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Abstract The study aimed to compare the effectiveness between Hiporfin-photodynamic therapy (PDT) and loop electrosurgical excision procedure (LEEP) in treating cervical high-grade squamous intraepithelial lesion (HSIL). We conducted a retrospective analysis of 104 women diagnosed with cervical HSIL at our hospital from April 2019 to July 2023. With 1:1 matched case-control, 52 cases received Hiporfin-PDT and 52 cases underwent LEEP. All PDT-treated cases received Hiporfin (2 mg/kg) I.V. and a diode laser at a wavelength of 630-nm. T-test, Chi-square test, Fisher’s exact test, and Yates’s correction for continuity were conducted for statistical. A P value

The deterioration in fruit quality of commercial tomatoes is a major concern of modern tomato breeding. However, the metabolism and genetics of fruit quality are poorly understood. Here, we performed transgenic and molecular biology experiments to reveal that tomato phytoene synthase 1 (SlPSY1) is responsible for the accumulation of an important flavor chemical, 6-methyl-5-hepten-2-one (MHO). To dissect the function of SlPSY1 in regulating fruit quality, we generated and analyzed a dataset encompassing over 2 000 compounds detected by GC–MS and LC-MS/MS along with transcriptomic data. The combined results illustrated that SlPSY1 deficiency imparts novel flavor to yellow tomatoes with 236 volatiles significantly changed and improves fruit firmness, possibly due to accumulation of seven cutins. Further analysis indicated SlPSY1 is essential for carotenoid-derived metabolite biosynthesis by catalyzing prephytoene-PP (PPPP) to 15-cis-phytoene. Notably, we showed that SlPSY1 can influence the metabolic flux between carotenoid and flavonoid pathways, and this metabolic flux was confirmed by silencing SlCHS1. Our study provided insights into the multiple effects of SlPSY1 on tomato fruit metabolome and highlights the potential to produce high-quality fruit by rational design of SlPSY1 expression.

This study investigates univalent log-harmonic mappings, a class of functions that map the unit disk into the complex plane. First, we establish the necessary and sufficient conditions for univalent log-harmonic mappings to map the unit disk onto a spirallike region. We then explore the relationship between starlike harmonic mappings and spirallike log-harmonic mappings, providing several examples to illustrate our results. Finally, under specific conditions, we present growth and covering theorems for univalent log-harmonic mappings and determine the radius of spirallikeness for starlike log-harmonic mappings.

Abstract Background Hyperglycemia upon admission is associated with poor prognosis of many cardiovascular diseases. However, the relationship of stress hyperglycemia ratio (SHR), admission blood glucose (ABG), and hemoglobin A1c (HbA1c) with pulmonary hypertension has not been reported. This study aimed to explore the association of hyperglycemia indices with disease severity and long-term adverse outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH). Methods This multi-center cohort study included 625 consecutive patients diagnosed with or treated for IPAH between January 2015 and June 2023. SHR was calculated using the followings: ABG (mmol/L)/(1.59 × HbA1c [%] − 2.59). The primary endpoint was defined as clinical worsening events. Multivariable Cox regression and restricted cubic spline analyses were employed to evaluate the association of SHR, ABG, and HbA1c with endpoint events. The mediating effect of pulmonary hemodynamics was evaluated to investigate the potential mechanism between hyperglycemia and clinical outcomes. Results During a mean follow-up period of 3.8 years, 219 (35.0%) patients experienced all-cause death or clinical worsening events. Hyperglycemia indices correlated with well-validated variables that reflected the severity of IPAH, such as the World Health Organization functional class, 6-min walk distance, and N-terminal pro-brain natriuretic peptide levels. Multivariable Cox regression analyses indicated that SHR (hazard ratio [HR] 1.328, 95% confidence intervals [CI]: 1.185, 1.489 per 0.1-unit increment, P

Abstract We present SpliceTransformer (SpTransformer), a deep-learning framework that predicts tissue-specific RNA splicing alterations linked to human diseases based on genomic sequence. SpTransformer outperforms all previous methods on splicing prediction. Application to approximately 1.3 million genetic variants in the ClinVar database reveals that splicing alterations account for 60% of intronic and synonymous pathogenic mutations, and occur at different frequencies across tissue types. Importantly, tissue-specific splicing alterations match their clinical manifestations independent of gene expression variation. We validate the enrichment in three brain disease datasets involving over 164,000 individuals. Additionally, we identify single nucleotide variations that cause brain-specific splicing alterations, and find disease-associated genes harboring these single nucleotide variations with distinct expression patterns involved in diverse biological processes. Finally, SpTransformer analysis of whole exon sequencing data from blood samples of patients with diabetic nephropathy predicts kidney-specific RNA splicing alterations with 83% accuracy, demonstrating the potential to infer disease-causing tissue-specific splicing events. SpTransformer provides a powerful tool to guide biological and clinical interpretations of human diseases.

