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Host cellular receptors play key roles in the determination of virus tropism and pathogenesis. However, little is known about SARS-CoV-2 host receptors with the exception of ACE2. Furthermore, ACE2 alone cannot explain the multi-organ tropism of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV, suggesting the involvement of other receptor(s). Here, we performed genomic receptor profiling to screen 5054 human membrane proteins individually for interaction with the SARS-CoV-2 capsid spike (S) protein. Twelve proteins, including ACE2, ASGR1, and KREMEN1, were identified with diverse S-binding affinities and patterns. ASGR1 or KREMEN1 is sufficient for the entry of SARS-CoV-2 but not SARS-CoV in vitro and in vivo. SARS-CoV-2 utilizes distinct ACE2/ASGR1/KREMEN1 (ASK) receptor combinations to enter different cell types, and the expression of ASK together displays a markedly stronger correlation with virus susceptibility than that of any individual receptor at both the cell and tissue levels. The cocktail of ASK-related neutralizing antibodies provides the most substantial blockage of SARS-CoV-2 infection in human lung organoids when compared to individual antibodies. Our study revealed an interacting host receptome of SARS-CoV-2, and identified ASGR1 and KREMEN1 as alternative functional receptors that play essential roles in ACE2-independent virus entry, providing insight into SARS-CoV-2 tropism and pathogenesis, as well as a community resource and potential therapeutic strategies for further COVID-19 investigations.

8-Oxo-7,8-dihydro-2′-deoxyguanosine (OG), one of the most common oxidative DNA damages, causes genome instability and is associated with cancer, neurological diseases and aging. In addition, OG and its repair intermediates can regulate gene transcription, and thus play a role in sensing cellular oxidative stress. However, the lack of methods to precisely map OG has hindered the study of its biological roles. Here, we developed a single-nucleotide resolution OG-sequencing method, named CLAPS-seq (Chemical Labeling And Polymerase Stalling Sequencing), to measure the genome-wide distribution of both exogenous and endogenous OGs with high specificity. Our data identified decreased OG occurrence at G-quadruplexes (G4s), in association with underrepresentation of OGs in promoters which have high GC content. Furthermore, we discovered that potential quadruplex sequences (PQSs) were hotspots of OGs, implying a role of non-G4-PQSs in OG-mediated oxidative stress response.

High-dimensional small sample data are prone to the curse of dimensionality and overfitting and contain many irrelevant and redundant features. In order to solve these feature selection problems, a new Two-stage Hybrid Feature Selection Algorithm (Ts-HFSA) is proposed. The first stage uses the Filter method combined with the Wrapper method to adaptively remove irrelevant features. In the second stage, a De-redundancy Algorithm of Fusing Approximate Markov Blanket with L1 Regular Term (DA2MBL1) is used to solve the AMB’s problem of information loss when deleting redundant features and potential redundancy in the subset of features obtained by AMB. The experimental results on multiple UCI public data sets and datasets from the material foundation of Chinese medicine showed that the Ts-HFSA better deleted irrelevant features and redundant features, found smaller and higher quality feature subsets, and improved stability, indicating that it offers more advantages than AMB, FCBF, RF, GBDT, XGBoost, Lasso, and CI_AMB. Moreover, in the face of data of the material foundation of Chinese medicine, with higher feature dimensions and fewer sample sizes, Ts-HFSA performed better, which can also improve the precision of the model after greatly reducing the dimension. The results indicated that Ts-HFSA is an effective method for feature selection of high-dimensional small samples and an excellent research method for the material foundation of Chinese medicine.

