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Abstract: To investigate the differential expression of the chemokine signaling pathway in lacrimal gland benign lymphoepithelial lesion (LGBLEL) and lacrimal lymphoma, providing insights into the mechanisms underlying malignant transformation and aiding clinical differentiation. Transcriptome analysis was conducted on patients with LGBLEL, lymphoma, and orbital cavernous hemangioma (CH). Three cases of LGBLEL and three cases of lymphoma were randomly selected as control and experimental groups, respectively. A real-time quantitative polymerase chain reaction (RT-qPCR) was used to validate genes associated with the chemokine signaling pathway. Immunohistochemical (IHC) staining and quantitative Western blotting (WB) were performed for precise protein quantification. Transcriptome analysis revealed differential expression of the chemokine signaling pathway between the LGBLEL and lymphoma groups, identifying ten differentially expressed genes: CCL17, VAV2, CXCR5, NRAS, HCK, RASGRP2, PREX1, GNB5, ADRBK2, and CCL22. RT-qPCR showed that, compared to the lymphoma group, the LGBLEL group had significantly higher expression of CCL28, CXCL17, HCK, GNB5, NRAS, and VAV2 (p = 0.001, CCR1 (p = 0.002). IHC staining and quantitative analysis confirmed significant differences in protein expression between the groups for CCL28, CCR1, CXCL17, HCK, GNB5, NRAS, and VAV2 (p = 0.003, 0.011, 0.001, 0.024, 0.005, 0.019, and 0.031, respectively). While IHC provided localization, WB offered greater precision. WB revealed that, compared to the lymphoma group, the LGBLEL group exhibited significantly higher expression of CCL28, CXCL17, HCK, GNB5, NRAS, and VAV2 (p = 0.012, 0.005, 0.009, 0.011, 0.008, and 0.003, respectively) and lower expression of CCR1 (p = 0.014). The chemokine signaling pathway plays a role in the malignant transformation of LGBLEL. The decreased expression of CCL28 and CXCL17, coupled with the increased expression of CCR1, may be linked to the progression of LGBLEL into lymphoma.

Abstract Objectives To retrospectively investigate clinical characterization and the long-term postoperative outcomes of retinoblastoma (RB) patients receiving enucleation with primary orbital implantation in early infancy (0–6 months old). Methods The clinical and follow-up data of 42 RB patients receiving enucleation with primary orbital implantation in early infancy at Beijing Tongren Hospital from December 2009 to January 2020 were analysed. The average follow-up time was 83 months. The patient group included 24 males and 18 females, 30 unilateral and 12 bilateral cases. A total of 44 eyes with 10 in stage D and 34 in stage E underwent 40 unilateral and 2 bilateral surgeries. 17 RB eyes received hydrogel and 27 RB eyes received hydroxyapatite implants. This study was performed by following the guideline of STROBE. Results Enucleation combined with primary orbital implantation promoted survival and was safe with few and minor complications such as increased secretion, upper eyelid ptosis, and sunken eye sockets which were not affected by stages, lateralities, or implant materials. 55-80% RB patients exhibited satisfactory appearance and obvious or moderate motility of orbital implants according to the evaluation by doctors and family members. Family members were likely more optimistic about the appearance and more pessimistic about motility of the orbital implantation than doctors did.The quality of life was high as indicated by PedsQL3.0 or PedsQL4.0 scores ( ≧ 90 for > 75% patients). It was not affected by the stages, laterality, and implant materials, nor affected by the appearance and motility of the implants. Conclusions The outcomes of the combination of enucleation and primary orbital implantation for pertinent RB patients in early infancy are generally satisfactory with few and minor complications, high safety, appearance, and overall quality of life. Enucleation combined with primary orbital implantation in early infancy benefits pertinent RB patients in appearance, survival, and quality of life.

Abstract Objective To examine the clinical characteristics, diagnosis and treatment, and prognosis of ocular amyloidosis in a Chinese population. Methods A retrospective case series study was conducted. The clinical data of 37 patients with ocular amyloidosis were collected and the clinical characteristics, diagnosis and treatment, and prognosis were summarized and analyzed. Results The 37 patients included 12 males and 25 females ranging in age from 22 to 75 years, with median age of 49 years. The clinical signs and symptoms included a conjunctival mass in 37 patients (100%), periorbital discomfort or pain in 29 patients (61.9%), ptosis in 18 patients (23.8%), exophthalmos or eyeball displacement in 3 patients (14.3%), restricted eye movement in 2 patients (9.52%), vision loss in 1 patient (4.76%), and diplopia in 1 patient (4.76%). A total of 29 patients had only conjunctival involvement and 8 patients had concomitant orbital and conjunctival involvement. The main treatment for patients with conjunctival involvement was surgical resection. Thirty-one patients had stable disease, 4 patients progressed or relapsed, and 2 patients were lost to follow-up. Conclusion Ocular amyloidosis most commonly presents as an eyelid or conjunctival mass or diffuse thickening and can also present as an orbital mass. Diagnosis is mainly dependent on histopathological examination. Surgery is the main treatment and is done to confirm the diagnosis to guide further treatment, preserve function, and prevent complications that threaten visual acuity. Close postoperative follow-up is necessary.

Abstract Background The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens. Methods In this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG). Results The PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events. Conclusions BIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes. Trial registration The study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391 ).

Abstract High‐grade serous tubo‐ovarian cancer (HGSTOC) is an aggressive gynecological malignancy including homologous recombination deficient (HRD) and homologous recombination proficient (HRP) groups. Despite the therapeutic potential of poly (ADP‐ribose) polymerase inhibitors (PARPis) and anti‐PDCD1 antibodies, acquired resistance in HRD and suboptimal response in HRP patients necessitate more precise treatment. Herein, single‐cell RNA and single‐cell T‐cell receptor sequencing on 5 HRD and 3 HRP tumors are performed to decipher the heterogeneous tumor immune microenvironment (TIME), along with multiplex immunohistochemistry staining and animal experiments for validation. HRD tumors are enriched with immunogenic epithelial cells, FGFR1+PDGFRβ+ myCAFs, M1 macrophages, tumor reactive CD8+/CD4+ Tregs, whereas HRP tumors are enriched with HDAC1‐expressing epithelial cells, indolent CAFs, M2 macrophages, and bystander CD4+/CD8+ T cells. Significantly, customized therapies are proposed. For HRD patients, targeting FGFR1+PDGFRβ+ myCAFs via tyrosine kinase inhibitors, targeting Tregs via anti‐CCR8 antibodies/TNFRSF4 stimulation, and targeting CXCL13+ exhausted T cells by blocking PDCD1/CTLA‐4/LAG‐3/TIGIT are proposed. For HRP patients, targeting indolent CAFs, targeting M2 macrophages via CSF‐1/CSF‐1R inhibitors, targeting bystander T cells via tumor vaccines, and targeting epithelial cells via HDAC inhibitors. The study provides comprehensive insights into HRD and HRP TIME and tailored therapeutic approaches, addressing the challenges of PARPi‐resistant HRD and refractory HRP tumors.

Earthworms are keystone regulators of carbon exchange between terrestrial ecosystems and the atmosphere. However, exactly how earthworms regulate the composition of microbial and plant-derived carbon in soil organic matter remains poorly understood. Here we conducted a microcosm experiment with two species of endogeic earthworms (Drawida gisti and Metaphire guillelmi) to investigate their effects on cellular and extracellular-microbial residues versus fast and slow-decaying plant materials. We found that both species of earthworms reduced microbial residues (amino sugars or the protein content of extracellular polymeric substances (EPS)) and facilitated the decomposition of microbial residues rather than their formation. Neither earthworm species affected slow-decaying plant residues (lignin phenols). However, their effects on the fast-decaying fraction of plant residues (particulate organic matter (POM)) depended on the earthworm species. Principal component analysis (PCA) revealed that earthworms mediated two gradients between microbial and plant residues. The first gradient was between the nitrogenous fraction of microbial residues (e.g., amino sugars and EPS-protein) versus slow-decaying plant lignin, while the second gradient was between the fast-decaying POM versus EPS-polysaccharide. Our results suggest that earthworms play vital roles in mediating plant and microbial residue fractions in soil through their multifaceted mechanisms in regulating the chemical composition of organic carbon, and in understanding biological control of the global soil carbon cycle.

