Hapln1 promotes dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping.

Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and an adult mouse model of myocardial infarction. HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models, respectively. Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration. The results showed that recombinant human Hapln1 (rhHapln1) promotes the proliferation of hiPSC-CMs in a dose-dependent manner. As a physical binding protein of Hapln1, versican interacted with Nodal growth differentiation factor (NODAL) and growth differentiation factor 11 (GDF11). GDF11, but not NODAL, was expressed by hiPSC-CMs. GDF11 expression was unaffected by rhHapln1 treatment. However, this molecule was required for rhHapln1-mediated activation of the transforming growth factor (TGF)-ß/Drosophila mothers against decapentaplegic protein (SMAD)2/3 signaling in hiPSC-CMs, which stimulates cell dedifferentiation and proliferation. Recombinant mouse Hapln1 (rmHapln1) could induce cardiac regeneration in the adult mouse model of myocardial infarction. In addition, rmHapln1 induced hiPSC-CM proliferation. In conclusion, Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-ß/SMAD2/3 signaling pathway. Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.

Defect-rich sonosensitizers based on CeO2 with Schottky heterojunctions for boosting sonodynamic/chemodynamic synergistic therapy.

Sonodynamic therapy (SDT) has been recognized as a promising treatment for cancer due to its advantages of superior specificity, non-invasiveness, and deep tissue penetration. However, the antitumor effect of SDT remains restricted by the limited generation of reactive oxygen species (ROS) due to the lack of highly efficient sonosensitizers. In this work, we developed the novel sonosensitizer Pt/CeO2-xSx by constructing oxygen defects through S doping and Pt loading in situ. Large amounts of oxygen defects have been obtained by S doping, endowing Pt/CeO2-xSx with the ability to suppress electron-hole recombination, further promoting ROS production. Moreover, the introduction of Pt nanoparticles can not only produce oxygen in situ for relieving hypoxia but also form a Schottky heterojunction with CeO2-xSx for further inhibiting electron-hole recombination. In addition, Pt/CeO2-xSx could effectively deplete overexpressed glutathione (GSH) via redox reactions, amplifying oxidative stress in the tumor microenvironment (TME). Combined with the excellent POD-mimetic activity, Pt/CeO2-xSx can achieve highly efficient synergistic therapy of SDT and chemodynamic therapy (CDT). All these findings demonstrated that Pt/CeO2-xSx has great potential for cancer therapy, and this work provides a promising direction for designing and constructing efficient sonosensitizers.

Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Highly Selective Hydrogenation of Unsaturated Aldehydes in Aqueous Phase.

Chemoselective hydrogenation of carbonyl in unsaturated aldehydes is a significant process in the chemical industry, in which the development of aqueous-phase reaction systems as a substitution to organic ones is challenging. Herein, we report Ir atomic cluster catalysts anchored onto WO3-x nanorods via a reduction treatment at various temperatures (denoted as Ir/WOx-T, T = 200, 300, 400, and 500 °C), which accelerates the chemoselective hydrogenation of carbonyl groups in aqueous solutions. The optimal catalyst Ir/WOx-300 exhibits exceptional activity (TOF value: 1313.7 min-1) and chemoselectivity toward cinnamaldehyde (CAL) hydrogenation to cinnamyl alcohol (COL) (yield: ∼98.0%) in water medium, which is, to the best of our knowledge, the highest level compared with previously reported heterogeneous catalysts in liquid-phase reaction. Ac-HAADF-STEM, XAFS, and XPS verify the formation of interface structure (Irδ+-Ov-W5+ (0 ≤ δ ≤ 4); Ov denotes oxygen vacancy) induced by metal-support interaction and the largest concentration of interfacial Ir (Irδ+) in Ir/WOx-300. In situ studies (Raman, FT-IR), isotopic labeling measurements combined with DFT calculations substantiate that the hydrogenation of the C=O group consists of two pathways: water-mediated hydrogenation (predominant) and direct hydrogenation via H2 dissociation (secondary). In the former case, W5+-Ov site accelerates the activation adsorption of H2O, while Ir0 site facilitates the H-H bond cleavage of H2 and Irδ+ promotes the CAL adsorption. H2O molecule, as the source of hydrogen species, participates directly in the hydrogenation of the carbonyl group through a hydrogen-bonded network, with a largely reduced energy barrier relative to the H2 dissociation path. This work demonstrates a green catalytic route that breaks the activity-selectivity trade-off toward the selective hydrogenation of unsaturated aldehydes, which shows great potential in heterogeneous catalysis.