Abstract Essential oils (EOs) are complex and susceptible to environmental conditions, they have a wide range of biological activities and are often used to differentiate between similar species. In this study, gas chromatography-mass spectrometry (GC–MS) coupled with chemometric analysis was applied to systematically analyse and evaluate EOs constituents and antioxidant activity of six Chinese Cupressaceae taxa (Platycladus orientalis Franco, P. orientalis Franco ‘Sieboldii’, P. orientalis Franco ‘Aurea’, Juniperus chinensis Roxb., J. chinensis Roxb. ‘Kaizuca’, and J. sabina L.) under identical conditions. The antioxidant activity of the EOs was evaluated using 2,2 -diphenyl-1-picrylhydrazyl (DPPH), 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), and ferric reducing power (FRAP), and the total phenolic content (TPC) of the EOs was determined by Folin–Ciocalteau reagent. In total, seventy individual constituents were identified with the main components being α-pinene, sabinene, d-limonene, bornyl acetate, δ-3-carene and β-myrcene. Principal component analysis (PCA) and hierarchal cluster analysis (HCA) successfully discriminated the six taxa into three chemotypes and the unique chemotype revealed that J. chinensis ‘Kaizuca’ may be a species rather than a cultivar of J. chinensis. The results of OPLS-DA analysis showed that the three compounds screened, namely, α-pinene, sabinene, and δ-3-carene, can completely distinguish Platycladus spp. from Juniperus spp. The DPPH assay results ranged from 576.14 (J. chinensis ‘Kaizuca’) to 1146.12 (J. sabina) μmol eq Trolox/mL EO, while the ABTS values ranged from 1579.62 (P. orientalis ‘Aurea’) to 5071.82 (J. sabina) μmol eq Trolox/mL. In the FRAP assay, the values ranged from 1086.50 (J. chinensis ‘Kaizuca’) to 1191.18 (J. sabina) μmol eq Trolox/ml and the TPC of the EOs studied ranged from 15.17 (J. chinensis ‘Kaizuca’) to 39.37 (J. sabina) mg GAE/mL EO. The results consistently showed that J. sabina possessed the strongest antioxidant activity and can be preferentially used as a rich source of potentially natural antioxidants.

Abstract Background Malnutrition is common in patients with chronic cardiovascular disease and is associated with significantly higher all-cause mortality. Approximately one-third of patients with heart failure are malnourished. However, the relationship between malnutrition and idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study aimed to clarify the prognostic value of malnutrition in patients with IPAH. Methods A total of 432 consecutive participants with IPAH were included in this study between March 2013 and August 2021. Three common malnutrition assessment tools, including the geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status (CONUT) score, were used to evaluate the nutritional status of patients with IPAH. The relationships between the malnutrition tools and long-term adverse outcomes were determined using restricted cubic splines and multivariate Cox regression models. Results During a mean follow-up of 3.1 years, 158 participants experienced clinical worsening or all-cause death. Patients were stratified into the low-, intermediate- and high-risk groups based on the European Society of Cardiology (ESC) risk stratification, and the PNI (55.9 ± 5.7 vs. 54.4 ± 7.2 vs. 51.1 ± 7.1, P = 0.005) and CONUT score (2.1 ± 0.9 vs. 2.5 ± 1.2 vs. 3.3 ± 1.1, P

Abstract Hybrid mapping is a powerful approach to efficiently identify and characterize genes regulated through mechanisms in cis. In this study, using reciprocal crosses of the phenotypically divergent Duroc and Lulai pig breeds, we perform a comprehensive multi-omic characterization of regulatory variation across the brain, liver, muscle, and placenta through four developmental stages. We produce one of the largest multi-omic datasets in pigs to date, including 16 whole genome sequenced individuals, as well as 48 whole genome bisulfite sequencing, 168 ATAC-Seq and 168 RNA-Seq samples. We develop a read count-based method to reliably assess allele-specific methylation, chromatin accessibility, and RNA expression. We show that tissue specificity was much stronger than developmental stage specificity in all of DNA methylation, chromatin accessibility, and gene expression. We identify 573 genes showing allele specific expression, including those influenced by parent-of-origin as well as allele genotype effects. We integrate methylation, chromatin accessibility, and gene expression data to show that allele specific expression can be explained in great part by allele specific methylation and/or chromatin accessibility. This study provides a comprehensive characterization of regulatory variation across multiple tissues and developmental stages in pigs.

Resilience assessment and enhancement in distribution networks primarily focus on the ability to support and recover critical loads after extreme events. With the increasing integration of new energy sources and power electronics, distribution networks have gained a degree of resilience. However, the impact of power quality issues on these networks has become more severe. In some cases, even networks assessed as highly resilient by users suffer equipment damage and substantial economic losses due to power quality issues. To address this issue, this paper builds upon conventional distribution network resilience assessment methods by supplementing and modifying indices in the dimensions of resistance and recovery to account for power quality issues. Furthermore, an optimized energy storage system (ESS) configuration model is proposed as a technical means to minimize the total operational cost of the distribution network while enhancing comprehensive resilience indices. The proposed nonlinear optimization model is solved using second-order cone relaxation techniques. Finally, the proposed strategy is simulated on the IEEE 33-node distribution network. The simulation results demonstrate that the proposed strategy effectively improves the comprehensive resilience indices of the distribution network and reduces the total operational cost.

Podocyte injury is a critical event in the pathogenesis of diabetic nephropathy (DN). Hyperglycemia, oxidative stress, inflammation, and other factors contribute to podocyte damage in DN. In this study, we demonstrate that signaling regulatory protein alpha (SIRPα) plays a pivotal role in regulating the metabolic and immune homeostasis of podocytes. Deletion of SIRPα in podocytes exacerbates, while transgenic overexpression of SIRPα alleviates, podocyte injury in experimental DN mice. Mechanistically, SIRPα downregulation promotes pyruvate kinase M2 (PKM2) phosphorylation, initiating a positive feedback loop that involves PKM2 nuclear translocation, NF-κB activation, and oxidative stress, ultimately impairing aerobic glycolysis. Consistent with this mechanism, shikonin ameliorates podocyte injury by reducing PKM2 nuclear translocation, preventing oxidative stress and NF-κB activation, thereby restoring aerobic glycolysis.

