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Abstract Objective To assess whether diffusion and perfusion MRI derived parameters could non-invasively predict PD-L1 and Ki-67 status in primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). Methods We retrospectively analyzed DWI, DSC-PWI, and morphological MRI (mMRI) in 88 patients with PCNS-DLBCL. The mMRI features were compared using chi-square tests or Fisher exact test. Minimum ADC (ADCmin), mean ADC(ADCmean), relative minimum ADC (rADCmin), relative mean ADC (rADCmean), and relative maximum CBV (rCBVmax) values were compared in PCNS-DLBCL with different molecular status by using the Mann-Whitney U test. The diagnostic performances were evaluated by receiver operating characteristic curves. Results PCNS-DLBCL with high PD-L1 expression demonstrated a significantly higher ADCmin value than those with low PD-L1. The ADCmean and rADCmean values were significantly lower in PCNS-DLBCL with high Ki-67 status compared with those in low Ki-67 status. Other ADC, CBV parameters, and mMRI features did not show any association with these molecular statuses The diagnostic efficacy of ADC values in assessing PD-L1 and Ki-67 status was relatively low, with area under the curves (AUCs) values less than 0.7. Conclusions DWI-derived ADC values can provide some relevant information about PD-L1 and Ki-67 status in PCNS-DLBCL, but may not be sufficient to predict their expression due to the rather low diagnostic performance.

Abstract Backgroud Type II congenital pulmonary airway malformation (CPAM) is a rare pulmonary microcystic developmental malformation. Surgical excision is the primary treatment for CPAM, although maternal steroids and betamethasone have proven effective in reducing microcystic CPAM. Disturbed intercellular communication may contribute to the development of CPAM. This study aims to investigate the expression profile and analyze intercellular communication networks to identify genes potentially associated with type II CPAM pathogenesis and therapeutic targets. Methods RNA sequencing (RNA-seq) was performed on samples extracted from both the cystic area and the adjacent normal tissue post-surgery in CPAM patients. Iterative weighted gene correlation network analysis (iWGCNA) was used to identify genes specifically expressed in type II CPAM. Single-cell RNA-seq (scRNA-seq) was integrated to unveil the heterogeneity in cell populations and analyze the communication and interaction within epithelial cell sub-populations. Results A total of 2,618 differentially expressed genes were identified, primarily enriched in cilium-related biological process and inflammatory response process. Key genes such as EDN1, GPR17, FPR2, and CHRM1, involved in the G protein-coupled receptor (GPCR) signaling pathway and playing roles in cell differentiation, apoptosis, calcium homeostasis, and the immune response, were highlighted based on the protein-protein interaction network. Type II CPAM-associated modules, including ciliary function-related genes, were identified using iWGCNA. By integrating scRNA-seq data, AGR3 (related to calcium homeostasis) and SLC11A1 (immune related) were identified as the only two differently expressed genes in epithelial cells of CPAM. Cell communication analysis revealed that alveolar type 1 (AT1) and alveolar type 2 (AT2) cells were the predominant communication cells for outgoing and incoming signals in epithelial cells. The ligands and receptors between epithelial cell subtypes included COLLAGEN genes enriched in PI3K-AKT singaling and involved in epithelial to mesenchymal transition. Conclusions In summary, by integrating bulk RNA-seq data of type II CPAM with scRNA-seq data, the gene expression profile and critical signaling pathways such as GPCR signaling and PI3K-AKT signaling pathways were revealed. Abnormally expressed genes in these pathways may disrupt epithelial-mesenchymal transition and contribute to the development of CPAM. Given the effectiveness of prenatal treatments of microcystic CPAM using maternal steroids and maternal betamethasone administration, targeting the genes and signaling pathways involved in the development of CPAM presents a promising therapeutic strategy.

Abstract Background Oculocutaneous albinism (OCA) is a group of autosomal recessive hereditary disorders that affect melanin biosynthesis, resulting in abnormalities in hair, skin, and eyes. Retinopathy of prematurity (ROP) is a proliferative retinopathy mainly observed in premature infants with low birth weight and early gestational age, but it can also affect full-term infants or children with normal weight, particularly in developing countries. The coexistence of ROP and OCA is rare. There is limited documentation regarding treatment approaches, with few studies reporting positive outcomes with laser treatment due to the absence of melanin pigment. This study discusses the treatment challenges in a female infant diagnosed with ROP and OCA, and underscores the importance of genetic analysis in guiding therapeutic decisions for this rare comorbid condition. Case presentation The study presents a case of ROP occurring concurrently with OCA. Genetic testing revealed two variants, c.727C > T (p.R243C) and c.1832 T > C (p.L611P), in the OCA2 gene, inherited from the patient's mother and father, respectively. The identified mutations were consistent with a diagnosis of OCA2, classified as a subtype of OCA. The patient initially received intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection, followed by laser photocoagulation therapy for a recurrent event. A favorable outcome was observed during the 2-month follow-up period. Conclusions The co-occurrence of ROP and OCA is a rare phenomenon, and this is the first recorded case in the Chinese population. The current case supports the use of laser as the primary treatment modality for ROP in OCA2 patients with partial pigmentation impairment. Furthermore, genetic analysis can aid in predicting the effectiveness of laser photocoagulation in this patient population.

Abstract Background Ovarian cancer is the most common cause of gynecological cancer death. Pak4 has been proved to be tumorigenic in many types of cancers, but its role in ovarian cancer is still not clarified. Methods In this study, we used immunohistochemistry to investigate into Pak4 expression in different histological types of ovarian cancer. TIMER, TISCH2, GEPIA, ualcan, KM plotter, GSCA and GeneMANIA were used to identify the prognostic roles and gene regulation networks of Pak4 in ovarian cancer. Immune infiltration levels were investigated using TIMER database. Results Pak4 was highly expressed in ovarian cancers, regardless of different FIGO stages and histological grades. Single cell sequencing database proved that Pak4 was highly expressed in malignant ovarian cancer cells. Pak4 level was significantly correlated with different histological types of ovarian cancer. Pak4 expression was negatively connected with OS and PFS of ovarian cancer patients. Functions of Pak4 and its interacted genes were mainly involved in protein serine/threonine kinase activity, regulation of actin filament-based process and regulation of cytoskeleton organization. Pak4 level was negatively correlated with immune biomarkers of B cell infiltration (p = 2.39e-05), CD8 + T cell infiltration (p = 1.51e-04), neutrophil (p = 1.74e-06) and dendritic cell (p = 4.41e-08). Close correlation was found between Pak4 expression and T cell exhaustion (p

Abstract In order to safeguard the surface structures from mining damage while optimizing the liberation of coal resources under the dense surface buildings of the Cedi River coal mine. Considering that the analysis of the structure and type of surface buildings and the geological mining conditions of the mine, a wide strip mining design with a retention width of 70 m and a mining width of 50 m was finally determined by using the pressure arch theory and Wilson’s theory, combined with the actual layout of working faces 51,002, 51,004 and 51,006 at the site.The strip mining design is verified by probability integral method and FLAC3D numerical simulation calculation respectively, The findings indicate that the highest value of earth surface subsidence created by the mining of the wide strip is 210 mm, the surface horizontal deformation value is 1.0 to − 1.4 mm/m, the damage to surface buildings is less than Level I, which satisfying the prerequisites of the surface building protection level, and can realize the continuous advancement of mine 51,002, 51,004 and 51,006 working faces, The coal pillars of the retained strip have sufficient support strength and long-term consistency, and the movement and deformation of the overburden after mining will not cause undulating subsidence of the surface, which effectively solve the mine's technical difficulties in safely coal mining under surface buildings.

