Search

Abstract The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17fl/fl and A17α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.

Abstract Concessions—defined as the urban elements built by Western powers while ‘occupying’ various parts of the Chinese territory—have recently been granted heritage status by the Chinese national and local authorities. However, in many respects, they are ‘dissonant’ heritage sites since they are the result of the several-decade-long ‘colonial’ presence in Tianjin of nine foreign powers. The aim of this study is to understand how former international concessions are featured in museums and interpretation centres in present-day Tianjin. Using an approach that draws on dissonant heritage; literature on postcolonial museums, nostalgia and forgetting mechanisms; and the relationship between museographic narratives and patriotism, this article analyses a corpus of eight museums located in three former international concessions (Marshal Zhang’s Mansion, the Former Residence of Ma Zhanshan, the Museum of Modern History of Tianjin, the Five Avenues History Museum, the Museum of the Department Store Quan Ye Chang, Zhang House, the Astor Hotel Museum, the Tianjin Planning Exhibition Hall and the Tianjin Museum). The analysis is based on a common observation grid and semidirect interviews conducted with museum staff. The article captures and examines the main narratives from three perspectives: 1) revisiting the concession period as evidence of the beginning of modernity in China, which was a time in which celebrity life stories and the emergence of modern urban elements were praised; 2) considering the concessions as a dreamlike past of ‘others’ and ‘elsewheres’ belonging to a ‘foreign land’ and a context far removed from contemporary life in China, which favours the thematisation and leisure of Western architecture; and 3) selecting and targeting narratives focused on the heroes of the Republic of China (1912–1949) and the People’s Republic of China. This paper highlights and further develops how former Western concessions are imbued with a sense of both nostalgia and patriotism and sets out to gain a deeper understanding of the tension between these two attitudes.

Dietary nutrient manipulation (e.g. protein fractions) could lower the environmental footprints of ruminants, especially reactive nitrogen (N). This study investigated the impacts of dietary soluble protein (SP) levels with decreased crude protein (CP) on intestinal N absorption, hindgut N metabolism, fecal microbiota and metabolites, and their linkage with N metabolism phenotype. Thirty-two male Hu sheep, with an age of six months and an initial BW of 40.37 ± 1.18 kg, were randomly assigned to four dietary groups. The control diet (CON), aligning with NRC standards, maintained a CP content of 16.7% on a dry matter basis. Conversely, the experimental diets (LPA, LPB, and LPC) featured a 10% reduction in CP compared with CON, accompanied by SP adjustments to 21.2%, 25.9%, and 29.4% of CP, respectively. Our results showed that low-protein diets led to significant reductions in the concentrations of plasma creatinine, ammonia, urea N, and fecal total short-chain fatty acids (SCFA) (P

Abstract Two‐dimensional (2D) semiconductors, such as monolayer MoS2, has emerged as a profound material platform in the post‐Moore era due to their versatile applications for high‐performance transistors, memories, photodetectors, neuristors, and so on. Nevertheless, the inherent defects in these atomically thin materials have given rise to significant hysteresis in their field‐effect transistors (FETs), resulting in shifted threshold voltages and elevated power consumptions not only on single‐device levels but also at circuitry scales. We herein report that, by vertically integrating an in‐plane ferroelectric, NbOCl2, with monolayer MoS2 FETs, the hysteresis in both the output and transfer curves of the latter can be greatly suppressed, which we attribute to compensated electromigration currents by the polarization currents of the 2D ferroelectric. This work opens a new avenue to hysteresis‐free 2D transistors without necessitating defect‐free channels, thus allowing for their use in high driving‐voltage scenarios such as power electronics.