In previous studies, the implementation of vegetation structure information remains underutilized during the assessment of burn severity. A PolSAR-based burn severity assessment model was proposed by incorporating polarimetric decomposition features. Based on coherence matrix, three polarimetric decomposition features (i.e. Entropy, Anisotropy, and Alpha) which might be related with some field variables of burn severity (e.g. percent foliage altered, percent change in cover, percent canopy mortality, and percent tree mortality) were extracted. Then, a sensitivity analysis of 20 PolSAR features was performed and a principal component analysis (PCA) was applied. Finally, the combination of polarimetric decomposition features and new PCA vectors were used as inputs and CBI values as outputs of random forest algorithm to assess burn severity. The Jinyun Mountain in the Chongqing municipality of China was used as study area and the C-band of dual-polarization SAR data acquired from Sentinel-1 satellite were used as remotely sensed data. The sensitivity analysis of PolSAR features showed that H, A, and α features exhibited higher correlations with CBI values, compared to SAR indices. For proposed model, the R was 0.60 and the RMSE was 0.55. This study offered a new research perspective for future investigations on PolSAR-based burn severity assessment of wildfires.

Antimicrobial resistance is among the greatest threats to public health globally, and drug repurposing strategies may be advantageous to addressing this problem. Mefloquine, a drug traditionally used to treat malaria, has emerged as a promising antibiotic adjuvant, due to its ability to enhance the effectiveness of conventional antibiotics against resistant bacterial strains. In this paper, we first outline the enhancement properties of mefloquine and its mechanisms of action as an adjuvant antibiotic against multidrug-resistant bacteria. Mefloquine exhibits synergistic bacteriostatic effects when combined with colistin, β-lactams, antituberculosis drugs, quinolones, and linezolid. Potential mechanisms underlying its synergistic effects include inhibition of antibiotic efflux, disruption of bacterial cell membrane integrity, and disturbance of biofilm formation. In addition, we explore the bacteriostatic effects of several mefloquine derivatives against Mycobacterium tuberculosis and some fungi. Further, we summarize the findings of recent studies on other aspects of mefloquine activity, including its antiviral and antitumor effects. Finally, the advantages and challenges of mefloquine use as an antibiotic adjuvant in combination with antibiotics for bacterial inhibition are discussed. Overall, mefloquine shows excellent potential as an antibiotic adjuvant therapy against multidrug-resistant bacteria and is a promising candidate for combination therapy; however, further studies are needed to fully elucidate its mechanism of action and address the challenges associated with its clinical application.

Yesso scallop Patinopecten yessoensis is an economically and ecologically important cold-water bivalve molluscs. Elucidating the molecular mechanism regulating its early larval development holds great significance in aquaculture. This study performed comparative transcriptomic analysis across nine developmental stages from fertilized eggs to spats. A variety of differentially expressed genes (DEGs) were identified to be potentially involved in larval development, including cell proliferation (cyclins, CDKs, BMPs, TGF-β), immunity (TLR7, CTLs, cathepsins, SOD, GSTs), larval settlement and metamorphosis (MHC, MELC, paramyosin, DβH, GABA receptor), shell formation (iMSP5, MSP1, CHS1, CHI3, CAM, CAML5) as well as energy metabolism (glycolysis, TCA cycle and oxidative phosphorylation components). Additionally, weighted gene co-expression network analysis (WGCNA) identified the key indianred4 module, which may play vital roles in body axis formation, neurogenesis and myogenesis in scallop larvae. An integrative framework was established delineating molecular drivers of embryogenesis, larval growth, immune defense, metamorphosis, shell production and bioenergetics throughout larval development in scallops. These findings will help understand the molecular strategies governing larval developmental process, yielding great insights to inform ecological conservation and aquaculture practices.

Cellulose has advantages of easy availability, low price, renewability and biodegradability, making it a very promising substitute for fossil-based materials. A safe composite cellulose membrane for quasi-solid-state lithium ion batteries has been developed by coating cellulose separators with poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and lithium aluminum titanium phosphate (LATP). This membrane exhibits excellent electrochemical performance, with an ionic conductivity as high as 2.1 mS cm−1, and a lithium-ion transference number of 0.57. The membrane shows good electrolyte wetting properties, with porosity and liquid electrolyte uptake of 47.2 % and 401.7 %, respectively. It has good thermal stability and can maintain its dimensional stability even at 200 ℃. The capacity retention of the quasi-solid-state LiFePO4/Li battery assembled with this membrane after 200 cycles at 0.2 C is about 86.7 %. The quasi-solid-state battery has good thermal stability and is not prone to thermal runaway.