Abstract Complete removal of all tumor tissue with a wide surgical margin is essential for the treatment of osteosarcoma (OS). However, it's difficult, sometimes impossible, to achieve due to the invisible small satellite lesions and blurry tumor boundaries. Besides, intraoperative frozen‐section analysis of resection margins of OS is often restricted by the hard tissues around OS, which makes it impossible to know whether a negative margin is achieved. Any unresected small tumor residuals will lead to local recurrence and worse prognosis. Herein, based on the high expression of B7H3 in OS, a targeted probe B7H3‐IRDye800CW is synthesized by conjugating anti‐B7H3 antibody and IRDye800CW. B7H3‐IRDye800CW can accurately label OS areas after intravenous administration, thereby helping surgeons identify and resect residual OS lesions (

Introduction: Lacrimal gland adenoid cystic carcinoma (LGACC) is characterized by a high rate of recurrence, perineural invasion, and propensity for distant metastasis, resulting in poor prognosis. This case report aimed to highlight the diagnostic and therapeutic challenges of LGACC, underscore the importance of resectioning the tumor as completely as possible for the first time, adhere to postoperative adjuvant therapy, and provide detailed insights into its surgical and diagnostic management that may not be extensively covered in large case series and meta-analyses. Case presentation: A 34-year-old man presented with progressive left eye proptosis for 4 months. Initial evaluation and imaging led to a high suspicion of LGACC, which was confirmed after an eye-sparing excision of the left orbital tumor. The patient declined to undergo postoperative radiotherapy, which was recommended after the surgery. Thus, despite surgical intervention, the patient experienced tumor recurrence 3 months post-surgery, leading to orbital exenteration. Pathological examination confirmed the presence of poorly differentiated LGACC.This time the patient underwent postoperative radiotherapy, as recommended. However, despite local control, the patient developed an intracranial metastasis within a year. Conclusion: LGACC presents significant diagnostic and therapeutic challenges owing to its insidious onset, lack of specific symptoms, and high potential for recurrence and metastasis. Thus, this case emphasizes the need for early diagnosis, aggressive treatment, and adherence to postoperative adjuvant therapy to improve patient outcomes. Future research should focus on understanding the pathogenesis of LGACC and on developing standardized diagnostic and treatment protocols to enhance patient prognosis and survival.

BackgroundSepsis is one of the major causes of death and increased health care burden in modern intensive care units. Immune checkpoints have been prompted to be key modulators of T cell activation, T cell tolerance and T cell exhaustion. This study was designed to investigate the role of the negative immune checkpoint, T cell immunoglobulin and ITIM domain (TIGIT), in the early stage of sepsis.MethodAn experimental murine model of sepsis was developed by cecal ligation and puncture (CLP). TIGIT and CD155 expression in splenocytes at different time points were assessed using flow cytometry. And the phenotypes of TIGIT-deficient (TIGIT-/-) and wild-type (WT) mice were evaluated to explore the engagement of TIGIT in the acute phase of sepsis. In addition, the characteristics were also evaluated in the WT septic mice pretreated with anti-TIGIT antibody. TIGIT and CD155 expression in tissues was measured using real-time quantitative PCR and immunofluorescence staining. Proliferation and effector function of splenic immune cells were evaluated by flow cytometry. Clinical severity and tissue injury were scored to evaluate the function of TIGIT on sepsis. Additionally, tissue injury biomarkers in peripheral blood, as well as bacterial load in peritoneal lavage fluid and liver were also measured.ResultsThe expression of TIGIT in splenic T cells and NK cells was significantly elevated at 24 hours post CLP.TIGIT and CD155 mRNA levels were upregulated in sepsis-involved organs when mice were challenged with CLP. In CLP-induced sepsis, CD4+ T cells from TIGIT-/- mice shown increased proliferation potency and cytokine production when compared with that from WT mice. Meanwhile, innate immune system was mobilized in TIGIT-/- mice as indicated by increased proportion of neutrophils and macrophages with potent effector function. In addition, tissue injury and bacteria burden in the peritoneal cavity and liver was reduced in TIGIT-/- mice with CLP induced sepsis. Similar results were observed in mice treated with anti-TIGIT antibody.ConclusionTIGIT modulates CD4+ T cell response against polymicrobial sepsis, suggesting that TIGIT could serve as a potential therapeutic target for sepsis.

The use of liquid biopsy in cancer research has grown exponentially, offering potential for early detection, treatment stratification, and monitoring residual disease and recurrence. Exosomes, released by cancer cells, contain tumor-derived materials and are stable in biofluids, making them valuable biomarkers for clinical evaluation. Bibliometric research on osteosarcoma (OS) and exosome-derived diagnostic biomarkers is scarce. Therefore, we aimed to conduct a bibliometric evaluation of studies on OS and exosome-derived biomarkers. Using the Web of Science Core Collection database, Microsoft Excel, the R “Bibliometrix” package, CiteSpace, and VOSviewer software, quantitative analyses of the country, author, annual publications, journals, institutions, and keywords of studies on exosome-derived biomarkers for OS from 1995 to 2023 were performed. High-quality records (average citation rate ≥ 10/year) were filtered. The corresponding authors were mainly from China, the USA, Australia, and Canada. The University of Kansas Medical Center, National Cancer Center, Japan, and University of Kansas were major institutions, with limited cooperation reported by the University of Kansas Medical Center. Keyword analysis revealed a shift from cancer progression to mesenchymal stem cells, exosome expression, biogenesis, and prognostic biomarkers. Qualitative analysis highlighted exosome cargo, including miRNAs, circRNAs, lncRNAs, and proteins, as potential diagnostic OS biomarkers. This research emphasizes the rapid enhancement of exosomes as a diagnostic frontier, offering guidance for the clinical application of exosome-based liquid biopsy in OS, contributing to the evolving landscape of cancer diagnosis.

Abstract Multiple surface treatment methods for titanium alloy prostheses, widely used in orthopedics, are available; however, these can affect bone integration and regeneration efficiency. In this study, through cell and animal experiments, we devised seven bone implant categories of Ti6Al4V based on surface preparation and post-processing technology (polishing, grit-blasting, fine titanium spraying, coarse titanium spraying, electron beam melting [EBM] printing, selective laser melting [SLM] printing, and post-processed SLM printing) and imaged each microscopic surface structure with a scanning electron microscope (SEM). Mechanical testing revealed excessive post-processing damaged the mechanical properties of the implants. In vitro, human bone marrow mesenchymal stem cells (hBMSCs) were cultured with implants, and the morphology of the cells adhering to the implant surface was observed using SEM and confocal laser scanning microscopy. Cell Counting Kit-8 (CCK-8) semi-quantitatively determined cell activity, indirectly reflecting the proliferation of hBMSCs. Alizarin red and alkaline phosphatase experiments assessed osteogenic differentiation. In vivo, experiments utilized the New Zealand rabbit femoral condyle bone defect model to assess bone regeneration and integration using micro-computed tomography, Van Giesen staining, and Masson staining. We found that 3D-printed implants with regular pore structures were more conducive to hBMSC osteogenic differentiation, while the presence of metal powder on NPT-SLM-printed implants hindered such differentiation. The post-treatment SLM scaffold surface may have some residual semi-melted powder; however, these powder residues have no significant effect on cell activity and differentiation. Surface treatment (grit-blasting and titanium spraying) of planar structures can enhance hBMSC adhesion but does not necessarily promote their differentiation. The framework structure of 3D printing may affect the osteogenic differentiation of hBMSCs, and for SLM-printed implants, excessive pursuit of a “powderless” state will damage the mechanical properties of the implant.

Abstract Background Cervical cancer (CC) is the fourth most common cancer in women worldwide. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of CC immune remodeling and exploration of novel treatment targets. This study aimed to investigate the mechanism of CC immune remodeling and explore potential therapeutic targets. Methods We conducted single‐cell RNA sequencing on a total of 17 clinical specimens, including normal cervical tissues, high‐grade squamous intraepithelial lesions, and CC tissues. To validate our findings, we conducted multicolor immunohistochemical staining of CC tissues and constructed a subcutaneous tumorigenesis model in C57BL/6 mice using murine CC cell lines (TC1) to evaluate the effectiveness of combination therapy involving indoleamine 2,3‐dioxygenase 1 (IDO1) inhibition and immune checkpoint blockade (ICB). We used the unpaired two‐tailed Student's t‐test, Mann‐Whitney test, or Kruskal‐Wallis test to compare continuous data between two groups and one‐way ANOVA with Tukey's post hoc test to compare data between multiple groups. Results Malignant cervical epithelial cells did not manifest noticeable signs of tumor escape, whereas lysosomal‐associated membrane protein 3‐positive (LAMP3+) dendritic cells (DCs) in a mature state with immunoregulatory roles were found to express IDO1 and affect tryptophan metabolism. These cells interacted with both tumor‐reactive exhausted CD8+ T cells and CD4+ regulatory T cells, synergistically forming a vicious immunosuppressive cycle and mediating CC immune escape. Further validation through multicolor immunohistochemical staining showed co‐localization of neoantigen‐reactive T cells (CD3+, CD4+/CD8+, and PD‐1+) and LAMP3+ DCs (CD80+ and PD‐L1+). Additionally, a combination of the IDO1 inhibitor with an ICB agent significantly reduced tumor volume in the mouse model of CC compared with an ICB agent alone. Conclusions Our study suggested that a combination treatment consisting of targeting IDO1 and ICB agent could improve the therapeutic efficacy of current CC immunotherapies. Additionally, our results provided crucial insights for designing drugs and conducting future clinical trials for CC.

