Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.

PURPOSE: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML). METHODS: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups. CONCLUSION: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

Application of"Spinal cord fusion" in spinal cord injury repair and its neurological mechanism.

Spinal cord injury (SCI) is a severely disabling and catastrophic condition that poses significant global clinical challenges. The difficulty of SCI repair results from the distinctive pathophysiological mechanisms, which are characterised by limited regenerative capacity and inadequate neuroplasticity of the spinal cord. Additionally, the formation of cystic cavities and astrocytic scars after SCI further obstructs both the ascending and descending neural conduction pathways. Consequently, the urgent challenge in post-SCI recovery lies in repairing the damaged spinal cord to reconstruct a functional and intact neural conduction circuit. In recent years, significant advancements in biological tissue engineering technology and novel therapies have resulted in a transformative shift in the field of SCI repair. Currently, SCI treatment primarily involves drug therapy, stem cell therapy, the use of biological materials, growth factors, and other approaches. This paper comprehensively reviews the progress in SCI research over the years, with a particular focus on the concept of "Spinal Cord Fusion" as a promising technique for SCI reconstruction. By discussing this important research progress and the neurological mechanisms involved, our aim is to help solve the problem of SCI repair as soon as possible and to bring new breakthroughs in the treatment of paraplegia after SCI.

Wireless Gold/Boron-Nitrogen-Codoped Graphene-Based Antenna Immunosensor for the Rapid Detection of Neuron-Specific Enolase.

Tumor-marker immunosensors for rapid on-site detection have not yet been developed because of immunoreaction bottlenecks, such as shortening the reaction time and facilitating incubation. In this study, a gold-boron-nitrogen-codoped graphene (Au-BNG)-based immunosensor antenna was constructed for the rapid detection of neuron-specific enolase (NSE). A Au-BNG radiation electrode with dual functions of antibody protein fixation and signal transmission was developed for the first time. A radiation sample cell was constructed by embedding a radiation electrode into the groove of a poly(dimethylsiloxane) dielectric substrate. The constructed sense antenna achieves accurate detection of NSE with a range from 50 fg mL-1 to 40,000 pg mL-1 and a limit of detection of 10.99 fg mL-1, demonstrating excellent selectivity, stability, and reliability. The tumor-marker detection meter can provide NSE detection results as rapidly as within 2 min by using the new strategy of the microwave self-incubation of tumor markers. This antenna immunosensor is suitable for rapid detection in outpatient clinics and can be developed into household tumor-marker detectors, which would be significant in the early detection, long-term monitoring, and efficacy evaluation of tumors.

Iodine enrichment in the groundwater in South China and its hydrogeochemical control.

In North China, iodine-rich groundwater has been extensively studied, but few in South China. This study aimed to investigate the characteristics of iodine-rich groundwater in South China and identify potential contamination sources. The results revealed that the average concentration of iodine in groundwater was 890 µg/L, with a maximum concentration of 6350 µg/L, exceeding the permitted levels recommended by the World Health Organization (5-300 µg/L). Notably, the enrichment of iodide occurred in acidic conditions (pH = 6.6) and a relatively low Eh environment (Eh = 198.4 mV). Pearson correlation and cluster analyses suggested that the enrichment of iodide could be attributed to the intensified redox process involving Mn(II), iodine (I2), or iodate (IO3-) in the soil. The strong affinity between Mn(II) and I2/IO3- facilitated their interaction, resulting in the formation and mobilization of I- from the soil to the groundwater. Leaching experiments further confirmed that reducing substances (such as sodium sulfides, ascorbic acids, and fulvic acids) in the soil with low dissolved oxygen (DO) levels (< 1.0 mg/L) enhanced the dissolution of iodine species. Conversely, higher DO content (> 3.8 mg/L) promoted the oxidation of I- into I2 or IO3-, leading to its stabilization. This research provides new insights into the characteristics and mechanisms of I- enrichment in groundwater in South China, and emphasizes the significance of the redox reactions involving Mn(II) and I2/IO3-, as well as the influence of soil properties in regulating the occurrence and transportation of iodine species within groundwater systems.

Pulmonary thromboembolism associated with hereditary antithrombin III deficiency: A case report.