Ternary two-dimentional (2D) materials exhibit diverse physical properties depending on their composition, structure, and thickness. Through forming heterostructures with other binary materials that show similar structure, there can be numerous potential applications of these ternary 2D materials. In this work, we reported the structure of few-layer CrPS4 by X-ray diffraction, transmission electron microscope, and electron-density distribution calculation. We also demonstrated a new application of the CrPS4/MoS2 heterobilayer: visible-infrared photodetectors with type-II staggered band alignment at room temperature. The response of the heterostructure to infrared light results from a strong interlayer coupling that reduces the energy interval in the junction area. Since the intrinsic bandgap of individual components determines wavelengths, the decrease in energy interval allows better detection of light that has a longer wavelength. We used photoluminescence (PL) spectroscopy, Kelvin probe force microscopy (KPFM) under illumination, and electrical transport measurements to verify the photoinduced charge separation between the CrPS4/MoS2 heterostructures. At forward bias, the device functioned as a highly sensitive photodetector, as the wavelength-dependent photocurrent measurement achieved the observation of optical excitation from 532 to 1,450 nm wavelength. Moreover, the photocurrent caused by interlayer exciton reached around 1.2 nA at 1,095 nm wavelength. Our demonstration of the strong interlayer coupling in the CrPS4/MoS2 heterostructure may further the understanding of the essential physics behind binary-ternary transition metal chalcogenides heterostructure and pave a way for their potential applications in visible-infrared devices.

Geothermal energy is new, environmentally friendly, and clean energy, which is of great significance to realize energy saving and emission reduction. The study of the genesis mechanism of geothermal water is the key to its rational development and utilization. In this study, based on 14 sets of water samples from the eastern section of the copper well mining area of Yinan Gold Mine, mineral saturation index, isotope analysis (δ

Excessive acid deposition causes soil acidification, and changes the soil microhabitat, thus affecting the survival and reproduction of soil organisms. Folsomia candida (Collembola, Isotomidae), as a model organism, is widely used to assess the chemical toxicity in soil, and its avoidance response can indicate the environmental changes. In this study, we used Folsomia candida to assess the risks of acid deposition on soil ecosystems. Different pH (3.0, 3.5, 4.0, 4.5, 5.0, and 5.5) treatments were set up in petri dish experiments, and the avoidance behavior of Folsomia candida was measured after 12, 24, and 48 h exposure to the pH conditions. The results indicated that (1) both the exposure duration and pH level influenced avoidance behavior of collembolan. (2) After 12 h exposure, most of the individuals showed avoidance behavior but without significant differences among the treatments. (3) After 24 h exposure, significant avoidance behavior was observed at pH 3.0, 3.5, and 4.0. (4) After 48 h exposure, avoidance behavior was found in all treatment conditions except for pH 5.5. This study clarified the direct responses of soil fauna to acid deposition, and indicated that both pH and length of exposure influenced the avoidance behavior of Folsomia candida. During the experimental period, the collembolan reacted negatively and showed consistent avoidance behavior at pH 3.0, 3.5, and 4.0. Reversed avoidance behavior was apparent between pH 4.5 and 5.0 and not observed at pH 5.5, indicating that the latter was the preferred pH environment.

The ten-eleven translocation (Tet) family of dioxygenases convert 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Previous studies have shown that 5hmC-mediated epigenetic modifications play essential roles in diverse biological processes and diseases. Here, we show that Tet proteins and 5hmC display dynamic features during postnatal cardiac development and that Tet2 is the predominant dioxygenase present in heart. Tet2 knockout results in abnormal cardiac function, progressive cardiac hypertrophy and fibrosis. Mechanistically, Tet2 deficiency leads to reduced hydroxymethylation in the cardiac genome and alters the cardiac transcriptome. Mechanistically, Tet2 loss leads to a decrease of Hspa1b expression, a regulator of the extracellular signal-regulated protein kinase (Erk) signaling pathway, which leads to over-activation of Erk signaling. Acute Hspa1b knock down (KD) increased the phosphorylation of Erk and induced hypertrophy of cardiomyocytes, which could be blocked by Erk signaling inhibitor. Consistently, ectopic expression of Hspa1b was able to rescue the deficits of cardiomyocytes induced by Tet2 depletion. Taken together, our study’s results reveal the important roles of Tet2-mediated DNA hydroxymethylation in cardiac development and function.

