: A total of 4402 papers in total were selected for study; 29.2% of all articles globally were from the USA, followed by the Netherlands and England. The University of Amsterdam, University of Oslo, and University of Western Australia are the 3 institutions with the most publications in this area. Gerald F. Watts, Raul D. Santos, and John J. P. Kastelein wrote the majority of the pieces that were published. The New England Journal of Medicine, Circulation, and Atherosclerosis were the journals with the greatest number of papers in this field. Prevalence and genetic analysis of FH, proprotein convertase subtilisin/kexin 9 inhibitors, and inclisiran are current research hotspots for the condition. Future research in this area will be focused on gene therapy. CONCLUSIONS: FH research has shown shows a trend of ascending followed by leveling off. The prevalence and diagnosis of FH, proprotein convertase subtilisin/kexin 9 inhibitors, inclisiran, and gene therapy are current research hotspots. This report may serve as a reference for current research trends.

Improvement of Bemisia tabaci (Hemiptera: Aleyrodidae) Fitness on Chinese Kale upon Simultaneous Herbivory by Plutella xylostella (Lepidoptera: Plutellidae).

Bemisia tabaci and the diamondback moth (DBM), Plutella xylostella, are two major cosmopolitan pests that often occur together and cause severe economic losses to cruciferous crops. However, little is known about how they interact with each other. To determine the effects of defense responses induced by the two pests on the biology and population dynamics of the herbivores, we studied the performance and fitness of B. tabaci and DBM when they damaged Chinese kale simultaneously and in different orders. The results showed that DBM pre-infestation shortened the developmental duration, increased longevity, oviposition days, and fecundity of B. tabaci. Meanwhile, the intrinsic rate of increase (r), net reproductive rate (R0) and finite rate of increase (λ) of B. tabaci increased significantly with dual infection as compared with only B. tabaci infestation. In contrast, B. tabaci pre-infestation reduced the longevity and oviposition days of DBM, but the population parameters r, R0, and λ did not vary significantly compared with only DBM infestation. Thus, co-infestation of B. tabaci and DBM was beneficial to the performance of the B. tabaci population. The present findings highlight that B. tabaci has become a dominant competitor when mixing with DBM on the same host plant.

A bibliometric analysis on the progress of myocardial bridge from 1980 to 2022.

Introduction: Although the vast majority of patients with a myocardial bridge (MB) are asymptomatic, the anomaly was found to be associated with stable or unstable angina, vasospastic angina, acute coronary syndrome, and even malignant arrhythmias and sudden cardiac death in some cases. Methods: By retrieving the relevant literature on MB from 1 January 1980 to 31 July 2022 from the Web of Science Core Collection (WoSCC) database, we used the bibliometric tools, including CiteSpace, VOS viewer, and alluvial generator, to visualize the scientific achievements on MB. Results: A total of 630 articles were included. The number of published articles was in a fluctuating growth trend. These publications came from 37 contries, led by the USA and China. The leading country on MB was the United States, the leading position among institutions was Stanford University, and the most productive researcher on MB was Jennifer A. Tremmel. After analysis, the most common keywords were myocardial bridge, mortality, coronary angiography, descending coronary artery, and sudden death. Conclusion: Our findings can aid researchers in understanding the current state of MB research and in choosing fresh lines of inquiry for forthcoming investigations. Prevalence and prognosis, mechanism atherosclerosis, hemodynamic significance, and molecular autops will likely become the focus of future research. In addition, more studies and cooperations are still needed worldwide.

Association Between Triglyceride-Glucose Index and 2-Year Adverse Cardiovascular and Cerebrovascular Events in Patients with Type 2 Diabetes Mellitus Who Underwent Off-Pump Coronary Artery Bypass Grafting.

BACKGROUND: Data on the relationship between the triglyceride glucose (TyG) index and prognosis after off-pump coronary artery bypass grafting (OPCABG) are limited. This retrospective observational cohort study evaluated the association of the TyG index with prognosis in patients with diabetes mellitus who underwent OPCABG. METHODS: The TyG index was calculated using the following equation: TyG index = ln (fasting triglyceride level [mg/dL] × fasting glucose level [mg/dL]/2). The primary outcomes included the occurrence of major adverse cardiovascular and cerebrovascular events (MACCEs), which were defined as all-cause death, nonfatal myocardial infarction, nonfatal stroke and symptomatic graft failure. The association between the TyG index and MACCEs was assessed by Cox proportional hazards regression analysis. RESULTS: A total of 1578 patients with diabetes who underwent OPCABG (mean age, 62.9 ± 8.0 years; men, 72.7%) were enrolled in this study. Over the follow-up of 2 years, 176 patients (11.2%) had at least 1 primary endpoint event. The follow-up incidence of the primary endpoint rose with increasing TyG index tertiles. The multivariate Cox proportional hazards regression analysis adjusted for multiple confounders revealed a hazard ratio for the primary endpoint of 2.133 (95% CI 1.347-3.377; P for trend = 0.001) when the highest and lowest TyG index tertiles were compared. CONCLUSION: The TyG index was significantly and positively associated with MACCEs, suggesting that the TyG index may be a valuable predictor of adverse cardiovascular and cerebrovascular outcomes after OPCABG in patients with T2DM.

Mendelian randomization analysis identified causal Association of Childhood Obesity with adult major depressive disorder.