BACKGROUND: Thrombophilia is a coagulation disorder closely associated with venous thromboembolism. Hereditary antithrombin III (AT III) deficiency is a type of genetic thrombophilia. In China, genetic thrombophilia patients mainly suffer from deficiencies in AT III, protein S, and protein C. Multiple mutations in the serpin family C member 1 (SERPINC1) can affect AT III activity, resulting in thrombosis. CASE PRESENTATION: This case presented a 17-year-old adolescent female who developed lower extremity venous thrombosis and subsequently pulmonary embolism (PE) following a right leg injury. A missense mutation in gene SERPINC1 of c.331 T > C, p.S111P was detected on the patient, resulting in a decreased AT III activity and an elevated risk of thrombosis. The patient received anticoagulation treatment for approximately 5 months. During follow-up, the blood clot gradually dissolved, and there have been no recurrent thrombotic events reported thus far. DISCUSSION: Hereditary AT deficiency can be classified into two types based on the plasma levels of the enzymatic activity and antigen. Type I is a quantitative defect, while Type II is a qualitive defect. Until 2021, 486 SERPINC1 gene mutations have been registered, more than 18% of which are point mutations. The SERPINC1 mutation c.331 T > C in was firstly reported in 2017, which was classified into type I AT III deficiency. CONCLUSION: Hereditary thrombophilia is a coagulation disorder with a high omission diagnostic rate. Minor mutations in the SERPINC1 gene can also lead to hereditary AT III deficiency, which in turn can cause PE. We emphasized the importance of etiological screening for hereditary thrombophilia in venous thromboembolism patients without obvious high-risk factors. Long-term anticoagulation treatment and avoidance of potential thrombosis risk factors are critical for such patients.

Electron Donor-Acceptor Complex Driven Photocatalyst-Free Trifluoromethylation of Heterocycles.

Heterocyclic trifluoromethylation is efficiently initiated through a photochemical reaction utilizing an electron donor-acceptor (EDA) complex, proceeding smoothly without the use of photocatalysts, transition-metal catalysts, or additional oxidants. This method has been optimized through extensive experimentation, demonstrating its versatility and efficacy across various substrates, including quinoxalinones, coumarins, and indolones. Notably, this approach enables the practical synthesis of trifluoromethylated quinoxalinones on a gram scale. Mechanistic investigations that incorporate radical trapping and ultraviolet/visible spectroscopy, confirmed the formation of the an EDA complex and elucidated the reaction pathways. This study highlights the crucial role of EDA photoactivation in trifluoromethylation, significantly expanding the application scope of EDA complexes in chemical synthesis.

Effects of Different Volumes of Ropivacaine for Pericapsular Nerve Group Block on Incidence of Quadriceps Weakness and Analgesic Efficacy Following Hip Arthroplasty: A Randomized Controlled Trial.

INTRODUCTION: The pericapsular nerve group (PENG) block has been shown to be an effective approach to alleviating pain and reducing the need for opioids among older adults following hip surgery, with possible motor-sparing effects. No reports to date, however, have described appropriate ropivacaine volumes for use in the context of PENG block. The present prospective randomized controlled study was thus developed to assess the quadriceps muscle strength and analgesic efficacy associated with PENG block performed using three different volumes of 0.33% ropivacaine following general anesthesia in older adults undergoing hip arthroplasty. METHODS: In this prospective randomized double-blind controlled clinical study, 60 patients were assigned at random to undergo ultrasound-guided PENG block for hip arthroplasty using different volumes of ropivacaine. Specifically, these patients were administered 10 ml (Group A, n = 20), 20 ml (Group B, n = 20), or 30 ml (Group C, n = 20) of 0.33% ropivacaine. Quadriceps muscle strength was evaluated at 6 h post-surgery. Visual analog scale (VAS) scores at rest and with movement were assessed at 4, 6, 12, and 24 h post-surgery. Block duration, adverse event incidence, and patient satisfaction were evaluated at 24 h post-surgery. RESULTS: Quadriceps motor block incidence rates at 6 h post-surgery in the 10 ml, 20 ml, and 30 ml groups were 5%, 20%, and 75%, respectively. Quadriceps muscle weakness at 6 h post-surgery was significantly more common in the 30 ml group relative to the others (p < 0.001). Patients administered 10 ml 0.33% ropivacaine exhibited significantly higher VAS pain scores at rest and with movement relative to those patients in the 20 ml and 30 ml treatment groups at all time points (p < 0.05). No apparent differences in analgesic efficacy were observed when comparing the 20 ml and 30 ml groups at 4, 6, 12, and 24 h post-surgery. No significant differences in block duration, satisfaction, or adverse event incidence were observed among groups. CONCLUSIONS: The preservation of motor function in the 20 ml 0.33% ropivacaine group was superior to that in the 30 ml 0.33% ropivacaine group. Relative to the group that received 10 ml 0.33% ropivacaine during PENG block, those elderly patients administered 20 ml and 30 ml volumes of 0.33% ropivacaine experienced superior postoperative pain relief following hip arthroplasty.