Stacking fermentation is a crucial step in producing sauce-flavor Baijiu. The relationship between microbial diversity and volatile flavor substances is complex and dynamic. To better understand the correlation between microorganisms and flavor substances in Dongniang sauce-flavor Baijiu during the five-round stacking fermentation of Jiupei, high-throughput sequencing (HTS) technology and headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME/GC-MS) were used to identify the microbial flora diversity and volatile flavor compounds. In addition, the Pearson correlation coefficient was computed, and a visualizable correlation network diagram was drawn based on the detection results. The results identified 55 volatile flavor compounds, including 25 esters, 5 alcohols, 7 aldehydes, 4 acids, 4 phenols, 3 alkanes, and 7 others. The main volatile components were ethyl lactate, phenylethyl alcohol, ethyl phenylacetate, and phenethyl acetate. The dominant microorganism genera in the floral structure were Virgibacillus, Kroppenstedtia, Bacillus, Oceanobaciillus, Thermomyces, Zygosaccharomyces, and Thermoascus. Kroppenstedtia, Monascus, Bacillus, and Zygosaccharomyces significantly affected flavor substances among the flora. Overall, the purpose and significance of this study are to provide a theoretical foundation for enhancing the quality of Dongniang sauce-flavor Baijiu.

Abstract Introduction Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG + 3TC) are well tolerated and effective in clinical trials. This study aimed to evaluate the safety and efficacy of these two schemes in a real-world setting and to obtain the first dataset for switching to BIC/FTC/TAF and DTG + 3TC in a Chinese population. Methods This retrospective single-center cohort study in China included participants who switched to DTG + 3TC or BIC/FTC/TAF between January 2020 and February 2023. The main endpoint was the proportion of participants with HIV-1 RNA levels of ≥ 50 copies/mL. Safety, tolerance, and the incidence of low-level viremia (LLV) were evaluated. Results A total of 525 participants were included, 454 of whom were included in the PP analysis. At week 48, the proportions of participants with HIV-1 RNA ≥ 50 copies/mL were 4.4% (10/225) for DTG + 3TC and 6.1% (14/229) for BIC/FTC/TAF; virological efficacy did not differ significantly between the two groups. Consistent results were obtained in an intent-to-treat (ITT) analysis. The incidences of LLV were 3.6% (7/193) and 4.9% (10/206), respectively. During the study, none of the participants stopped taking drugs because of a lack of efficacy or adverse reactions. Conclusions Both regimens are well tolerated and effective for switching HIV-1 infection therapy. However, the detection of genotypic drug resistance should be considered when baseline virological non-suppression is observed.

Abstract Introduction Ainuovirine/lamivudine/tenofovir is a novel antiretroviral therapy regimen used to treat human immunodeficiency virus-1 (HIV-1) infection. This study aimed to compare the pharmacokinetics of ainuovirine/lamivudine/tenofovir in HIV-1-infected patients aged ≥ 65 (elderly patients) and ≤ 40 years (young patients). Methods This prospective, open-label, parallel controlled clinical study included 15 young and 15 elderly patients. Blood (1 mL) was collected 30 min before dosing and at 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, and 24 h after dosing, to measure the plasma concentrations of ainuovirine/lamivudine/tenofovir. Safety was assessed by monitoring the adverse events, physical examinations, and clinical laboratory tests. Results Plasma concentrations of each ainuovirine/lamivudine/tenofovir component reached peak levels 1–4 h after dosing and gradually decreased during the remaining observation period. Compared with the young group, ainuovirine had significantly higher T 1/2Ke, AUC0–24, and AUC0–inf (all P

Abstract Immunogenic cell death (ICDs) has gained increasing attention for its significant clinical efficacy in various diseases. Similarly, more and more attention has been paid in the role of immune factors in the pathological process of osteoarthritis (OA). The objective of this study is to reveal the relationship between ICD-related genes and the process of OA at the gene level through bioinformatics analysis. In this study, Limma R package was applied to identify differentially expressed genes (DEG), and OA related module genes were determined by weighted gene co-expression network analysis. The ICD-related genes were extracted from a previous study. The module genes related to DEGs and ICD were overlapped. Then, hub genes were identified by a series of analyses using the Least absolute shrinkage and selection operator and random forest algorithm, the expression level and diagnostic value of hub genes were evaluated by Logistic regression. In addition, we used Spearman rank correlation analysis to clarify the relationship between hub genes and infiltrating immune cells and immune pathways. The expression levels of FPR1, FPR2, IL17RA, and TLR7 was verified in SD rat knee joint model of OA by immunohistochemistry. The expression levels of FPR1, FPR2, IL17RA, and TLR7 mRNA were detected in the IL-1β induced rat chondrocytes in qPCR experiment in vitro. Four hub genes (FPR1, FPR2, IL17RA, and TLR7) were ultimately identified as OA biomarkers associated with ICD. And knockdown of TLR7 reversed collagen II and ADAMTS-5 degradation in IL-1β-stimulated chondrocytes. This research may provide new immune related biomarkers for the diagnosis of OA and serve as a reference for disease treatment monitoring.

Abstract Background Sjögren’s Syndrome (SS) is an inflammatory autoimmune disease, and Mikulicz’s disease (MD) is a lymphoproliferative disorder. Both MD and SS are more common in middle-aged female, and the dry eyes could be presented in both of them with different degree. The MD patients are characterized by symmetrical swelling of the lacrimal glands which also can occur in the early stage of SS. And the imaging findings between early stage of SS and MD are lack of specificity. Therefore, SS and MD have similarities in the clinical manifestations, imaging and pathological findings and are confused in diagnosis. Case presentation A 51-year-old female patient presented with bilateral swelling of the upper eyelids for 2 years. She also reported having dry mouth and dry eyes which could be tolerated. The Schirmer’s test result is positive and the laboratory tests indicate serum total IgG increased. In the bilateral lacrimal gland area could palpate soft masses. The orbital magnetic resonance imaging (MRI) examination showed bilateral lacrimal gland prolapse. While the histopathological result was considered as MD. The immunohistochemical (IHC) staining results were positive for IgG and negative for IgG4. To clarify the diagnosis, SS-related laboratory tests were performed: anti-SSA antibody (+++), anti-SSB antibody (+++), anti-Ro-52 antibody (+++). With a comprehensive consideration, the final diagnosis was SS. Conclusion When the clinical manifestations are atypical, it is necessary to pay attention to the differential diagnosis of SS and MD.

Abstract Background Ligneous conjunctivitis (LC) is a rare inflammatory lesion of the conjunctiva with an unknown etiology. It is easily confused with conjunctiva lymphoma or other diseases in clinical diagnosis, and the lesion is very difficult to treat. Case presentation We presented a 41-year-old female patient presented with bilateral conjunctival masses for more than six months. The patient had no contributory history of ocular trauma, family history of tumor and drug allergy. Taking the patient’s clinical and pathological features together, we considered this was a case of IgG4 + LC. Completely surgical resection combined with local glucocorticoid treatment might be effective. Conclusions This is a very rare case report of immunoglobulin G4 positive LC with only one published case in literature. The typical manifestations of LC are with the appearance of a hard, fibrin-rich, woody pseudomembranous lesion. A large number of lymphocyte and plasma cell are infiltrated in the pathological tissue. Inflammation of LC may cause immune abnormalities, resulting in IgG4 increasing.

Background The prevalence of loneliness among older adults is of great importance in the field of public health. Numerous studies have provided evidence supporting the effectiveness of social support as a powerful intervention for reducing loneliness in older individuals. However, the specific types of social support that yield positive results are yet to be determined. Therefore, this study aims to conduct a comprehensive review to compare and analyse the effectiveness of different support mechanisms in alleviating loneliness among community-dwelling older adults.Methods and analysis A thorough search will be conducted on various electronic databases, including EMBASE, PubMed, the Cochrane Library, Web of Science, PsycINFO, Scopus, Google Scholar, China National Knowledge Infrastructure Library, China Science and Technology Journal Database (Weipu), WanFang Database, and China Biology Medicine Disc. The search will include randomised controlled trials published in English or Chinese that focus on interventions for loneliness in older individuals, with loneliness as the primary measure of interest. The selection and choice of articles will be the responsibility of both reviewers. The JBI Critical Appraisal Checklist for Randomised Controlled Trials will be used to assess the methodological quality of the included trials. When sufficient data are obtained and the study is relatively homogeneous, a random-effects or fixed-effects model will be employed to conduct a meta-analysis, yielding a descriptive synthesis of the findings.Ethics and dissemination Ethics approval will not be sought for this systematic review as it will exclusively focus on published papers. The review findings will be showcased at a conference dedicated to this specific field and published in an appropriate journal that undergoes peer evaluation.PROSPERO registration number CRD42020226523.