MTAP deletion is common in about 15% of all human cancers and coincides with the deletion of tumor suppressor locus containing CDKN2A/B. Methylthioadenosine (MTA), the substrate of MTAP, accumulates as a result of MTAP deletion. Increased levels of MTA result in partial inhibition of the PRMT5 enzyme by competing with S-adenosylmethionine (SAM, the methyl donor for PRMT5 substrate) due to structural similarity. Cancer cell lines with MTAP-deletion exhibit profound sensitivity to PRMT5 inhibition, suggesting MTAPnull-selective PRMT5 inhibitors have the potential to treat patients with MTAP deficiency (Kryukov et al., 2016). We identified CTS3157 as an orally bioavailable small molecule MTA-cooperative PRMT5 inhibitor that binds to PRMT5-MTA complex and inhibits PRMT5 enzymatic activity. Cell-based assays revealed that CTS3157 demonstrated potent PRMT5 inhibition as evidenced by suppression of symmetric dimethylarginine (SDMA) and cell growth inhibitory activity for MTAP-deleted cell lines over isogenic MTAPWT cell lines. Moreover, CTS3157 series compounds exhibited strong cell growth inhibition in a diverse panel of MTAPnull human tumor cell lines across several lineages. In vivo, CTS3157 demonstrated potent antitumor response after once-daily oral administration in MTAP-deleted xenograft models. The anti-tumor activity is correlated with PRMT5 modulation as measured by reduced SDMA levels. At molecular level, PRMT5 inhibition by CTS3157 resulted in massive RNA splicing defects and differentially expressed genes involving key cellular activities in MTAPnull cells. In summary, MTAPnull-selective PRMT5 inhibitor CTS3157 showed strong and durable antitumor responses in vitro and in vivo in MTAP-deleted tumors across diverse lineages. CTS3157 is an effective and promising therapeutics against MTAP-deleted tumors. Citation Format: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6273.

Methylation of arginine residues by protein arginine methyltransferases (PRMTs) is involved in the regulation of fundamental cellular processes. Type I PRMTs are frequently overexpressed in a variety of human cancers and associated with poor prognosis. Knockout (KO) of Prmt1 in mice results in decreased asymmetric dimethylarginine (ADMA) on cellular proteins, together with increased monomethylarginine (MMA) and symmetric dimethylarginine (SDMA) (Dhar et al., 2013). A structure-based drug discovery effort led to the identification of CTS2190 that showed single-digit nanomolar enzymatic inhibitory activity on type I PRMTs. Here, we report the development and preclinical characterization of CTS2190, a potent, orally bioavailable small molecule type I PRMT inhibitor. CTS2190 demonstrated strong cellular proliferation inhibitory activity in a large, diverse panel of human hematological and solid tumor cell lines across several lineages. In vivo, oral CTS2190 administration once daily resulted in tumor regression in a variety of xenograft (both CDX and PDX) models across different lineages with good tolerance. The anti-tumor activity was dose-dependent and correlated with the inhibition of type I PRMT activity as measured by decrease in ADMA and increase in MMA. In summary, CTS2190 is a promising type I PRMT inhibitor and clinical trial is underway to explore the proof-of-concept anti-tumor benefit for patients. Citation Format: Hui Shi, Xingnian Fu, Qiugeng Ouyang, Jiaxin Huang, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6279.

Chromobox 4 (CBX4) is a core component of polycomb-repressive complex 1 with important roles in cancer biology and tissue homeostasis. Aberrant expression of CBX4 has been implicated in several human malignancies. However, its role and underlying mechanisms in the tumorigenesis of lung adenocarcinoma (LUAD) have not been defined in vivo. Here, we found that expression of CBX4 was frequently up-regulated in human LUAD samples and correlated with poor patient survival. Importantly, genetic ablation of CBX4 greatly dampened lung tumor formation and improved survival in the KrasG12D/P53L/L (KP) autochthonous mouse model of LUAD. In addition, CBX4 depletion significantly inhibited proliferation and anchorage-independent growth of KP mouse embryonic fibroblasts. Moreover, ectopic CBX4 expression clearly promoted proliferation and anchorage-independent growth in both human and mouse LUAD cells, whereas silencing of CBX4 exerted opposite effects. Mechanistically, CBX4 promoted growth of LUAD cells through activation of the Wnt/β-catenin pathway. Furthermore, expression levels of CBX4 were positively correlated with β-catenin in human LUAD samples. In conclusion, our data suggest that CBX4 plays an oncogenic role via the Wnt/β-catenin pathway and could serve as a potential therapeutic target in LUAD.