Congenital diaphragmatic hernia (CDH) is a congenital malformation characterized by failure of diaphragm closure during embryonic development, leading to pulmonary hypoplasia and pulmonary hypertension, which contribute significantly to morbidity and mortality. The occurrence of CDH and pulmonary hypoplasia is theorized to result from both abnormalities in signaling pathways of smooth muscle cells in pleuroperitoneal folds and mechanical compression by abdominal organs within the chest cavity on the developing lungs. Although, the precise etiology of diaphragm maldevelopment in CDH is not fully understood, it is believed that interplay between genes and the environment contributes to its onset. Approximately 30% of patients with CDH possess chromosomal or single gene defects and these patients tend to have inferior outcomes compared with those without genetic associations. At present, approximately 150 gene variants have been linked to the occurrence of CDH. The variable expression of the CDH phenotype in the presence of a recognized genetic predisposition can be explained by an environmental effect on gene penetrance and expression. The retinoic acid pathway is thought to play an essential role in the interactions of genes and environment in CDH. However, apart from the gradually maturing retinol hypothesis, there is limited evidence implicating other environmental factors in CDH occurrence. This review aims to describe the pathogenesis of CDH by summarizing the genetic defects and potential environmental influences on CDH development.

Abstract The macro petrographic compositions and its pore characteristics of coal reservoir play critical role in the accumulation and development of coalbed methane (CBM). In this paper, the pore characteristics of vitrain and durain were analyzed through the experiment and fractal theory. The results indicated that the micropores and microfractures develop in vitrain, and that transitional pores develop in durain. The pore volume and specific surface area (SSA) of vitrain are larger than those of durain, with the micropore SSA of vitrain being 35% higher than that of durain. The threshold pressure and tortuosity of vitrain are greater than that of durain, but the mean pore size of vitrain is smaller than that of durain. The fractal dimension D 1 of vitrain is greater than that of durain, while the fractal dimension D 2 is opposite, indicating that the pore surface of vitrain is coarser, and the pore structure of durain is more complex. The fractal dimension D k of vitrain is larger than that of durain, the mean fractal dimension D s of vitrain is smaller than that of durain, which shows that the diffusivity of vitrain is weak but the seepage capacity is strong due to the developed fractures. The difference in material composition and pore characteristics between vitrain and durain provides a new understanding for the development of CBM in low rank coal.

Intratumoral microbiota can regulate the tumor immune microenvironment (TIME) and mediate tumor prognosis by promoting inflammatory response or inhibiting anti-tumor effects. Recent studies have elucidated the potential role of local tumor microbiota in the development and progression of lung adenocarcinoma (LUAD). However, whether intratumoral microbes are involved in the TIME that mediates the prognosis of LUAD remains unknown. Here, we obtained the matched tumor microbiome and host transcriptome and survival data of 478 patients with LUAD in The Cancer Genome Atlas (TCGA). Machine learning models based on immune cell marker genes can predict 1- to 5-year survival with relative accuracy. Patients were stratified into high- and low-survival-risk groups based on immune cell marker genes, with significant differences in intratumoral microbial communities. Specifically, patients in the high-risk group had significantly higher alpha diversity (p < 0.05) and were characterized by an enrichment of lung cancer-related genera such as Streptococcus. However, network analysis highlighted a more active pattern of dominant bacteria and immune cell crosstalk in TIME in the low-risk group compared to the high-risk group. Our study demonstrated that intratumoral microbiota-immune crosstalk was strongly associated with prognosis in LUAD patients, which would provide new targets for the development of precise therapeutic strategies.

Cancer is a multi-factor systemic malignant disease, which has seriously threatened human health and created a heavy burden on the world economy. Metabolic reprogramming, one of the important signs of malignant tumours, provides necessary nutrition for tumorigenesis and cancer development; thus, it has recently become a research hot spot, even though the metabolic mechanism is quite intricate. Circular RNA (circRNA) affects cancer cell metabolism through various molecular mechanisms, playing an important role in promoting or suppressing cancer. Because of the structure characteristics, circRNA is quite stable, and can be utilized as biomarkers. In this review, we analysed and summarized the characteristics and biological functions of circRNA and comprehensively reviewed and discussed the important role of circRNA in cancer metabolic reprogramming. This review will provide new ideas for developing new anti-cancer therapeutic targets, mining cancer diagnostic and prognostic markers, and will provide guidance for other researchers to design circRNA-related experiments and develop anti-tumour drugs.

Abstract Background Heavy metal contamination has been a severe worldwide environmental issue. For industrial pollutions, heavy metals rarely exist as singular entities. Hence, researches have increasingly focused on the detrimental effect of mixed heavy metal pollution. Genome analysis of Lampropedia strains predicted a repertoire of heavy metal resistance genes. However, we are still lack of experimental evidence regarding to heavy metal resistance of Lampropedia, and their potential in mixed heavy metal removal remain elusive. Results In this study, a Lampropedia aestuarii strain GYF-1 was isolated from soil samples near steel factory. Heavy metal tolerance assay indicated L. aestuarii GYF-1 possessed minimal inhibition values of 2 mM, 10 mM, 6 mM, 4 mM, 6 mM, 0.8 mM, and 4 mM for CdCl2, K2CrO4, CuCl2, NiCl2, Pb(CH3COO)2, ZnSO4, and FeCl2, respectively. The biosorption assay demonstrated its potential in soil remediation from mixed heavy metal pollution. Next the draft genome of L. aestuarii GYF-1 was obtained and annotated, which revealed strain GYF-1 are abundant in heavy metal resistance genes. Further evaluations on differential gene expressions suggested adaptive mechanisms including increased lipopolysaccharides level and enhanced biofilm formation. Conclusion In this study, we demonstrated a newly isolated L. aestuarii GYF-1 exhibited mixed heavy metal resistance, which proven its capability of being a potential candidate strain for industrial biosorption application. Further genome analysis and differential gene expression assay suggest enhanced LPS and biofilm formation contributed to the adaptation of mixed heavy metals.