Abstract Tumor thrombus of bone sarcomas represents a unique reservoir for various types of cancer and immune cells, however, the investigation of tumor thrombus at a single-cell level is very limited. And it is still an open question to identify the thrombus-specific tumor microenvironment that is associated with the tumor-adaptive immune response. Here, by analyzing bulk tissue and single-cell level transcriptome from the paired thrombus and primary tumor samples of osteosarcoma (OS) patients, we define the immunostimulatory microenvironment in tumor thrombus of OS with a higher proportion of tumor-associated macrophages with M1-like states (TAM-M1) and TAM-M1 with high expression of CCL4. OS tumor thrombus is found to have upregulated IFN-γ and TGF-β signalings that are related to immune surveillance of circulating tumor cells in blood circulation. Further multiplexed immunofluorescence staining of the CD3/CD4/CD8A/CD68/CCL4 markers validates the immune-activated state in the tumor thrombus samples. Our study first reports the transcriptome differences at a single-cell level between tumor thrombus and primary tumor in sarcoma.

Sports are essential to everyone’s health because they assist athletes to establish physical and mental balance by strengthening muscles and ligaments. High-intensity training and low-quality equipment for sports tend to cause a wide range of injuries to the athlete. Higher education graduates’ regular education and lives are disrupted, either directly or indirectly, by sports injuries. Therefore, understanding the prevalence and root causes of college athletes’ injuries is crucial for enhancing student athletes’ performance and fostering healthy development. The ever-changing nature of injuries associated with sports and the patchy availability of rehabilitation facilities across India cause alarm. Inaccurately identifying players’ physical indications, uncomfortable clothing, and dissatisfaction with sports equipment are among the issues that can arise. The study investigates the potential of nanoparticles combined with sports flexible conjugate materials for injury prevention in athletes. The article proposed nanotechnology combined with flexible conjugated materials in sports events (Nano-FCM-SE) in sports training, explores the possibility of conjugated materials in enhancing the training effects of athletes, monitoring the status of sports, and bettering equipment. Sports equipment can help keep athletes safe by incorporating nanotechnology and flexible conjugated materials with superior optical, electrical, and other capabilities. Convenience, waterproof materials, flexibility, lightweight, aesthetics, breathability, and durability are evaluated for use in Nano-conjugated sports equipment materials. Evidence suggests that using flexible conjugated materials in athletic training can improve athlete performance and help the overall development of sports. The proposed method yields less negative results than MSI-TENG, TCM-MS, and RANSAC. The proposed damage severity model performs poorly relative to competitors (0.2). Compared to conventional models, the given models are effective on equipment. The sports injury protection system reported in this research has 5.17 percentage points greater detection efficiency than the current state of the art. Hierarchical strategies have the best RMSE for athlete safety. The findings of such methodologies in athlete safety on Nano conjugate materials and sports biology on sporting events and equipment underline the importance of precise data for athlete safety and performance.

Chordoma is a rare malignant bone tumor with limited therapeutic options, which is resistant to conventional chemotherapy and radiotherapy, and targeted therapy is also shown with little efficacy. The long-standing delay in researching its mechanisms of occurrence and development has resulted in the dilemma of no effective treatment targets and no available drugs in clinical practice. In recent years, the role of the tumor immune microenvironment in driving tumor growth has become a hot and challenging topic in the field of cancer research. Immunotherapy has shown promising results in the treatment of various tumors. However, the study of the immune microenvironment of chordoma is still in its infancy. In this review, we aim to present a comprehensive reveal of previous exploration on the chordoma immune microenvironment and propose promising immunotherapy strategies for chordoma based on these characteristics.

Osteosarcoma (OS) is a malignant mesenchymal tissue tumor known to occur in children and adolescents, and pulmonary metastasis often leads to death in these patients. The mechanism underlying OS progression remains unclear. Therefore, identifying new therapeutic targets and treatment modalities for OS is urgently needed. Abnormally expressed non-coding circular RNAs (circRNAs) are crucial for the occurrence and development of OS. The purpose of this study was to explore the expression and role of a novel circRNA circ_000203 in OS and elucidate the underlying mechanism. circ_000203 was demonstrated highly expressed in OS cell lines and tissues, and circ_000203 knockdown significantly inhibited OS progression in vitro and in vivo. Furthermore, we found that circ_000203 is a sponge of miR-26b-5p, an upstream regulator of bone morphogenetic protein receptor 2 (BMPR2). Thus, the overexpression of BMPR2 could reduce the inhibitory effect on OS progression. This indicates that knockdown of circ_000203 suppresses OS progression through microRNA (miRNA)-mediated BMPR2 downregulation. Our findings provide important insights for understanding the occurrence and development of OS.

Abstract Background Eosinophilic angiocentric fibrosis (EAF) is a rare inflammatory lesion, especially in orbit. EAF is believed to be related to IgG4-related disease (IgG4-RD), but the clinical manifestations of systemic involvement are relatively rare and easy to be confused with tumors or other inflammatory diseases. Histopathological examination is the most important way of its diagnosis and differentiation. Case presentation We presented a 55-year-old female patient presented with recurrent swelling of the right lower eyelid for more than 2 months. The pathological diagnosis was EAF. Positive immunostaining for IgG, CD34, κ, and λ, while negative immunostaining for IgG4. Conclusions Complete surgical resection is the preferred treatment, histopathological examination is the main diagnostic standard.

Abstract CircRNAs play crucial roles in various malignancies via an increasing number of reported regulatory mechanisms, including the classic sponging mechanism between circRNAs and micro RNAs (miRNAs). We performed bioinformatic analyses and identified circTLK1 as a regulator of malignant chordoma progression. Moreover, we observed that circTLK1 showed high expression in chordoma cells and tissues, while circTLK1 interference suppressed chordoma cell proliferation and invasion. In addition, circTLK1 directly interacted with miR-16-5p, which has previously been shown to repress chordoma, and circTLK1 knockdown suppressed Smad3 expression. Chromatin immunoprecipitation sequencing further demonstrated that Smad3 acts as a positive regulator by interacting with TLK1, thereby mediating the circTLK1/miR-16-5p/Smad3 positive feedback axis. Taken together, our findings suggested that the disruption of the circTLK1/miR-16-5p/Smad3 positive feedback pathway, particularly via the Smad3 inhibitor SIS3, could be a promising therapeutic strategy.

Abstract Aspergillus genus is a key component in fermentation and food processing. However, sterigmatocystin (STE)—a mycotoxin produced by several species of Aspergillus—limits the use of some Aspergillus species (such as Aspergillus versicolor, Aspergillus inflatus, and Aspergillus parasiticus) because of its toxicity and carcinogenicity. Here, we engineered an STE‐free Aspergillus versicolor strain based on genome mining techniques. We sequenced and assembled the Aspergillus versicolor D5 genome (34.52 Mb), in which we identified 16 scaffolds and 54 biosynthetic gene clusters (BGCs). We silenced cytochrome P450 coding genes STC17 and STC27 by insertional inactivation. The production of STE in the Δstc17 mutant strain was increased by 282% but no STE was detected in the Δstc27 mutant. Metabolites of Δstc27 mutant exhibited growth‐promoting effect on plants. Our study makes significant progress in improving the application of some Aspergillus strains by restricting their production of toxic and carcinogenic compounds.

Abstract Osteosarcoma (OS) is a mesenchymal-origin tumor that constitutes the most common primary malignant bone tumor. The survival rate of the patients has significantly improved since the introduction of neoadjuvant chemotherapy and extensive resection, but it has stagnated in recent 40 years. Tyrosine kinase inhibitors (TKIs) have played a key part in the treatment of malignant tumors. In advanced OS, TKIs including anlotinib, apatinib, sorafenib, etc. have significantly improved the progression-free survival of patients, while the overall survival remains unchanged. The main reason is the rapid and inevitable progress of acquired drug resistance of OS. However, as the application of TKIs in OS and other tumors is still in the exploratory phase, its drug resistance mechanism and corresponding solutions are rarely reported. Hence, in this review, we summarize knowledge of the applications of TKIs, the mechanism of TKIs resistance, and the attempts to overcome TKIs resistance in OS, which are the three potentially novel insights of TKIs in OS. Because most evidence is derived from studies using animal and cell models, we also reviewed clinical trials and related bioinformatics data available in public databases, which partially improved our understanding of TKIs applications.

Based on the multi-element thermoelectric generator model established in the previous literature, finite-time thermodynamic theory is used to deduce the efficient power expression of the thermoelectric generator. For a fixed number of thermoelectric elements and total heat exchanger area, the maximum efficient power is obtained by optimizing heat exchangers area distribution and output current. The effects of the number of thermoelectric elements and the total heat exchanger area on the maximum efficient power are analyzed. The results show that there is an optimal heat exchangers area distribution and an optimal output current to maximize the efficient power of the thermoelectric generator. Thermal efficiency at maximum efficient power is always better than at maximum power output. The total heat exchanger area is increased from 0.03 m2to 0.09 m2, the maximum efficient power is increased from 0.02 W to 0.26 W, and the corresponding optimal output current and optimal heat exchangers area distribution are increased by 138% and 6.7%, respectively. In the actual designing process of the thermoelectric generator, the influences of the number of thermoelectric elements, the total heat exchanger area, the output current and the heat exchangers area distribution on its performance should be considered.