Design, Synthesis, Antifungal Activity, and 3D-QASR of Novel Oxime Ether-Containing Coumarin Derivatives as Potential Fungicides.

Structural modification of natural products is an effective approach for improving antifungal activity and has, therefore, been used extensively in the development of new agrochemical products. In this work, a series of novel coumarin derivatives containing oxime ether structures were designed, synthesized, and evaluated for antifungal activity. Some of the designed compounds exhibited promising antifungal activities against tested fungi, and compounds 4a, 4c, 5a, and 6b had EC50 values equivalent to those of commercial fungicides. Compound 6b was the most promising candidate fungicide against Rhizoctonia solani (EC50 = 0.46 µg/mL). In vivo antifungal bioassays suggested that compounds 5a and 6b could serve as novel agricultural antifungals. Furthermore, microscopy demonstrated that compound 6b induced the sprawling growth of hyphae, distorted the outline of cell walls, and reduced mitochondrial numbers. Additionally, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields were elucidated using an accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The results presented here will guide the discovery of potential novel fungicides for plant disease control in agriculture.

Novel 5-Sulfonyl-1,3,4-thiadiazole-Substituted Flavonoids as Potential Bactericides and Fungicides: Design, Synthesis, Three-Dimensional Quantitative Structure-Activity Relationship Studies.

Flavonoids, ubiquitous natural products, provide sources for drug discovery owing to their structural diversity, broad-spectrum pharmacological activity, and excellent environmental compatibility. To develop antibacterial and antifungal agents with novel mechanisms of action and innovative structures, a series of novel 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoids were designed and synthesized, and their biological activities against seven agriculturally common phytopathogenic microorganisms were evaluated. The results of the antimicrobial bioassay showed that most of the target compounds displayed excellent inhibitory effects against Xanthomonas oryzae, Rhizoctonia solani, and Colletotrichum orbiculare. Compounds 1, 3, 7, 9, 13, and 14 exhibited remarkable antibacterial activity against X. oryzae pv. oryzae with EC50 values below 10 µg/mL, which were superior to bismerthiazol (70.89 µg/mL). Compound 2 (EC50 = 0.41 µg/mL) displayed the most effective inhibitory potency against R. solani in vivo, comparable protective effects with the positive control carbendizam. Preliminary mechanistic studies indicated that compound 2 induced disordered entanglement of hyphae, shrinkage of hyphal surfaces, extravasation of cellular contents, and vacuole swelling and rupture, which disrupted normal hyphal growth. Subsequently, compounds 35-53 with good antifungal activity were designed and synthesized based on reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) models. Compound 49 showed high efficacy and superior antifungal activity against R. solani, with an EC50 value of 0.28 µg/mL and a half-maximal effective concentration of 0.46 µg/mL.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study.

BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.

BET bromodomain inhibitors PFI-1 and CPI-203 suppress the development of follicular lymphoma via regulating Wnt/ß-catenin signaling.

Objective: Follicular lymphoma (FL) is an indolent B-cell lymphoproliferative disorder, characterized by a lymphoid follicular pattern of growth. PFI-1 or CPI-203 has been known to effectively promote the inhibition of primary effusion lymphoma progression. This study aimed at investigating the anti-tumor properties of PFI-1 and CPI-203 on FL cells and uncover the underlying mechanism of action. Methods: FL cells were treated with PFI-1 and CPI-203, and the treated cells were evaluated for their cell viability, cell cycle and apoptosis using CCK8, flow cytometry, and Western blot assays. A xenograft mouse model was used for assessing the in vivo effects of CPI-203 on tumorigenesis. Results: PFI-1 or CPI-203 showed potential inhibitory effects on the cell viability of DOHH2 and RL cells in a dose-response-dependent manner. Furthermore, PFI-1 and CPI-203 inhibited cell growth, induced apoptosis of FL cells in vitro, and facilitated the translocation of ß-catenin into cytoplasm both in vitro and in vivo. After engrafted with FL cells, CPI-203-treated mice got a longer duration of survival and a smaller tumor size than control mice. Mechanistically, PFI-1 and CPI-203 impede the activity of ß-catenin and its downstream molecules by regulating the DVL2/GSK3ß axis. Conclusion: In conclusion, PFI-1 and CPI-203 may serve as potential anti-tumor inhibitors for the therapy of FL.