Abstract Objective To investigate the therapeutic efficacy of total flavonoids of Rhizoma Drynariae (TFRD) in conjunction with a calcium phosphate/collagen scaffold for the repair of cranial defects in rats. Methods The subjects, rats, were segregated into four groups: Control, TFRD, Scaffold, and TFRD + Scaffold. Cranial critical bone defects, 5 mm in diameter, were artificially induced through precise drilling. Post-surgery, at intervals of 2, 4, and 8 weeks, micro-CT scans were conducted to evaluate the progress of skull repair. Hematoxylin–eosin and Masson staining techniques were applied to discern morphological disparities, and immunohistochemical staining was utilized to ascertain the expression levels of local osteogenic active factors, such as bone morphogenetic protein 2 (BMP-2) and osteocalcin (OCN). Results Upon examination at the 8-week mark, cranial defects in the Scaffold and TFRD + Scaffold cohorts manifested significant repair, with the latter group displaying only negligible foramina. Micro-CT examination unveiled relative to its counterparts, and the TFRD + Scaffold groups exhibited marked bone regeneration at the 4- and 8-week intervals. Notably, the TFRD + Scaffold group exhibited substantial bone defect repair compared to the TFRD and Scaffold groups throughout the entire observation period, while histomorphological assessment demonstrated a significantly higher collagen fiber content than the other groups after 2 weeks. Immunohistochemical analysis further substantiated that the TFRD + Scaffold had augmented expression of BMP-2 at 2, 4 weeks and OCN at 2 weeks relative to other groups. Conclusions The synergistic application of TFRD and calcium phosphate/collagen scaffold has been shown to enhance bone mineralization, bone plasticity, and bone histomorphology especially during initial osteogenesis phases.

Magnesium alloys are widely used as biodegradable medical biomaterials due to their density and modulus of elasticity close to that of human bone. However, too rapid degradation in the physiological environment limits their application. In this paper, the non-toxic and easy alloying properties of liquid metal gallium are utilized to make it a coating material for biomedical Mg–Nd alloys, which is used to solve the problem of the rapid degradation rate of Mg alloys. The corrosion resistance of the Ga–Mg alloy layer was investigated by in vitro immersion in simulated body fluid (SBF) and electrochemical experiments, and a microhardness tester characterized the surface hardness. In addition, the phase transformation of the Ga–Mg alloy layer was systematically investigated in combination with XRD diffraction results. The results showed that by adjusting the alloying time of Ga with Mg–Nd in liquid metal, a “retarded layer” with high hardness, stability, and good corrosion resistance was obtained. This study is expected to expand the application of Mg alloy materials in medicine.

BackgroundPsychiatric disorders (PD) pose a significant burden, with vast prevalence and mortality, inflicting substantial costs on individuals and society. Despite its widespread prevalence, the complex pathogenesis of PD remains elusive, leading to limited and challenging therapeutic development. An emerging risk factor for chronic diseases, prolonged sedentary behavior, contrasts with the therapeutic potential of exercise, regardless of its intensity, for various ailments, including PD. Yet, the diversity in exercise modalities and intensities may offer varied impacts on health. This study, leveraging Mendelian Randomization (MR), seeks to investigate the causal relationship between exercise and PD, aiming to elucidate the optimal exercise modality and intensity for PD mitigation while addressing potential confounders.MethodsThis study employed a Mendelian randomization analysis using the genome-wide association study (GWAS) database to investigate the causal relationship between types of physical activity and psychiatric disorders. Sensitivity analysis was conducted to demonstrate the reliability and robustness of the results.ResultsIn the past 4 weeks, engaging in a substantial amount of DIY physical activity was found to have a causal relationship with psychiatric disorders (IVW: OR = 0.228, 95% CI: 0.113–0.461, P = 0.000038). As for the types of exercises, there may be a potential causal association between aerobic training (including swimming, cycling, fitness, and bowling) and psychiatric disorders (IVW: OR = 0.322, 95% CI = 0.148–0.704, P = 0.004). However, there was no causal relationship found between mild DIY physical activity and psychiatric disorders (IVW: OR = 0.918, 95% CI = 0.417–2.021, P = 0.831). Furthermore, it seems that there is no causal relationship between vigorous exercise and psychiatric disorders (IVW: OR = 2.705, 95% CI = 0.081–3.419, P = 0.578).ConclusionOur study confirms that only a certain level of training activity can have a protective effect on psychiatric disorders, while mild physical activity or vigorous training does not have an impact on psychiatric disorders.

Counting and analyzing of blood cells, as well as their subcellular structures, are indispensable for understanding biological processes, studying cell functions, and diagnosing diseases. In this paper, we combine digital holographic microscopy with cell segmentation guided by the Sobel operator using Dice coefficients for automatic threshold selection and aimed to automatic counting and analysis of blood cells in flow and different kinds of cells in the static state. We demonstrate the proposed method with automatic counting and analyzing rat red blood cells (RBCS) flowing in a microfluidic device, extracting quickly and accurately the size, concentration, and dry mass of the sample in a label-free manner. The proposed technique was also demonstrated for automatic segmentation of different cell types, such as COS7 and Siha. This method can help us in blood inspection, providing pathological information in disease diagnosis and treatment.

Abstract Introduction This retrospective cohort study aimed to compare the change in upper airway and craniocervical posture after orthodontic treatment between adolescent and adult patients with Class II high-angle malocclusion. Methods A total of 12 adolescent (mean ± standard deviation age = 13.0 ± 2.0 years) and 12 adult patients with Class II high-angle malocclusion (mean ± standard deviation age = 23.7 ± 6.4 years) were selected in this study. The lateral cephalograms and cone beam computed tomography images of adolescent and adult patients were taken before and after treatment, which can be employed to evaluate the variables of craniofacial morphology, upper airway, and craniocervical posture through paired t tests, respectively. An independent sample t test was performed to observe the differences between two groups after orthodontic intervention. For adults and adolescents, the correlation between craniofacial morphology, upper airway, and craniocervical posture was determined through Pearson correlation analysis. Results In all subjects, the improvements in vertical and sagittal facial morphology after treatment were observed. Anterior and inferior movements of the hyoid bone, an increase of upper airway dimension, posterior tipping of the head and a reduction of cervical inclination in the lower and middle segments post-treatment were identified in adolescence (P 0.05). Mandibular plane inclination, growth pattern, occlusal plane inclination, and chin position were all significantly correlated with craniocervical posture in adolescent patients. Besides, the mandibular growth pattern and chin position in adult patients were significantly correlated with craniocervical posture (P