The poly (ethylene oxide) (PEO) solid polymer electrolytes suffer from narrow electrochemical stability window and cannot match high voltage lithium cobalt oxide (LCO) cathode. Herein, an ultrathin Al2O3 nanolayer was uniformly deposited on the surface of LCO via powder atomic layer deposition (PALD) to realize poly (ethylene oxide) polymer electrolyte cycling stability. The PEO solid polymer electrolyte contains 20 % (w/w) lithium difluoro(oxalate)borate (LiDFOB) and 7.5 % (w/w) lithium titanium aluminum phosphate (LATP) with cellulose nonwoven as a support substrate. The electrolyte exhibitsionic conductivity of 1.2×10−4 S cm−1, an electrochemical stability window of 4.5 V (vs. Li+/Li) and lithium-ion transference number of 0.38. Al2O3@LCO/PEO-LiDFOB20%-LATP7.5%/Li cell at high cut-off 4.5 V delivered better initial discharge specific capacity of 178.5 mAh g−1 and achieved a capacity retention ratio of 81.6 % after 200 cycles under 0.1 C at 50 °C. Further analysis showed that Al2O3 layer served as stable a protective layer to suppress the generation of strong oxidative Co4+ and O– species and separate from the PEO solid polymer electrolyte, inhibiting the side reactions at the cathode-side interface. Therefore, architecting precise and ultrathin protective nanolayer interface on high voltage LCO cathode via PALD is conducive to cycling performance of solid polymer electrolyte.

Abstract Background Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. Methods Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. Results Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-β-muricholic acid (Tβ-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. Conclusions Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism. Graphical Abstract Schematic model depicting the proposed mechanism of cholestasis-mediated progression of colorectal liver metastasis. As cholestasis progresses, excessive primary bile acids that accumulate in the liver intoxicates hepatocytes, which lead to exacerbated release of chemokines, particularly CXCL2 and CXCL5. Neutrophils are then accumulated by CXCL2 and CXCL5 and undergo an immunosuppressive-phenotypic alteration induced by direct stimulation of BAs via activating the p38 MAPK signaling pathway, which eventually led to the dysfunction of T cells and progression of LM. Targeting bile acid anabolism can effectively restore the immune-activated microenvironment and prevent the progression of LM.

Abstract Interregional grain trade affects the environment while balancing supply and demand. However, what relationship exist between national carbon emissions reduction and nitrogen losses reduction in each export region is unclear. Here we used maize as a case study to address this gap by combining life cycle assessment method with linear programming model. We found that interprovincial maize trade can reduce the country’s overall carbon emissions and nitrogen losses. However, the carbon and nitrogen reduction potential varied across exporting provinces. Northeast provinces have great potential to reduce the country’s overall carbon emissions and nitrogen losses via interprovincial maize trade. Northwest provinces increase the overall carbon emissions but reduce the overall nitrogen losses when transferring out maize. Optimizing interprovincial maize trade schemes can further enhance the country’s overall carbon and nitrogen reduction potential. The research results provide a theoretical reference for China to develop carbon neutral and nitrogen reduction trade schemes.

Abstract Peroxisomal l-bifunctional enzyme (EHHADH) plays a role in the classic peroxisomal fatty acid β-oxidation pathway; however, the relationship between EHHADH expression and diabetic kidney disease has not been well understood. Here, we found that endogenous EHHADH levels were strongly correlated with the progression and severity of diabetic nephropathy in T2D patients. EHHADH knockout mice exhibited worsened renal tubular injury in diabetic mice. Furthermore, EHHADH is a modulator of pexophagy. In renal tubular epithelial cells (RTECs) in vitro, the knockdown of EHHADH induced a dramatic loss of peroxisomes. The loss of peroxisomes in EHHADH-deficient RTECs was restored by either an autophagic inhibitor 3-methyladenine or bafilomycin A1 both in vitro and in vivo. NBR1 was required for pexophagy in EHHADH-knockdown cells, where the level of reactive oxygen species (ROS) was increased, while inhibition of ROS blocked pexophagy. In summary, our findings revealed EHHADH deficiency accelerated renal injury in DKD as a modulator of pexophagy.

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. Methods and design The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. Conclusions As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. Registration Number in ClinicalTrials.gov NCT05311072.

In the present study, laser welding of medium-thick TWIP steel plates was studied and the microstructures and mechanical properties of the welded joints obtained at varied welding speeds were characterized. It is shown that a full penetration was achieved in the welded joint, which exhibits a keyhole-shaped configuration. The welded joint displays a single austenitic phase and typical solidification structure composed of cellular, columnar and dendrite grains. With increasing the welding speed, the grains in both the central fusion zone and adjacent heat-affected zone were refined. The latter was attributed to inadequate recrystallization because of decreased heating time at elevated welding speed. The mechanical properties of all welded joints were lower than those of base metal, in which the decline of elongation was more serious than that of strength. This is attributed to the formation of thick columnar crystals and the Al2O3 core-shell structured nanoscale precipitates in the grains of the fusion zone. Moreover, there existed a certain degree of non-uniformity in the microstructures and mechanical properties along the thickness direction of welding seam, and the samples in the upper area of welding seam showed better comprehensive properties than the lower ones. When welded at a moderate speed as 1.0 m/min, the welding seams exhibited the best mechanical properties and the least difference across the thickness direction of the welding seam. This is because the moderate welding speed resulted in the most beneficial macro- and micro-structures as well as grain boundary characteristics.

Abstract Disease modeling with isogenic Induced Pluripotent Stem Cell (iPSC)-differentiated organoids serves as a powerful technique for studying disease mechanisms. Multiplexed coculture is crucial to mitigate batch effects when studying the genetic effects of disease-causing variants in differentiated iPSCs or organoids, and demultiplexing at the single-cell level can be conveniently achieved by assessing natural genetic barcodes. Here, to enable cost-efficient time-series experimental designs via multiplexed bulk and single-cell RNA-seq of hybrids, we introduce a computational method in our Vireo Suite, Vireo-bulk, to effectively deconvolve pooled bulk RNA-seq data by genotype reference, and thereby quantify donor abundance over the course of differentiation and identify differentially expressed genes among donors. Furthermore, with multiplexed scRNA-seq and bulk RNA-seq, we demonstrate the usefulness and necessity of a pooled design to reveal donor iPSC line heterogeneity during macrophage cell differentiation and to model rare WT1 mutation-driven kidney disease with chimeric organoids. Our work provides an experimental and analytic pipeline for dissecting disease mechanisms with chimeric organoids.