Abstract Insecticide resistance has been a problem in both the agricultural pests and vectors. Revealing the detoxification mechanisms may help to better manage insect pests. Here, we showed that arylalkylamine N-acetyltransferase 1 (AANAT1) regulates intestinal detoxification process through modulation of reactive oxygen species (ROS)-activated transcription factors cap“n”collar isoform-C (CncC): muscle aponeurosis fibromatosis (Maf) pathway in both the oriental fruit fly, Bactrocera dorsalis, and the arbovirus vector, Aedes aegypti. Knockout/knockdown of AANAT1 led to accumulation of biogenic amines, which induced a decreased in the gut ROS level. The reduced midgut ROS levels resulted in decreased expression of CncC and Maf, leading to lower expression level of detoxification genes. AANAT1 knockout/knockdown insects were more susceptible to insecticide treatments. Our study reveals that normal functionality of AANAT1 is important for the regulation of gut detoxification pathways, providing insights into the mechanism underlying the gut defense against xenobiotics in metazoans.

The goal of combination cancer therapy, including chemo-phototherapy, is to achieve highly efficient antitumor effects while minimizing the adverse reactions associated with conventional chemotherapy. Nevertheless, enhancing the contribution of non-chemotherapeutic strategies in combination therapy is often challenging because this requires multiple active ingredients to be encapsulated in a single delivery system. However, most commonly used photothermal reagents are challenging to be loaded in large quantities and have poor biocompatibility. Herein, we developed photothermal co-micelles through a co-assembly strategy using a cholesterol-based liquid crystal block copolymer (LC-BCP) with disulfide bonds in the side chain of the LC blocks and a croconaine-based amphiphile (CBA) containing a cholesterol moiety. This approach allowed the CBA to be effectively embedded within LC-BCPs, serving as the functional component of the drug-loaded carrier. These co-micelles could encapsulate doxorubicin (DOX), showed tunable reduction-responsive drug release, and enabled near-infrared laser-triggered photothermal therapy as well as in vivo fluorescence and photothermal imaging. Following laser irradiation, the photothermal activity of the co-micelles rapidly induced tumor cell death and accelerated drug release. In vitro and in vivo experiments demonstrated that the synergistic photo-chemotherapeutic effects of these drug-loaded co-micelles offer a promising avenue for synergistic precision photothermal-chemotherapy.

Summary: Tank-binding kinase 1 (TBK1) is a critical signal transducer in the nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, essential for innate immunity. However, its negative regulation mechanisms remain unclear. This study demonstrates that TBK1 succinylation, regulated by desuccinylase SIRT5, inhibits lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4)-mediated NF-κB and IRF signaling activation. We identified three key succinylation sites on TBK1: K38, K154, and K692. In endotoxemia and sepsis models, reduced SIRT5 levels in macrophages increased TBK1 succinylation, inhibiting its binding to IRF3 and TRAF2 and suppressing the inflammatory response. In vivo, adoptive transfer of macrophages expressing the succinylation-resistant TBK1-2KR (K154/692R) mutant reversed the inflammatory cytokine suppression caused by SIRT5 deficiency, exacerbating sepsis-induced lung injury. These findings reveal a novel mechanism by which SIRT5 modulates TBK1 activity and macrophage-mediated inflammation during sepsis.

Abstract Protein surfaces have pivotal roles in interactions between proteins and other biological molecules. However, the structural dynamics of protein surfaces have rarely been explored and are poorly understood. Here, the surface of a single‐stranded DNA (ssDNA) binding protein (SSB) with four DNA binding domains that bind ssDNA in binding site sizes of 35, 56, and 65 nucleotides per tetramer is investigated. Using oligonucleotides as probes to sense the charged surface, NaCl induces a two‐state structural transition on the SSB surface even at moderate concentrations. Chelation of sodium ions with charged amino acids alters the network of hydrogen bonds and/or salt bridges on the surface. Such changes are associated with changes in the electrostatic potential landscape and interaction mode. These findings advance the understanding of the molecular mechanism underlying the enigmatic salt‐induced transitions between different DNA binding site sizes of SSBs. This work demonstrates that monovalent salt is a key regulator of biomolecular interactions that not only play roles in non‐specific electrostatic screening effects as usually assumed but also may configure the surface of proteins to contribute to the effective regulation of biomolecular recognition and other downstream events.