UCHL1 contributes to insensitivity to endocrine therapy in triple-negative breast cancer by deubiquitinating and stabilizing KLF5.

BACKGROUND: Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that regulates ERα expression in triple-negative cancer (TNBC). This study aimed to explore the deubiquitination substrates of UCHL1 related to endocrine therapeutic responses and the mechanisms of UCHL1 dysregulation in TNBC. METHODS: Bioinformatics analysis was conducted using online open databases. TNBC representative MDA-MB-468 and SUM149 cells were used for in vitro and in-vivo studies. Co-immunoprecipitation was used to explore the interaction between UCHL1 and KLF5 and UCHL1-mediated KIF5 deubiquitination. CCK-8, colony formation and animal studies were performed to assess endocrine therapy responses. The regulatory effect of TET1/3 on UCHL1 promoter methylation and transcription was performed by Bisulfite sequencing PCR and ChIP-qPCR. RESULTS: UCHL1 interacts with KLF5 and stabilizes KLF5 by reducing its polyubiquitination and proteasomal degradation. The UCHL1-KLF5 axis collaboratively upregulates EGFR expression while downregulating ESR1 expression at both mRNA and protein levels in TNBC. UCHL1 knockdown slows the proliferation of TNBC cells and sensitizes the tumor cells to Tamoxifen and Fulvestrant. KLF5 overexpression partially reverses these trends. Both TET1 and TET3 can bind to the UCHL1 promoter region, reducing methylation of associated CpG sites and enhancing UCHL1 transcription in TNBC cell lines. Additionally, TET1 and TET3 elevates KLF5 protein level in a UCHL1-dependent manner. CONCLUSION: UCHL1 plays a pivotal role in TNBC by deubiquitinating and stabilizing KLF5, contributing to endocrine therapy resistance. TET1 and TET3 promote UCHL1 transcription through promoter demethylation and maintain KLF5 protein level in a UCHL1-dependent manner, implying their potential as therapeutic targets in TNBC.

Effects of grazing exclusion on soil properties, fungal community structure, and diversity in different grassland types.

Soil fungi are involved in the decomposition of organic matter, and they alter soil structure and physicochemical properties and drive the material cycle and energy flow in terrestrial ecosystems. Fungal community assembly processes were dissimilar in different soil layers and significantly affected soil microbial community function and plant growth. Grazing exclusion is one of the most common measures used to restore degraded grasslands worldwide. However, changes in soil fungal community characteristics during grazing exclusion in different types of grasslands are unknown. Here, we investigated the effects of a 9-year grazing exclusion on soil properties, fungal community composition, and diversity in three grassland types (temperate desert, temperate steppe, and mountain meadow). The results showed that (1) in the 0-5 cm soil layer, grazing exclusion significantly increased the differences in SWC, SOC, KN, and N:P among the three grassland types, while the final pH, BD, TP, C:N, and C:P values were consistent with the results before exclusion. In the 5-10 cm soil layer, grazing exclusion significantly increased total phosphorus (TP) in temperate deserts by 34.1%, while significantly decreasing bulk density (BD) by 9.8% and the nitrogen: phosphorus ratio (N:P) by 47.1%. (2) The soil fungal community composition differed among the grassland types, For example, significant differences were found among the three grassland types for the Glomeromycota and Mucoromycota. (3) Under the influence of both grazing exclusion and grassland type, there was no significant change in soil fungal alpha diversity, but there were significant differences in fungal beta diversity. (4) Grassland type was the most important factor influencing changes in fungal community diversity, and vegetation cover and soil kjeldahl nitrogen were the main factors influencing fungal diversity. Our research provides a long-term perspective for better understanding and managing different grasslands, as well as a better scientific basis for future research on grass-soil-microbe interactions.

Chromosomal level genome assemblies of two Malus crabapple cultivars Flame and Royalty.