PurposeAnlotinib, a tyrosine kinase inhibitor (TKI) has been in clinical application to inhibit malignant cell growth and lung metastasis in osteosarcoma (OS). However, a variety of drug resistance phenomena have been observed in the treatment. We aim to explore the new target to reverse anlotinib resistance in OS.Materials and MethodsIn this study, we established four OS anlotinib-resistant cell lines, and RNA-sequence was performed to evaluate differentially expressed genes. We verified the results of RNA-sequence by PCR, western blot and ELISA assay. We further explored the effects of tocilizumab (anti- IL-6 receptor), either alone or in combined with anlotinib, on the inhibition of anlotinib-resistant OS cells malignant viability by CCK8, EDU, colony formation, apoptosis, transwell, wound healing, Cytoskeletal stain assays, and xenograft nude mouse model. The expression of IL-6 in 104 osteosarcoma samples was tested by IHC.ResultsWe found IL-6 and its downstream pathway STAT3 were activated in anlotinib-resistant osteosarcoma. Tocilizumab impaired the tumor progression of anlotinib-resistant OS cells, and combined treatment with anlotinib augmented these effects by inhibiting STAT3 expressions. IL-6 was highly expressed in patients with OS and correlated with poor prognosis.ConclusionTocilizumab could reverse anlotinib resistance in OS by IL-6/STAT3 pathway and the combination treatment with anlotinib rationalized further studies and clinical treatment of OS.

Background: Osteosarcoma initially metastasing to bone only shows distinct biological features compared to osteosarcoma that firstly metastasizes to the lung, which suggests us underlying different genomic pathogenetic mechanism. Methods: We analyzed whole-exome sequencing (WES) data for 38 osteosarcoma with paired samples in different relapse patterns. We also sought to redefine disease subclassifications for osteosarcoma based on genetic alterations and correlate these genetic profiles with clinical treatment courses to elucidate potential evolving cladograms. Results: We investigated WES of 12/38 patients with high-grade osteosarcoma (31.6%) with initial bone metastasis (group A) and 26/38 (68.4%) with initial pulmonary metastasis (group B), of whom 15/38 (39.5%) had paired samples of primary lesions and metastatic lesions. We found that osteosarcoma in group A mainly carries single-nucleotide variations displaying higher tumor mutation burden and neoantigen load and more tertiary lymphoid structures, while those in group B mainly exhibits structural variants. High conservation of reported genetic sequencing over time in their evolving cladograms. Conclusions: Osteosarcoma with mainly single-nucleotide variations other than structural variants might exhibit biological behavior predisposing toward bone metastases as well as better immunogenicity in tumor microenvironment.

Background Chordoma is an extremely rare, locally aggressive malignant bone tumor originating from undifferentiated embryonic remnants. There are no effective therapeutic strategies for chordoma. Herein, we aimed to explore cellular interactions within the chordoma immune microenvironment and provide new therapeutic targets.Methods Spectrum flow cytometry and multiplex immunofluorescence (IF) staining were used to investigate the immune microenvironment of chordoma. Cell Counting Kit-8, Edu, clone formation, Transwell, and healing assays were used to validate tumor functions. Flow cytometry and Transwell assays were used to analyze macrophage phenotype and chemotaxis alterations. Immunohistochemistry, IF, western blot, PCR, and ELISA assays were used to analyze molecular expression. An organoid model and a xenograft mouse model were constructed to investigate the efficacy of maraviroc (MVC).Results The chordoma immune microenvironment landscape was characterized, and we observed that chordoma exhibits a typical immune exclusion phenotype. However, macrophages infiltrating the tumor zone were also noted. Through functional assays, we demonstrated that chordoma-secreted CCL5 significantly promoted malignancy progression, macrophage recruitment, and M2 polarization. In turn, M2 macrophages markedly enhanced the proliferation, invasion, and migration viability of chordoma. CCL5 knockdown and MVC (CCL5/CCR5 inhibitor) treatment both significantly inhibited chordoma malignant progression and M2 macrophage polarization. We established chordoma patient-derived organoids, wherein MVC exhibited antitumor effects, especially in patient 4, with robust killing effect. MVC inhibits chordoma growth and lung metastasis in vivo.Conclusions Our study implicates that the CCL5–CCR5 axis plays an important role in the malignant progression of chordoma and the regulation of macrophages, and that the CCL5–CCR5 axis is a potential therapeutic target in chordoma.

BackgroundNear-infrared fluorescence (NIRF) imaging has recently emerged as a promising tool for noninvasive cancer imaging. However, lack of tumor sensitivity and specificity restricts the application of NIRF dyes in surgical navigation.MethodsHerein, we investigated the imaging features of NIRF dye MHI-148 and indocyanine green (ICG) in live cell imaging and xenograft nude mice models. TCGA dataset analysis and immunohistochemistry were conducted to investigate the expression of OATPs or ABCGs in hepatocellular carcinoma (HCC) tissues. OATPs or ABCGs were knocked down and overexpressed in HCC cells using transient transfection by siRNA and plasmids or stable transfection by lentivirus. Further, qRT-PCR ,Western blotting and the use of agonists or inhibitors targeting β-catenin signaling pathway were applied to explore its important role in regulation of OATP2B1 and ABCG2 expression.ResultsHere we demonstrated that NIRF dye MHI-148 was biocompatible as indocyanine green (ICG) but with higher imaging intensity and preferential uptake and retention in hepatocellular carcinoma (HCC) cells and tissues. Moreover, our data indicated that membrane transporters OATP2B1 and ABCG2, which regulated by β-catenin signaling pathway, mediated tumor-specific accumulation and retention of MHI-148 in HCC cells. In addition, the treatment with β-catenin inhibitor significantly enhanced the accumulation of MHI-148 in HCC tissues and improved the efficacy of tumor imaging with MHI-148 in vivo.ConclusionsOur study uncovers a mechanism that links the distribution and expression of the membrane transporters OATP2B1 and ABCG2 to the tumor-specific accumulation of MHI-148, and provides evidence supporting a regulating role of the β-catenin signaling pathway in OATP2B1 and ABCG2- induced retention of MHI-148 inHCC tissues, and strategy targeting key components of MHI-148 transport machinery may be a potential approach to improve HCC imaging.

Salt stress is a serious abiotic stress that primarily inhibits plant growth, resulting in severe yield losses. Our previous research found that flavonoids play important roles in A. venetum salt stress tolerance. In response to salt stress, we noted that the flavonoid content was depleted in A. venetum. However, the detailed mechanism is still not clear. In this study, the expression patterns of three flavonoids synthetase genes, AvF3H, AvF3’H, and AvFLS were systemically analyzed under salt stress in A. venetum seedlings. The salt tolerance of transgenic Arabidopsis plants was improved by heterologous overexpression of these synthetase genes. The NBT and DAB staining results as well as H2O2 and O2•- content analysis revealed that under salt stress, ROS molecules were reduced in transgenic plants compared to WT plants, which corresponded to the activation of the antioxidant enzyme system and an increase in total flavonoid content, particularly rutin, eriodictyol, and naringerin in transgenic plants. External application of flavonoids reduced ROS damage in WT plants just like what we observed in the transgenic plants (without the external application). Additionally, our transcriptome analysis demonstrated that auxin and jasmonic acid biosynthesis genes, as well as signaling transduction genes, were primarily activated in transgenic plants under salt stress, leading to activation of the cell wall biosynthesis or modification genes that promote plant growth. As a result, we investigated the mechanism through flavonoids enhance the salt tolerance, offering a theoretical foundation for enhancing salt tolerance in plants.