Abstract Background Insulin resistance (IR) plays an important role in the pathophysiology of cardiovascular disease. Recent studies have shown that diabetes mellitus and impaired lipid metabolism are associated with the severity and prognosis of idiopathic pulmonary arterial hypertension (IPAH). However, the relationship between IR and pulmonary hypertension is poorly understood. This study explored the association between four IR indices and IPAH using data from a multicenter cohort. Methods A total of 602 consecutive participants with IPAH were included in this study between January 2015 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass index (TyG-BMI) were used to quantify IR levels in patients with IPAH. The correlation between non-insulin-based IR indices and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. Results During a mean of 3.6 years’ follow-up, 214 participants experienced all-cause death or worsening condition. Compared with in low to intermediate-low risk patients, the TG/HDL-C ratio (2.9 ± 1.7 vs. 3.3 ± 2.1, P = 0.003) and METS-IR (34.5 ± 6.7 vs. 36.4 ± 7.5, P

Abstract Background Glomerular lesions are the main injuries of diabetic nephropathy (DN) and are used as a crucial index for pathologic classification. Manual quantification of these morphologic features currently used is semi-quantitative and time-consuming. Automatically quantifying glomerular morphologic features is urgently needed. Methods A series of convolutional neural networks (CNN) were designed to identify and classify glomerular morphologic features in DN patients. Associations of these digital features with pathologic classification and prognosis were further analyzed. Results Our CNN-based model achieved a 0.928 F1-score for global glomerulosclerosis and 0.953 F1-score for Kimmelstiel-Wilson lesion, further obtained a dice of 0.870 for the mesangial area and F1-score beyond 0.839 for three glomerular intrinsic cells. As the pathologic classes increased, mesangial cell numbers and mesangial area increased, and podocyte numbers decreased (p for all

Abstract Background Patients with pulmonary arterial hypertension (PAH) exhibit a distinct gut microbiota profile; however, the causal association between gut microbiota, associated metabolites, and PAH remains elusive. We aimed to investigate this causal association and to explore whether dietary patterns play a role in its regulation. Methods Summary statistics of gut microbiota, associated metabolites, diet, and PAH were obtained from genome-wide association studies. The inverse variance weighted method was primarily used to measure the causal effect, with sensitivity analyses using the weighted median, weighted mode, simple mode, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger methods. A reverse Mendelian randomisation analysis was also performed. Results Alistipes (odds ratio [OR] = 2.269, 95% confidence interval [CI] 1.100–4.679, P = 0.027) and Victivallis (OR = 1.558, 95% CI 1.019–2.380, P = 0.040) were associated with an increased risk of PAH, while Coprobacter (OR = 0.585, 95% CI 0.358–0.956, P = 0.032), Erysipelotrichaceae (UCG003) (OR = 0.494, 95% CI 0.245–0.996, P = 0.049), Lachnospiraceae (UCG008) (OR = 0.596, 95% CI 0.367–0.968, P = 0.036), and Ruminococcaceae (UCG005) (OR = 0.472, 95% CI 0.231–0.962, P = 0.039) protected against PAH. No associations were observed between PAH and gut microbiota-derived metabolites (trimethylamine N-oxide [TMAO] and its precursors betaine, carnitine, and choline), short-chain fatty acids (SCFAs), or diet. Although inverse variance-weighted analysis demonstrated that elevated choline levels were correlated with an increased risk of PAH, the results were not consistent with the sensitivity analysis. Therefore, the association was considered insignificant. Reverse Mendelian randomisation analysis demonstrated that PAH had no causal impact on gut microbiota-derived metabolites but could contribute to increased the levels of Butyricicoccus and Holdemania, while decreasing the levels of Clostridium innocuum, Defluviitaleaceae UCG011, Eisenbergiella, and Ruminiclostridium 5. Conclusions Gut microbiota were discovered suggestive evidence of the impacts of genetically predicted abundancy of certain microbial genera on PAH. Results of our study point that the production of SCFAs or TMAO does not mediate this association, which remains to be explained mechanistically.

Abstract Aims Despite refinements in balloon pulmonary angioplasty (BPA), total occlusion remains a challenge in chronic thromboembolic pulmonary hypertension (CTEPH). Owing to their low success and high complication rates, most interventional cardiologists are reluctant to address total occlusion, and there is a paucity of literature on BPA performance in total occlusion. We aimed to classify total occlusion according to morphology and present an illustrative approach for devising a tailored treatment strategy for each distinct type of total occlusion. Methods and results All patients diagnosed with CTEPH who underwent BPA between May 2018 and May 2022 at Fuwai Hospital in Beijing, China, were included retrospectively. A total of 204 patients with CTEPH who underwent BPA were included in this study. Among these, 38 occluded lesions were addressed in 33 patients. Based on the morphology, we categorized the lesions into three groups: pointed‐head, round‐head, and orifice occlusions. Pointed‐head occlusion could be successfully addressed using soft‐tip wire, round‐head occlusion warranted hard‐tip wire and stronger backup, and orifice occlusion warranted the strongest backup force. The success rates for each group were as follows: pointed‐head (95.45%), round‐head (46.15%), and orifice occlusion (33.33%), with orifice occlusion having the highest complication rate (50%). The classification of occlusion was associated with BPA success (round‐head occlusion vs. pointed‐head occlusion, OR 24.500, 95% CI 2.498–240.318, P = 0.006; orifice occlusion vs. pointed‐head occlusion, OR 42.000, 95% CI 3.034–581.434, P = 0.005). Conclusions Occlusion morphology has a significant impact on BPA success and complication rates. A treatment strategy tailored to each specific occlusive lesion, as outlined in the present study, has the potential to serve as a valuable guide for clinical practitioners.

