Structure-based discovery of novel piperidine-biphenyl-DAPY derivatives as non-nucleoside reverse transcriptase inhibitors featuring improved potency, safety, and selectivity: From piperazine-biphenyl-DAPYs to piperidine-biphenyl-DAPYs.

Starting from our previously reported nonnucleoside reverse transcriptase inhibitor (NNRTI, 3), continuous efforts were made to enhance its potency and safety through a structure-based drug design strategy. This led to the discovery of a series of novel piperidine-biphenyl-diarylpyrimidines (DAPYs). Compound 10p, the most active compound in this series, exhibited an EC50 value of 6 nM against wide-type HIV-1 strain, which was approximately 560-fold more potent than the initial compound 3 (EC50 = 3.36 µM). Furthermore, significant improvements were observed in cytotoxicity and selectivity (CC50 > 202.17 µM, SI > 33144) compared to compound 3 (CC50 = 14.84 µM, SI = 4). Additionally, compound 10p demonstrated increased inhibitory activity against clinically mutant virus strains (EC50 = 7-63 nM). Further toxicity evaluation revealed that compound 10p exhibited minimal CYP enzyme and hERG inhibition. Importantly, single-dose acute toxicity testing did not result in any fatalities or noticeable pathological damage in mice. Therefore, compound 10p can be regarded as a lead candidate for guiding further development of biphenyl-diarylpyrimidine NNRTIs with favorable druggability for HIV therapy.

Affecting Factors of Choroidal Circulation Parameters in 4-14-Year-Old Chinese Children Measured by SS-OCT/OCTA.

PURPOSE: To measure the choroidal circulatory parameters Han Chinese children aged 4-14 years from Southwest China, and to explore the relationships between these parameters and age, axial length (AL), and choroidal thickness (ChT). METHODS: 284 eyes from 142 subjects were included in this cross-sectional study. All participants underwent cycloplegic refraction and IOLMaster500 examination. Swept-source optical coherence tomography (SS-OCT) was used to measure submacular choroidal thickness, choroidal vascular volume (CVV), choroidal stromal volume (CSV), choroidal vascularity index (CVI), and CVV/CSV ratio. RESULTS: In this population, the mean CVV was 2.92 ± 0.55 mm3, CSV was 4.69 ± 0.68 mm3, CVI was 38.22 ± 2.46 %, and CVV/CSV ratio was 62.11 ± 6.44 %. Multivariable regression analyses showed that both CVV and CSV were negatively correlated with AL (both P < 0.001) and positively correlated with ChT (both P < 0.001), while age showed no significant correlation with them (both P > 0.05). However, the correlations between CVI and age were not uniform rectilinear. Among participants aged ≤8 years, CVI showed no correlation with age (P > 0.05), while among those aged >8 years, it was positively correlated with age (P < 0.01). CVV/CSV ratio was positively correlated with ChT and age (both P < 0.01). CONCLUSION: After the age of 8, age was positively correlated with CVI. ChT was well correlated with CVI. Longer AL and thinner ChT were associated with reduced CVV and CSV, with CVV decreasing more rapidly than CSV.

Application of whole exome sequencing in carrier screening for high-risk families without probands.

Purpose: This study aimed to screen the genetic etiology for the high-risk families including those with an adverse pregnancy history, a history of consanguineous marriages, or a history of genetic diseases, but lack of proband via whole exome sequencing (WES). Methods: 128 individuals from high-risk family were tested by WES. The candidate variants were analyzed according to the ACMG criteria to screen the potential carriers. At-risk couples (ARCs) who harbored the same causative gene were provided with precise fertility guidance to avoid the birth of children with birth defects. Results: The total detection rate was 36.72%, with pathogenic/likely pathogenic (P/LP) variants found in 47 individuals, and variants of uncertain significance (VUS) were found in 34. Among couples with adverse pregnancy history: P/LP variants were found in 38 individuals, and VUS were found in 26, for a detection rate of 34.55%; among members of family history of genetic disease or consanguineous marriages: P/LP variants were found in nine individuals, and VUS were found in 8, for a detection rate of 50.00%. Otherwise, we detected 19 ARCs who both carried P/LP variants in the same gene, with a theoretical offspring prevalence of up to 7.42%. Conclusion: In the absence of probands, carrier screening using WES can provide an efficient tool for screening the molecular etiology of high-risk families.