ABSTRACT Background Bullous pemphigoid (BP) and atopic dermatitis (AD) are currently thought to be tightly related, yet studies of the mechanisms of co‐morbidities are lacking. Methods We obtained GWAS data for BP (N = 376,274) and AD (N = 796,661) from the Finnish Genetic Research Program dataset and the UK Biobank, separately. Then, the following four analyses were performed: (1) cross‐trait linkage disequilibrium score regression (LDSC) to assess the genetic correlation between BP and AD, (2) cross‐phenotype association analysis (CPASSOC) to identify multiple effector loci shared by BP and AD, (3) transcriptome‐wide association study (TWAS) to determine whether their cross‐organizational expression patterns share genes with a common biological mechanism of relevance, and (4) bidirectional Mendelian randomization (MR) analysis to assess bidirectional causal effects of BP and AD. Results We found a positive genetic association between BP and AD (rg = 0.5476, p = 0.0495) as well as identified four pleiotropic loci and 59 common genes affecting BP and AD. Bidirectional MR analysis suggested that BP promotes the risk of AD. Conclusions We revealed a genetic link between BP and AD, which is associated with biological pleiotropy and causality. Awareness of the association between BP and AD helps dermatologists manage patients with these illnesses.

It has been proven that robot-assisted rehabilitation training can effectively promote the recovery of upper-limb motor function in post-stroke patients. Increasing patients’ active participation by providing assist-as-needed (AAN) control strategies is key to the effectiveness of robot-assisted rehabilitation training. In this paper, a greedy assist-as-needed (GAAN) controller based on radial basis function (RBF) network combined with 3 degrees of freedom (3-DOF) potential constraints was proposed to provide AAN interactive forces of an end-effect upper limb rehabilitation robot. The proposed 3-DOF potential fields were adopted to constrain the tangential motions of three kinds of typical target trajectories (one-dimensional (1D) lines, two-dimensional (2D) curves and three-dimensional (3D) spirals) while the GAAN controller was designed to estimate the motor capability of a subject and provide appropriate robot-assisted forces. The co-simulation (Adams-Matlab/Simulink) experiments and behavioral experiments on 10 healthy volunteers were conducted to validate the utility of the GAAN controller. The experimental results demonstrated that the GAAN controller combined with 3-DOF potential field constraints enabled the subjects to actively participate in kinds of tracking tasks while keeping acceptable tracking accuracies. 3D spirals could be better in stimulating subjects’ active participation when compared to 1D and 2D target trajectories. The current GAAN controller has the potential to be applied to existing commercial upper limb rehabilitation robots.