In this paper, we propose to apply data augmentation approaches that provide more diverse training images, thus helping train more robust deep models for the Scene Text Recognition (STR) task. The data augmentation methods are Random Blur Region (RBR) and Random Blur Units (RBUs). Specifically, we first introduce RBR designed for the STR task. In training, RBR randomly selects a region and sets the pixels in this region with an average value. However, when RBR provides more various training samples for STR, it may make the samples ambiguous and reduce the recognition accuracy. To address the above problem, we also propose RBUs that divides the blur region into several units. Note that the pixels of one unit share the same value. In this way, RBUs can provide additional readable training samples and help train more robust deep models. Extensive experiments on several STR datasets show that RBUs achieve highly competitive performance. Besides, RBUs are complementary to commonly used data augmentation techniques.

Selective aerobic oxidation of alcohols under mild conditions is of great importance yet challenging, with the activation of molecular oxygen (O2) as a crucial capability of the catalysts. Herein, we demonstrate that an Al2O3-supported Pd single-atom catalyst leads to higher activity and selectivity compared to Pd nanoparticles for the oxidation of cinnamyl alcohol. The Al2O3 support used in this study is rich in coordinately unsaturated Al3+ sites, which are apt for binding to Pd atoms through oxygen bridges and present a distinct metal-support interaction (MSI). The suitable MSI then leads to a unique electronic characteristic of the Pd single atoms, which can be confirmed via X-ray photoelectron spectroscopy, normalized X-ray absorption near-edge structure, and diffuse reflectance Fourier transform infrared spectroscopy. Moreover, this unique electronic state is proposed to be responsible for its high catalytic activity. With the help of in-situ UV-vis spectra and electron spin resonance spectra, a specific alcohol oxidation route with O2 activation mechanism is then identified. Active oxygen species behaving chemically like singlet-O2 are generated from the interaction of O2 with Pd1/Al2O3, and then oxidize the partially dehydrogenated intermediates produced by the adsorbed allylic alcohols and Pd atoms to the desired alkenyl aldehyde. This work provides a promising path for the design and development of high-activity catalysts for aerobic oxidation reactions.

The repertoire of nucleobase methylation in DNA and RNA, introduced by chemical agents or enzymes, is large. Most methylation can be reversed either directly by restoration of the original nucleobase or indirectly by replacement of the methylated nucleobase with an unmodified nucleobase. In many direct and indirect demethylation reactions, ALKBH (AlkB homolog) and TET (ten eleven translocation) hydroxylases play a role. Here, we suggest a chemical classification of methylation types. We then discuss pathways for removal, emphasizing oxidation reactions. We highlight the recently expanded repertoire of ALKBH- and TET-catalyzed reactions and describe the discovery of a TET-like protein that resembles the hydroxylases but uses an alternative co-factor and catalyzes glyceryl transfer rather than hydroxylation.