The Chishui River basin is the main production area of the sauce-flavor Baijiu. Due to the particularity of sauce-flavor Baijiu technology, a large site of workshops needs to be built for brewing and storage. Therefore, used the natural karst caves of Guizhou province to manufacture the sauce-flavor Baijiu, which has enriched the connotation of sauce-flavor Baijiu and saved valuable land resources. In this study, the fermentation grains in the seven stages during the Xiasha round of the cave-brewed sauce-flavor Baijiu (CBSB) were detected using a combination of physicochemical analysis, Headspace solid-phase microextraction gas chromatography-mass detection, and Illumina HiSeq sequencing methods. The results showed Unspecified_Leuconostocaceae, Weissella, Unspecified_Bacillaceae, Saccharomycopsis, Thermomyces, and Unspecified_Phaffomycetaceae were the main bacterial and fungal genera in the stacking fermentation (SF). In the cellar fermentation (CF), the Lactobacillus, Unspecified_Lactobacillaceae, Thermoactinomyces, Saccharomycopsis, Unspecified_Phaffomycetaceae, and Wickerhamomyces were the main bacterial and fungal genera. A total of 72 volatiles were detected in the fermented grains. Linear discriminant analysis Effect Size (LEfSe) identified 23 significantly different volatile metabolites in the fermentation process, including 7 esters, 6 alcohols, 4 acids, 3 phenols, 1 hydrocarbon, and 2 other compounds. Redundancy analysis was used to explore the correlation between dominant microbial genera and physicochemical properties. Starch was the main physicochemical property affecting microbial succession in the SF. Acidity, moisture, and reducing sugar were the main driving factors of microbial succession in the CF. The Pearson correlation coefficient revealed the correlation between dominant microbial genera and significantly different volatile flavor substances. A total of 18 dominant microbial genera were associated with significantly different volatile metabolites, Lactobacillus, Weissella, Wickerhamomyces, and Aspergillus were shown to play crucial roles in metabolite synthesis. On this basis, a metabolic map of the dominant microbial genera was established. This study provides a theoretical basis for the production and quality control of sauce-flavor Baijiu brewed in natural karst caves and lays a foundation for studying the link between flavor formation and microorganisms.

BackgroundDepression is common psychiatric morbidity in breast cancer survivors, seriously affecting patients’ quality of life and mental health. A growing body of research has investigated depression in breast cancer. However, no visual bibliometric analysis was conducted in this field. This study aimed to visualize the literature to identify hotspots and frontiers in research on breast cancer and depression.MethodsThe publications related to depression in breast cancer were retrieved in the Web of Science Core Collection between 1 January 2002 and 17 March 2022. VOSviewer was used to identify co-occurrences and collaborations among countries, institutions, and keywords. CiteSpace was used to detect keyword bursts.ResultsA total of 7,350 articles and reviews related to depression in breast cancer were identified. From 2002 to 2022, the United States and the People’s Republic of China were the most productive countries in this field. The University of California, Los Angeles, and the University of Toronto were the most productive institutions in this field. The Journal of Psycho-oncology, followed by Supportive Care in Cancer and the Journal of Clinical Oncology, had the most publications on depression in breast cancer. Of the top 10 journals, seven were from the United States, two were from England, and one was from Germany. Five research hotspots of depression in breast cancer were identified by co-word analysis. Research on post-traumatic growth, spiritual interventions, cognitive-behavioral therapy, physical activity, and symptom cluster management of depression in breast cancer was relatively mature in the core hotspots. Burst detection of keywords on depression in breast cancer showed the latest hotspots, such as mental health, cancer survivor mortality, and activity.ConclusionThe research on depression in breast cancer is growing. Attention should be paid to the latest hotspots, such as mental health, cancer survivor, mortality, exercise, and physical activity.

Recent studies have shown that tumor stemness has biological significance in tumorigenicity and tumor progression. However, the characteristics of TME immune infiltration in osteosarcoma mediated by the combined effects of multiple cancer stem cell-related genes remain unknown.MethodsIn this study, we identified different cancer stem cell-associated subtypes in osteosarcoma based on 25 cancer stem cell-associated genes by consensus clustering analysis, and we comprehensively evaluated the association between these subtypes and immunocytes infiltration in the TME. The cancer stem cell (CSC) score was constructed to quantify the stemness of individual tumors.ResultsWe performed a comprehensive evaluation of 218 osteosarcoma patients based on 25 cancer stem cell-related genes. Three different cancer stem cells related subtypes were identified, which were related to different biological processes and clinical outcomes. The three subtypes have different TME cells infiltrating characteristics, and CSC Cluster A had a higher level of immunocyte infiltration compared to CSC Cluster B and C. We constructed a scoring system, called the CSC score, to assess the stemness of individual patients. Then we found that the prognosis of patients was predicted by CSC score, and patients with low CSC score had prolonged survival. Further analyses showed that low CSC score was correlated with enhanced immune infiltration. CSC score may predict the effect of immunotherapy, and patients with low CSC score may have better immune response and clinical prognosis.ConclusionsThis study demonstrates that there could be three cancer stem cell-associated subtypes in osteosarcoma and that they were associated with different patient prognosis and TME immune infiltration characteristics. CSC score could be used to assess the stemness of individual patients, improve our comprehension of TME characteristics, and direct more effective immune therapy.

Abstract Background Mitochondrial dysfunction has been implicated as a significant factor in the liver disease process. Blueberry juice and probiotics (BP) synergistically improve liver function in alcoholic fatty liver disease (AFLD), although the mechanism for this effect was unclear. This study aims to investigate the effect and specific mechanisms of BP on AFLD. Methods C57/BL6 mice were randomly divided into seven groups: CG (control), MG (AFLD model), BJ (MG mice treated with blueberry), BJB (MG mice treated with BP), SI (AFLD mice treated with SIRT1 siRNA), BJSI (SI mice treated with blueberry), and BJBSI (SI mice treated with BP). The mice were fed an alcohol liquid diet for 10 days to establish the AFLD model, and subjected to BP and SIRT1 siRNA intervention for 10 days. Liver pathology was performed on day 11, and biochemical and molecular analyses of liver mitochondria were employed on day 12. Results BP significantly ameliorated hepatic mitochondrial injury, mitochondrial swelling, and hepatic necrosis in AFLD. BP alleviated hepatic mitochondrial dysfunction by increasing the expression of succinate dehydrogenase and cytochrome c oxidase, increasing respiratory control rate and the ADP/O ratio, and facilitating the synthesis of energy-related molecules. Besides, BP increased the expression of glutathione and superoxide dismutase, and inhibited malondialdehyde expression and reactive oxygen species activity. BP-induced sirtuin 1 (SIRT1), which activates peroxisome proliferator-activated receptor-gamma coactivator-1α, both of which mediate mitochondrial homeostasis. SIRT1 silencing suppressed the BP-induced changes in liver mitochondria, blunting its efficacy. Conclusions The ingredients of BP ameliorate hepatocyte mitochondrial dysfunction in AFLD mice.

Abstract Background Osteosarcoma (OS) is the most common primary malignant bone tumor in young people. Tumor-associated macrophages (TAMs) have been reported to play an important role in the development of osteosarcoma. However, the detailed molecular mechanisms remain largely unknown and need to be elucidated. Recently, exosomes have been reported as the crucial mediator between tumor cells and the tumor microenvironment. And a lot of lncRNAs have been reported to act as either oncogenes or tumor suppressors in osteosarcoma. In this research, we aim to explore the role of macrophages-derived exosomal lncRNA in osteosarcoma development and further elucidated the potential molecular mechanisms involved. Methods TAMs were differentiated from human mononuclear cells THP-1, and a high-throughput microarray assay was used to analyze the dysregulated lncRNAs and miRNAs in osteosarcoma cells co-cultured with macrophages-derived exosomes. Western blot, qRT-PCR assays, and Dual-luciferase reporter assay were used to verify the interaction among LIFR-AS1, miR-29a, and NFIA. Cck-8, EdU, colony formation assay, wound-healing, and transwell assay were performed to explore the characterize the proliferation and metastasis ability of OS cells. And qPCR, Western blots, immunohistochemistry, and cell immunofluorescence were used to detect the expression of relative genes or proteins. Results In this study, we found that THP-1-induced macrophage-derived exosomes could facilitate osteosarcoma cell progression both in vitro and in vivo. Then, the results of the high-throughput microarray assay showed that LIFR-AS1 was highly expressed and miR-29a was lowly expressed. Furthermore, LIFR-AS1 was identified as a miR-29a sponge, and NFIA was validated as a direct target of miR-29a. Functional assays demonstrated that knockdown of exosomal LIFR-AS1 could attenuate the promotion effects of macrophages-derived exosomes on osteosarcoma cell progression and miR-29a inhibition could reserve the effect of LIFR-AS1-knockdown exosomes. Correspondingly, NFIA-knockdown could partially reverse the tumor inhibition effect of miR-29a on osteosarcoma cells. Conclusions Taken together, macrophages-derived exosomal lncRNA LIFR-AS1 can promote osteosarcoma cell proliferation, invasion, and restrain cell apoptosis via miR-29a/NFIA axis, which can act as a potential novel therapeutic target for osteosarcoma therapy.

Abstract Quantitative real-time polymerase chain reaction (qPCR) using a stable reference gene is widely used for gene expression research. Suaeda glauca L. is a succulent halophyte and medicinal plant that is extensively used for phytoremediation and extraction of medicinal compounds. It thrives under high-salt conditions, which promote the accumulation of high-value secondary metabolites. However, a suitable reference gene has not been identified for gene expression standardization in S. glauca under saline conditions. Here, 10 candidate reference genes, ACT7, ACT11, CCD1, TUA5, UPL1, PP2A, DREB1D, V-H + -ATPase, MPK6, and PHT4;5, were selected from S. glauca transcriptome data. Five statistical algorithms (ΔCq, geNorm, NormFinder, BestKeeper, and RefFinder) were applied to determine the expression stabilities of these genes in 72 samples at different salt concentrations in different tissues. PP2A and TUA5 were the most stable reference genes in different tissues and salt treatments, whereas DREB1D was the least stable. The two reference genes were sufficient to normalize gene expression across all sample sets. The suitability of identified reference genes was validated with MYB and AP2 in germinating seeds of S. glauca exposed to different NaCl concentrations. Our study provides a foundational framework for standardizing qPCR analyses, enabling accurate gene expression profiling in S. glauca.