[Improvement of the mastication function of orthodontics combined with restoration in the treatment of deep overbite with severe lower anterior teeth attrition].

PURPOSE: To observe the effect of orthodontics combined with restoration on masticatory function in deep overbite patients with severe lower anterior teeth attrition. METHODS: From January 2018 to January 2022, a total of 164 deep overbite patients with severe lower anterior teeth attrition were collected and divided into two groups according to different treatment plans: control group(72 patients, with restoration treatment) and experimental group(92 patients, with orthodontics combined with restoration treatment). The chewing efficiency of the two groups was evaluated, temporomandibular joint dysfunction index (DI), muscle palpation index (PI) and cranio-mandibular index (CMI) were calculated. The satisfaction with facial esthetic, the Chinese version of Oral Health Impact Scale-14(OHIP-14) and the repair satisfaction score were evaluated, the occurrence of adverse events between the two groups was compared. SPSS 23.0 software package was used for statistical analysis. RESULTS: After treatment, the chewing efficiency of the experimental group was significantly improved compared to the control group, while the DI, PI, and CMI were significantly reduced compared to the control group(P＜0.05). Compared with the control group, the satisfaction degree with facial esthetic and restoration in the experimental group was significantly higher, while the OHIP-14 score was significantly lower after treatment(P＜0.05). The incidence of adverse events in the experimental group was significantly decreased compared with the control group (6.52% vs 25.00%, P＜0.05). CONCLUSIONS: Combination of orthodontics and restoration treatment can enhance the effectiveness of restoration treatment for deep overbite with severe lower anterior teeth attrition, improve the mastication function and temporomandibular joint balance,satisfaction and quality of life of patients, as well as reduce the risk of adverse events.

Artesunate inhibits vasculogenic mimicry in choroidal melanoma through HIF-1 α/ VEGF/PDGF pathway.

Choroidal melanoma (CM), a highly metastatic eye tumor, exhibits vasculogenic mimicry (VM) facilitated by hypoxia-induced angiogenesis. This study explored the inhibitory impact of the anti-malarial drug Artesunate (ART) on CM VM through modulation of the HIF-1α/VEGF/PDGF pathway. Immunohistochemistry (IHC) confirmed VM in CM with elevated VEGF and PDGF expression. Hypoxia promoted CM proliferation, upregulating HIF-1α, VEGF and PDGF. VEGF and PDGF enhanced CM migration, invasion and VM, with HIF-1α playing a crucial role. ART mitigated VM formation by suppressing the HIF-1α/VEGF/PDGF pathway, highlighting its potential as an anti-tumor agent in CM.

Association of urinary metal element with semen quality: a cross-sectional study from Eastern China.

The effect of metallic elements on semen quality remains controversial, with limited evidence on the effects of metal mixtures. We conducted a study involving 338 participants from multiple centers in Eastern China, measuring 17 urinary metals and semen quality parameters. Our analysis used various statistical models, including multivariate logistic and linear regression, Bayesian Kernel Machine Regression, and weighted quantile sum models, to examine the associations between metal levels and semen quality. Logistic regression showed that higher urinary lead was associated with increased risk of abnormal sperm concentration (OR = 1.86, p = 0.021), arsenic to higher abnormal progressive motility risk (OR = 1.49, p = 0.027), and antimony to greater abnormal total motility risk (OR = 1.37, p = 0.018). Conversely, tin was negatively correlated with the risk of abnormal progressive motility (OR = 0.76, p = 0.012) and total motility (OR = 0.74, p = 0.003), respectively. Moreover, the linear models showed an inverse association between barium and sperm count, even after adjusting for other metals (ß = - 0.32, p < 0.001). Additionally, the WQS models showed that the metal mixture may increase the risk of abnormal total motility (ßWQS = 0.55, p = 0.046). In conclusion, semen quality may be adversely affected by exposure to metals such as arsenic, barium, lead, and antimony. The combined effect of the metal mixture appears to be particularly impaired total motility.