To understand the seasonal variations in shellfish community structure, the composition and diversity of shellfish in the intertidal zone of the Changshan Archipelago, China, were investigated. We investigated the composition and diversity of shellfish species in the intertidal zone (including NCD1, NCD2, BCD1, BCD2, TJD1, TJD2, DQD1, DQD2, NHD1, and NHD2) of five representative islands and 10 survey stations in the Changshan Archipelago during the low tide period in July and October 2021 and February and May 2022, and the water quality parameters of point water and interstitial water were analyzed. The results showed that the bottom material of the Changshan Archipelago was generally rock or gravel and the salinity fluctuated with the seasons. The salinity was high in summer and fall while low in spring and winter, with an average of 30.92±0.84. Compared with spring, summer, and fall, the temperature changed significantly in winter, with an average of (4.51±0.32) ℃ and the highest temperature being 23.48 ℃ during spring, summer, and fall. In general, the dissolved oxygen in the main islands of Changshan Archipelago (North and South Changshan Islands) was relatively low, with an average of (8.59±0.38) mg/L, while that in Tuoji Island, Daqin Island, and Nanhuangcheng Island was relatively high, with an average of (9.95±0.51) mg/L. A total of 12 species of shellfish were collected in this survey, including Crassostrea sp., Monodonta labio Linnaeus, Littorina brevicula, Mytilus galloprovincialis, Patelloida pygmaea, Chlorostoma rustica, Reishia clavigera, Thais luteostoma, Ocinebrellus inornata, Cellana toreuma, Ruditapes philippinarum, and Rapana venosa. The number of shellfish species in each season was the highest in spring, with an average of eight species, followed by in fall, with an average of six species. Winter had the least number of shellfish species collected, with an average of four species. In addition, the North and South Changshan Islands presented the most shellfish species at eight and nine species, respectively. The number of shellfish collected in DQD was the least (six species). There were differences in shellfish density at different survey sites, among which DQD2 had the highest density, with an average density of 41.26 ind./m2. The lowest density was in NCD2, and the average density was 13.71 ind./m2. In the same season, the shellfish density at different survey sites was different, the proportion of dominant species at different survey sites was also different. In spring, the density of Crassostrea sp., Cellana toreuma, and Chlorostoma rustica was high, while in summer, the density of Crassostrea sp., Mytilus galloprovincialis, Littorina brevicula, and Cellana toreuma was high. In fall, the density of Crassostrea sp., Littorina brevicula, and Mytilus galloprovincialis was the highest, while in winter, the density of Crassostrea sp., Patelloida pygmaea, and Cellana toreuma was the highest. The species diversity (H´) of shellfish in each tidal area of the survey site is shown as middle tidal zone (1.44) > low tidal zone (1.40) > high tidal zone (0.44). Overall, the average shellfish species diversity in the 10 survey sites was spring (1.26) > winter (1.21) > fall (1.11) > summer (0.95). The average evenness index of species (J´) in the 10 survey stations was 0.55, among which the evenness index of DQD2, NCD2, NHD2, and TJD1 shellfish was 0.67, 0.64, 0.64, and 0.55, respectively. The evenness index of shellfish in each tidal area of the survey site was in order of middle tidal zone (0.67) > low tidal zone (0.59) > high tidal zone (0.29). The seasonal change was not obvious. The average shellfish abundance at the survey site was 0.533, including 0.82, 0.68, 0.60, and 0.53 shellfish abundance at NCD2, NHD2, BCD2, and NCD1, respectively. The abundance index of shellfish in each tidal area of the survey site was in order of middle tidal zone (0.56) > low tidal zone (0.52) > high tidal zone (0.17). Overall, the average shellfish abundance in the 10 survey sites was spring (0.681) > fall (0.573) > summer (0.458) > winter (0.418). Seasons (temperatures) have the most obvious impact on the diversity and abundance of intertidal shellfish resources. Anthropogenic activities, such as aquaculture and tourism, also affect the distribution and quantity of shellfish species. The results of this study not only enrich the data of intertidal shellfish resources on islands in China but also provide basic information and reference for biodiversity and environmental protection of intertidal shellfish on the Changshan Islands.