Graph convolutional networks (GCNs) have achieved remarkable performance on skeleton-based action recognition. Existing GCN-based methods usually apply the fixed graph topology and one fixed temporal convolution kernel to extract the spatial features of joints and temporal features, which is from a single-scale perspective. Actually, human actions are coordinated by various body parts in the spatial domain, and exhibit different characteristics in the temporal domain. Therefore, it is appropriate to model the multi-scale information that can enhance both the explainability and stability, which is ignored in current literatures. To address this issue, we propose a multi-scale spatial-temporal graph neural network (MSTGNN) to discover multi-scale discriminative features from spatial and temporal aspects simultaneously. Our contributions are three-folds: 1) For the spatial domain, inspired by the kinematics of the human action, we develop a three-scale graph data structures in a fine-to-coarse way. A novel hybrid spatial pooling module is then proposed to dynamically exploit the global and comprehensive information step-by-step. 2) For the temporal domain, we design a multi-scale temporal convolution module adaptively fusing the temporal features extracted by different scale convolution kernels. 3) As utilizing one-stream architecture instead of multi-stream architecture, the proposed model can be trained in an end-to-end manner. MSTGNN achieves state-of-the-art performance with less computation complexity. Experimental results conducted on two large datasets (NTU-RGB+D and NTU-RGB+D-120) demonstrate the superiority of MSTGNN.

Abstract Background Recent studies indicated that exosomal programmed death-ligand 1 (PD-L1) derived from cancers could induce immunosuppression and tumor pathogenesis. However, it is unclear how exosomes influence osteosarcoma (OS) progression and whether PD-L1 also exists in serum exosomes (Sr-exosomes) of patients with osteosarcoma. We examined serum exosomes from 70 OS patients, 9 patients with benign tumors and 22 healthy donors. OS-derived exosomes were functionally evaluated in vivo and in vitro. Results The characteristics of exosomes derived from OS patient serum and OS cell lines were confirmed by several methods. We found OS patients had a higher level of exosomal PD-L1 compared to healthy donors. Meanwhile, OS patients with pulmonary metastasis also showed a relatively higher level of exosomal PD-L1 than patients without metastasis. Next, bioinformatic analysis demonstrated that Sr-exosomes isolated from OS patients may involve in the important process of immune function and cancer pathogenesis for OS patients. Co-expression network centered with PD-L1 among Sr-exosomal differently expressed mRNA demonstrated exosomal N-cadherin had a close relationship with exosomal PD-L1 expression. Then, we confirmed higher level of Sr-exosomal N-cadherin in OS patients with pulmonary metastasis compared to ones without metastasis. Furthermore, we elucidated osteosarcoma-derived exosomes and exosomal-PD-L1 promoted the pulmonary metastasis in metastatic models. ROC (Receiver Operating Characteristic Curve) analysis showed AUC (Area Under Curve) of 0.823 for exosomal PD-L1, 0.806 for exosomal N-cadherin and 0.817 for exosomal N-cadherin/E-cadherin to distinguish OS patients with pulmonary metastasis from ones without metastasis. Conclusions Osteosarcoma stimulates pulmonary metastasis by releasing exosomes, that carry PD-L1 and N-cadherin. Detection of exosomal PD-L1 and N-cadherin from serum of OS patients may predict pulmonary metastasis progression for OS patients.

Leaf is essential for plant growth and development; however, the relative importance of environmental filtering and phylogeny in determining leaf size across different spatial scales in grassland ecosystems remains poorly explored. We used transect methodology to explore the spatial variation in leaf size and its underlying mechanisms in grasslands along three topographically and floristically distinctive plateaus in northern China. We measured leaf size of a total of 1192 grassland species in the Tibetan Plateau (TP, temperature limited), Loess Plateau (LP, soil-nutrient limited), and Mongolia Plateau (MP, precipitation limited) along three transects encompassing meadow, typical, and desert steppes. Leaf size ranged from 0.01 to 258.16 cm2, with an average of 5.54 cm2. The smallest leaves were measured in the TP. At the vegetation association level, the largest leaves were present in the meadow steppe, followed by those in typical and desert steppes, irrespective of the plateau. Unexpectedly, phylogeny had a negligible effect on the spatial variation in leaf size in the grasslands. Leaf size was positively correlated with growing-season temperature and precipitation but negatively correlated with ultraviolet (UV) radiation, suggesting that environmental filtering plays a more important role in affecting leaf size than phylogeny. Furthermore, leaf size in the TP and MP was mainly affected by precipitation and UV radiation, respectively, whereas that in the LP was affected by temperature, precipitation, soil nutrients and UV light. Specifically, our results underscored the importance of environmental filtering rather than phylogeny in determining plant leaf size and shed light on the unexpected role of UV radiation in contributing to leaf size variations in these plateaus. Our study provides novel insights into the response of plants to global change, especially in plateaus, alpine zone, and high-latitude areas.

Specific leaf area (SLA) is one of the most widely researched plant traits, integrating multiple functions and reflecting plant resource acquisition strategies. However, the underlying mechanisms that drive temporal and spatial variation in SLA are still not clear. We used a combination of transect investigation and short-term manipulative experiments to identify patterns of variation in SLA over naturally occurring and simulated environmental gradients. We measured SLA of 631 species from the Tibetan (TP), Loess (LP), and Mongolian Plateaus (MP), where plant growth is limited by temperature, soil nutrient availability, and precipitation, respectively. In each plateau, we established an east–west transect of 10 sites, including meadow steppe (meadow), typical steppe (steppe), and desert steppe (desert) habitats. We further measured SLA of 15 species from the TP and MP, using manipulative experiments that altered temperature, precipitation and soil nitrogen levels. SLA ranged from 0.9 to 58.90 m2 kg−1 on average, and was significantly larger in desert than in meadow and steppe, except in the LP. Plants from the TP had significantly lower SLA than those from the LP and MP, but variation in SLA across the environmental gradients was small and consistent across the three plateaus. Conversely, the short-term manipulative experiments revealed that SLA increased with resource availability. Shifts in SLA across the broad environmental gradients was relatively small, and SLA had high sensitivity to short-term resource enrichment, suggesting that grassland species in these plateaus express divergent short- (acclimation) and long-term responses (adaptation) to the environment, which may be an important strategy for coping with ongoing shifts in climate.

Background: Abnormal expression of lncRNA is closely related to the occurrence and metastasis of osteosarcoma. The tumor immune microenvironment (TIM) is considered to be an important factor affecting the prognosis and treatment of osteosarcoma. This study aims to explore the effect of immune-related lncRNAs (IRLs) on the prognosis of osteosarcoma and its relationship with the TIM.Methods: Ninety-five osteosarcoma samples from the TARGET database were included. Iterative LASSO regression and multivariate Cox regression analysis were used to screen the IRLs signature with the optimal AUC. The predict function was used to calculate the risk score and divide osteosarcoma into a high-risk group and low-risk group based on the optimal cut-off value of the risk score. The lncRNAs in IRLs signature that affect metastasis were screened for in vitro validation. Single sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithms were used to evaluate the role of TIM in the influence of IRLs on osteosarcoma prognosis.Results: Ten IRLs constituted the IRLs signature, with an AUC of 0.96. The recurrence and metastasis rates of osteosarcoma in the high-risk group were higher than those in the low-risk group. In vitro experiments showed that knockdown of lncRNA (AC006033.2) could increase the proliferation, migration, and invasion of osteosarcoma. ssGSEA and ESTIMATE results showed that the immune cell content and immune score in the low-risk group were generally higher than those in the high-risk group. In addition, the expression levels of immune escape-related genes were higher in the high-risk group.Conclusion: The IRLs signature is a reliable biomarker for the prognosis of osteosarcoma, and they alter the prognosis of osteosarcoma. In addition, IRLs signature and patient prognosis may be related to TIM in osteosarcoma. The higher the content of immune cells in the TIM of osteosarcoma, the lower the risk score of patients and the better the prognosis. The higher the expression of immune escape-related genes, the lower the risk score of patients and the better the prognosis.