BackgroundThere is a high morbidity of polyps in the digestive tract, and certain subtypes of polyps are thought to induce cancer progression and often recur, which may be associated with chronic inflammation. Mendelian randomization (MR) can help identify potential causative relationships and inform early treatment action.MethodsWe performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and three types of polyps from European ancestry, respectively, including gastric polyp (6,155 cases vs. 341,871 controls), colonic polyp (22,049 cases vs. 332,368 controls) and gallbladder polyp (458 cases vs. 340,083 controls). Inverse-variance weighted (IVW), weight median (WM), and MR-Egger methods were used for calculating causal estimates. Furthermore, Bayesian model averaging MR (MR-BMA) method was employed to detect the dominant causal circulatory cytokines with adjustment for pleiotropy effects.ResultsOur univariable MR using inverse-variance weight method identified causal associations of IL-2ra (OR: 0.892, 95%CI: 0.828–0.961, p = 0.003), MIG (OR: 1.124, 95%CI: 1.046–1.207, p = 0.001) and IL-18 (OR: 0.912, 95%CI: 0.852–0.977, p = 0.008) with gastric polyp, MIP1b (OR: 0.956, 95%CI: 0.927–0.987, p = 0.005) and IL-6 (OR: 0.931, 95%CI: 0.870–0.995, p = 0.035) with colonic polyp and IL-9 (OR: 0.523, 95%CI: 0.345–0.794, p = 0.0007) with gallbladder polyp. Finally, our MR-BMA analysis prioritized MIG (MIP = 0.332, MACE = 0.022; PP: 0.264, MSCE = 0.059), IL-18 (MIP = 0.302, MACE = −0.020; PP: 0.243, MSCE = −0.059) and IL-2ra (MIP: 0.129; MACE: −0.005; PP: 0.112, MSCE: −0.031) for gastric polyp, and MIP1b (MIP = 0.752, MACE = −0.033; PP: 0.665, MSCE = −0.044) and IL-6 (MIP: 0.196; MACE: −0.012; PP: 0.140, MSCE: −0.064) for colonic polyp, and IL-9 (MIP = 0.936, MACE = −0.446; PP: 0.781, MSCE = −0.478) for gallbladder polyp as the top-ranked protective factors.ConclusionOur research advances the current understanding of the function of certain inflammatory biomarker pathways in the genesis and malignant mutation of polyps in the digestive tract. Deeper substantiation is necessary to assess the potential of these cytokines as pharmacological or lifestyle targets for digestive polyps prevention.

In a study of DNA methylation changes in melatonin-deficient rice mutants, mutant plants showed premature leaf senescence during grain-filling and reduced grain yield. Melatonin deficiency led to transcriptional reprogramming, especially of genes involved in chlorophyll and carbon metabolism, redox regulation, and transcriptional regulation, during dark-induced leaf senescence. Hypomethylation of mCG and mCHG in the melatonin-deficient rice mutants was associated with the expression change of both protein-coding genes and transposable element-related genes. Changes in gene expression and DNA methylation in the melatonin-deficient mutants were compensated by exogenous application of melatonin. A decreased S-adenosyl-L-methionine level may have contributed to the DNA methylation variations in rice mutants of melatonin deficiency under dark conditions.

Background and objective Bone is a common site for metastasis in lung adenocarcinoma, but the mechanism behind lung adenocarcinoma bone metastasis is still unclear. And currently, there is a lack of easily traceable and stable lung adenocarcinoma bone metastasis cell models, which limits the research on the mechanism of lung adenocarcinoma bone metastasis. The establishment of human lung adenocarcinoma cell line that are highly metastatic to bone, labeled with green fluorescent proteins (GFP) and fireflies luciferase (LUC), along with transcriptomic characterization, would be beneficial for research on lung adenocarcinoma bone metastasis and provide new experimental methods. Methods The human lung adenocarcinoma cell line A549-GFP-LUC was injected into nude mice via the left ventricle to construct a bone metastasis model, and was domesticated in vivo for three consecutive times to obtain the human high bone metastasis lung adenocarcinoma cell line A549-GFP-LUC-BM3; cell counting kit-8 (CCK-8), colony formation assay, scratch wound assays, Transwell assay and Western blot were used to compare the proliferation and invasion abilities of A549-GFP-LUC-BM3 with the parental cells. A549-GFP-LUC-BM3 cells and parental cells were further analyzed by transcriptomic sequencing. Results Human high-bone metastatic lung adenocarcinoma cells A549-GFP-LUC-BM3 was successfully established. Compared to parental cells, this cells exhibited a significantly higher incidence of bone metastasis and enhanced in vitro proliferation, migration, and invasion abilities. Transcriptomic sequencing results revealed that the A549-GFP-LUC-BM3 cell line had 2954 differentially expressed genes compared to the parental cells, with 1021 genes up-regulated and 1933 genes down-regulated. Gene Ontology (GO) functional enrichment analysis indicated that the differentially expressed genes were primarily localized in cellular components such as the cell periphery. The molecular functions identified as significantly enriched included signaling receptor activity, calcium ion binding, and extracellular matrix structural constituent. Additionally, the biological processes found to be enriched were cell adhesion and biological adhesion. The enrichment analysis conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the differentially expressed genes were primarily involved in the metabolism of xenobiotics by cytochrome P450, retinol metabolism, drug metabolism-cytochrome P450, cell adhesion molecules, steroid hormone biosynthesis, and the nuclear factor kappa B (NF-κB) signaling pathway. Conclusion The highly bone-metastatic human lung adenocarcinoma cell line with GFP and luciferase double labeling was successfully established. The biological behavior and transcriptome sequencing of the cell line suggest that it has a high bone-metastatic potential.