Malus hybrid 'Flame' and Malus hybrid 'Royalty' are representative ornamental crabapples, rich in flavonoids and serving as the preferred materials for studying the coloration mechanism. We generated two sets of high-quality chromosome-level and haplotype-resolved genome of 'Flame' with sizes of 688.2 Mb and 675.7 Mb, and those of 'Royalty' with sizes of 674.1 Mb and 663.6 Mb, all anchored to 17 chromosomes and with a high BUSCO completeness score nearly 99.0%. A total of 47,833 and 47,307 protein-coding genes were annotated in the two haplotype genomes of 'Flame', and the numbers of 'Royalty' were 46,305 and 46,920 individually. The assembled high-quality genomes offer new resources for studying the origin and adaptive evolution of crabapples and the molecular basis of the accumulation of flavonoids and anthocyanins, facilitating molecular breeding of Malus plants.

Programmed Targeting Pyruvate Metabolism Therapy Amplified Single-Atom Nanozyme-Activated Pyroptosis for Immunotherapy.

Increasing cellular immunogenicity and reshaping the immune tumor microenvironment (TME) are crucial for antitumor immunotherapy. Herein, this work develops a novel single-atom nanozyme pyroptosis initiator: UK5099 and pyruvate oxidase (POx)-co-loaded Cu-NS single-atom nanozyme (Cu-NS@UK@POx), that not only trigger pyroptosis through cascade biocatalysis to boost the immunogenicity of tumor cells, but also remodel the immunosuppressive TME by targeting pyruvate metabolism. By replacing N with weakly electronegative S, the original spatial symmetry of the Cu-N4 electron distribution is changed and the enzyme-catalyzed process is effectively regulated. Compared to spatially symmetric Cu-N4 single-atom nanozymes (Cu-N4 SA), the S-doped spatially asymmetric single-atom nanozymes (Cu-NS SA) exhibit stronger oxidase activities, including peroxidase (POD), nicotinamide adenine dinucleotide (NADH) oxidase (NOx), L-cysteine oxidase (LCO), and glutathione oxidase (GSHOx), which can cause enough reactive oxygen species (ROS) storms to trigger pyroptosis. Moreover, the synergistic effect of Cu-NS SA, UK5099, and POx can target pyruvate metabolism, which not only improves the immune TME but also increases the degree of pyroptosis. This study provides a two-pronged treatment strategy that can significantly activate antitumor immunotherapy effects via ROS storms, NADH/glutathione/L-cysteine consumption, pyruvate oxidation, and lactic acid (LA)/ATP depletion, triggering pyroptosis and regulating metabolism. This work provides a broad vision for expanding antitumor immunotherapy.

USP14 promotes the cancer stem-like cell properties of OSCC via promoting SOX2 deubiquitination.

OBJECTIVE: USP14 (Ubiquitin-specific-processing protease 14) is a deubiquitinating enzyme with oncogenic effects in oral squamous cell carcinoma (OSCC). This study aims to identify new substrates of USP14 and elucidate their role in modulating cancer stem-like cells (CSCs) in OSCC. MATERIALS AND METHODS: Bioinformatics prediction and docking were performed using UbiBrowser 2.0 and HDOCK, respectively. OSCC cell lines and patient-derived cells were used for experimental validation, employing co-immunoprecipitation, cycloheximide chase assays, and tumor sphere formation to evaluate the effects of USP14 on SOX2 stability, ubiquitination, and CSC phenotypes. RESULTS: USP14 upregulation was associated with worse overall survival and progression-free interval in OSCC. USP14 interacted with SOX2 with its ubiquitin carboxyl-terminal hydrolase domain. USP14 knockdown impaired SOX2 stability by increasing its polyubiquitination. Ectopic overexpression of wild-type USP14, but not the hydrolase-deficient-mutant USP14C114A , enhanced SOX2 stability by reducing polyubiquitination. USP14 knockdown suppressed OSCC cell proliferation, colony formation, and tumor sphere formation in vitro and tumor growth in vivo. However, the reduction of CSC markers following USP14 knockdown was mitigated by overexpressing SOX2. These findings were verified in OSCC patient-derived CSC cells. CONCLUSION: This study revealed a USP14-SOX2 axis regulating the CSC properties of OSCC.