[Analysis of three Chinese pedigrees affected with Genetic epilepsy with febrile seizures plus due to variants of SCN1A gene].

OBJECTIVE: To analyze the clinical and genetic characteristics of three Chinese pedigrees affected with Genetic epilepsy with febrile seizures plus (GEFS+). METHODS: Three GEFS+ probands and their pedigree members presented at the Children's Hospital of Zhengzhou University from January 2020 to December 2021 were selected as the study subjects. Clinical data of the pedigrees were collected. Whole exome sequencing was carried out for the probands, and Sanger sequencing was used to verify the candidate variants. RESULTS: Proband 1 was a 3-year-and-2-month-old male with febrile seizure plus. His father, two aunts, grandmother, aunt grandmother, uncle grandfather, and paternal great-grandmother also had onset of febrile seizures at 1 ~ 2 years of age with remission before 6 years old. Proband 2 was a 1-year-and-4-month-old male with complex febrile seizure. His mother, maternal uncle, and maternal grandmother also had febrile seizures before 5 ~ 6 years of age. Proband 3 was a 3-year-and-11-month-old male with febrile seizure plus. His father and grandfather also had febrile seizures plus with remission at 7 ~ 8 years of age. Genetic testing revealed that proband 1 had harbored a paternally derived heterozygous SCN1A: c.1613T>C variant, proband 2 had harbored a maternally derived heterozygous SCN1A: c.2804A>G variant, and proband 3 had harbored a paternally derived heterozygous SCN1A: c.1271T>C variant. All of the three variants were predicted as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (PM1+PM2_Supporting+PP1+PP3+PP4). CONCLUSION: The c.1613T>C, c.2804A>G and c.1271T>C variants probably underlay the pathogenesis of GEFS+ in these pedigrees.

Discovery of Dehydroabietylamine Derivatives as Antibacterial and Antifungal Agents.

A diverse array of biologically active derivatives was derived by modifying the chemically active sites of dehydroabietylamine. Herein, we describe the synthesis of a new series of C-19-arylated dehydroabietylamine derivatives using a palladium-catalyzed C(sp3)-H activation reaction. Five analogues (3b, 3d, 3h, 3n, and 4a) exhibited antibacterial activity against Escherichia coli. Compound 4a exhibited strong inhibitory activity against DNA Topo II and Topo IV. Molecular docking modeling indicated that it can bind effectively to the target through interactions with amino acid residues. The synthesized compounds were tested in vitro for their antifungal activity against six common phytopathogenic fungi. The mechanism of action of compound 4c against Rhizoctorzia solani was investigated, revealing that it disrupts the morphology of the mycelium and enhances cell membrane permeability.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

Hydrogen sulfide improves endothelial barrier function by modulating the ubiquitination degradation of KLF4 through TRAF7 S-sulfhydration in diabetic aorta.

Anomalous vascular endothelium significantly contributes to various cardiovascular diseases. VE-cadherin plays a vital role in governing the endothelial barrier. Krüppel-like factor 4(KLF4), as a transcription factor, which binds the VE-cadherin promoter and enhances its transcription. Tumor necrosis factor receptor-associated factor 7 (TRAF7) is an E3 ubiquitin ligase that has been shown to modulate the degradation of KLF4. H2S can covalently modify cysteine residues on proteins through S-sulfhydration, thereby influencing the structure and functionality of the target protein. However, the role of S-sulfhydration on endothelial barrier integrity remains to be comprehensively elucidated. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates endothelial integrity and its underlying mechanism. In this study, we observed that protein S-sulfhydration was reduced in the endothelium during diabetes and TRAF7 was the main target. Overexpression of TRAF7-Cys327 mutant could mitigate the endothelial barrier damage by weakening TRAF7 interaction with KLF4 and reducing ubiquitination degradation of KLF4. In conclusion, our research demonstrates that H2S plays a pivotal role in regulating S-sulfhydration of TRAF7 at Cys327. This regulation effectively inhibits the ubiquitin-mediated degradation of KLF4, resulting in an upregulation of VE-cadherin levels. This molecular mechanism contributes to the prevention of endothelial barrier damage.

Identification of differentially expressed miRNAs in plasma exosomes from patients with early-onset pre-eclampsia using next generation sequencing.