Abstract Background Epigenetic marks are reprogrammed during sexual reproduction. In flowering plants, DNA methylation is only partially remodeled in the gametes and the zygote. However, the timing and functional significance of the remodeling during plant gametogenesis remain obscure. Results Here we show that DNA methylation remodeling starts after male meiosis in rice, with non-CG methylation, particularly at CHG sites, being first enhanced in the microspore and subsequently decreased in sperm. Functional analysis of rice CHG methyltransferase genes CMT3a and CMT3b indicates that CMT3a functions as the major CHG methyltransferase in rice meiocyte, while CMT3b is responsible for the increase of CHG methylation in microspore. The function of the two histone demethylases JMJ706 and JMJ707 that remove H3K9me2 may contribute to the decreased CHG methylation in sperm. During male gametogenesis CMT3a mainly silences TE and TE-related genes while CMT3b is required for repression of genes encoding factors involved in transcriptional and translational activities. In addition, CMT3b functions to repress zygotic gene expression in egg and participates in establishing the zygotic epigenome upon fertilization. Conclusion Collectively, the results indicate that DNA methylation is dynamically remodeled during male gametogenesis, distinguish the function of CMT3a and CMT3b in sex cells, and underpin the functional significance of DNA methylation remodeling during rice reproduction.

Background Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer.Methods Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor.Results GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors.Conclusion Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.

BackgroundGut microbiota is closely related to the occurrence and development of sepsis. However, the causal effects between the gut microbiota and sepsis, and whether circulating inflammatory proteins act as mediators, remain unclear.MethodsGut microbiota, circulating inflammatory proteins, and four sepsis-related outcomes were identified from large-scale genome wide association studies (GWAS) summary data. Inverse Variance Weighted (IVW) was the primary statistical method. Additionally, we investigated whether circulating inflammatory proteins play a mediating role in the pathway from gut microbiota to the four sepsis-related outcomes.ResultsThere were 14 positive and 15 negative causal effects between genetic liability in the gut microbiota and four sepsis-related outcomes. Additionally, eight positive and four negative causal effects were observed between circulating inflammatory proteins and the four sepsis-related outcomes. Circulating inflammatory proteins do not act as mediators.ConclusionsGut microbiota and circulating inflammatory proteins were causally associated with the four sepsis-related outcomes. However, circulating inflammatory proteins did not appear to mediate the pathway from gut microbiota to the four sepsis-related outcomes.

We revisit the previously known local inversion symmetry of the five-dimensional Kerr-AdS metric that relates the over-rotating black hole to the under-rotating one and reinterpret it as an interchanging symmetry between time and the longitudinal angular coordinates. We generalize this to all D dimensions, including D=4, thereby enlarging the trivial linear ZN symmetry of the N=⌊(D−1)/2⌋ longitudinal angular coordinates to the nonlinearly realized ZN+1 symmetry that involves time.

IntroductionIn goal-directed tasks, visual prompts before the appearance of goals can make people ready in advance, which helps them to complete the movement better, and the presentation type of the visual prompt is very important. In previous studies, it has not been clear how different types of visual prompts guide attention in goal-directed tasks.MethodsAccording to the characteristics of goal-directed tasks, our research designed three different prompts: the cue prompt (featuring static arrow), the preparation prompt (involving dynamic countdown), and the combination prompt of cue and preparation information (simultaneously incorporating arrow and countdown). We used event-related potential components (CNV and P300) and graph theory indicators (clustering coefficient and characteristic path length) under the brain function connection to analyze the attention state of the brain.ResultsThe results showed that the combination prompts better guided the participants’ sustained attention during the prompt stage, making them well prepared for the movement. Thus, after the target appeared, the participants had better executive control and achieved a faster response to the target. However, under the combination prompt, the participants consumed more attention resources during the prompt stage.DiscussionWe believe that for the participants with impaired cognitive function, cue prompts or preparation prompts can be considered, which also play a role in guiding the participants’ attention and helping them make motor preparations when less attention resources are consumed. This study provides a neurophysiological and behavioral foundation for the design of visual prompts in goal-directed tasks.

PRKCI is abnormally expressed in various cancers, but its role in osteosarcoma is unknown. This study aimed to explore the biological function of PRKCI in osteosarcoma and its potential molecular mechanism. PRKCI expression was evaluated in osteosarcoma cell lines using Western blot analysis and reverse transcription PCR. The CCK-8 assay, colony formation assay, flow cytometry, Transwell assay, and wound-healing assay were used to detect the proliferation, colony-forming capacity, cell cycle, migration, and invasion of osteosarcoma cells when PRKCI was overexpressed or knocked down. The interaction between PRKCI and SQSTM1 was explored using immunoprecipitation. Finally, the protein molecule expression of the Akt/mTOR signaling pathway in osteosarcoma was detected when PRKCI was knocked down. Our study found that PRKCI was overexpressed in osteosarcoma cell lines. The overexpression of PRKCI promoted the proliferation and colony-forming capacity of osteosarcoma cells, while silencing PRKCI inhibited the proliferation, colony-forming capacity, migration, and invasion of osteosarcoma cells and arrested the cell cycle at the G2/M phase. Both PRKCI and SQSTM1 were overexpressed in osteosarcoma. The expression of PRKCI was only related to histological type, while that of SQSTM1 was not related to clinical characteristics. The expression of PRKCI and SQSTM1 in osteosarcoma was higher than that in chondrosarcoma. Knockdown of PRKCI inhibited the proliferation of osteosarcoma cells by inactivating the Akt/mTOR signaling pathway, suggesting that PRKCI was a potential target for osteosarcoma therapy.

Background and purpose: The plasma used for routine coagulation test (CCT) can only reflect a single component at a certain coagulation time point/segment, while thromboelastography (TEG) can depict the overall dynamic process curve of coagulation and fibrinolysis, which can more independently and completely reflect the true state of the blood and can serve as a supplement to coagulation function testing. This study aimed to evaluate the application value of combined coagulation function indexes in monitoring the hypercoagulable state of patients with colorectal cancer after chemotherapy, and to explore the risk factors of thrombosis in patients with colorectal cancer after chemotherapy, so as to provide reference for clinical monitoring of hypercoagulable state. Methods: A total of 160 patients with colorectal cancer from Fudan University Shanghai Cancer Center from June 2021 to June 2023 were selected as the experimental group, and 80 healthy subjects were selected as the control group. Then the experimental group was divided into a group without thrombosis (82 cases) and a group with thrombosis (78 cases) according to whether they had thrombosis or not. The determinations of thromboelastography (TEG) [coagulation reaction time (R), coagulation formation time (K), blood clot formation rate (α-Angle), maximum amplitude (MA) and coagulation index (CI)], conventional coagulation tests (CCT) [activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fib), D-dimer (DD), fibrinogen degradation products (FDP)] and platelet count (PLT) were studied among three groups. With or without thrombosis as the criterion of hypercoagulable state, statistically significant indicators were selected to be included in the binary logistic regression analysis, and the receiver operating characteristic (ROC) curve was drawn to analyze the diagnostic efficacy of single and combined detection of the coagulation function indicators for hypercoagulable state in patients with colorectal cancer after chemotherapy. Basic information, tumor stage and Autar score of deep vein thrombosis were collected in 160 patients with colorectal cancer. Logistic regression analysis was performed to explore the risk factors of thrombosis. This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (number: 050432-4-2108*). Results: Compared with the control group, the R, TT and PLT of the group with thrombosis were decreased (P

Abstract Background Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. Methods Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR). Results Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy. Conclusions This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.

Abstract Background Long noncoding RNA thymopoietin-antisense RNA 1 (TMPO-AS1) is recognized as a participant in cancer progression. Nevertheless, its biological function in colorectal cancer remains obscure and needs further elucidation. Methods and Results First, we discovered enriched TMPO-AS1 in the tumor tissues that were related to poor prognosis. TMPO-AS1 knockdown enhanced SW480 cell apoptosis but inhibited invasion, proliferation, migration, and glucose metabolism. Further, MiR-1270 is directly bound with TMPO-AS1. MiR-1270 mimics were confirmed to inhibit cell proliferation, invasion, and glucose metabolism in our study. Mechanistically, miR-1270 directly is bound with the 3' untranslated regions (3'UTR) of PKM2 to downregulate PKM2. MiR-1270 inhibitors reversed the TMPO-AS1 knockdown’s effect on suppressing the tumor cell proliferation, invasion, and glycolysis, while the knockdown of PKM2 further inverted the function of miR-1270 inhibitors on the TMPO-AS1 knockdown. Conclusions This study illustrated that TMPO-AS1 advanced the development and the glycolysis of colorectal cancer by modulating the miR-1270/PKM2 axis, which provided a new insight into the colorectal cancer therapeutic strategy.

Abstract Single-atom catalysts show excellent catalytic performance because of their coordination environments and electronic configurations. However, controllable regulation of single-atom permutations still faces challenges. Herein, we demonstrate that a polarization electric field regulates single atom permutations and forms periodic one-dimensional Au single-atom arrays on ferroelectric Bi4Ti3O12 nanosheets. The Au single-atom arrays greatly lower the Gibbs free energy for CO2 conversion via Au-O=C=O-Au dual-site adsorption compared to that for Au-O=C=O single-site adsorption on Au isolated single atoms. Additionally, the Au single-atom arrays suppress the depolarization of Bi4Ti3O12, so it maintains a stronger driving force for separation and transfer of photogenerated charges. Thus, Bi4Ti3O12 with Au single-atom arrays exhibit an efficient CO production rate of 34.15 µmol·g−1·h−1, ∼18 times higher than that of pristine Bi4Ti3O12. More importantly, the polarization electric field proves to be a general tactic for the syntheses of one-dimensional Pt, Ag, Fe, Co and Ni single-atom arrays on the Bi4Ti3O12 surface.

Abstract Ferroelectric tunnel junctions are promising towards high-reliability and low-power non-volatile memories and computing devices. Yet it is challenging to maintain a high tunnelling electroresistance when the ferroelectric layer is thinned down towards atomic scale because of the ferroelectric structural instability and large depolarization field. Here we report ferroelectric tunnel junctions based on samarium-substituted layered bismuth oxide, which can maintain tunnelling electroresistance of 7 × 105 with the samarium-substituted bismuth oxide film down to one nanometer, three orders of magnitude higher than previous reports with such thickness, owing to efficient barrier modulation by the large ferroelectric polarization. These ferroelectric tunnel junctions demonstrate up to 32 resistance states without any write-verify technique, high endurance (over 5 × 109), high linearity of conductance modulation, and long retention time (10 years). Furthermore, tunnelling electroresistance over 109 is achieved in ferroelectric tunnel junctions with 4.6-nanometer samarium-substituted bismuth oxide layer, which is higher than commercial flash memories. The results show high potential towards multi-level and reliable non-volatile memories.