Astragaloside IV alleviates macrophage senescence and d-galactose-induced bone loss in mice through STING/NF-κB pathway.

BACKGROUND: Senile osteoporosis (SOP) is an age-related metabolic bone disease that currently lacks specific therapeutic interventions. Thus, this study aimed to investigate the effect of Astragaloside IV (AS-IV) on macrophage senescence, bone marrow mesenchymal stem cell (BMSC) osteogenesis, and SOP progression. METHODS: A senescent macrophage model was established and treated with varying concentrations of AS-IV. Cell activity was measured using the CCK8 assay. The senescence levels of macrophages were evaluated through ß-galactosidase staining, PCR, and immunofluorescence. Macrophage mitochondrial function was assessed using ROS and JC-1 staining. Macrophage polarization was evaluated through PCR, Western blot, and immunofluorescence. The inhibitory effects of AS-IV on macrophage senescence were investigated using Western blot analysis. Furthermore, the effects of macrophage conditioned medium (CM) on BMSCs osteogenic were detected using ALP, alizarin red, and PCR. RESULTS: AS-IV inhibited macrophage senescence and M1 polarization, alleviated mitochondrial dysfunction, and promoted M2 polarization. Mechanistically, it suppressed the STING/NF-κB pathway in H2O2-activated macrophages. Conversely, the STING agonist c-di-GMP reversed the effects of AS-IV on macrophage senescence. Additionally, AS-IV-induced macrophage CM promoted BMSC osteogenic differentiation. In vivo, AS-IV treatment ameliorated aberrant bone microstructure and bone mass loss in the SOP mouse model, inhibited macrophage senescence, and promoted M2 polarization. CONCLUSIONS: By modulating the STING/NF-κB signaling pathway, AS-IV potentially inhibited macrophage senescence and stimulated osteogenic differentiation of BMSCs, thus exerting an anti-osteoporotic effect. Consequently, AS-IV may serve as an effective therapeutic candidate for the treatment of osteoporosis.

Robust changes in global subtropical circulation under greenhouse warming.

The lower tropospheric subtropical circulation (SC) is characterized by monsoons and subtropical highs, playing an important role in global teleconnections and climate variability. The SC changes in a warmer climate are influenced by complex and region-specific mechanisms, resulting in uneven projections worldwide. Here, we present a method to quantify the overall intensity change in global SC, revealing a robust weakening across CMIP6 models. The weakening is primarily caused by global-mean surface warming, and partly counteracted by the direct CO2 effect. The direct CO2 effect is apparent in the transient response but is eventually dominated by the surface warming effect in a slow response. The distinct response timescales to global-mean warming and direct CO2 radiative forcing can well explain the time-varying SC changes in other CO2 emission scenarios. The declined SC implies a contracted monsoon range and drying at its boundary with arid regions under CO2-induced global warming.

A Study on the Growth and Development Characteristics of Lindian Chickens.

As an excellent chicken breed found in a high-altitude zone of northern China, Lindian chickens are characterized by good egg and meat production, strong adaptability, cold tolerance, rough feeding resistance, excellent egg quality, and delicious meat quality. To facilitate the exploitation of the unique qualities of the Lindian chicken, the varying patterns and correlations of various body size and carcass traits of 3-22-week-old Lindian chickens were analyzed in this study. The optimal growth model of these traits was determined by growth curve fitting analysis. The results showed that most traits of Lindian chickens increased steadily with increasing age, and most of them increased rapidly before 10 weeks of age. In addition, the inflection point age of each trait was predicted to be between 4 and 10 weeks. Furthermore, this study revealed that body size traits were closely related to carcass traits in Lindian chickens. In summary, Lindian chickens are in a rapid growth stage before the age of 10 weeks, and better slaughter performance can be achieved through good feeding management during this stage. The reproductive traits and muscles are the main developmental focus after the age of 19 weeks, so it is important to adequately meet their energy requirements for subsequent good breeding performance.

Silky Liquid Metal Electrodes for On-Skin Health Monitoring.