BACKGROUND: Childhood obesity is associated with adult major depressive disorder (MDD), but their causality is not clear. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to explore the causality of childhood body mass index (BMI) and childhood obesity on MDD, followed by a multivariable MR (MVMR) analysis to investigate the potential role of adult BMI in mediating such effect. We accessed genome-wide association summary statistics of childhood BMI, childhood obesity, adult BMI and adult MDD from the Early Growth Genetics consortium (nBMI  = 47 541, nobesity  = 24 160), the Genetic Investigation of Anthropometric Traits consortium (nadult_BMI  = âˆ¼700 000) and the Psychiatric Genomics consortium (nMDD  = 500 199), respectively. The MR-PRESSO test was performed to remove SNPs with potential pleiotropic effect. The MR analysis was performed by inverse-variance weighted test. Further sensitivity analyses, including the MR-Egger intercept test and leave-one-out analysis, were performed to evaluate the reliability of the results. RESULTS: Our study found that childhood obesity might increase the odds of developing MDD in adults (OR = 1.03, 95% CI: 1.01-1.06, p = 2.6 × 10-3 ). Children with higher BMI were more likely to develop MDD in adulthood, with an OR of 1.12 per standard deviation score (SDS) increase in BMI (95% CI: 1.07-1.17, p = 4.4 × 10-7 ). Sensitivity analyses verified the reliability of the causality between childhood BMI/obesity and MDD. Further MVMR results revealed that the impact of childhood BMI on MDD risk was predominantly mediated by adult BMI. CONCLUSION: Our findings provided evidence of a causal relationship between childhood BMI/obesity and adult MDD, thus providing new insights into the prevention of MDD.

A method for reconstruction of vermilion tubercle.

BACKGROUND: This article reports on the bilateral lip mucosa flaps (BLMFs) for reconstruction of the vermilion tubercle of the corrected cleft lip deformity. METHODS: From 2005 to 2013, the bilateral mucosa flaps procedures were performed on 34 secondary cleft lip patients (bilateral, n = 25; unilateral, n = 9). We retrospectively reviewed the pre-, intra-, and postoperative data of these 34 cases receiving BLMFs. RESULTS: Satisfactory results were obtained, both cosmetically and functionally, in all 34 patients. Lateral projection measurements of the reconstructive vermilion tubercle showed a mean increase of 151%. There were minimal perioperative complications. The color and texture matched well with the surrounding tissue. The postoperative scars are not remarkable at all. CONCLUSIONS: The technique is relatively simple. The BLMFs provided a versatile and reliable option for the reconstruction of the vermilion tubercle from secondary cleft lip deformities.

Biomechanical and histological research on in vivo engineered tendon with tendon synovial sheaths in Roman chicken / 医用生物力学

Objective To explore the role of tendon synovial sheaths in tendon regeneration in vivo. Methods Thirty-six Roman chicken were randomly divided into Group A and B, with 18 chicken in each group. In Group A, the synovial sheaths of the deep flexor tendons in the left middle toes were separated from the up, right and down side without cutting off the tendons themselves. The allograft decellularized tendons were coated with synovial sheaths which were detached partly and fixed on the left side of the normal deep flexor tendons in the middle toes of the left foot. In Group B, the allograft decellularized tendons were directly implanted on the left side of the deep flexor tendons without coating of synovial sheaths. The normal deep flexor tendons from the right foot were used as the control group. The maximum loads and elastic modulus of the tendons at 4th, 8th and 12th week were obtained by mechanical testing, and HE staining was conducted to observe histological changes of the tendons. Results The maximum load at 8th and 12th week and elastic modulus at 4th, 8th and 12th week in Groups A were greater than those in Group B, with significant differences (P<0.05). Group A showed more densely deposited matrices and longitudinally aligned collagen fibers than Group B, and inflammatory cells and fibrous tissues could hardly be found in Group A. In Group B, the collagen fibers were decreased gradually, with disordered alignment. Furthermore, more inflammatory cells infiltration and hyperplasia of fibrous tissues were found in Group B. Conclusions The synovial sheaths can contribute to tendon regeneration, indicating that a proper environment in vivo plays an important role in the engineered tendons. This study has a positive effect on finding proper tendon replacements for patients with tendon deficiency.

Derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide as new antibacterial agents: synthesis and bioactivity.

AIM: The aim of the present study was to design, synthesize, and evaluate novel antibacterial agents, derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide. METHODS: A total of 44 derivatives of aryl-4-guanidin-omethylbenzoate (series A) and N-aryl-4-guanidinomethylbenzamide (series B) were synthesized and their antibacterial activities were assessed in vitro against a variety of Gram-positive and Gram-negative bacteria by an agar dilution method. RESULTS: Twelve compounds showed potent bactericidal effects against a panel of Gram-positive germs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate Staphylococcus aureus (VISA), and methicillin-resistant coagulase-negative staphylococci (MRCNS), with minimum inhibitory concentrations (MIC) ranging between 0.5 and 8 microg/mL, which were comparable to the MIC values of several marketed antibiotics. They exhibited weak or no activity on the Gram-negative bacteria tested. In addition, these compounds displayed high inhibitory activities towards oligopeptidase B of bacterial origin. CONCLUSION: In comparison with the previously reported MIC values of several known antibiotics, the derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide showed comparable in vitro bactericidal activities against VRE and VISA as linezolid. Their growth inhibitory effects on MRSA were similar to vancomycin, but were less potent than linezolid and vancomycin against MRCNS. This class of compounds may have the potential to be developed into narrow spectrum antibacterial agents against certain drug-resistant strains of bacteria.