Shenfu Injection (SFI) is a common drug used to treat cardiovascular diseases and has a significant effect on cardiogenic shock. Ginsenoside Rc (G-Rc) was an anticardiogenic shock effect component of SFI screened by UHPLC-Q-TOF/MS and multivariate statistical analysis and further selected by molecular docking experiment in our previous study. However, most studies on SFI in the treatment of cardiogenic shock focus on the overall efficacy, and little is known about its effective component on energy metabolism in hypoxia/reoxygenation- (H/R-) induced myocardial injury cells. Therefore, the present study was performed to investigate the dose-effect and time-effect relationship of G-Rc in protecting hypoxic injury of H9c2 cardiomyocytes, and its mechanism on the energy metabolism-related indicators, i.e., adenosine triphosphate (ATP) content, lactate dehydrogenase (LDH) release, and creatine kinase (CK) activity of the myocardial cells, was explored. In this paper, a stable and reliable H/R model of H9c2 cardiomyocytes was established. Compared with the control group, the activity of cardiomyocytes in the H/R group was significantly reduced (P<0.01). The dose-effect and time-effect studies showed that G-Rc could significantly increase cell viability at certain point compared with the H/R group (P<0.01), and the optimum intervention dose and time was 3.33 μmol/L for 12 h. The results concerning energy metabolism mechanism demonstrated that G-Rc pretreatment could improve ATP content, attenuate the LDH leakage, and decrease CK activity and apoptosis rate of H/R cardiomyocytes. Taken together, our findings suggest that G-Rc pretreatment can significantly protect myocardial cells from H/R injury. In addition, G-Rc is able to improve the energy metabolism ability of the injury cardiomyocytes by direct synthesis of ATP and reducing the activity of LDH, CK, and apoptosis rate. These results indicate that G-Rc may be a promising therapeutic candidate for the treatment of cardiovascular disease caused by myocardial H/R injury.

The development of abnormal lipid-induced atherosclerosis is initiated with endothelial cell apoptosis. Vascular endothelial cells possess highly developed endoplasmic reticulum (ER), which is involved in lipid metabolism, indicating that ER stress may contribute chiefly to the induction of endothelial cell apoptosis. Based on its ability to reduce cholesterol levels, rosuvastatin may play an endothelial and vascular protective role by regulating ER stress. In the present study, the involvement of the inhibition of the ER stress-induced endothelial injury was investigated in combination with the lipid lowering effects of rosuvastatin. This compound can be used to inhibit cholesterol synthesis in atherosclerosis. Rosuvastatin decreased the apoptotic rates of human umbilical vascular endothelial cells (HUVECs) that had been stimulated with ox-low density lipoprotein (LDL) in vitro and repressed the mRNA levels of CHOP, sXBP1 and caspase-12, and decreased caspase-12 activity, as well as the content of glucose-regulated protein 78 (GRP78), phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-inositol-requiring protein 1α (IRE1α) and p-eIF2α proteins. In addition, ApoE-/- mice were fed with atherogenic chow for 8 weeks for atherosclerosis induction and rosuvastatin was provided by intragastric administration for an additional 4 weeks. Subsequently, the atherosclerotic plaque formation in the aorta was evaluated by Oil Red O and hematoxylin and eosin staining, and the serum LDL, high-density lipoprotein, total cholesterol (TC) and triacylglycerol (TG) levels were measured. In addition, the induction of apoptosis of endothelial cells and the expression levels of GRP78, p-PERK, p-IRE1α and p-eIF2α were assessed in the aorta. Rosuvastatin repressed atherosclerotic plaque formation and endothelial apoptosis in the aorta and decreased LDL and TG levels in the serum, as determined by in vivo results. Furthermore, it downregulated the expression levels of protein chaperone GRP78, p-PERK, p-IRE1α and p-eIF2α in the aortic intima. The data indicated that rosuvastatin could protect HUVECs from ER stress-induced apoptosis triggered by oxidized LDL. It could also inhibit atherosclerosis formation in ApoE-/- mice aorta by regulating the PERK/eIF2α/C/EBPα-homologous protein and IRE1α/sXBP1 signaling pathways. Taken collectively, the present study demonstrated the preventive and therapeutic effects of rosuvastatin in protecting from the development of endothelial cell dysfunction diseases.

Skyrmions with topologically nontrivial spin textures are promising information carriers in next-generation ultralow power consumption and high-density spintronic devices. To promote their further development and utilization, the search for new room temperature skyrmion-hosting materials is crucial. Considering that most of the previous skyrmion-hosting materials are noncollinear magnets, here, the detection of the topological Hall effect (THE) and the discovery of skyrmions at room temperature are first reported in a centrosymmetric complex noncollinear ferromagnet NdMn2Ge2. Below 330 K, the compound can host stable Bloch-type skyrmions with about 75 nm diameter in a wide window of magnetic field and temperature, including zero magnetic field and room temperature. Moreover, the skyrmions can induce a giant topological Hall effect in a wide temperature range with a maximum value of -2.05 μΩ cm. These features make the compound attractive for both fundamental research and potential application in novel spintronic devices.

A nucleosome contains two copies of each histone H2A, H2B, H3 and H4. Histone H3 K4me0 and K36me3 are two key chromatin marks for de novo DNA methylation catalyzed by DNA methyltransferases in mammals. However, it remains unclear whether K4me0 and K36me3 marks on both sister histone H3s regulate de novo DNA methylation independently or cooperatively. Here, taking advantage of the bivalent histone H3 system in yeast, we examined the contributions of K4 and K36 on sister histone H3s to genomic DNA methylation catalyzed by ectopically co-expressed murine Dnmt3a and Dnmt3L. The results show that lack of both K4me0 and K36me3 on one sister H3 tail, or lack of K4me0 and K36me3 on respective sister H3s results in a dramatic reduction of 5mC, revealing a synergy of two sister H3s in DNA methylation regulation. Accordingly, the Dnmt3a or Dnmt3L mutation that disrupts the interaction of Dnmt3aADD domain-H3K4me0, Dnmt3LADD domain-H3K4me0, or Dnmt3aPWWP domain-H3K36me3 causes a significant reduction of DNA methylation. These results support the model that each heterodimeric Dnmt3a-Dnmt3L reads both K4me0 and K36me3 marks on one tail of sister H3s, and the dimer of heterodimeric Dnmt3a-Dnmt3L recognizes two tails of sister histone H3s to efficiently execute de novo DNA methylation.

In recent years, speech recognition technology based on deep learning model has made great progress, and the accuracy of speech recognition has reached more than 90%. In foreign language learning, speech evaluation is an important application. Billions of foreign language learners need to practice effective pronunciation. However, due to the different goals between speech recognition and speech evaluation, a single speech recognition model cannot be directly applied to pronunciation evaluation. This paper proposes a DDNN (double-layer deep neural network) model, which includes the speech text alignment model and speech recognition model. In the first layer of the speech alignment model, a new Viterbi algorithm method is proposed to find the best path for the alignment of speech and text. In the second layer of speech evaluation and scoring, we are the first to use the CNN (Convolutional Neural Network) and RNN (Recurrent Neural Network) on the encoding part of Attention. The accuracy of CTC model reaches 76.7%, and that of attention model is 81.2%. The experimental results show that the speech and text alignment method is effective, and the speech evaluation results based on the Attention model are better. The FRR (false rejection rate), FAR (false acceptance rate), and DER (diagnostic rate) in the Attention model were 4.5%, 5.1%, and 17.9%, respectively. At the same time, the evaluation of each sentence of the DDNN model in the online experiment is within 1 second, so the model can also be applied to the online real-time evaluation of speech pronunciation.

Tire pressure monitoring is essential to driving safety. Indirect tire pressure monitoring system (TPMS) is a cost-effective alternative to direct tire pressure monitoring system. Its performance depends on the algorithm for data pre-processing and analysis which is normally complicated, sensitive to initial calibration with limited working range. In this work, four tests were carried out with Baojun 530 with a different deflated tire in each case. Speed data read through ABS CAN bus was analyzed and traditional frequency based method was employed to identify the deflated tire. To simplify the data pre-processing and improve response speed and working range, a new artificial neural network (ANN) based method was also proposed to identify deflated tire based on speed data point collected through antilock brake system (ABS) sensors in tests. A long short-term memory (LSTM) network was developed to locate the deflated tire with an accuracy of 0.83 after training for individual data points. And performance of this method can be further improved by employing a soft voting mechanism with 3 LSTM networks. In proposed ANN based method, benchmark data from properly inflated tire is not required, which makes it a promising solution for multiple deflated tires cases which is challenging for traditional frequency-based method.