Pulsatilla decoction alleviates DSS-induced UC by activating FXR-ASBT pathways to ameliorate disordered bile acids homeostasis.

Ethnopharmacological relevance: Pulsatilla decoction (PD) is a classical prescription for the treatment of ulcerative colitis. Previous studies have demonstrated that the therapeutic efficacy of PD is closely associated with the activation of Farnesoid X receptor (FXR). The activity of FXR is regulated by apical sodium-dependent bile acid transporter (ASBT), and the FXR-ASBT cascade reaction, centered around bile acid receptor FXR, plays a pivotal role in maintaining bile acid metabolic homeostasis to prevent the occurrence and progression of ulcerative colitis (UC). Aim of the study: To elucidate the underlying mechanism by which PD exerts its proteactive effects against Dextran Sulfate Sodium Salt (DSS)-induced ulcerative colitis, focusing on the modulation of FXR and ASBT. Materials and methods: To establish a model of acute ulcerative colitis, BALB/C mice were administered 3.5% DSS in their drinking water for consecutive 7 days. The disease activity index (DAI) was employed to evaluate the clinical symptoms exhibited by each group of mice. Goblet cell expression in colon tissue was assessed using glycogen schiff periodic acid-Schiff (PAS) and alcian blue staining techniques. Inflammatory cytokine expression in serum and colonic tissues was examined through enzyme-linked immunosorbent assay (ELISA). A PCR Array chip was utilized to screen 88 differential genes associated with the FXR-ASBT pathway in UC treatment with PD. Western blotting (WB) analysis was performed to detect protein expression levels of differentially expressed genes in mouse colon tissue. Results: The PD treatment effectively reduced the Disease Activity Index (DAI) score and mitigated colon histopathological damage, while also restoring weight and colon length. Furthermore, it significantly alleviated the severity of ulcerative colitis (UC), regulated inflammation, modulated goblet cell numbers, and restored bile acid balance. Additionally, a PCR Array analysis identified 21 differentially expressed genes involved in the FXR-ASBT pathway. Western blot results demonstrated significant restoration of FXR, GPBAR1, CYP7A1, and FGF15 protein expression levels following PD treatment; moreover, there was an observed tendency towards increased expression levels of ABCB11 and RXRα. Conclusion: The therapeutic efficacy of PD in UC mice is notable, potentially attributed to its modulation of bile acid homeostasis, enhancement of gut barrier function, and attenuation of intestinal inflammation.

[Effect of Photoaging on Adsorption of Cu(â ¡) by Polystyrene Microplastics with Different Particle Sizes].

In order to evaluate the effect of aging and particle size on the adsorption of heavy metals by microplastics, the adsorption behavior of Cu(Ⅱ) by three different particle sizes of polystyrene (PS; 1, 50, and 100 µm) under UV irradiation was systematically studied. The results demonstrated that UV aging significantly changed the surface morphology and physicochemical properties of PS, and 1 µm PS had the strongest aging degree. The adsorption kinetics of PS on Cu(Ⅱ) conformed to the pseudo-second-order kinetic model, and the Freundlich model was more suitable for the experimental data of isothermal adsorption of Cu(Ⅱ) by PS. These results indicated that the adsorption of Cu(Ⅱ) by PS occurred on the non-uniform surface of PS, and the adsorption behavior was multilayer adsorption. Parameter "n" of the Freundlich model was less than 1, indicating that the adsorption behavior of PS on Cu(Ⅱ) was a higher intensity physical adsorption behavior. The order of theoretical maximum adsorption capacity of different particle sizes PS for Cu(Ⅱ) was as follows:1 µm > 50 µm > 100 µm, indicating that the size of PS was an important influence factor for the adsorption capacity of PS to pollutants. For the same particle size PS, aging enhanced its adsorption capacity for Cu(Ⅱ). The results on the adsorption of Cu(Ⅱ) by PS under different environmental conditions indicated that the adsorption capacity of PS for Cu (II) increased with the increase in pH, whereas an increase in salinity had the opposite effect. Surface complexation and electrical adsorption were the main mechanisms of adsorption of Cu(Ⅱ) by PS. This study provides an important scientific basis for understanding the adsorption behavior of microplastics to heavy metals in the environment.