Next generation on-skin electrodes will require soft, flexible, and gentle materials to provide both high-fidelity sensing and wearer comfort. However, many commercially available on-skin electrodes lack these key properties due to their use of rigid hardware, harsh adhesives, uncomfortable support structures, and poor breathability. To address these challenges, this work presents a new device paradigm by joining biocompatible electrospun spider silk with printable liquid metal to yield an incredibly soft and scalable on-skin electrode that is strain-tolerant, conformable, and gentle on-skin. These electrodes, termed silky liquid metal (SLiM) electrodes, are found to be over five times more breathable than commercial wet electrodes, while the silk's intrinsic adhesion mechanism allows SLiM electrodes to avoid the use of harsh artificial adhesives, potentially decreasing skin irritation and inflammation over long-term use. Finally, the SLiM electrodes provide comparable impedances to traditional wet and other liquid metal electrodes, offering a high-fidelity sensing alternative with increased wearer comfort. Human subject testing confirmed the SLiM electrodes ability to sense electrophysiological signals with high fidelity and minimal irritation to the skin. The unique properties of the reported SLiM electrodes offer a comfortable electrophysiological sensing solution especially for patients with pre-existing skin conditions or surface wounds.

Pan-cancer analysis of the prognostic significance of ACKR2 expression and the related genetic/epigenetic dysregulations.

OBJECTIVE: ACKR2 is a scavenger for most inflammation-related CC chemokines. This study aimed to assess the pan-cancer prognostic significance of ACKR2 and the genetic and epigenetic mechanisms underlying its dysregulation. METHODS: Pan-cancer data from The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and The Genotype-Tissue Expression (GTEx) were integrated and analyzed. RESULTS: ACKR2 is consistently associated with favorable progression-free interval (PFI) and overall survival (OS) in TCGA-uveal melanoma (UVM) and TCGA-liver hepatocellular carcinoma (LIHC). ACKR2 is negatively correlated with the expression of CCL1, CCL4, CCL5, CXCL8, CCL17, and CCL20 in TCGA-UVM and TCGA-LIHC. The group with gene copy gain had significantly higher ACKR2 expression than those with loss. The lower ACKR2 expression groups were associated with a significantly higher ratio of BAP1 mutations. In addition, ACKR2 was negatively corrected with DNMT1 expression but was positively corrected with ZC3H13, an m6A writer gene and NSUN3, an RNA m5C writer gene. CONCLUSIONS: ACKR2 expression was associated with favorable prognosis in patients with uveal melanoma and hepatocellular carcinoma. ACKR2 dysregulation might be an accumulated result of gene copy number alterations, transcriptional disruption, and RNA modifications.

Research on Positioning Accuracy of Mobile Robot in Indoor Environment Based on Improved RTABMAP Algorithm.

Visual simultaneous localization and mapping is a widely used technology for mobile robots to carry out precise positioning in the environment of GNSS technology failure. However, as the robot moves around indoors, its position accuracy will gradually decrease over time due to common and unavoidable environmental factors. In this paper, we propose an improved method called RTABMAP-VIWO, which is based on RTABMAP. The basic idea is to use an Extended Kalman Filter (EKF) framework for fusion attitude estimates from the wheel odometry and IMU, and provide new prediction values. This helps to reduce the local cumulative error of RTABMAP and make it more accurate. We compare and evaluate three kinds of SLAM methods using both public datasets and real indoor scenes. In the dataset experiments, our proposed method reduces the Root-Mean-Square Error (RMSE) coefficient by 48.1% compared to the RTABMAP, and the coefficient is also reduced by at least 29.4% in the real environment experiments. The results demonstrate that the improved method is feasible. By incorporating the IMU into the RTABMAP method, the trajectory and posture errors of the mobile robot are significantly improved.

Association of air pollution exposure and increased coronary artery disease risk: the modifying effect of genetic susceptibility.

