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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.

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.

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.

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.

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.

Event factuality is the description of the real situation of events in text.It is the basic task of many related applications in the field of natural language processing.At present,most researches on event factuality use labeled events to identify event factuality,which is inconvenient for practical application,and ignores the impact of different event sources on event factuality.Aiming at the existing problems,an end-to-end joint model JESF for event factuality identification is proposed.The model can carry out three tasks at the same time:event identification,event source identification and event factuality identification.Using bidirectional encoder representations from transformers(BERT)and linguistic features to strengthen the semantic representation of words.Graph convolutional network(GCN) is constructed by using attention mechanism and dependency syntax tree to effectively extract semantic and syntactic features.In particular,the model can also be applied to the task of event factuality considering only the default source(text author).Experimental results on FactBank,Meantime,UW and UDS-IH2 show that the proposed model is better than the benchmark model.

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.

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.

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: 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.

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.

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.

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.

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.

Female mosquitoes require a vertebrate blood meal to activate reproduction, transmitting numerous devastating human diseases. Vitellogenesis is a central event of female reproduction that involves the massive production of vitellogenin (Vg) in the fat body and the maturation of ovaries. This process is controlled by the steroid hormone 20-hydroxyecdysone (20E); however, its molecular regulatory basis remains not completely understood. We found that the expression of Aedes aegypti muscle aponeurosis fibromatosis B (AaMafB), coding for a basic leucine zipper (bZIP) transcription factor, was significantly up-regulated after a blood meal. The 20E-bound ecdysone receptor-ultraspiracle heterodimer directly targeted the ecdysone response element in the promoter of AaMafB, activating its transcription. Coimmunoprecipitation assays illustrated the interaction between AaMafB and Cap "n" collar C (AaCncC), another bZIP transcription factor. RNA interference-mediated depletion of AaMafB or AaCncC led to impaired ovarian growth, decreased expression of AaVg and Halloween genes, and reduced 20E levels. The AaMafB-AaCncC heterodimer directly activated the transcription of AaVg and AaShade by targeting the antioxidant response element in their promoters. Together, our results indicate that AaMafB functions as an early 20E response gene, the product of which heterodimerizes with AaCncC to maintain high 20E levels and facilitates activation of AaVg in mosquitoes after a blood meal. [ABSTRACT FROM AUTHOR]

Tilapia is a kind of fish with a huge amount of aquaculture, and a lot of byproducts are wasted in processing. Of these, fish skin is the most valued due to its high content of gelatin, which has good characteristics such as low hypoallergenic, biocompatibility, and permeability. In this study, a novel pentapeptide (Leu‐Ser‐Gly‐Tyr‐Gly, LYG) was isolated from gelatin gastrointestinal digests of tilapia skin and verified the anti‐inflammatory and antiangiogenic activity of LYG, which can inhibit scar formation. In addition, the active sites were analyzed using molecular docking. The key active amino acids Leu and Tyr of LYG were able to form hydrogen bonds and good hydrophobic structures with transforming growth factor β1 (TGF‐β1). Hyperplastic scar (HS) is a common fibrous proliferative disorder of the skin, and fibrosis is the process of scar formation. It is well known that the inhibition of collagen and angiogenesis is an effective way to combat HS. The results of this study show that LYG inhibited collagen synthesis and inflammatory stress in mouse fibroblasts (L929), suppressed the angiogenic signaling pathway in vascular endothelial cells (HUVECs), and reduced scar formation after wound healing in mice. This study provides new ideas for improving the diversified use of tilapia resources. [ABSTRACT FROM AUTHOR]

This paper focuses on document-level event factuality identification (DEFI), which predicts the factual nature of an event from the view of a document. As the document-level sub-task of event factuality identification (EFI), DEFI is a challenging and fundamental task in natural language processing (NLP). Currently, most existing studies focus on sentence-level event factuality identification (SEFI). However, DEFI is still in the early stage and related studies are quite limited. Previous work is heavily dependent on various NLP tools and annotated information, e.g., dependency trees, event triggers, speculative and negative cues, and does not consider filtering irrelevant and noisy texts that can lead to wrong results. To address these issues, this paper proposes a reinforced multi-granularity hierarchical network model: Reinforced Semantic Learning Network (RSLN), which means it can learn semantics from sentences and tokens at various levels of granularity and hierarchy. Since integrated with hierarchical reinforcement learning (HRL), the RSLN model is able to select relevant and meaningful sentences and tokens. Then, RSLN encodes the event and document according to these selected texts. To evaluate our model, based on the DLEF (Document-Level Event Factuality) corpus, we annotate the ExDLEF corpus as the benchmark dataset. Experimental results show that the RSLN model outperforms several state-of-the-arts. [ABSTRACT FROM AUTHOR]

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.

In order to obtain bright aluminum alloy wires and eliminate the environmental and human hazards of traditional chemical polishing, the H _3 PO _4 -H _2 SO _4 system chemical polishing process was developed for SAL5087, and the surface roughness was measured by laser confocal microscopy and the surface morphology was observed by sweeping electron microscopy as the evaluation index of the polishing quality. The process optimization was carried out by orthogonal experiments and the role of each component was analyzed. The experiments showed that phosphoric acid dominates the polishing process, which can effectively enhance the polishing effect under the synergistic effect with various additives. The surface roughness of the polished wire was reduced to 0.257 μm in the optimum process, and the surface was free of defects such as burrs and scratches.

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.