Impact of imidacloprid exposure on gestational hyperglycemia: A multi-omics analysis.

Imidacloprid (IMI), a commonly utilized neonicotinoid insecticide, has been identified to adversely impact glucose homeostasis. Pregnant women are believed to be more sensitive to toxins than non-pregnant women, and the impact of IMI exposure on gestational hyperglycemia remain unclear. To explore the impact, pregnant mice fed a high-fat diet were exposed to different doses (0.06, 0.6, 6 mg/kg bw/day) of IMI by gavage. Glucose homeostasis-related parameters were measured. The glucose homeostasis influenced by IMI treatment was explored through integrating gut microbiota, metabolomic and transcriptomic analysis. Results showed that IMI-H (6 mg/kg bw/day) exposure notably restricted gestational weight gain and perturbed glucose homeostasis characterized by reduced glucose tolerance and insulin sensitivity, alongside elevated levels of fasting blood glucose and insulin. Multi-omics analysis revealed that IMI-H exposure induced significant changes in the richness and composition of the gut microbiome. The metabolite profiles of serum samples and cecal contents, and transcriptome of liver and ileum were all affected by IMI-H treatment. The altered gut microbiota, metabolites and genes exhibited significant correlations with glucose homeostasis-related parameters. These differential metabolites and genes were implicated in various metabolic pathways including bile secretion, glucagon signaling pathway, lipid metabolism, fatty acid metabolism. Significant correlations were observed between the altered gut microbiota and caecum metabolome as well as liver transcriptome. For example, the abundance of Oscillibacter was strongly correlated with gut microflora-related metabolites (Icosenoic acid, Lysosulfatide, and fluticasone) and liver differential genes (Grin3b, Lifr, and Spta1). Together, IMI exposure resulted in significant changes in microbial composition, along with alterations in certain metabolites and genes associated with metabolic process, which may promote gestational hyperglycemia.

New Clerodane Diterpenoids from Tinospora capillipes with Antibacterial and Anti-Inflammatory Properties.

Four new clerodane diterpenoids, namely tinocapills A-D (1-4), and one known analogue (5) were isolated from the roots of Tinospora capillipes in the present study. The structures of these new compounds, including their absolute configurations, were determined through a combination of detailed spectroscopic analysis and theoretical statistical approaches, including electronic circular dichroism (ECD) analyses and quantum mechanical (QM)-NMR methods. Additionally, the stereostructure of 5 was confirmed via X-ray diffraction analysis. Furthermore, all these isolates were evaluated for their antibacterial and anti-inflammatory activities. Compounds 1, 2 and 5 demonstrated antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) with MICs ranging from 4 to 64 µg/mL, and compounds 3 and 4 exhibited potential anti-inflammatory effects by suppressing LPS-induced TNF-α and NO releases in RAW264.7 cells.

Incidence and clinical analysis of asymptomatic intracranial hemorrhage in neonates with cerebral hypoxic-ischaemic risk based on multisequence MR images.