Summary: Background: Pulmonary embolism (PE) as a preventable and potentially fatal noncommunicable disease was believed to have a lower incidence in Asian populations compared to Western populations. However, the incidence and mortality rates of PE in China and the impact of venous thromboembolism (VTE) prevention system constructions on PE still lack nationwide evidence. Methods: For this nationwide hospital-based observational study, we used data from the National Hospital Quality Monitoring System (HQMS) and public database in China. We estimated the incidence and in-hospital mortality rates of PE by age group, sex, and regions of geographical and socioeconomic level. VTE prevention and management system constructions were quantified by geographical density. We then calculated the incidence and mortality rates in different conditions of VTE prevention and management system construction. Findings: During the 12 months period between January and December 2021, a total number of 200,112 PE patients and 14,123 deaths were recorded from 5101 hospitals in the HQMS database. The incidence of PE was 14.19 (200,112, 95% CI 14.13–14.26) per 100,000 population and the mortality rate was 1.00 (95% CI 0.99–1.02) per 100,000 population. The incidence of PE was higher in male patients (14.43 per 100,000 population) than in female patients (13.95 per 100,000 population). Disparities of incidence and mortality rates were shown within age groups and geographical regions. The incidence and mortality rates of PE showed decreasing trend with increasing geographical density of VTE-related facilities and VTE prevention system developments. Interpretation: China had a substantially large number of PE patients. The incidence and mortality rates of PE showed disparities in terms of sex, age, and geography. The incidence and mortality rates of PE decrease across regions with increasing levels of socioeconomic development, potentially influenced by the existing VTE prevention and management systems. Optimizing the health policies and healthcare investment in VTE prevention may help reduce the disease burden of PE. Funding: CAMS Innovation Fund for Medical Sciences (CIFMS) (2023-I2M-A-014); National High Level Hospital Clinical Research Funding (2022-NHLHCRF-LX-01-0108); National Key Research and Development Program of China (2023YFC2507200); Discipline-Innovation and Talent-Introduction Program for Colleges and Universities (111 Plan, B23038).

BackgroundThe association between the rapid increase in myopia among adolescents and the amount of outdoor artificial light at night (ALAN) remains unclear. The aim of this study was to investigate the association between outdoor ALAN and myopia in adolescents.MethodsStratified cluster random sampling was used to obtain a sample of 33,160 students (age range: 9–18 years; mean: 13.51 years) with complete data from 120 primary and secondary schools across the Ningxia region in China in 2021. Myopia was defined as a spherical equivalent (SE) ≤−0.5 diopters (D) in at least one eye, determined by automated refractometers without cycloplegia. Outdoor ALAN data were obtained from satellite data and the two-year average outdoor ALAN exposure for each participant was determined by matching it to their school address (home addresses were not available). The association between ALAN and myopia was assessed using multiple logistic regression models and restricted cubic spline (RCS) regression. Stratified analyses were performed by age, sex, residence, school level, and outdoor exercise time.ResultsThe myopia group had higher outdoor ALAN levels than the non-myopia group [median (interquartile spacing): 14.44 (3.88–26.56) vs. 6.95 (1.21–21.74) nanoWatts/cm2/sr]. After adjusting for covariates identified through stepwise regression, it was observed that the prevalence of myopia increased by 4% for every 10-unit change [95% confidence interval (CI): 1.02–1.07]. Compared to the first quantile (Q1) of outdoor ALAN exposure, the odds ratio (OR) of myopia was 1.20 (95% CI: 1.08–1.34) in the fourth quantile. RCS further showed a positive nonlinear relationship between outdoor ALAN exposure and myopia (p for nonlinear

Abstract Objectives To assess the efficacy and safety of preoperative neoadjuvant everolimus in renal angiomyolipomas (AML) patients with or without Tuberous Sclerosis Complex (TSC). Materials and Methods This multi‐institutional retrospective study enrolled renal AML patients who underwent partial nephrectomy (PN) or total nephrectomy after receiving at least 1 month of pre‐operative everolimus. Imaging evaluations were collected before and after treatment, along with demographic, surgical, and follow‐up information. The primary outcome was tumor volume reduction of ≥25%, with additional outcomes including recurrence, perioperative outcomes, renal function, and safety. Results From January 2015 to July 2022, 68 renal AML patients were studied—41 with TSC and 27 without. During everolimus treatment, 61.0% (25/41) of TSC patients and 44.4% (12/27) of non‐TSC patients achieved tumor reduction of ≥25%. Additionally, 41.5% (17/41) of TSC patients and 18.5% (5/27) of non‐TSC patients achieved a ≥ 50% reduction. Three TSC patients and 1 non‐TSC patient discontinued treatment due to side‐effects. Most patients (92.7% TSC, 85.2% non‐TSC) underwent PN. After everolimus treatment, the necessary total nephrectomy decreased to 41.2% (7/17) from baseline. Postoperatively, 1 grade 3 and 3 grade 2 complications occurred, with no grade 4 or 5 complications. After a median follow‐up of 24 months, only 1 TSC patient recurred with a diameter >3 cm. Retrospective nature is the major limitation of this study. Conclusion Everolimus was effective and well‐tolerated in neoadjuvant treatment for renal AML, especially in TSC patients. This neoadjuvant combination strategy of everolimus and PN could effectively controls recurrence and preserves renal function.