Soil salinization is a widespread environmental hazard and a major abiotic constraint affecting global food production and threatening food security. Salt-affected cropland is widely distributed in China, and the problem of salinization in the Hetao Irrigation District (HID) in the Inner Mongolia Autonomous Region is particularly prominent. The salt-affected soil in Inner Mongolia is 1.75 million hectares, accounting for 14.8% of the total land. Therefore, mapping saline cropland in the irrigation district of Inner Mongolia could evaluate the impacts of cropland soil salinization on the environment and food security. This study hypothesized that a reasonably accurate regional map of salt-affected cropland would result from a ground sampling approach based on PlanetScope images and the methodology developed by Sentinel multi-sensor images employing the machine learning algorithm in the cloud computing platform. Thus, a model was developed to create the salt-affected cropland map of HID in 2021 based on the modified cropland base map, valid saline and non-saline samples through consistency testing, and various spectral parameters, such as reflectance bands, published salinity indices, vegetation indices, and texture information. Additionally, multi-sensor data of Sentinel from dry and wet seasons were used to determine the best solution for mapping saline cropland. The results imply that combining the Sentinel-1 and Sentinel-2 data could map the soil salinity in HID during the dry season with reasonable accuracy and close to real time. Then, the indicators derived from the confusion matrix were used to validate the established model. As a result, the combined dataset, which included reflectance bands, spectral indices, vertical transmit–vertical receive (VV) and vertical transmit–horizontal receive (VH) polarization, and texture information, outperformed the highest overall accuracy at 0.8938, while the F1 scores for saline cropland and non-saline cropland are 0.8687 and 0.9109, respectively. According to the analyses conducted for this study, salt-affected cropland can be detected more accurately during the dry season by using just Sentinel images from March to April. The findings of this study provide a clear explanation of the efficiency and standardization of salt-affected cropland mapping in arid and semi-arid regions, with significant potential for applicability outside the current study area.

To study the effect of SAP incorporation on the early shrinkage of SAP internally cured concrete with the aim to solve the problems of early shrinkage and cracking of bridge leveling-layer concrete, using the SAP incorporation method as a parameter, the mechanical properties test of internally cured concrete, the shrinkage performance test of ring restraint and the scanning electron microscope observation test were carried out. The effects of the SAP content and incorporation method on the flowability, mechanical properties, shrinkage performance and microstructure of internally cured concrete were analyzed. The experimental results show that when the content of the SAP in concrete is 0.2% of the mass of cementitious materials, it has the least influence on the compressive strength of concrete. The addition of preabsorbed water to the SAP can delay early cement hydration, increase the later cement hydration rate and final hydration degree, and improve the concrete strength. Preabsorbed water mixed with an SAP can effectively improve the shrinkage of concrete, and the shrinkage reduction effect is more obvious than that from the dry addition of the SAP; the early cracking risk of concrete without an SAP is high, and it will crack before day 28. The addition of an SAP can strengthen the microstructure of concrete and improve its density and crack resistance, effectively avoiding concrete cracking. It is recommended that the water-absorbent resin be incorporated in a preabsorbent manner, and the SAP preabsorbent ratio is equal to the maximum water storage rate of the SAP.

Growing evidence indicates that the dysregulation of mitochondrial calcium (Ca2+) plays a critical role in the growth of tumor cells, including colorectal cancer (CRC). However, the underling mechanism is not fully elucidated. In this study, the regulatory effects of mitochondrial Ca2+ on phosphodiesterase 2 (PDE2)/cAMP/PKA axis and the phosphorylation of mitochondrial transcription factor A (TFAM) as well as the growth of CRC cells were systematically investigated both in vitro and in vivo. Our findings demonstrated that MCU-induced mitochondrial Ca2+ uptake activated mitochondrial PDE2 in CRC cells. Moreover, overexpression MCU in CRC led to a 1.9-fold increase in Ca2+ uptake compared to control cells. However, knockdown of MCU resulted in 1.5-fould decrease in Ca2+ uptake in mitochondria compared to the controls. Activation of mitochondrial PDE2 significantly inhibited the activity of mitochondrial protein kinase A (PKA), which subsequently leads to decreased phosphorylation of TFAM. Our data further revealed that PKA regulates the phosphorylation of TFAM and promotes the degradation of phosphorylated TFAM. Thus, TFAM protein levels accumulated in mitochondria when the activity of PKA was inhibited. Overall, this study showed that the overexpression of MCU enhanced CRC growth through promoting the accumulation of TFAM proteins in mitochondria. Conversely, knockdown of MCU in CRC cells resulted in decreased CRC growth. Collectively, these data suggest that the mitochondrial Ca2+-activated PDE2/cAMP/PKA axis plays a key role in regulating TFAM stability and the growth of CRC cells.

Abstract Background Malignant peripheral nerve sheath tumours (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome, neurofibromatosis type 1 (NF1). This study aimed to examine the function of High mobility group protein A2 (HMGA2) in NF1 MPNST progression and the underlying molecular mechanism. Methods Immunohistochemistry (IHC) was used to detect HMGA2 expression in MPNST and neurofibroma patient samples. Cell Cycle Kit-8 (CCK-8) and 5-ethynyl-20-deoxyuridine (EdU) assays, terminal deoxynucleotidyl transferase-mediated nick end labelling, and transmission electron microscopy were performed to reveal HMGA2 functions in NF1 MPNST cells in vitro and in vivo. Chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq) were used to detect HMGA2-modulated genes regulating autophagy and growth in NF1 MPNSTs in vitro and in vivo. Results NF1 MPNST samples exhibit higher HMGA2 positivity rates (13/16) than sporadic MPNST (16/41) and neurofibroma (0/7) patient samples. High HMGA2 expression is correlated with poor prognosis. Neurofibromin 1 (NF1)-deficient MPNST cells display elevated HMGA2 expression. Functional experiments revealed that HMGA2 knockdown inhibits NF1 MPNST cell growth in vitro and in vivo. In addition to promoting cell cycle arrest and apoptosis, HMGA2 knockdown inhibits autophagy, favouring cell death. RNA-Seq and ChIP-Seq revealed that HMGA2 directly activates the Musashi-2 (MSI2) promoter region, and MSI2 overexpression reverses autophagy and growth in shHMGA2-transfected cells. MSI2 interacts with Beclin1, and Beclin1 blockade inhibits autophagy, thereby inhibiting cell proliferation. Conclusions HMGA2 knockdown regulates autophagy via MSI2-Beclin1 interactions to inhibit NF1 MPNST growth, revealing potential therapeutic targets for these untreatable tumours.

Abstract Background Mitochondrial Ca2+ plays a critical role in tumorigenesis, including cell proliferation and metastasis. Mitochondrial calcium uniporter regulator 1 (MCUR1) has been shown to be frequently upregulated in HCC and promote cancer cell survival. However, whether MCUR1 is involved in the metastasis of HCC and its underlying mechanisms remain unknown. Methods The effect of MCUR1 expression on epithelial-mesenchymal transition (EMT) in HCC cells was first evaluated by immunofluorescent staining and Western blot. Then, in vitro invasion and in vivo metastasis assays were used to evaluate the function of MCUR1 in HCC metastasis. The underlying mechanism has also been explored by investigating the effect of MCUR1 on ROS/Nrf2/Notch1 pathway. Results MCUR1 expression was significantly higher in HCC with metastasis and associated with tumor progression. MCUR1 promoted in vitro invasion and in vivo metastasis of HCC cells by promoting EMT via Snail. Mechanistically, MCUR1-mediated mitochondrial Ca2+ signaling promoted the EMT of HCC cells by activating ROS/Nrf2/Notch1 pathway. Inhibition of ROS production, mitochondrial Ca2+ uptake, Nrf2 expression or Notch1 activity significantly suppressed MCUR1-induced EMT of HCC cells. In addition, treatment with the mitochondrial Ca2+-buffering protein parvalbumin significantly inhibited ROS/Nrf2/Notch pathway and MCUR1-induced EMT and HCC metastasis. Conclusions Our study provides evidence supporting a metastasis-promoting role for MCUR1-dependent mitochondrial Ca2+ uptake in HCC. Our findings suggest that MCUR1 may be a potential therapeutic target for HCC treatment.

Driving behavior recognition is a challenging task that exploits the acceleration and angular velocity information of the vehicle collected by smartphone to identify various driving events. Traditional methods usually extract hand-crafted features from raw data, leading to under-explored temporal features of driving behaviors. To address the issue of hand-designed limitation for features, this paper proposes an end-to-end deep learning framework to automatically extract the features of driving behaviors. The mechanism behind our method is to model temporal features, capture salient structure features, and explore the correlation among the high-dimensional sensor data by fusing convolutional neural network (CNN) and recurrent neural network (RNN) with an attention unit. Moreover, a novel approach is introduced to build driving behavior dataset, which considers the effect of gravity in modeling smartphone sensor data. Subsequently, sensor data with device position independence is collected, and six types of driving events (straight driving, static, left turn, right turn, breaking, and acceleration) are annotated, which provides rich sensor information compared with other methods. The experimental results indicate that the proposed model outperforms other competing methods significantly, which possesses good generalization ability in the identification of driving behaviors.