BACKGROUND: Both genetic factors and air pollution are risk factors for coronary artery disease (CAD), but their combined effects on CAD are uncertain. The study aimed to comprehensively investigate their separate, combined and interaction effects on the onset of CAD. METHODS: We utilized data from the UK Biobank with a recruitment of 487,507 participants who were free of CAD at baseline from 2006 to 2010. We explored the separate, combined effect or interaction association among genetic factors, air pollution and CAD with the polygenic risk score (PRS) and Cox proportional hazard models. RESULTS: The hazard ratios (HRs) [95% confidence interval (CI)] of CAD for 10-µg/m3 increases in PM2.5, NO2 and NOx concentrations were 1.25 (1.09, 1.44), 1.03 (1.01, 1.05) and 1.01 (1.00, 1.02), respectively. Participants with high PRS and air pollution exposure had a higher risk of CAD than those with the low genetic risk and low air pollution exposure, and the HRs (95% CI) of CAD in the PM2.5, PM10, NO2 and NOx high joint exposure groups were 1.56 (1.48, 1.64), 1.55(1.48, 1.63), 1.57 (1.49, 1.65), and 1.57 (1.49, 1.65), respectively. Air pollution and genetic factors exerted significant additive effects on the development of CAD (relative excess risk due to the interaction [RERI]: 0.12 (0.05, 0.19) for PM2.5, 0.17 (0.10, 0.24) for PM10, 0.14 (0.07, 0.21) for NO2, and 0.17 (0.10, 0.24) for NOx; attributable proportion due to the interaction [AP]: 0.09 (0.04, 0.14) for PM2.5, 0.12 (0.07, 0.18) for PM10, 0.11 (0.06, 0.16) for NO2, and 0.13 (0.08, 0.18) for NOx). CONCLUSION: Exposure to air pollution was significantly related to an increased CAD risk, which could be further strengthened by CAD gene susceptibility. Additionally, there were positive additive interactions between genetic factors and air pollution on the onset of CAD. This can provide a more comprehensive, precise and individualized scientific basis for the risk assessment, prevention and control of CAD.

Optimization of Arrhythmia-based ECG-lead Selection for Computer-interpreted Heart Rhythm Classification.

The 12-lead ECG only has 8 independent ECG leads, which leads to diagnostic redundancy when using all 12 leads for heart arrhythmias classification. We have previously developed a deep learning (DL)-based computer-interpreted ECG (CIE) approach to identify an optimal 4-lead ECG subset for classifying heart arrhythmias. However, the clinical diagnostic criteria of cardiac arrhythmia types are often lead-specific, so this study is going to explore the selection of arrhythmia-based ECG-lead subsets rather than one general optimal ECG-lead subset, which could improve the classification performance for the CIE. The DL-based CIE model previously developed was used to learn 4 common types of heart arrhythmias (LBBB, RBBB, AF, and I-AVB) for identifying corresponding optimal ECG-lead subsets. A public dataset that splits into training (approx. 70%), validation (approx. 15%), and test (approx. 15%) sets from the PhysioNet Cardiology Challenge 2020 was used to explore the study. The results demonstrated that the DL-based CIE model identified an optimal ECG-lead subset for each arrhythmia: I, II, aVR, aVL, V1, V3, and V5 for I-AVB; I, II, aVR, and V3 for AF; I, II, aVR, aVF, V1, V3, and V4 for LBBB; and I, II, III, aVR, V1, V4, and V6 for RBBB. For each arrhythmia classification, the DL-based CIE model using the optimal ECG-lead subset significantly outperformed the model using the full 12-lead ECG set on the validation set and on the external test dataset.The results support the hypothesis that using an optimal ECG-lead subset instead of the full 12-lead ECG set can improve the classification performance of a specific arrhythmia when using the DL-based CIE approach.Clinical Relevance- Using an arrhythmia-based optimal ECG-lead subset, the classification performance of a deep-learning-based model can be achieved without loss of accuracy in comparison with the full 12-lead set (p<0.05).

Ser252Asn Mutation Introduces a New N-Linked Glycosylation Site and Causes Type IIb Protein C Deficiency.

BACKGROUND: Protein C (PC) is a vitamin K-dependent anticoagulant serine protease zymogen which upon activation by the thrombin-thrombomodulin (TM) complex downregulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. We identified a thrombosis patient who carried a heterozygous mutation c.881G > A, p.Ser252Asn (S252N) in PROC. This mutation was originally described in a report of novel mutations in patients presenting with defective PC anticoagulant activity in Paris. The research identified PC-S252N (the "Paris" mutation) in a propositus and her family members and highlighted the critical role of Ser252 in the anticoagulation process of activated PC (APC). MATERIAL AND METHODS: We expressed the PC-S252N mutant in mammalian cells and characterized the properties in coagulation assays to decipher the molecular basis of anticoagulant defect of this mutation. RESULTS: We demonstrated that PC-S252N had a diminished ability to TM binding, which resulted in its impaired activation by the thrombin-TM complex. However, APC-S252N exhibited a slightly stronger cleavage capacity for the chromogenic substrate. Meanwhile, the catalytic activity of APC-S252N toward FVa was significantly reduced. Sequence analysis revealed that Ser252 to Asn substitution introduced a new potential N-linked glycosylation site (252NTT254) in the catalytic domain of PC, which adversely affected both the activation process of PC and anticoagulant activity of APC. CONCLUSION: The new N-glycosylation site (252NTT254) resulting from the mutation of Ser252 to Asn252 in PROC affects the overall structure of the protease, thereby adversely affecting the anticoagulant function of protein C. This modification has a negative impact on both TM-promoted activation of protein C and APC cleavage of FVa, ultimately leading to thrombosis in the patient.

A deep learning-based model (DeepMPM) to help predict survival in patients with malignant pleural mesothelioma.

Background: Malignant pleural mesothelioma (MPM) is a rare disease with limited treatment and poor prognosis, and a precise and reliable means to predicting MPM remains lacking for clinical use. Methods: In the population-based cohort study, we collected clinical characteristics from the Surveillance, Epidemiology, and End Results (SEER) database. According to the time of diagnosis, the SEER data were divided into 2 cohorts: the training cohort (from 2010 to 2016) and the test cohort (from 2017 to 2019). The training cohort was used to train a deep learning-based predictive model derived from DeepSurv theory, which was validated by both the training and the test cohorts. All clinical characteristics were included and analyzed using Cox proportional risk regression or Kaplan-Meier curve to determine the risk factors and protective factors of MPM. Results: The survival model included 3,130 cases (2,208 in the training cohort and 922 in the test cohort). As for model's performance, the area under the receiver operating characteristics curve (AUC) was 0.7037 [95% confidence interval (CI): 0.7030-0.7045] in the training cohort and 0.7076 (95% CI: 0.7067-0.7086) in the test cohort. Older age; male sex, sarcomatoid mesothelioma; and T4, N2, and M1 stage tended to be the risk factors for survival. Meanwhile, epithelioid mesothelioma, surgery, radiotherapy, and chemotherapy tended to be the protective factors. The median overall survival (OS) of patients who underwent surgery combined with radiotherapy was the longest, followed by those who underwent a combination of surgery, radiotherapy, and chemotherapy. Conclusions: Our deep learning-based model precisely could predict the survival of patients with MPM; moreover, multimode combination therapy might provide more meaningful survival benefits.

Epithelial Membrane Protein-3 and Chitinase-3-like Protein-1 as New Prognostic Predictors of Glioma, a Two-Gene Study.

BACKGROUND: Glioblastoma multiforme is the most common primary intracranial tumor, with a high degree of malignancy, poor therapeutic effect, and poor prognosis. According to previous studies, CHI3L1 and EMP3 are two independent tumor predictors that are of great significance for the prognostic prediction of other tumors, and their expression levels may be related to the prognosis of glioma patients. METHODS: using Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), the Chinese Glioma Genome Atlas (CGGA), cBioPortal, LinkedOmics, and other databases, 693 glioma patients were screened to analyze the relationship between EMP3 and CHI3L1 expression and prognosis in glioma patients. RESULTS: low-grade glioma patients with a low expression of EMP3/CHI3L1 had a better prognosis, and the combination of EMP3/CHI3L1 is a new predictor for glioma patients. CONCLUSION: We used the TCGA and CGGA databases to analyze the effect of EMP3 and CHI3L1 expression on the prognosis of glioma patients and their correlation with gene expression using bioinformation analysis. The results showed that low-grade glioma patients with a low expression of EMP3 and CHI3L1 had a better prognosis, and EMP3 and CHI3L1 co-expression genes were correlated. The combination of these two factors could be a new prognostic index for glioma patients.