Pre-eclampsia (PE), a major cause of perinatal morbidity and mortality, accounts for up to 14 % mortality of maternal and 18 % of fetal or infant mortalities. However, the pathogenesis process of PE remains unclear. The aim of this study was to identify differentially expressed microRNAs (miRNAs) in the peripheral blood exosomes of early-onset PE patients versus healthy pregnant women using high-throughput sequencing, and to find candidate miRNAs as molecular markers. Methods: Peripheral blood samples were collected from five preeclamptic patients and five healthy women. Exosomal miRNAs were sequenced using the Illumina HiSeq4000 sequencing platform. The target gene prediction, biological function enrichment, and signaling pathway prediction of the miRNAs with significant differences were carried out using the Starbase database software, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, respectively. Our results showed 65 significantly differentially expressed miRNAs in the exosomes of early-onset PE patients compared to control group, with 17 up-regulated and 48 down-regulated (P < 0.05). A total of 2231 target genes were predicted for all differentially expressed miRNAs. Biological functions enriched by these target genes were mainly associated with Ras protein signal transduction, GTPase-mediated signal transduction regulation, histone modification, and ß-transforming growth factor regulatory process. Key regulatory signaling pathways included TGF-ß signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway, tumor necrosis factor signaling pathway and EGFR tyrosine kinase inhibition signaling pathways. QPCR validation in 40 independent samples for 10 miRNAs, identified three miRNAs were confirmed in the second population. MIR7151 was a most significant differentially expressed miRNAs, and predicted its downstream regulatory gene, KCNQ10T1, using Starbase software. There were significant differences in miRNA expression profiles between peripheral blood exosomes of early-onset PE patients and normal pregnant women, suggesting that these miRNAs may contribute to the pathophysiology of early-onset PE by regulating various biological functions and signaling pathways.

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Optimization of colored pavement considering driving behavior and psychological characteristics under dynamic low-visibility conditions related to fog-a driving simulator study.

OBJECTIVE: Colored pavement is commonly used to reduce the road traffic risk and promote road traffic safety, but its performance in foggy environments has not been fully assessed. The goal of this research is to explore the effectiveness and optimization of colored pavement in a dynamic low-visibility environment. METHODS: A driving simulation experiment is conducted. Three road risk sections in which collisions are common, including a long straight section, a sharp bend section, and a long downslope section, are considered, and three forms of colored pavement are used in five different visibility environments. The effectiveness of the colored pavement is explored by collecting and analyzing driving behavior and physiological characteristic data for 30 drivers in the established driving environment, and information is obtained through a subjective colored evaluation questionnaire. Eight evaluation indexes are selected from the perspectives of driving behavior and physiological characteristics, and the gray premium evaluation method is applied to evaluate the effectiveness of different forms of colored pavement considering the influence of visibility. Finally, the optimal colored pavement under various visibility and road alignment conditions is proposed. RESULTS: The results show that reasonably selecting colored pavement can effectively improve drivers' behaviors and physiological characteristics under foggy conditions. For different road alignments and visibility conditions, different forms of colored pavement should be used to ensure road traffic safety. CONCLUSIONS: The findings provide a theoretical reference for the optimization of colored pavement in foggy conditions.

The Construction of lncRNA/circRNA-miRNA-mRNA Networks Reveals Functional Genes Related to Growth Traits in Schima superba.

Schima superba is a precious timber and fire-resistant tree species widely distributed in southern China. Currently, there is little knowledge related to its growth traits, especially with respect to molecular breeding. The lack of relevant information has delayed the development of modern breeding. The purpose is to identify probable functional genes involved in S. superba growth through whole transcriptome sequencing. In this study, a total of 32,711 mRNAs, 525 miRNAs, 54,312 lncRNAs, and 1522 circRNAs were identified from 10 S. superba individuals containing different volumes of wood. Four possible regulators, comprising three lncRNAs, one circRNA, and eleven key miRNAs, were identified from the regulatory networks of lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA to supply information on ncRNAs. Several candidate genes involved in phenylpropane and cellulose biosynthesis pathways, including Ss4CL2, SsCSL1, and SsCSL2, and transcription factors, including SsDELLA2 (SsSLR), SsDELLA3 (SsSLN), SsDELLA5 (SsGAI-like2), and SsNAM1, were identified to reveal the molecular regulatory mechanisms regulating the growth traits of S. superba. The results not merely provide candidate functional genes related to S. superba growth trait and will be useful to carry out molecular breeding, but the strategy and method also provide scientists with an effective approach to revealing mechanisms behind important economic traits in other species.