Abstract Background Endothelial-mesenchymal transition (EndoMT) is an emerging adaptive process that modulates lymphatic endothelial function to drive aberrant lymphatic vascularization in the tumour microenvironment (TME); however, the molecular determinants that govern the functional role of EndoMT remain unclear. Here, we show that cancer-associated fibroblast (CAF)-derived PAI-1 promoted the EndoMT of lymphatic endothelial cells (LECs) in cervical squamous cell carcinoma (CSCC). Methods Immunofluorescent staining of α-SMA, LYVE-1 and DAPI were examined in primary tumour samples obtained from 57 CSCC patients. Assessment of cytokines secreted by CAFs and normal fibroblasts (NFs) was performed using human cytokine antibody arrays. The phenotype of EndoMT in lymphatic endothelial cells (LECs), gene expression levels, protein secretion and activity of signaling pathways were measured by real-time RT-PCR, ELISA or western blotting. The function of lymphatic endothelial monolayers was examined by transwell, tube formation assay, transendothelial migration assay in vitro. Lymphatic metastasis was measured using popliteal lymph node metastasis model. Furthermore, association between PAI-1 expression and EndoMT in CSCC was analyzed by immunohistochemistry. The Cancer Genome Atlas (TCGA) databases was used to assess the association of PAI-1 with survival rate in CSCC. Results CAF-derived PAI-1 promoted the EndoMT of LECs in CSCC. LECs undergoing EndoMT could initiate tumour neolymphangiogenesis that facilitated cancer cell intravasation/extravasation, which in turn promoted lymphatic metastasis in CSCC. Mechanistically, PAI-1 activated the AKT/ERK1/2 pathways by directly interacting with low-density lipoprotein receptor-related protein (LRP1), thereby leading to elevated EndoMT activity in LECs. Blockade of PAI-1 or inhibition of LRP1/AKT/ERK1/2 abrogated EndoMT and consequently attenuated CAF-induced tumour neolymphangiogenesis. Furthermore, clinical data revealed that increased PAI-1 levels positively correlated with EndoMT activity and poor prognosis in CSCC patients. Conclusion Our data indicate that CAF-derived PAI-1 acts as an important neolymphangiogenesis-initiating molecular during CSCC progression through modulating the EndoMT of LECs, resulting in promotion of metastasis ability in primary site. PAI-1 could serve as an effective prognostic biomarker and therapeutic target for CSCC metastasis.

AIM: To investigate the difference, correlation, and consistency of corneal thickness and the thinnest point position detected by Pentacam HR corneal topography map and RTVue optical coherence tomography(OCT)in patients with keratoconus.METHODS: Cross-sectional comparative study. The corneal curvature map, corneal thickness map, thinnest point position, and thinnest point thickness were detected by Pentacam HR and RTVue OCT. Paired sample t-test was used for data consistent with normal distribution, and paired sample rank sum test was used for data inconsistent with normal distribution. Spearman correlation analysis and Bland-Altman analysis were used for the correlation and consistency of the two measurement methods.RESULTS: A total of 63 patients(105 eyes)with keratoconus were included in this study, including 49 males(77.8%)and 14 females(22.2%), aged 22.24±6.19 years; among them, relevant data of Pentacam HR topographic map: Km was 47.85±4.73D and Kmax was 55.43±8.72D. In measuring central corneal thickness and the thinnest point thickness of keratoconus, the Pentacam HR was 4.70μm and 19.46μm thicker than the mean value measured by RTVue OCT(P0.05). The central corneal thickness and the thinnest point thickness measured by the two devices were highly correlated, the horizontal coordinate of the thinnest point was moderately correlated, and the vertical coordinate of the thinnest point was weakly correlated. Bland-Altman analysis showed that the central corneal thickness, the thinnest point thickness, the horizontal coordinate of the thinnest point, and the vertical coordinate of the thinnest point were 95.2%(100/105)and 93.3%(98/105), 95.2%(100/105), 95.2%(100/105)respectively, which were within the 95% consistency limit, while the consistency ranges were -36.00～+26.62μm, -42.27～+3.36μm, -0.80～+0.84mm, and -1.95～+1.06mm, respectively.CONCLUSION: In keratoconus, the central corneal thickness and the thinnest point thickness measured by Pentacam HR were higher than those measured by RTVue OCT. It is not recommended that the central corneal thickness and the thinnest point thickness measured by the two instruments be interchangeable in clinical use because of the wide range of consistency between the two instruments' results. The position of the thinnest corneal point measured by the two instruments is similar and consistent, so it could be considered to replace the measured values of the two instruments in clinical use.

Abstract Background Congenital pulmonary airway malformation (CPAM) is the most frequent pulmonary developmental malformation and the pathophysiology remains poorly understood. This study aimed to identify the characteristic gene expression patterns and the marker genes essential to CPAM. Methods Tissues from the cystic area displaying CPAM and the area of normal appearance were obtained during surgery. Bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) were performed for integrating analysis. Iterative weighted gene correlation network analysis (iWGCNA) was used to identify specifically expressed genes to CPAM. Results In total, 2074 genes were significantly differentially expressed between the CPAM and control areas. Of these differentially expressed genes (DEGs), 1675 genes were up-regulated and 399 genes were down-regulated. Gene ontology analysis revealed these DEGs were specifically enriched in ciliated epithelium and involved in immune response. We also identified several CPAM-related modules by iWGCNA, among them, P15_I4_M3 module was the most influential module for distinguishing CPAMs from controls. By combining the analysis of the expression dataset from RNA-seq and scRNA-seq, SPOCK2, STX11, and ZNF331 were highlighted in CPAM. Conclusions Through our analysis of expression datasets from both scRNA-seq and bulk RNA-seq of tissues obtained from patients with CPAM, we identified the characteristic gene expression patterns associated with the condition. Our findings suggest that SPOCK2 could be a potential biomarker gene for the diagnosis and therapeutic target in the development of CPAM, whereas STX11 and ZNF331 might serve as prognostic markers for this condition. Further investigations with larger samples and function studies are necessary to confirm the involvement of these genes in CPAM.

Abstract Introduction Our previous study has proofed the glucose sensitive gene-thioredoxin-interacting protein (TXNIP) expression was up in the placenta of the patients with gestational diabetes mellitus (GDM), but the pathological mechanisms underlying abnormal TXNIP expression in the placenta of patients with GDM is completely unclear and additional investigations are required to explain the findings we have observed. In the present study, we simulated the high TXNIP expression via introducing the Tet-On “switch” in vitro, approximate to its expression level in the real world, to explore the following consequence of the abnormal TXNIP. Methods The expression and localization of TXNIP in the placenta of GDM patients and the health control was investigated via immunofluorescent staining, western blot and RT-qPCR. Overexpression of TXNIP was achieved through transfecting Tet-on system to the human trophoblastic cell line-HTR-8/Svneo cell. TXNIP knockout was obtained via CRISPR-Cas9 method. The cell phenotype was observed via IncuCyte Imaging System and flow cytometry. The mechanism was explored via western blot and RT-qPCR. Results The expression level of TXNIP in the GDM placenta was nearly 2–3 times higher than that in the control. The TXNIP located at trophoblastic cells of the placenta. When the expression of TXNIP was upregulated, the migration and invasion of the cells accelerated, but cell apoptosis and proliferation did not changed compared with the control group. Furthermore, the size of the TetTXNIP cells became larger, and the expression level of Vimentin and p-STAT3 increased in the TetTXNIP cells. All the changes mentioned above were opposite in the TXNIP-KO cells. Conclusions Abnormal expression of TXNIP might be related to the impairment of the GDM placental function, affecting the migration and invasion of the placental trophoblast cells through STAT3 and Vimentin related pathway; thus, TXNIP might be the potential therapeutic target for repairing the placental dysfunction deficient in GDM patients.