BackgroundMigraine patients have an increased long-term risk of cardio and cerebrovascular events. However, whether these patients are more susceptible to white matter lesions (WMLs) remains debated. To explore this question, our study assessed the proportion of RLS in migraine patients and explored the association between right-to-left shunt (RLS) and WMLs.MethodsIn this study, we included 998 migraine patients. Contrast transcranial doppler (c-TCD) was used to diagnose RLS and assess the extent of the shunt in RLS patients. Of the 998 patients, 505 underwent cranial magnetic resonance imaging (MRI) assessments. WMLs were classified into periventricular white matter lesions (pvWMLs) and deep white matter lesions (dWMLs).ResultsAmong the 998 migraine patients, 946 had migraine without aura (MO; mean age 36.68 ± 10.46 years; 80.5% female), and 52 had migraine with aura (MA; mean age 29.85 ± 8.59 years; 71.2% female). Compared with MO patients, MA patients had an earlier onset age (23.1 ± 7.97 vs. 28.44 ± 10.38 years, p

Glycogen, a highly branched polysaccharide of essential energy and carbon resource, is an important flavor quality trait of oysters, and its content is closely linked to the reproductive cycle of these mollusks. However, there is a significant lack of research on the regulatory mechanisms governing glycogen in oysters. Here, we investigated the variations in glycogen levels during the reproductive cycle of Jinjiang oyster Crassostrea (Magallana) ariakensis. It revealed that glycogen content was highest during the formative stage and lowest during the mature stage in gonadal tissues. Subsequently, transcriptome and metabolome analyses were conducted, revealing 3016 differentially expressed genes (DEGs) and 162 differentially accumulated metabolites (DAMs). Comprehensive analysis indicated that glycogenesis, glycogenolysis, glycolysis, and tricarboxylic acid (TCA) cycle played crucial roles in energy supply during the formative stage. Gluconeogenesis was more important during the mature stage as it facilitated glycogen storage for reproduction preparation. These findings provide valuable insights into the mechanisms underlying gonad development-related glycogen metabolism and offer a theoretical foundation for enhancing oyster flavor.

Abstract Wilms tumor‐1(WT1) is a crucial transcription factor that regulates podocyte development. However, the epigenomic mechanism underlying the function of WT1 during podocyte development has yet to be fully elucidated. Here, single‐cell chromatin accessibility and gene expression maps of foetal kidneys and kidney organoids are generated. Functional implications of WT1‐targeted genes, which are crucial for the development of podocytes and the maintenance of their structure, including BMPER/PAX2/MAGI2 that regulates WNT signaling pathway, MYH9 that maintains actin filament organization and NPHS1 that modulates cell junction assembly are identified. To further illustrate the functional importance of WT1‐mediated transcriptional regulation during podocyte development, cultured and implanted patient‐derived kidney organoids derived from the Induced Pluripotent Stem Cell (iPSCs) of a patient with a heterozygous missense mutation in WT1 are generated. Results from single‐cell RNA sequencing (scRNA‐seq) and functional assays confirm that the WT1 mutation leads to delays in podocyte development and causes damage to cell structures, due to its failure to activate the targeting genes MAGI2, MYH9, and NPHS1. Notably, correcting the mutation in the patient iPSCs using CRISPR‐Cas9 gene editing rescues the podocyte phenotype. Collectively, this work elucidates the WT1‐related epigenomic landscape with respect to human podocyte development and identifies the disease‐causing role of a WT1 mutation.

Sheep body size can directly reflect the growth rates and fattening rates of sheep and is also an important index for measuring the growth performance of meat sheep.Inner Mongolia Cashmere Goat is a local excellent breed of cashmere and meat dual-purpose, which is a typical heterogeneous indumentum. The hair follicles cycle through periods of vigorous growth (anagen), a regression caused by apoptosis (catagen), and relative rest (telogen). At present, it is not clear which genes affect the cycle transformation of hair follicles and unclear how proteins impact the creation and expansion of hair follicles.we using multi-omics joint analysis methodologies to investigated the possible pathways of transformation and apoptosis in goat hair follicles. The results showed that 917,1,187, and 716 proteins were specifically expressed in anagen, catagen andtelogen. The result of gene ontology (GO) annotation showed that differentially expressed proteins (DEPs) are in different growth cycle periods, and enriched GO items are mostly related to the transformation of cells and proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment result indicated that the apoptosis process has a great impact on hair follicle’s growth cycle. The results of the protein interaction network of differential proteins showed that the ribosomal protein family (RPL4, RPL8, RPS16, RPS18, RPS2, RPS27A, RPS3) was the core protein in the network. The results of combined transcriptome and proteomics analysis showed that there were 16,34, and 26 overlapped DEGs and DEPs in the comparison of anagen VS catagen, catagen VS telogen and anagen VS telogen, of which API5 plays an important role in regulating protein and gene expression levels. We focused on API5 and Ribosomal protein and found that API5 affected the apoptosis process of hair follicles, and ribosomal protein was highly expressed in the resting stage of hair follicles. They are both useful as molecular marker candidate genes to study hair follicle growth and apoptosis,and they both have an essential function in the cycle transition process of hair follicles. The results of this study may provide a theoretical basis for further research on the growth and development of hair follicles in Inner Mongolian Cashmere goats.

Cracks of varying lengths may occur in galleries throughout dam construction, operation, and management processes. This study investigates the influence of age and crack length on the fracture parameters of gallery concrete, which is crucial for understanding the mechanisms and risks associated with gallery cracking and for developing appropriate treatment measures. Wedge-splitting tests were performed on gallery concrete specimens with varying crack lengths and at different ages. It was found that the fracture parameters measured at different ages all decrease with the increase of crack length. Based on the test results, size-independent material constants such as fracture toughness and the effective length of the fracture process zone were derived and modeled using an exponential function to reflect their time-varying characteristics. A fracture model was proposed and validated, which can accurately predict the fracture behavior of gallery concrete across varying ages and crack lengths, and is applicable in practical dam gallery crack analysis for assessing crack stability and evaluating the effectiveness of treatment measures.