The incidence and clinical distribution of intracranial haemorrhage (ICH) in neonates at risk of cerebral hypoxia-ischaemia have not been reported in specific studies. Based on conventional magnetic resonance imaging (MRI) versus susceptibility weighted imaging (SWI), this study aimed to analyse the occurrence of asymptomatic ICH in newborns with or without risk of cerebral hypoxia-ischaemia and to accumulate objective data for clinical evaluations of high-risk neonates and corresponding response strategies. 317 newborns were included. MRI revealed that the overall incidence of ICH was 59.31%. The most common subtype was intracranial extracerebral haemorrhage (ICECH) which included subarachnoid haemorrhage (SAH) and subdural haemorrhage (SDH). ICECH accounted for 92.02% of ICH. The positive detection rate of ICECH by SWI was significantly higher than that by T1WI. The incidence of total ICH, ICECH and SAH was greater among children who were delivered vaginally than among those who underwent caesarean delivery. Asymptomatic neonatal ICH may be a common complication of the neonatal birth process, and SWI may improve the detection rate. Transvaginal delivery and a weight greater than 2500 g were associated with a high incidence of ICECH in neonates. The impact of neonatal cerebral hypoxia-ischaemia risk factors on the occurrence of asymptomatic ICH may be negligible.

Evaluation of Neonatal Cerebral Circulation Under Hypoxic Ischemic Risk Factors Based on Quantitative Analysis of Cerebral Veins with Magnetic Resonance Susceptibility Weighted Imaging.

PURPOSE: To observe the regulation of cerebral circulation in vivo based on image segmentation algorithms for deep learning in medical imaging to automatically detect and quantify the neonatal deep medullary veins (DMVs) on susceptibility weighted imaging (SWI) images. To evaluate early cerebral circulation self-rescue for neonates undergoing risk of cerebral hypoxia-ischaemia in vivo. METHODS: SWI images and clinical data of 317 neonates with or without risk of cerebral hypoxia-ischaemia were analyzed. Quantitative parameters showing the number, width, and curvature of DMVs were obtained using an image segmentation algorithm. RESULTS: The number of DMVs was greater in males than in females (p < 0.01), and in term than in preterm infants (p = 0.001). The width of DMVs was greater in term than in preterm infants (p < 0.01), in low-risk than in high-risk group (p < 0.01), and in neonates without intracranial extracerebral haemorrhage (ICECH) than with ICECH (p < 0.05). The curvature of DMVs was greater in term than in preterm infants (P < 0.05). The width of both bilateral thalamic veins and anterior caudate nucleus veins were positively correlated with the number of DMVs; the width of bilateral thalamic veins was positively correlated with the width of DMVs. CONCLUSION: The DMVs quantification based on image segmentation algorithm may provide more detailed and stable quantitative information in neonate. SWI vein quantification may be an observable indicator for in vivo assessment of cerebral circulation self-regulation in neonatal hypoxic-ischemic brain injury.

Advancements in Ultrasound Techniques for Evaluating Intracranial Pressure Through Optic Nerve Sheath Diameter Measurement.

Elevated intracranial pressure (ICP) in patients with cerebral lesions has garnered considerable attention in research. It often manifests as a common symptom in conditions such as intracranial tumors, intracerebral hemorrhage, and cerebral edema. This paper provides an overview of ICP concepts, discusses the advantages and disadvantages of traditional monitoring methods, explores the physiological and anatomical aspects of the optic nerve sheath, examines the utility of ultrasound measurement of optic nerve sheath diameter (ONSD) in both nervous system and nonnervous system disorders, and outlines the cutoff values and normal ranges for assessing elevated ICP using ultrasound measurement of ONSD. The review underscores ultrasound measurement of ONSD as a promising noninvasive, safe, straightforward, and repeatable examination technique for various diseases. Nevertheless, the lack of standardized cutoff values for elevated ICP remains a challenge. Summarizing studies on optic nerve sheaths is crucial for enhancing the efficacy of ultrasound measurement of ONSD in assessing ICP.

High-performance electrode materials of heteroatom-doped lignin-based carbon materials for supercapacitor applications.