Three compounds of novel pyrazolo[3,4-d]pyrimidin-4-one derivatives (A~C) were synthesized through a multi-step reaction using ethyl-2-cyano-3-ethoxyacrylate and 3,4-dimethylphenylhydrazine. The structures of these compounds were identified by nuclear magnetic resonance (NMR, i.e., 1H NMR, 13C NMR), and liquid chromatography-mass spectrum (LC-MS), and the 1H NMR signals of each compound were fully assigned. The in vivo analgesic activity of synthesized compound A was preliminarily evaluated through mass spectrometry brain imaging and formalin induced pain model in mice. The imaging data and results showed that compound A could cross the blood-brain barrier and penetrate into the brain of mice, and produce a dose-dependent analgesic activity. This study provided a piece of fundamental research data on structural and in vivo activity for developing anti-pain drugs based on pyrazolo[3,4-d]pyrimidin-4-one scaffold.

Purpose: To evaluate whether the toric intra-ocular lens (IOL) power calculation based on total corneal astigmatism (TCA) in eyes with high posterior corneal astigmatism (PCA) could result in a systematic over-correction or under-correction after operation. Methods: The present study included a mono-centric retrospective study design. The data were collected from 62 consecutive eyes during uncomplicated cataract surgery by a single surgeon with a measured PCA of 0.50 diopters (D) or higher. Toric IOL calculations were made using TCA measurements. The eyes were grouped as either “with-the-rule” (WTR) or “against-the-rule” (ATR) on the basis of the steep anterior corneal meridian. The post-operative refractive astigmatic prediction error was analyzed 1 month post-operatively using the vector analysis by the Alpins method and double-angle plots method. Results: The correction indexes were 1.14 ± 0.29 in the ATR eyes and 1.25 ± 0.18 for the WTR eyes, indicating a tendency toward over-correction. The mean over-correction was 0.22 ± 0.52D in the ATR group and 0.65 ± 0.60D in the WTR group. The magnitude of error (ME) values were significantly different from the ideal value of zero in both groups (ATR: P = 0.03; WTR: P = 0.00). No significant difference in mean absolute error (MAE) in predicted residual astigmatism was found between ATR and WTR groups (0.61 ± 0.42 D versus 0.64 ± 0.39 D; P = 0.54). The ATR group yielded better results, with 48%

The major histocompatibility complex (MHC) can recognize and bind to external peptides to generate effective immune responses by presenting the peptides to T cells. Therefore, understanding the binding modes of peptide–MHC complexes (pMHC) and predicting the binding affinity of pMHCs play a crucial role in the rational design of peptide vaccines. In this study, we employed molecular dynamics (MD) simulations and free energy calculations with an Alanine Scanning with Generalized Born and Interaction Entropy (ASGBIE) method to investigate the protein–peptide interaction between HLA-A*02:01 and the G9209 peptide derived from the melanoma antigen gp100. The energy contribution of individual residue was calculated using alanine scanning, and hotspots on both the MHC and the peptides were identified. Our study shows that the pMHC binding is dominated by the van der Waals interactions. Furthermore, we optimized the ASGBIE method, achieving a Pearson correlation coefficient of 0.91 between predicted and experimental binding affinity for mutated antigens. This represents a significant improvement over the conventional MM/GBSA method, which yields a Pearson correlation coefficient of 0.22. The computational protocol developed in this study can be applied to the computational screening of antigens for the MHC1 as well as other protein–peptide binding systems.

Background: Passive immune agents play an important role in the prevention of rabies following exposure. This trial investigated the safety, tolerability, and pharmacokinetics of recombinant human monoclonal antibodies against rabies virus (rhRIG). Method: This clinical trial was conducted on healthy Chinese adults. The subjects were enrolled into three dosage groups. The safety of the drug was assessed, and the blood concentration of the monoclonal antibody (NM57) and the neutralizing antibody levels were measured. Results: The rhRIG presented favorable safety and tolerability.The subjects in the low(10 IU/kg), medium(20 IU/kg), and high(40 IU/kg) dosage groups reported the Cmax of 87.15 ± 18.86, 210.92 ± 77.5, and 394.11 ± 134.98 ng/ml, respectively, and the AUC0-t of 2115.8 ± 791.3, 6064 ± 1890, and 10735.6 ± 4090 ng/mL*d, and the T1/2 z of 15.82 ± 3.03, 15.96 ± 2.37, and 14.34 ± 3.84 d. The Tmax of neutralizing antibody levels in the serum was about 10d (5-14d). The detectable rate of neutralizing antibody levels in the medium dosage group was close to that in the high dosage group and higher than that in the low dosage group. Conclusions: The 10–40IU/kg rhRIG was well tolerated by the participants. The results of the pharmacokinetic analysis were consistent with the characteristics of linear elimination. The neutralizing antibody levels was positively correlated with the dosage of rhRIG.

Cancer has keeping the main threat to the health of human being. Its overall survival rate has shown rare substantial progress in spite of the improving diagnostic and treatment techniques for cancer in recent years. Indeed, such classic strategies for malignant tumor as surgery, radiation and chemotherapy have been developed and bring more hope to the patients, but still been accompanied by certain limitations, which include the challenge of managing large wound sizes, systemic toxic side effects, and harmful to the healthy tissues caused by imprecise alignment with tumors in radiotherapy. Furthermore, immunotherapy exhibits a limited therapeutic effect in advanced tumors which is reported only up to 25%–30%. The combination of nanomaterials and cancer treatment offers new hope for cancer patients, demonstrating strong potential in the field of medical research. Among the extensively utilized nanomaterials, calcium carbonate nanomaterials (CCNM) exhibit a broad spectrum of biomedical applications due to their abundant availability, cost-effectiveness, and exceptional safety profile. CCNM have the potential to elevate intracellular Ca2+ levels in tumor cells, trigger the mitochondrial damage and ultimately lead to tumor cell death. Moreover, compared with other types of nanomaterials, CCNM exhibit remarkable advantages as delivery systems owing to their high loading capacity, biocompatibility and biodegradability. The purpose of this review is to provide an overview of CCNM synthesis, focusing on summarizing its diverse roles in cancer treatment and the benefits and challenges associated with CCNM in cancer therapy. Hoping to present the significance of CCNM as for the clinical application, and summarize information for the design of CCNM and other types of nanomaterials in the future.

Purpose: This study aims to evaluate the capability of optical coherence tomography angiography (OCTA) for imaging the microvasculature within a critical bone defect, to longitudinally observe vascular alterations, and quantify the microvascular density and morphology in a model of a critical-sized defect.Methods: An OCTA system was used to longitudinally monitor angiogenesis in four rat models presenting critical-sized defects with observations recorded on days 7, 14, and 28 post-defect creation. Simultaneously, angiogenesis in three additional rat models was evaluated through a conventional histological analysis involving hematoxylin and eosin staining.Results: OCTA was successful in acquiring in vivo 3D vascular perfusion mapping within the critical-sized defect, and it allowed for quantitative analysis of the microvasculature’s density and morphology. The OCTA imagery of the blood microvasculature revealed a noticeable augmentation in the number and size of vessels, with more extensive vessel convergence observed on day 14 compared to both days 7 and 28. Complementing these observations, quantitative analysis demonstrated that the vessel area density (VAD) and maximum vascular diameter index (MVDI) were significantly larger on day 14 in comparison to measurements taken on days 7 and 28.Conclusion: Leveraging its ability to capture high-resolution images, OCTA facilitated longitudinal monitoring of angiogenesis in models of critical-sized defects. Therefore, it potentially serves as a non-invasive experimental tool beneficial for bone regeneration research.

Abstract Objective This study aimed to explore the correlation between T1 and T2 relaxation times of synthetic MRI (SyMRI) and gestational age (GA) in each hemisphere of preterm and term newborns at the initial 28 days of birth. Methods Seventy preterm and full‐term infants were prospectively included in this study. All subjects completed 3.0 T routine MRI and SyMRI (MAGiC) one‐stop scanning within 28 days of birth (aged 34–42 W at examination). The SyMRI postprocessing software (v8.0.4) was used to measure the T1 and T2 relaxation values of each brain region. The linear regression equations of quantitative relaxation values with GA were established to compare the variation speed in each brain region. Results A significant linear and negative correlation was found between relaxation times and GA in the neonate cerebral cortex and subcortical gray and white matter regions (All p

This study proposes a strategy for screening and validating of antioxidant compounds and components from leaves of yacon (Smallanthus sonchifolius Poepp. and Endl.) by variable selection based on weight analysis. The theoretical basis of variable selection lies in that the varied quantity of variables will influence the activity results of samples. The ethyl acetate fraction (sample 0) with high DPPH scavenging activity was further separated using silica gel chromatographic column to obtain 17 subfractions (samples 1–17). The 18 samples contain different compounds exhibited different DPPH radical scavenging activities. Two components A and B with time range of 2.00–12.00 min and 53.00–64.00 min on the chromatogram were selected by variable selection, respectively. Simultaneously, a large number of compounds with different retention times (RTs) were screened out. Five predicted compounds, including chlorogenic acid, methyl caffeate, ethyl caffeate, homoeriodictyol, quercetin 3,7-dimethyl ether were isolated and verified by DPPH radical scavenging ability assay. The radical scavenging rates of those compounds were higher than that of ethyl acetate fraction and the positive control butylated hydroxyltoluene (BHT). Meanwhile, components A and B also show strong antioxidant activity. The radical scavenging activity of component A is higher than that of compounds which contained in component A, indicating the existence of synergistic antioxidant activity of compounds. The results of variable selection show that the proposed method is simple and reliable in screening the most active components and compounds. The method could be used for screening of compounds and components from other herbal plants with other activities.

Abstract Ferroptosis, a newly discovered irondependent form of regulated cell death caused by excessive accumulation of lipid peroxides, is linked to the development and treatment response of various types of cancer, including gastric cancer (GC). Noncoding RNAs (ncRNAs), as key regulators in cancer, have both oncogenic and tumor suppressive roles. However, studies on ferroptosis-related ncRNA networks in GC are still lacking. Here, we first identified 61 differentially expressed genes associated with ferroptosis in GC by computing and analyzing gene expression profile of tumor and normal tissues for GC. Then, upstream lncRNAs and miRNAs interacting with them were found through miRNet and miRBase databases, and hub lncRNAs and miRNAs were obtained through topological analysis. Finally, the ceRNA regulatory network linked to ferroptosis in GC was established, which includes two ferroptosis marker genes (TXNIP and TSC22D3), one driver gene (GABARAPL1), and one suppressor gene (CAV1). Kaplan-Meier survival analysis showed that changes in the expression of these genes were associated with the survival of GC patients. Furthermore, our study revealed that this ceRNA network may influence the progression of GC by regulating ferroptosis process. These results will help experimental researchers to design an experiment study to further explore the roles of this regulatory network in GC ferroptosis.

Background Sepsis is a serious infection-induced response in the host, which can result in life-threatening organ dysfunction. It is of great importance to unravel the relationship between sepsis and host immune response and its mechanisms of action. Liver is one of the most vulnerable organs in sepsis, however, the specific pathogenesis of septic liver injury has not been well understood at the protein level. Methods A total of 12 healthy Sprague–Dawley (SD) male rats aged from 6 to 8 weeks were adaptively housed in individual cages in the specific pathogen free animal room. These lab rats were grouped into two groups: treatment (N = 9) and control (N = 3) groups; only three mice from the treatment group survived and were used for subsequent experiments. A TMT-based proteomic analysis for liver tissue was performed in the septic rat model. Results A total of 37,012 unique peptides were identified, and then 6,166 proteins were determined, among which 5,701 were quantifiable. Compared to the healthy control group, the septic rat group exhibited 162 upregulated and 103 downregulated differentially expressed proteins (DEPs). The upregulated and downregulated DEPs were the most significantly enriched into the complement and coagulation cascades and metabolic pathways. Protein-protein interaction (PPI) analysis further revealed that the upregulated and downregulated DEPs each clustered in a PPI network. Several highly connected upregulated and downregulated DEPs were also enriched into the complement and coagulation cascades pathways and metabolic pathways, respectively. The parallel reaction monitoring (PRM) results of the selected DEPs were consistent with the results of the TMT analysis, supporting the proteomic data. Conclusion Our findings highlight the roles of complement and coagulation cascades and metabolic pathways that may play vital roles in the host immune response. The DEPs may serve as clinically potential treatment targets for septic liver injury.

The liver is the most common and lethal metastatic site in patients with extensive-stage small-cell lung cancer (ES-SCLC), and median survival with current standard treatment is only 9–10 months from diagnosis. Clinical observations show that a complete response (CR) is extremely rare in ES-SCLC patients with liver metastasis. Moreover, to the best of our knowledge, complete regression of liver metastasis induced by the abscopal effect, boosted primarily by permanent radioactive iodine-125 seeds implantation (PRISI), combined with a low-dose metronomic temozolomide (TMZ) regimen, has not been recorded. Here, we present the case of a 54-year-old male patient who developed multiple liver metastases from ES-SCLC after multiple lines of chemotherapy. The patient was given partial PRISI therapy (two out of six tumor lesions; 38 iodine-125 seeds in one dorsal lesion and 26 seeds in one ventral lesion), which was combined with TMZ metronomic chemotherapy (50 mg/m2/day, days 1–21, every 28 days). The abscopal effect was observed for 1 month after PRISI treatment. After about 1 year, all the liver metastases had completely disappeared, and the patient experienced no relapse. The patient eventually died of malnutrition caused by a non-tumor intestinal obstruction and had an overall survival of 58.5 months after diagnosis. PRISI combined with TMZ metronomic chemotherapy might be considered a potential therapy to trigger the abscopal effect in patients with liver metastases.

Biochar-based fertilizers are used to improve soil’s physiochemical and biological properties and increase fertilizer utilization rate. Therefore, a technological model of biochar-based fertilizers is essential for the reduced application. This study was conducted to determine the effects of the different levels of biochar-based fertilizer applications on soil and plant nutrient content, as well as maize yield. Biochar-based fertilizer increased the total N content of maize stem and kernel and the total P content of maize axis and kernel. Biochar-based fertilizer increased the total P but decreased the total K of maize plants while increasing the fertilizer’s partial productivity. Treatment B1 (600.00 kg hm−2 of biochar-based fertilizer) increased the dry-matter weight of the maize at silking and filling stages by 1.60 and 15.83%. Treatment B1 increased the ear length, diameter, and plant height. Compared with BCK (600.00 kg hm−2 of conventional fertilizer), the yield of B1 was increased by 9.23%, and the difference was significant (p < 0.05). Biochar-based fertilizer treatments B2–B5 (biochar-based fertilizer reduced by 5–20%) reduced maize yield, but there was no significant difference between their yield and BCK. This study aimed to provide a basic understanding and reference for maize fertilizer reduction with good application prospects.

Abstract Bone injury caused changes to surrounding tissues, leading to a large number of osteoclasts appeared to clear the damaged bone tissue before bone regeneration. However, overactive osteoclasts will inhibit bone formation. In this study, we prepared methacrylylated gelatin (GelMA)‐based hydrogel to co‐crosslink with OP3‐4 peptide, a receptor activator of NF‐κB ligand (RANKL) binding agent, to achieve the slow release of OP3‐4 peptide to inhibit the activation of osteoclasts, thus preventing the long‐term existence of osteoclasts from affecting bone regeneration, and promoting osteogenic differentiation. Moreover, CXCL9 secreted by osteoblasts will bind to endogenous VEGF and inhibit vascularization, finally hinder bone formation. Thus, anti‐CXCL9 antibodies (A‐CXCL9) were also loaded in the hydrogel to neutralize excess CXCL9. The hydrogel slow released of OP3‐4 cyclic peptide and A‐CXCL9 to simultaneously inhibiting osteoclast activation and promoting vascularization, thereby accelerating the healing of femur defect. Further analysis of osteogenic protein expression and signal pathways showed that the hydrogel may be through activating the AKT‐RUNX2‐ALP pathway and ultimately promote osteogenic differentiation. This dual‐acting hydrogel can effectively prevent nonunion caused by low vascularization and provide long‐term support for the treatment of bone injury.

Preimplantation embryo arrest (PREMBA) is a common cause of female infertility and recurrent failure of assisted reproductive technology. However, the genetic basis of PREMBA is largely unrevealed. Here, using whole-exome sequencing data from 606 women experiencing PREMBA compared with 2,813 controls, we performed a population and gene–based burden test and identified a candidate gene, karyopherin subunit α7 (KPNA7). In vitro studies showed that identified sequence variants reduced KPNA7 protein levels, impaired KPNA7 capacity for binding to its substrate ribosomal L1 domain-containing protein 1 (RSL1D1), and affected KPNA7 nuclear transport activity. Comparison between humans and mice suggested that mouse KPNA2, rather than mouse KPNA7, acts as an essential karyopherin in embryonic development. Kpna2–/– female mice showed embryo arrest due to zygotic genome activation defects, recapitulating the phenotype of human PREMBA. In addition, female mice with an oocyte-specific knockout of Rsl1d1 recapitulated the phenotype of Kpna2–/– mice, demonstrating the vital role of substrate RSL1D1. Finally, complementary RNA (cRNA) microinjection of human KPNA7, but not mouse Kpna7, was able to rescue the embryo arrest phenotype in Kpna2–/– mice, suggesting mouse KPNA2 might be a homologue of human KPNA7. Our findings uncovered a mechanistic understanding for the pathogenesis of PREMBA, which acts by impairing nuclear protein transport, and provide a diagnostic marker for PREMBA patients.

Electrospinning technology is famous for its simple preparation, and accurate and easy control of process parameters. It is widely used in ultrafine filtration membrane and biological tissue engineering support. Polycaprolactone (PCL) and poly(butylene succinate) (PBS) have good biocompatibility and are commonly used materials in electrospinning. In this study, the relationship between the electrospun sample, process parameters, and spinning solution of PCL/PBS blend system was systematically studied in an electrospinning experiment. The morphology characteristics, thermodynamic properties, and microstructure of the electrospun sample were screened by scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction. The optimum conditions of electrospinning with high practical value were obtained.

The strong heterogeneity characteristics of deep-buried clastic low-permeability reservoirs may lead to great risks in hydrocarbon exploration and development, which makes the accurate identification of reservoir lithofacies crucial for improving the obtained exploration results. Due to the very limited core data acquired from deep drilling, lithofacies logging identification has become the most important method for comprehensively obtaining the rock information of deep-buried reservoirs and is a fundamental task for carrying out reservoir characterization and geological modeling. In this study, a machine learning method is introduced to lithofacies logging identification, to explore an accurate lithofacies identification method for deep fluvial-delta sandstone reservoirs with frequent lithofacies changes. Here Sangonghe Formation in the Central Junggar Basin of China is taken as an example. The K-means-based synthetic minority oversampling technique (K-means SMOTE) is employed to solve the problem regarding the imbalanced lithofacies data categories used to calibrate logging data, and a probabilistic calibration method is introduced to correct the likelihood function. To address the situation in which traditional machine learning methods ignore the geological deposition process, we introduce a depositional prior for controlling the vertical spreading process based on a Markov chain and propose an improved Bayesian inversion process for training on the log data to identify lithofacies. The results of a series of experiments show that, compared with the traditional machine learning method, the new method improves the recognition accuracy by 20%, and the predicted petrographic vertical distribution results are consistent with geological constraints. In addition, SMOTE and probabilistic calibration can effectively handle data imbalance problems so that different categories can be adequately learned. Also the introduction of geological prior has a positive impact on the overall distribution, which significantly improves the accuracy and recall rate of the method. According to this comprehensive analysis, the proposed method greatly enhanced the identification of the lithofacies distributions in the Sangonghe Formation. Therefore, this method can provide a tool for logging lithofacies interpretation of deep and strongly heterogeneous clastic reservoirs in fluvial-delta and other depositional environments.

The Junggar Basin is a multicycle intracontinental sedimentary basin developed on the pre-Mesozoic deformed basement. For a long time, the Junggar Basin and its adjacent Altai orogeny have been a focus of debate for geologists studying the opening and closing history of the Paleozoic Asian Ocean and Cenozoic intracontinental deformation. However, there has been no detailed research on the intracontinental tectonic activities of northern Xinjiang since the Mesozoic, particularly the Yanshanian tectonic activities in the northern Junggar Basin. Fission-track (FT) dating was conducted on 15 apatite samples and eight zircon samples obtained from the northern Junggar Basin to better understand the Yanshanian tectonic evolution. The results showed that apatite FT (AFT) ages ranged from 131 to 42 Ma and zircon FT ages ranged from 205 to 132 Ma. Based on the AFT track thermal history modeling and the regional geological data, we proposed that the northern Junggar Basin underwent three tectonic thermal events during 165–161, 93–81, and 72–66 Ma. The thermal events of 165–161 Ma may indicate magmatic activity during the Yanshanian, while the 93–86 and 72–66 Ma events reflect Late Cretaceous uplift and cooling. This study has confirmed the tectonic evolution of the Yanshanian in the northern Junggar Basin from the perspective of thermochronology. It has also revealed that the Yanshanian orogeny, a regional tectonic event, may have also occurred in northwest China.

BackgroundImmunotherapy for lung cancer has been a hot research area for years. This bibliometric analysis was intended to present research trends on melanoma immunotherapy.MethodOn April 1, 2022, the authors identified 2,109 papers on melanoma immunotherapy using the Web of Science and extracted their general information and the total number of citations. The authors then conducted a bibliometric analysis to present the research landscape, clarify the research trends, and determine the most cited papers (top-papers) as well as major journals on melanoma immunotherapy. Subsequently, recent research hotspots were identified by analyzing the latest articles in major journals.ResultsThe total and median number of citations of these 2,109 papers on melanoma immunotherapy was 137,686 and 11, respectively. “Improved survival with ipilimumab in patients with metastatic melanoma” by Hodi et al. was the most cited paper (9,824 citations). Among the journals, the top-paper number (16), average citations per paper (2,510.7), and top-papers rate (100%) of New England Journal of Medicine were the highest. Corresponding authors represented the USA took part in most articles (784). Since 2016, the hottest research area has changed from CTLA-4 to PD-1.ConclusionsThis bibliometric analysis comprehensively and quantitatively presents the research trends and hotspots based on 2,109 relevant publications, and further suggests future research directions. The researchers can benefit in selecting journals and in finding potential collaborators. This study can help researchers gain a comprehensive impression of the research landscape, historical development, and current hotspots in melanoma immunotherapy and can provide inspiration for future research.

An extreme ultraviolet (EUV) pellicle is an ultrathin membrane at a stand-off distance from the reticle surface that protects the EUV mask from contamination during the exposure process. EUV pellicles must exhibit high EUV transmittance, low EUV reflectivity, and superior thermomechanical durability that can withstand the gradually increasing EUV source power. This study proposes an optimal range of optical constants to satisfy the EUV pellicle requirements based on the optical simulation results. Based on this, zirconium disilicide (ZrSi2), which is expected to satisfy the optical and thermomechanical requirements, was selected as the EUV pellicle candidate material. An EUV pellicle composite comprising a ZrSi2 thin film deposited via co-sputtering was fabricated, and its thermal, optical, and mechanical properties were evaluated. The emissivity increased with an increase in the thickness of the ZrSi2 thin film. The measured EUV transmittance (92.7%) and reflectivity (0.033%) of the fabricated pellicle satisfied the EUV pellicle requirements. The ultimate tensile strength of the pellicle was 3.5 GPa. Thus, the applicability of the ZrSi2 thin film as an EUV pellicle material was verified.

Sr3YCo4O10.5+δ (314-SYCO), with an unusual ordered structure and a high Curie temperature (Tc ≈ 335 K), is attracting increasing attention. Herein, to improve the electrical performance of 314-SYCO, Cu-doped Sr3YCo4−xCuxO10.5+δ (x = 0–0.8) ceramics were prepared using a solid-state reaction method. Systematic research was conducted on both the ordered phase transformation and the effects of Cu doping on the microstructure, electrical transport characteristics, and magnetic properties. For x = 0–0.4, the (103) and (215) planes were observed and combined with Rietveld refinement results for the X-ray diffraction data, confirming the formation of ordered tetragonal Sr3YCo4−xCuxO10.5+δ. This phase was formed with a mass gain of ∼0.8% and heat released at ∼1,042°C. With increasing Cu content, the concentration of hole carriers also increased, leading to a substantial reduction in electrical resistivity. The electrical resistivity decreased by 92–99% at 300 K. The polycrystalline materials have semiconducting behaviour with a three-dimensional Mott variable-range hopping mechanism. For the magnetic properties, a Hopkinson peak was observed at 319 K, and the Tc was approximately 321 K for x = 0. The magnetisation and Tc decreased with increasing Cu content, and a G-type antiferromagnetic-to-ferromagnetic phase transition occurred due to the spin state change for some Co3+ ions from high/intermediate spin to low/intermediate spin. These results lay the groundwork for refinement of the sintering procedure and doping parameters to enhance the performance of 314-SYCO in the context of current applications such as microwave absorbers and solid oxide fuel cell cathodes.

Although multiple studies have shown that loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) locus is one of the mechanisms of immune escape, the effect of HLA LOH on the immunotherapy response of patients is still unclear. Based on the data of 425 Chinese lung cancer patients, the genomic characteristics with different HLA LOH statuses were analyzed. The driver genes mutation frequency, oncogenic signaling pathways mutation frequency, tumor mutational burden (TMB) and chromosomal instability (CIN) score in the HLA LOH high group was significantly higher than in the HLA LOH negative group. Transcriptome analyses revealed that pre-existing immunologically active tumor microenvironment (TME) was associated with HLA LOH negative patients. Non-small cell lung cancer (NSCLC) patients, especially for lung squamous cell carcinomas (LUSC), with HLA LOH negative have a longer survival period than those with HLA LOH. In addition, the combination of HLA LOH with TMB or programmed cell death-Ligand 1 (PD-L1) expression can further distinguish responders from non-responders. Furthermore, a comprehensive predictive model including HLA LOH status, TMB, PD-L1 expression and CD8+ T cells was constructed and exhibited a higher predictive value, which may improve clinical decision-making.

Backgroundradiotherapy is one of the major treatments for lung cancer and has been a hot research area for years. This bibliometric analysis aims to present the research trends on lung cancer radiotherapy.MethodOn August 31, 2022, the authors identified 9868 articles on lung cancer radiotherapy by the Web of Science (Science Citation Indexing Expanded database) and extracted their general information and the total number of citations. A bibliometric analysis was carried out to present the research landscape, demonstrate the research trends, and determine the most cited papers (top-papers) as well as top-journals on lung cancer radiotherapy. After that, the authors analyzed the recent research hotspots based on the latest publications in top-journals.ResultsThese 9868 papers were cited a total of 268,068 times. “Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer” published in 2017 by Antonia et al.was the most cited article (2110 citations). Among the journals, New England Journal of Medicine was most influential. Moreover, J. Clin. Oncol. and Int. J. