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Abstract Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent.

Abstract Approximately 70% of treatment failures in nasopharyngeal carcinoma (NPC) patients are attributed to distant metastasis, yet the underlying mechanisms remain unclear. RNA 5-methylcytosine (m5C) is an emerging regulatory modification that controls gene expression and plays a critical role in tumor progression. However, there is little information on the potential roles of RNA m5C modification in NPC metastasis. In this study, we found that the m5C reader Aly/REF export factor (ALYREF) is significantly upregulated in NPC, whereby its high expression is associated with metastasis and poor prognosis. ALYREF overexpression was found to promote tumor metastasis of NPC cells in vitro and in vivo. Mechanistically, m5C-modified NOTCH1 mRNA was identified as a target of ALYREF. Moreover, ALYREF was found to upregulate NOTCH1 expression by enhancing its RNA stability in an m5C modification-dependent manner, thereby promoting the activation of the NOTCH signaling pathway and facilitating NPC metastasis. Overall, our data reveal the crucial role of ALYREF in NPC metastasis and provide a potential therapeutic target for NPC.

Abstract Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein‐Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV‐ (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC‐associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene‐edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV‐coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV‐ and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies.

The coronary artery constitutes a vital vascular system that sustains cardiac function, with its primary role being the conveyance of indispensable nutrients to the myocardial tissue. When coronary artery disease occurs, it will affect the blood supply of the heart and induce myocardial ischemia. Therefore, it is of great significance to numerically simulate the coronary artery and evaluate its blood supply capacity. In this article, the coronary artery lumped parameter model was derived based on the relationship between circuit system parameters and cardiovascular system parameters, and the blood supply capacity of the coronary artery in healthy and stenosis states was studied. The aortic root pressure calculated by the aortic valve fluid-structure interaction (AV FSI) simulator was employed as the inlet boundary condition. To emulate the physiological phenomenon of sudden pressure drops resulting from an abrupt reduction in blood vessel radius, a head loss model was connected at the coronary artery's entrance. For each coronary artery outlet, the symmetric structured tree model was appended to simulate the terminal impedance of the missing downstream coronary arteries. The particle swarm optimization (PSO) algorithm was used to optimize the blood flow viscous resistance, blood flow inertia, and vascular compliance of the coronary artery model. In the stenosis states, the relative flow and fractional flow reserve (FFR) calculated by numerical simulation corresponded to the published literature data. It was anticipated that the proposed model can be readily adapted for clinical application, serving as a valuable reference for diagnosing and treating patients.

Aim: Retinal photochemical damage (RPD) plays a significant role in the development of various ocular diseases, with Caspase-1 being a key contributor. This study investigates the protective effects of Caspase-1 gene-mediated pyroptosis against RPD. Methods: Differentially expressed genes (DEGs) associated with RPD were identified through the analysis of two expression profiles from the GEO database. Correlation analysis was used to pinpoint pyroptosis-related genes (PRGs) linked to RPD. A Caspase-1 knockout 661 W cell line was generated via CRISPR-Cas9 gene editing, and single-cell colonies were screened and purified. Validation of knockout cells was performed through RT-qPCR, gene sequencing, and Western blot analysis. Comparative assays on cell proliferation, intracellular reactive oxygen species (ROS), and cytotoxicity were conducted between wild-type and Caspase-1 knockout cells under light exposure. Further RT-qPCR and Western blot experiments examined changes in the mRNA and protein levels of key pyroptosis pathway components. Results: Significant alterations in Caspase-1 expression were observed among PRGs. Homozygous Caspase-1 knockout cell lines were confirmed through RT-qPCR, genomic PCR product sequencing, and Western blot analysis. Compared to wild-type 661 W cells, Caspase-1 knockout cells exhibited higher viability and proliferation rates after 24 h of light exposure, alongside reduced LDH release. The expression of downstream pyroptosis factors at both the mRNA and protein levels was markedly decreased in the knockout group. Conclusion: CRISPR/Cas9-mediated Caspase-1 knockout enhanced the resistance of 661 W cells to photochemical damage, suggesting that Caspase-1 may serve as a potential therapeutic target for RPD-related diseases.

Lately, the inclusion of oleogels has emerged as an alternative strategy for the preparation of chocolate. The present study used Lycium barbarum seed oil-based oleogel through a combination of glyceryl monostearate and vegetable wax as gelling factor, and partially replaced cocoa butter for the preparation of chocolate. To further explore the storage stability of the oleogel chocolate, we measured the white index of the chocolate every five days, and also observed the surface morphology of the chocolate using 3D laser focusing microscopy. Then, we characterized the stability of resulting oleogel-chocolate stored at different temperature conditions using differential scanning calorimetry and X-ray diffraction. Our data showed that the polycrystalline morphology of the chocolate changed during storage, and the temperature differences led to variations in white index and surface roughness. The presence of oleogel attenuated the migration of liquid oils and fats in the chocolate system, and increased the stability of the chocolate system as well as relatively improved the frosting phenomenon of the chocolate. This study provides innovative avenue for the preparation of chocolates with lower saturated fatty acid content, higher storage stability, and improved nutritional value.

Designing photocatalysts with p-n heterojunction structures is an effective way to boost the separation of photogenerated carriers and stimulate the photocatalytic degradation activity. Herein, an efficient visible-light responsive AgI/BiSI p-n heterojunction photocatalyst was successfully constructed. X-ray photoelectron spectroscopy (XPS), photoluminescence (PL) spectroscopy, and electrochemical measurements confirmed that the AgI/BiSI p-n heterojunction structure was beneficial to the separation and transfer of photogenerated carriers, promoting the generation of main active species (•O2− and h+). Furthermore, the photocatalytic degradation rate constants of Acid Red 1 (0.4699 min−1) and metronidazole (0.0730 min−1) over the optimal AgI/BiSI were about 8.4 and 3.0 times higher than those over pure AgI, respectively. This work provides a heterojunction engineering strategy to design high-efficient photocatalysts for the degradation of refractory organic pollutants.

Objective: Prenatal hyperandrogenism, characterized by elevated androgen levels during pregnancy, has significant multisystem impacts on offspring health. This review systematically examines the effects of prenatal hyperandrogenism on the cardiovascular, metabolic, reproductive, and behavioral health of offspring. By analyzing existing research, this review aims to provide a comprehensive understanding of the long-term health impacts of prenatal hyperandrogenism, offering insights for clinical management and prevention of related diseases. Mechanism: A comprehensive search was performed in PubMed database with the key words: “hyperandrogenemia and child”, “hyperandrogenemia and offspring”, “androgen excess and child”, “androgen excess and offspring”, “prenatal hyperandrogenism”, “prenatal androgen excess”, and a combination of these terms to find quality articles published from 1995 to 2024. Findings in Brief: Elevated prenatal androgen levels disrupt normal fetal development, leading to long-term consequences such as cardiovascular dysfunction, including hypertension and cardiac hypertrophy, and metabolic abnormalities such as insulin resistance and metabolic syndrome. It has a significant impact on the long-term health of the offspring’s reproductive system, with potential links to conditions such as polycystic ovary syndrome (PCOS). Furthermore, prenatal hyperandrogenism is associated with increased risks of neuropsychiatric disorders, including autism spectrum disorder (ASD) and anxiety. Conclusions: Elevated prenatal androgen levels disrupt normal fetal development, leading to long-term cardiovascular, metabolic, reproductive, and neuropsychiatric disorders. The underlying mechanisms involve hormonal regulation, placental function, oxidative stress, gene expression alterations, and metabolic programming. Further research is needed to develop effective interventions to mitigate these adverse effects.

IntroductionCircadian syndrome (CircS) is proposed as a novel risk cluster based on reduced sleep duration, abdominal obesity, depression, hypertension, dyslipidemia and hyperglycemia. However, the association between CircS and chronic kidney disease (CKD) remains unclear. To investigate the cross-sectional and longitudinal association between CircS and CKD, this study was performed.MethodsA national prospective cohort (China Health and Retirement Longitudinal Study, CHARLS) was used in this study. To define CKD, the estimated glomerular filtration rate (eGFR) was calculated based on the 2012 CKD-EPI creatinine-cystatin C equation. Participants with eGFR

Abstract Background FLT-PET/CT can accurately identify and locate functional bone marrow (FBM) with hematopoietic capability, the FBM were divided into two levels as FBM1 (strongest hemopoietic ability region)and FBM2 (moderate hemopoietic ability region) via FLT-PET/CT. The purpose of this study was to explore the relationship between dose-volume parameters of pelvic FBM and hematologic toxicity (HT) during radiotherapy with or without concurrent chemotherapy for uterine cervical/endometrial cancer. Methods From December 2016 to September 2021, ninety-seven uterine cervical/endometrial cancer patients received intensity-modulated radiation therapy were prospectively recruited in this single-arm, prospective, phase II trial. Blood counts were reviewed weekly during radiotherapy. Single- and multifactor regression methods were used to analyze the relationships between dose-volume parameters of FBM1/2 and grade ≥ 2 HT. ROC curves were used to determine the cutoff values for the dose-volume parameters of FBM1/2. Results The incidence of grade ≥ 2 leukopenia, neutropenia, thrombocytopenia and anemia in patients during radiotherapy was 63.9%, 45.4%, 19.6% and 38.8% respectively, and the median occurrence time was the 29th, 42th, 35th and 31th day, respectively. Multivariate regression analysis showed that the Dmax of FBM1 was significantly related to grade ≥ 2 leukopenia (OR = 1.277 95% CI 1.067–1.528, P = 0.008), Dmean of FBM2 was significantly related to grade ≥ 2 thrombocytopenia (OR = 1.262 95% CI 1.066–1.494, P = 0.007), and V10 of FBM1 was significantly related to grade ≥ 2 anemia (OR = 1.198 95% CI 1.003–1.431, P = 0.046). The incidence of grade ≥ 2 leukopenia for patients with FBM1 Dmax < 53 Gy was lower than that for patients with FBM1 Dmax ≥ 53 Gy (53.4% vs. 95.8%, P

Apigenin, a natural flavonoid has been reported against a variety of cancer types. However, it is unclear whether apigenin can promote autophagy and ferroptosis in Ishikawa cells. There are few reports on the mechanism of apigenin on autophagy and ferroptosis of endometrial cancer Ishikawa cells. We found that iron accumulation, lipid peroxidation, glutathione consumption, p62, HMOX1, and ferritin were increased, while, solute carrier family 7 member 11 and glutathione peroxidase 4 were decreased. Ferrostatin-1, an iron-death inhibitor could reverse the effects of apigenin in Ishikawa cells. On the other hand, apigenin could promote autophagy via up-regulating Beclin 1, ULK1, ATG5, ATG13, and LC3B and down-regulating AMPK, mTOR, P70S6K, and ATG4. Furthermore, apigenin could inhibit tumor tissue proliferation and restrict tumor growth via ferroptosis in vivo.

ABSTRACTThe objective of this study was to investigate the effects of ultrasonically emulsified palm oil (UE-PA), peanut oil (UE-PE), and sunflower oil (UE-SU) on the whiteness, textural, rheological, and microstructural properties of surimi gels from silver carp. Three ultrasonically emulsified oils had different specific fatty acids and oil droplet sizes of 300-400 nm. Compared with the control group, low addition of UE-SU (2.5 g/100 g) showed the highest water-holding capacity (WHC), storage modulus (G’), and hydrogen bond in surimi gels. The low addition of UE-PE (2.5 g/100 g) increased disulfide bond, β-sheet, and β-turn of surimi gel, so had higher hardness and chewiness values, comparing to those with other emulsified oils. As ultrasonically emulsified oil addition increased in surimi gels (2.5–7.5 g/100 g), hardness, chewiness, WHC, G’ were decreased, while whiteness was increased (p

Abstract Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.

Abstract Nasopharyngeal carcinoma (NPC) is a common malignant epithelial tumor of the head and neck that often exhibits local recurrence and distant metastasis. The molecular mechanisms are understudied, and effective therapeutic targets are still lacking. In our study, we found that the transcription factor ZIC2 was highly expressed in NPC. Although ZIC family members play important roles in neural development and carcinogenesis, the specific mechanism and clinical significance of ZIC2 in the tumorigenesis and immune regulation of NPC remain elusive. Here, we first reported that high expression of ZIC2 triggered the secretion of MCSF in NPC cells, induced M2 polarization of tumor-associated macrophages (TAMs), and affected the secretion of TAM-related cytokines. Mechanistically, ChIP-seq and RNA-seq analyses identified JUNB as a downstream target of ZIC2. Furthermore, ZIC2 was significantly enriched in the promoter site of JUNB and activated JUNB promoter activity, as shown by ChIP-qPCR and luciferase assays. In addition, JUNB and MCSF participated in ZIC2-induced M2 TAMs polarization. Thus, blocking JUNB and MCSF could reverse ZIC2-mediated M2 TAMs polarization. Moreover, Kaplan-Meier survival analyses indicated that high expression of ZIC2, JUNB, and CD163 was positively associated with a poor prognosis in NPC. Overexpression of ZIC2 induced tumor growth in vivo, with the increase of JUNB, MCSF secretion, and CD163. In summary, our study implies that ZIC2 induces M2 TAM polarization, at least in part through regulation of JUNB/MCSF and that ZIC2, JUNB, and CD163 can be utilized as prognostic markers for NPC and as therapeutic targets for cancer immunotherapy.

Abstract Skeletal muscle makes up 30–40% of the total body mass. It is of great significance in maintaining digestion, inhaling and exhaling, sustaining body posture, exercising, protecting joints and many other aspects. Moreover, muscle is also an important metabolic organ that helps to maintain the balance of sugar and fat. Defective skeletal muscle function not only limits the daily activities of the elderly but also increases the risk of disability, hospitalization and death, placing a huge burden on society and the healthcare system. Sarcopenia is a progressive decline in muscle mass, muscle strength and muscle function with age caused by environmental and genetic factors, such as the abnormal regulation of protein post‐translational modifications (PTMs). To date, many studies have shown that numerous PTMs, such as phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, glycation, methylation, S‐nitrosylation, carbonylation and S‐glutathionylation, are involved in the regulation of muscle health and diseases. This article systematically summarizes the post‐translational regulation of muscle growth and muscle atrophy and helps to understand the pathophysiology of muscle aging and develop effective strategies for diagnosing, preventing and treating sarcopenia.

ObjectivesThis study aimed to assess the knowledge and awareness of nicotine, nicotine replacement therapy (NRT), and electronic cigarettes (e-cigarettes) among general practitioners with a special interest (GPwSIs) in respiratory medicine.MethodsA cross-sectional study was conducted from October 2021 to February 2022. Knowledge and awareness were compared among smokers and non-smokers, as well as different age and gender groups.ResultsThe study consisted of 102 GPwSIs from 21 cities in Sichuan Province, China. Most respondents would recommend NRT for long-term use. Only a few believed that e-cigarettes are an effective means of smoking cessation and 71.6% would not recommend e-cigarettes as a substitute for cigarettes to their patients. Additionally, the majority did not regularly provide extensive help to assist patients in quitting smoking and needed smoking cessation counseling training.ConclusionGPwSIs in respiratory medicine in China could have a relatively low level of knowledge and awareness regarding nicotine, NRT, and e-cigarettes. The study highlights the need for smoking cessation training among GPwSIs to improve their knowledge and provide better assistance to patients who want to quit smoking.

Abstract Epstein‐Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV‐associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA‐based therapeutic vaccines that express the T‐cell‐epitope‐rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc‐LMP2A), truncated EBV nuclear antigen 1 (Trunc‐EBNA1), and Trunc‐EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor‐bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc‐LMP2A, Trunc‐EBNA1, and Trunc‐EBNA3A, are more effective than full‐length antigens in activating antigen‐specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA‐based therapeutic vaccines targeting the T‐cell‐epitope‐rich domain of EBV latent proteins and providing new treatment options for EBV‐associated cancers.

Summary: Background: Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with a high incidence in Southern China and Southeast Asia. Patients with remote metastasis and recurrent NPC have poor prognosis. Thus, a better understanding of NPC pathogenesis may identify novel therapies to address the unmet clinical needs. Methods: H3K27ac ChIP-seq and HiChIP was applied to understand the enhancer landscapes and the chromosome interactions. Whole genome sequencing was conducted to analyze the relationship between genomic variations and epigenetic dysregulation. CRISPRi and JQ1 treatment were used to evaluate the transcriptional regulation of SOX2 SEs. Colony formation assay, survival analysis and in vivo subcutaneous patient-derived xenograft assays were applied to explore the function and clinical relevance of SOX2 in NPC. Findings: We globally mapped the enhancer landscapes and generated NPC enhancer connectomes, linking NPC specific enhancers and SEs. We found five overlapped genes, including SOX2, among super-enhancer regulated genes, survival related genes and NPC essential genes. The mRNA expression of SOX2 was repressed when applying CRISPRi targeting different SOX2 SEs or JQ1 treatment. Next, we identified a genetic variation (Chr3:181422197, G > A) in SOX2 SE which is correlated with higher expression of SOX2 and poor survival. In addition, SOX2 was highly expressed in NPC and is correlated with short survival in patients with NPC. Knock-down of SOX2 suppressed tumor growth in vitro and in vivo. Interpretation: Our study demonstrated the super-enhancer landscape with chromosome interactions and identified super-enhancer driven SOX2 promotes tumorigenesis, suggesting that SOX2 is a potential therapeutic target for patients with NPC. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

The dynamic and temporal changes of host genome architecture during Epstein-Barr virus (EBV) transformation are not well known. Here the authors transform human primary B lymphocyte into lymphoblastoid cell lines (LCLs) with EBV and show that the host 3D genome is rewired to facilitate expression of key oncogenes.

ABSTRACT: Mycoplasma gallisepticum (MG) is one of the important pathogens in poultry industry and has led to major economic losses. Understanding the epidemiology is crucial to improve the control and eradication program of MG. This study collected 1,250 chicken samples, including trachea and lung, from China in 2022 to investigate the epidemiology of MG. Among the collected samples, 938 samples were positive for MG infection, resulting in an average positive rate of 75.04%. Additionally, 570 samples were positive for both MG and Mycoplasma synoviae (MS) coinfection, with an average positive rate of 45.60%. A total of 183 MG infection positive samples in this study were selected for genotyping, and the multilocus sequence typing (MLST) method based on 7 housekeeping genes was used. As a result, 183 samples belonged to 11 sequence types (STs), with ST-78 being the most prevalent. After BURST analysis, all 183 sequences were divided into group 3. Besides, 119 reference sequences from database and 183 sequences of this study were selected to construct the phylogenetic tree using the neighbor-joining method. The results revealed that the sequences from China, total 196 sequences, were classified into 4 branches. The findings suggest that the MG strains in China exhibit diverse genotypes, which may be related to international trade and the use of live vaccines. Furthermore, we detected the drug susceptibility of 10 isolated strains randomly, which may be helpful to guide the clinical use of drugs to control MG infection.

BackgroundDepression and the increased risk of sarcopenia are prevalent among the elderly population. However, the causal associations between these factors remain unclear. To investigate the potential association between depression and the risk of sarcopenia in older adults, this study was performed.MethodsIn the baseline survey, a total of 14,258 individuals aged 40 and above from the China Health and Retirement Longitudinal Study (2015) participated. We initially described the baseline prevalence of the disease. Then, logistic regression and restricted cubic spline (RCS) regression were conducted to assess the relationship between depression and sarcopenia. Subgroup analysis was performed to validate the robustness of the findings. Additionally, we conducted Mendelian randomization analysis using the inverse variance weighting estimator to assess the causal relationship between depression and sarcopenia. Furthermore, we adopted six methods, including MR-Egger, simple median, weighted median, maximum likelihood, robust adjusted profile score (RAPS), and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), for sensitivity analyses.ResultsDepression patients exhibited higher risks of sarcopenia in all five models adjusting for different covariates (P < 0.05). The RCS analysis demonstrated a linear relationship between depression and sarcopenia (P < 0.05). In the subgroup analysis, increased risk was observed among participants aged 60−70, married or cohabiting individuals, non-smokers, non-drinkers, those with less than 8 h of sleep, BMI below 24, and individuals with hypertension (all P < 0.05). Mendelian randomization results revealed that genetically proxied depression led to a reduction in appendicular skeletal muscle mass (all P < 0.05).ConclusionOur study provides observational and causal evidences that depression can lead to sarcopenia. This finding emphasizes the importance of timely identification and management of depression, as well as implementing targeted educational programs as part of comprehensive strategies to prevent sarcopenia.

The activity of multiple enzymes is dysregulated in cancer, but this cannot always be measured through enzyme expression. Here, the authors develop methods to measure protease activity across the organism, tissue, and single cell scales, and identify protease dysregulation in lung cancer and its response to targeted therapy.

Abstract Endometrial cancer (EC) is the most common female reproductive tract cancer and its incidence has been continuously increasing in recent years. The underlying mechanisms of EC tumorigenesis remain unclear, and efficient target therapies are lacking, for both of which feasible endometrial cancer animal models are essential but currently limited. Here, an organoid and genome editing‐based strategy to generate primary, orthotopic, and driver‐defined ECs in mice is reported. These models faithfully recapitulate the molecular and pathohistological characteristics of human diseases. The authors names these models and similar models for other cancers as organoid‐initiated precision cancer models (OPCMs). Importantly, this approach can conveniently introduce any driver mutation or a combination of driver mutations. Using these models,it is shown that the mutations in Pik3ca and Pik3r1 cooperate with Pten loss to promote endometrial adenocarcinoma in mice. In contrast, the Kras G12D mutati led to endometrial squamous cell carcinoma. Then, tumor organoids are derived from these mouse EC models and performed high‐throughput drug screening and validation. The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy.

Abstract Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

ABSTRACT: Mycoplasma synoviae (M. synoviae) is an important pathogen in poultry industry and has led to major economic losses. Understanding the epidemiology is crucial to improve control and eradication program of M. synoviae. In this study, 487 samples suspected with M. synoviae infection were collected from August 2020 to June 2021 in China. Among 487 samples, 324 samples were MS positive, the positive rate was 66.53%, and 104 strains were isolated from 324 positive samples. The multilocus sequence typing (MLST) method based on seven housekeeping genes was used to conduct genotyping 104 M. synoviae strains isolated, and the 104 isolates belonged to 8 sequence types (STs) after MLST genotyping, and ST-34 had the highest proportion. After BURST analysis, all 104 isolates were divided into group 12 with other 56 strains isolated from China. Phylogenetic tree constructed by neighbor-joining method showed that nearly all of Chinese isolates (160 isolates) clustered together and separated from other reference isolates (217 isolates) in the PubMLST database. In conclusion, this study suggested that the M. synoviae strains in China were highly similar and independent of abroad strains.

In a Poynting-flux-dominated jet that exhibits an ordered magnetic field, a transition toward turbulence and magnetic disorder follows after magnetic reconnection and energy dissipation during the prompt emission phase. In this process, the configuration of the magnetic field evolves with time, rendering it impossible to entirely categorize the magnetic field as ordered. Therefore, we assumed a crude model that incorporates a random magnetic field and an ordered magnetic field, and takes into account the proportionality of the random magnetic field strength to the ordered magnetic field, in order to compute the polarization degree (PD) curve for an individual pulse. It has been discovered that the random magnetic field has a significant impact on the PD results of the low-energy X-ray. In an ordered magnetic field, the X-ray segment maintains a significant PD compared to those in the hundreds of keV and MeV ranges even after electron injection ceases, making PD easier to detect by polarimetry. However, when the random magnetic field is introduced, the low-energy and high-energy PDs exhibit a similar trend, with the X-ray PD being lower than that of the high-energy segment. Of course, this is related to the rate of disorder in the magnetic field. Additionally, there are two rotations of the polarization angles (PAs) that were not present previously, and the rotation of the PA in the high-energy segment occurs slightly earlier. These results are unrelated to the structure of the ordered magnetic field.

Abstract The ‘angiogenic switch’ is critical for tumor progression. However, the pathological details and molecular mechanisms remain incompletely characterized. In this study, we established mammal xenografts in zebrafish to visually investigate the first vessel growth (angiogenic switch) in real-time, by inoculating tumor cells into the perivitelline space of live optically transparent Transgenic (flk1:EGFP) zebrafish larvae. Using this model, we found that hypoxia and hypoxia-inducible factor (HIF) signaling were unnecessary for the angiogenic switch, whereas vascular endothelial growth factor A gene (Vegfa) played a crucial role. Mechanistically, transcriptome analysis showed that the angiogenic switch was characterized by inhibition of translation, but not hypoxia. Phosphorylation of eukaryotic translation initiation factor 2 alpha (Eif2α) and the expression of Vegfa were increased in the angiogenic switch microtumors, and 3D tumor spheroids, and puromycin-treated tumor cells. Vegfa overexpression promoted early onset of the angiogenic switch, whereas Vegfa knockout prevented the first tumor vessel from sprouting. Pretreatment of tumor cells with puromycin promoted the angiogenic switch in vivo similarly to Vegfa overexpression, whereas Vegfa knockdown suppressed the increase. This study provides direc and dynamic in vivo evidences that inhibition of translation, but not hypoxia or HIF signaling promotes the angiogenic switch in tumor by increasing Vegfa transcription.

Several preclinical studies have demonstrated that certain cytotoxic drugs enhance metastasis, but the importance of host responses triggered by chemotherapy in regulating cancer metastasis has not been fully explored. Here, we showed that multidose gemcitabine (GEM) treatment promoted breast cancer lung metastasis in a transgenic spontaneous breast cancer model. GEM treatment significantly increased accumulation of CCR2+ macrophages and monocytes in the lungs of tumor-bearing as well as tumor-free mice. These changes were largely caused by chemotherapy-induced reactive myelopoiesis biased toward monocyte development. Mechanistically, enhanced production of mitochondrial ROS was observed in GEM-treated BM Lin−Sca1+c-Kit+ cells and monocytes. Treatment with the mitochondria targeted antioxidant abrogated GEM-induced hyperdifferentiation of BM progenitors. In addition, GEM treatment induced upregulation of host cell–derived CCL2, and knockout of CCR2 signaling abrogated the pro-metastatic host response induced by chemotherapy. Furthermore, chemotherapy treatment resulted in the upregulation of coagulation factor X (FX) in lung interstitial macrophages. Targeting activated FX (FXa) using FXa inhibitor or F10 gene knockdown reduced the pro-metastatic effect of chemotherapy. Together, these studies suggest a potentially novel mechanism for chemotherapy-induced metastasis via the host response–induced accumulation of monocytes/macrophages and interplay between coagulation and inflammation in the lungs.

Human cytomegalovirus (HCMV) infection is associated with human glioblastoma, the most common and aggressive primary brain tumor, but the underlying infection mechanism has not been fully demonstrated. Here, we show that EphA2 was upregulated in glioblastoma and correlated with the poor prognosis of the patients. EphA2 silencing inhibits, whereas overexpression promotes HCMV infection, establishing EphA2 as a crucial cell factor for HCMV infection of glioblastoma cells. Mechanistically, EphA2 binds to HCMV gH/gL complex to mediate membrane fusion. Importantly, the HCMV infection was inhibited by the treatment of inhibitor or antibody targeting EphA2 in glioblastoma cells. Furthermore, HCMV infection was also impaired in optimal glioblastoma organoids by EphA2 inhibitor. Taken together, we propose EphA2 as a crucial cell factor for HCMV infection in glioblastoma cells and a potential target for intervention.

BackgroundThis randomized controlled trial (RCT) aimed to compare two different routes of postoperative estrogen treatment on the improvements of menstruation, postoperative endometrial thickness, and fertility outcomes in patients with moderate to severe intrauterine adhesions (IUA).MethodsThis study prospectively included 78 women (age: 25 to 45 years) with moderate to severe IUA who underwent hysteroscopic resection of adhesions between March 2019 and October 2020. The enrolled patients were randomized 1:1 into either the transdermal gel group (n = 39) or the estradiol valerate oral tablet group (n = 39) on the day of receiving hysteroscopy. Postoperative endometrial thickness, AFS (American Fertility Society) score, estrogen level, and the pattern and amount of menstruation were compared. Pregnancy information was actively collected during 1-year follow-up after the operation.ResultsThe postoperative endometrium thickness was improved in both groups, and both groups gained menstruation improvement rates of 67%. For patients who underwent second-look hysteroscopy (17 from the oral group and 19 from the transdermal group), the mean AFS score declined greater than 2 in both groups. For patients with postoperative pregnancy intention, the pregnancy rates at 1-year follow-up after the procedures were 40.5% and 28% in the transdermal group and oral group, respectively. Although no statistically significant difference was observed between the two groups, patients in the transdermal group had a tendency toward increased pregnancy rate.ConclusionsTransdermal administration of estrogen is equally efficacious as oral estrogen in postoperative treatment of IUA patients with a relatively safe profile. It is very likely to broaden its indication to the field of IUA.Trial Registrationhttp://www.chictr.org.cn/showproj.aspx?proj=37197, identifier ChiCTR1900022110.

In this study, Hawthorn oligomic procyanidins extracts (HPOE) were evaluated for their anticancer activity on colorectal cancer. Our results showed that HPOE arrested HCT116 cells cycle at G2/M phase through P53-Cyclin B pathway and promoted apoptosis partly via mitochondrial (Caspase 9-Caspase 3) and death receptor (Caspase 8-Caspase 3) pathways. Meanwhile, it was found that HPOE aggravated HCT116 cells death through lysosomal vacuolation, which was verified by inhibitor/activator of P53-ILC3 signaling pathway. Taken together, HPOE exerted anticancer effects which lays the foundation for the development of functional foods for clinical colon cancer patients.

Abstract Distant metastasis remains the major cause for treatment failure in patients with nasopharyngeal carcinoma (NPC). Thus, it is necessary to investigate the underlying regulation mechanisms and potential biomarkers for NPC metastasis. Nogo-B (neurite outgrowth inhibitor B), encoded by reticulon-4, has been shown to be associated with the progression and advanced stage of several cancer types. However, the relationship between Nogo-B and NPC remains unknown. In this study, we found that higher expression of Nogo-B was detected in NPC cells and tissues. Higher expression of Nogo-B was statistically relevant to N stage, M stage, and poor prognosis in NPC patients. Further functional investigations indicated that Nogo-B overexpression could increase the migration, invasion, and metastasis ability of NPC cells in vitro and in vivo. Mechanistically, Nogo-B promoted epithelial-mesenchymal transition (EMT) and enhanced the invasive potency by interacting directly with its receptor NgR3 in NPC. Additionally, overexpression of Nogo-B could upregulate the protein levels of p-RhoA, SRF, and MRTFA. A positive relationship was found between the expression of Nogo-B and the p-RhoA in NPC patients as well as in mouse lung xenografts. Nogo-Bhigh p-RhoAhigh expression was significantly associated with N stage, M stage, and poor prognosis in NPC patients. Notably, CCG-1423, an inhibitor of the RhoA-SRF-MRTFA pathway, could reverse the invasive potency of Nogo-B and NgR3 in NPC cell lines, and decrease the expression of N-Cadherin, indicating that CCG-1423 may be a potential target drug of NPC. Taken together, our findings reveal that Nogo-B enhances the migration and invasion potency of NPC cells via EMT by binding to its receptor NgR3 to regulate the RhoA-SRF-MRTFA pathway. These findings could provide a novel insight into understanding the metastasis mechanism and targeted therapy of advanced NPC.

ObjectiveCognitive and motor dysfunctions in older people become more evident while dual-tasking. Several dual-task paradigms have been used to identify older individuals at the risk of developing Alzheimer’s disease and dementia. This study evaluated gait kinematic parameters for dual-task (DT) conditions in older adults with mild cognitive impairment (MCI), subjective cognitive decline (SCD), and normal cognition (NC).MethodThis is a cross-sectional, clinical-based study carried out at the Zhongshan Rehabilitation Branch of First Affiliated Hospital of Nanjing Medical University, China.ParticipantsWe recruited 83 community-dwelling participants and sorted them into MCI (n = 24), SCD (n = 33), and NC (n = 26) groups based on neuropsychological tests. Their mean age was 72.0 (5.55) years, and male–female ratio was 42/41 (p = 0.112). Each participant performed one single-task walk and four DT walks: DT calculation with subtracting serial sevens; DT naming animals; DT story recall; and DT words recall.Outcome and measuresKinematic gait parameters of speed, knee peak extension angle, and dual-task cost (DTC) were obtained using the Vicon Nexus motion capture system and calculated by Visual 3D software. A mixed-effect linear regression model was used to analyze the data.ResultsThe difference in gait speed under DT story recall and DT calculation was −0.099 m/s and − 0.119 m/s (p = 0.04, p = 0.013) between MCI and SCD, respectively. Knee peak extension angle under DT story recall, words recall, and single task was bigger in the MCI group compared to the NC group, respectively (p = 0.001, p = 0.001, p = 0.004). DTC was higher in the DT story recall test than all other DT conditions (p

Abstract Histopathological examination (biopsy) is the “gold standard” for the diagnosis of colorectal cancer (CRC). However, biopsy is an invasive method, and due to the temporal and spatial heterogeneity of the tumor, a single biopsy cannot reveal the comprehensive biological characteristics and dynamic changes of the tumor. Therefore, there is a need for new biomarkers to improve CRC diagnosis and to monitor and treat CRC patients. Numerous studies have shown that “liquid biopsy” is a promising minimally invasive method for early CRC detection. A liquid biopsy mainly samples circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNA (miRNA) and extracellular vesicles (EVs). CTCs are malignant cells that are shed from the primary tumors and/or metastases into the peripheral circulation. CTCs carry information on both primary tumors and metastases that can reflect dynamic changes in tumors in a timely manner. As a promising biomarker, CTCs can be used for early disease detection, treatment response and disease progression evaluation, disease mechanism elucidation, and therapeutic target identification for drug development. This review will discuss currently available technologies for plasma CTC isolation and detection, their utility in the management of CRC patients and future research directions.

Abstract Background Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood. Methods We applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments. Results Our analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function. Conclusions We portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.

Background: Nasopharyngeal carcinomas (NPCs) are malignant tumors originating from the lining epithelium of the nasopharynx. Fusion genes have been confirmed to play important roles in the occurrence and development of various malignant tumors, but the role of fusion genes in NPC is poorly understood. We aimed to explore new fusion genes that promote the occurrence and development of NPC. Methods: RNA-seq was used to search for interchromosomal translocations in 18 NPC tissues. Polymerase chain reaction (PCR) and Sanger sequencing were applied to verify the presence of BCL6-SPECC1L (BS); quantitative PCR (qPCR) and Western blotting were used to measure the expression level of BCL-6 in NPC cells; MTT and in vivo tumorigenesis assays were applied to evaluate the cell proliferation ability; immunofluorescence assays were used to determine the cellular localization of BCL6 and BS; and a luciferase reporter assay was performed to evaluate the ability of BCL6 and BS to inhibit transcription. Results: BS was present in 5.34% (11/206) of primary NPC biopsies and 2.13% (1/47) of head and neck cancer biopsies. The expression of BCL6 was downregulated in NPC, and silencing of endogenous BCL6 promoted NPC cell proliferation in vitro . Overexpression of BCL6 but not BS inhibited the growth of NPC cells in vivo and in vitro . Mechanistically, BCL6 localized in the nucleus can inhibit the G1/S transition to suppress the growth of NPC cells. However, after the fusion of BCL6 and SPECC1L, the product cannot localize to the nucleus, and the transcriptional inhibitory function of BCL6 is abolished, eventually abolishing its tumor suppressor effect and leading to the development of NPC. Conclusion: BS is a novel fusion gene in NPC that may play an important role in the occurrence and development of this cancer. The clinical significance of the BS fusion gene needs further elucidation.

BackgroundUneven distribution of health resources is higher in Tibet than in other regions. The development of core professional capability for general practitioners (GPs) is the main goal of continuing medical education (CME) training programs.AimThis study aimed to explore the needs of CME for GPs and provide advice for the development of policy, practice, and CME curriculums.MethodsWe conducted a cross-sectional online survey among GPs in Tibet Autonomous Region, China. We designed an online questionnaire including the demographic section, training contents, and training formats about CME.ResultsA total of 108 questionnaires were included in this study. Notably, 79 (73.15%) were women and 56 participants (51.85%) were working in primary care settings. We developed a curriculum priority: first-choice, major alternatives, and secondary considerations. The topics identified as first-choice for CME were related to “cardiovascular disease” (85.19%), “respiratory disease” (81.48%), and “digestive disease” (80.56%). Major alternatives included two essential knowledge and eight clinical skill items. We rated 10 items as secondary considerations. Only 39.81% ranked mental health as an essential priority; bedside teaching (51.85%) was the first choice.ConclusionWe presented priority areas identified in this study to focus on CME for GPs in Tibet. The 23 topics may reflect the features of general practice, which increasingly require common disease management skills, while a demand-oriented curriculum and staged training plans should be adopted. CME programs should be adapted dynamically to respond to evolving needs.

For analyzing the properties of humidity-effect on the measurement of the inductance of multi-layer coils, a formula that establishes an approximate relationship between the coil’s inherent capacitance and interlayer parasitic capacitance has been derived. Such a derivation using the inductor’s equivalent circuit to include humidity effects clarifies the characterization of inductance, after more than half a century of neglect in the literature.

Several experimental and biological studies have emphasized the tumor suppression efficacy and low toxicity of Apigenin (API); however, its exact underlying mechanism on human endometrial carcinoma Ishikawa cell line (EC) is still unknown. We found that API could inhibit the proliferation of Ishikawa cells at IC50 of 45.55 μM, arrest the cell cycle at G2/M phase, induce apoptosis by inhibiting Bcl-xl and increasing Bax, Bak and Caspases. Further, API could induce apoptosis by activating the endoplasmic reticulum (ER) stress pathway by increasing the Ca2+, ATF4, and CHOP. It could impede cell migration and invasion through PI3K-AKT-GSK-3β signaling pathway, preventing wound healing, restraining cells migration from the upper chamber to the lower chamber. This study demonstrated that API can be used as a promising dietary supplement and an adjuvant chemotherapeutic agent for cancer treatment.

Hyaluronic acid (HA) is a natural linear polysaccharide extensively used in many fields, including the food, medicine, and cosmetics industries. Currently, species that produce HA synthetase (HAS) from microbial sources are relatively small and mainly pathogenic, such as Streptococcus pyogenes and Pasteurella multicide. Moreover, there is limited research on the safe microbial sources of HAS. Thus, we characterized SthasA, a HAS derived from the probiotic Streptococcus thermophilus, and used it for the de novo synthesis of HA in a chassis strain of Bacillus amyloliquefaciens. Metabolic engineering of the precursor supply modules suggested that hasB (encoding UDPG dehydrogenase), which was derived from Corynebacterium glutamicum ATCC 13032, effectively promoted the accumulation of HA products. Furthermore, by combining the expression of the global regulatory factor CcpA, HA yield from the recombinant strain reached 3.20 g/L. Finally, we obtained a yield of 5.57 g/L HA with a molecular weight of 1.7 × 106 Da using various process optimization strategies in a 5 L bioreactor. This study enriches our understanding of obtaining HAS from non-pathogenic bacteria and provides a safe and effective process for producing HA, which has the potential to promote the industrial applications of HA further.

In real applications, one common issue of parameter estimation using ensemble-based data assimilation methods is the accumulation of sampling errors when a large number of observations are used to update single-value parameters. In this article, a new parameter estimation method which assimilates a large number of observations to estimate the states while assimilates adaptive observations to update the parameters is introduced. The observations resulting in maximum total variance reduction to the parameter ensembles are identified to perform parameter estimation. To validate this new method, the two-scale Lorenz-96 model is used to generate true states, while a parameterized one-scale Lorenz-96 model is used to perform state and parameter estimation experiments. The comparison between state estimation and parameter estimation with fixed or adaptive observations shows the new method can be more effective in estimating the model parameters and providing more accurate analyses. This method also shows its potential to be used in the data assimilation with large general circulation models to better produce reanalyzes.

As an intermediate state between normal aging and dementia, mild cognitive impairment (MCI), especially amnestic MCI (aMCI), is a key stage in the prevention and intervention of Alzheimer’s disease (AD). Whether dancing could increase the hippocampal volume of seniors with aMCI remains debatable. The aim of this study was to investigate the influence of aerobic dance on hippocampal volume and cognition after 3 months of aerobic dance in older adults with aMCI. In this randomized controlled trial, 68 elderly people with aMCI were randomized to either the aerobic dance group or the control group using a 1:1 allocation ratio. Ultimately, 62 of 68 participants completed this study, and the MRI data of 54 participants were included. A specially designed aerobic dance routine was performed by the dance group three times per week for 3 months, and all participants received monthly healthcare education after inclusion. MRI with a 3.0T MRI scanner and cognitive assessments were performed before and after intervention. High-resolution three-dimensional (3D) T1-weighted anatomical images were acquired for the analysis of hippocampal volume. A total of 35 participants (mean age: 71.51 ± 6.62 years) were randomized into the aerobic dance group and 33 participants (mean age: 69.82 ± 7.74 years) into the control group. A multiple linear regression model was used to detect the association between intervention and the difference of hippocampal volumes as well as the change of cognitive scores at baseline and after 3 months. The intervention group showed greater right hippocampal volume (β [95% CI]: 0.379 [0.117, 0.488], p = 0.002) and total hippocampal volume (β [95% CI]: 0.344 [0.082, 0.446], p = 0.005) compared to the control group. No significant association of age or gender was found with unilateral or global hippocampal volume. There was a correlation between episodic memory and intervention, as the intervention group showed a higher Wechsler Memory Scale-Revised Logical Memory (WMS-RLM) score (β [95% CI]: 0.326 [1.005, 6.773], p = 0.009). Furthermore, an increase in age may cause a decrease in the Mini-Mental State Examination (MMSE) score (β [95% CI]: −0.366 [−0.151, −0.034], p = 0.002). In conclusion, 3 months of aerobic dance could increase the right and total hippocampal volumes and improve episodic memory in elderly persons with aMCI.Clinical Trial Registration: This study was registered on the Chinese Clinical Trial Registry [www.chictr.org.cn], identifier [ChiCTR-INR-15007420].

Abstract Metabolic reprogramming plays important roles in development and progression of nasopharyngeal carcinoma (NPC), but the underlying mechanism has not been completely defined. In this work, we found INSL5 was elevated in NPC tumor tissue and the plasma of NPC patients. Plasma INSL5 could serve as a novel diagnostic marker for NPC, especially for serum VCA‐IgA‐negative patients. Moreover, higher plasma INSL5 level was associated with poor disease outcome. Functionally, INSL5 overexpression increased, whereas knockdown of its receptor GPCR142 or inhibition of INSL5 reduced cell proliferation, colony formation, and cell invasion in vitro and tumorigenicity in vivo. Mechanistically, INSL5 enhanced phosphorylation and nuclear translocation of STAT5 and promoted glycolytic gene expression, leading to induced glycolysis in cancer cells. Pharmaceutical inhibition of glycolysis by 2‐DG or blockade of INSL5 by a neutralizing antibody reversed INSL5‐induced proliferation and invasion, indicating that INSL5 can be a potential therapeutic target in NPC. In conclusion, INSL5 enhances NPC progression by regulating cancer cell metabolic reprogramming and is a potential diagnostic and prognostic marker as well as a therapeutic target for NPC.

Abstract Background Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been shown to exhibit tumor-suppressive role in CRC. Methods The expression of CPEB3, CD68, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells overexpressing CPEB3 and LoVo or RKO cells with CPEB3 knockdown were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, macrophage polarization, and secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice. Results Decreased CPEB3 expression in CRC was associated with fewer CD86+ TAMs and more CD163+ TAMs. CPEB3 knockdown in CRC cells increased the number of CD163+ TAMs and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAM supernatants. TAMs enhanced CRC cell proliferation and invasion via IL-6, and then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein levels by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in CPEB3 knockdown cells, while CCL2 antibody treatment rescued the effect of CPEB3 knockdown in promoting CD163+ TAM polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAM polarization in vivo. Conclusions CPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.

By matching air quality index (AQI) data with the household data from China Family Panel Studies (CFPS), we identify the impact of air pollution on household medical expenses from a micro perspective. The results show that higher air pollution will increase household medical expenses and change household consumption structure. This effect is still significant after controlling for cities' relevant household and individual characteristics and economic characteristics. Under different educational backgrounds, income, hukou, gender, and other conditions, air pollution will significantly reduce medical spending. For those females in the urban areas with higher education backgrounds and higher income, the spending elasticity of air pollution is more significant than other corresponding groups. And air pollution will promote medical expenses through stronger individuals' environmental awareness, poor health conditions, bad emotional status, and positive risk aversion. Furthermore, we find that the impact of air pollution on healthcare spending remains significant after instrumental variables regression and geographical regression based on the Qinling Mountains-Huaihe River Line.

Mycoplasma synoviae (MS) is a major avian pathogen that causes respiratory damage, infectious synovitis, and arthritis in chickens and causes serious economic losses to the global poultry industry. Despite its significance, knowledge on pathogenicity and pathogenic mechanism of MS is lacking, especially regarding its antigens. Bioinformatic analysis showed that the known MS proteins are only the tip of the iceberg among many MS membrane proteins. In this study, we identified and expressed a novel MS membrane protein P35. Sequence similarity showed that P35 was conservative and commonly existed among MS strains. Membrane protein extraction and immunofluorescence assay confirmed that P35 was distributed on the surface of MS. The production of specific antibodies after immunization with recombinant protein rP35 suggested its immunogenicity. The antigenicity of P35 was evaluated from two aspects by using polyantiserum against MS and rP35. Furthermore, in assays to identify the immune peptides of P35, all successfully expressed truncated segments could react with positive polyantiserum of MS, suggesting that P35 had more than one immune peptide. In conclusion, our study successfully identified P35 as a conservative antigen of MS, which may act as a potential candidate for the future development of a vaccine against MS.

This paper uses the Difference-in-Differences method to test the impact of the promulgation of Green Credit Guidelines, a market-oriented environmental regulation, on the enterprise market expansion strategy, based on the panel data of Chinese A-share listed companies from 2008 to 2015. We find that the promulgation of Green Credit Guidelines significantly inhibited the market expansion strategy of high pollution enterprises. Two channels through which the Green Credit Guidelines affect the market expansion strategies of high polluters are increasing the cost of financing and promoting green R&D. Heterogeneity analysis finds that the impact of Green Credit Guidelines on the market expansion of highly polluting enterprises is more significant in non-state-owned enterprises and enterprises without equity incentive. Further analysis shows that the promulgation of Green Credit Guidelines damages the corporate image and profitability of high polluting enterprises, but it doesn't increase the risk of high polluting enterprises. The results of this research could help relevant government departments to formulate practical environmental regulations and promote sustainable economic development.