Supercapacitors are the preferred option for supporting renewable energy sources owing to many benefits, including fast charging, long life, high energy and power density, and saving energy. While electrode materials with environmentally friendly preparation, high performance, and low cost are important research directions of supercapacitors. At present, the growing global population and the increasingly pressing issue of environmental pollution have drawn the focus of numerous researchers worldwide to the development and utilization of renewable biomass resources. Lignin, a renewable aromatic polymer, has reserves second only to cellulose in nature. Ten million tonnes of industrial lignin are produced in pulp and paper mills annually, most of which are disposed of as waste or burned for fuel, seriously depleting natural resources and polluting the environment. One practical strategy to accomplish sustainable development is to employ lignin resources to create high-value materials. Based on the high carbon content and rich functional groups of lignin, the lignin-based carbon materials generated after carbonization treatment display specific electrochemical properties as electrode materials. Nevertheless, low electrochemical activity of untreated lignin precludes it from achieving its full potential for application in energy storage. Heteroatom doping is a common modification method that aims to improve the electrochemical performance of the electrode materials by optimizing the structure of the lignin, improving its pore structure and increasing the number of active sites on its surface. This paper aims to establish theoretical foundations for design, preparation, and optimizing the performance of heteroatom-doped lignin-based carbon materials, as well as for developing high-value-added lignin materials. The most reported the mechanism of supercapacitors, the doping process involving various types of heteroatoms, and the analysis of how heteroatoms affect the performance of lignin-based carbon materials are also detailed in this review.

Pd(II)/N,N'-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Synthesis of Cyclic Quaternary Centers and Mechanistic Investigations.

A Pd(II)/N,N'-disulfonyl bisimidazoline-catalyzed asymmetric 1,4-conjugate addition reaction of low-cost arylboronic acids with readily available ß-substituted cyclic enones is described, providing a straightforward way of constructing cyclic all-carbon quaternary stereocenters with high enantioselectivity, in which ≥96% ee was obtained in most cases. The reaction proceeded without the protection of inert gas, making the operation process simple. Theoretical calculations have been applied to understand the origins of enantioselectivity.

ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis.

Suppression of neuroinflammation using small molecule compounds targeting the key pathways in microglial inflammation has attracted great interest. Recently, increasing attention has been gained to the role of the second bromodomain (BD2) of the bromodomain and extra-terminal (BET) proteins, while its effect and molecular mechanism on microglial inflammation has not yet been explored. In this study, we evaluated the therapeutic effects of ABBV-744, a BD2 high selective BET inhibitor, on lipopolysaccharide (LPS)-induced microglial inflammation in vitro and in vivo, and explored the key pathways by which ABBV-744 regulated microglia-mediated neuroinflammation. We found that pretreatment of ABBV-744 concentration-dependently inhibited the expression of LPS-induced inflammatory mediators/enzymes including NO, TNF-α, IL-1ß, IL-6, iNOS, and COX-2 in BV-2 microglial cells. These effects were validated in LPS-treated primary microglial cells. Furthermore, we observed that administration of ABBV-744 significantly alleviated LPS-induced activation of microglia and transcriptional levels of pro-inflammatory factors TNF-α and IL-1ß in mouse hippocampus and cortex. RNA-Sequencing (RNA-seq) analysis revealed that ABBV-744 induced 508 differentially expressed genes (DEGs) in LPS-stimulated BV-2 cells, and gene enrichment and gene expression network analysis verified its regulation on activated microglial genes and inflammatory pathways. We demonstrated that pretreatment of ABBV-744 significantly reduced the expression levels of basic leucine zipper ATF-like transcription factor 2 (BATF2) and interferon regulatory factor 4 (IRF4), and suppressed JAK-STAT signaling pathway in LPS-stimulated BV-2 cells and mice, suggesting that the anti-neuroinflammatory effect of ABBV-744 might be associated with regulation of BATF2-IRF4-STAT1/3/5 pathway, which was confirmed by gene knockdown experiments. This study demonstrates the effect of a BD2 high selective BET inhibitor, ABBV-744, against microglial inflammation, and reveals a BATF2-IRF4-STAT1/3/5 pathway in regulation of microglial inflammation, which might provide new clues for discovery of effective therapeutic strategy against neuroinflammation.

Squamous cell carcinoma of ear and temporal bone: A retrospective study on clinicopathological predictors.

BACKGROUND: Ear and temporal bone squamous cell carcinoma (ETBSCC) is a rare and aggressive malignant tumor with minimal clinicopathological studies. The object of this study was to retrospectively evaluate the predictive effect of clinicopathological variables on the 5-year overall survival (OS) rate of ETBSCC patients in a single tertiary medical center in Tianjin, China. METHODS: A cohort of 44 patients with diagnosed ETBSCC from December 2012 to August 2022 were retrospectively studied. Univariate and multivariate analysis were, respectively, performed for the assessment of clinicopathological predictors, including sex, age, history of chronic suppurative otitis media (CSOM), lesion side, diameter, the choice of surgical approach, parotidectomy, neck dissection, adjuvant therapies, T stage, lymph node metastasis, tumor grade, margin, perineural invasion (PNI), and Ki-67 index. RESULTS: Seventeen females and 27 males were included, with the mean age of 65 years old, ranging from 36 to 89 years. The 5-year OS rate was 43% (mean 51 months, 95% confidence interval [CI] = 39-64). Significant prediction of a worse prognosis for 5-year OS rate was observed under univariate analysis for advanced T stage, positive margin, identified PNI, and higher Ki-67 index, respectively. Advanced T stage was confirmed to be an independent prognostic factor strongly affecting 5-year OS rate among this cohort of patients using a multivariate cox proportional hazard model. CONCLUSION: We found that clinicopathological parameters, especially postoperative pathological parameters, play a critical role in predicting the prognosis of ETBSCC patients.

Susceptibility gene identification and risk evaluation model construction by transcriptome-wide association analysis for salt sensitivity of blood pressure.

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is an intermediate phenotype of hypertension and is a predictor of long-term cardiovascular events and death. However, the genetic structures of SSBP are uncertain, and it is difficult to precisely diagnose SSBP in population. So, we aimed to identify genes related to susceptibility to the SSBP, construct a risk evaluation model, and explore the potential functions of these genes. METHODS AND RESULTS: A genome-wide association study of the systemic epidemiology of salt sensitivity (EpiSS) cohort was performed to obtain summary statistics for SSBP. Then, we conducted a transcriptome-wide association study (TWAS) of 12 tissues using FUSION software to predict the genes associated with SSBP and verified the genes with an mRNA microarray. The potential roles of the genes were explored. Risk evaluation models of SSBP were constructed based on the serial P value thresholds of polygenetic risk scores (PRSs), polygenic transcriptome risk scores (PTRSs) and their combinations of the identified genes and genetic variants from the TWAS. The TWAS revealed that 2605 genes were significantly associated with SSBP. Among these genes, 69 were differentially expressed according to the microarray analysis. The functional analysis showed that the genes identified in the TWAS were enriched in metabolic process pathways. The PRSs were correlated with PTRSs in the heart atrial appendage, adrenal gland, EBV-transformed lymphocytes, pituitary, artery coronary, artery tibial and whole blood. Multiple logistic regression models revealed that a PRS of P < 0.05 had the best predictive ability compared with other PRSs and PTRSs. The combinations of PRSs and PTRSs did not significantly increase the prediction accuracy of SSBP in the training and validation datasets. CONCLUSIONS: Several known and novel susceptibility genes for SSBP were identified via multitissue TWAS analysis. The risk evaluation model constructed with the PRS of susceptibility genes showed better diagnostic performance than the transcript levels, which could be applied to screen for SSBP high-risk individuals.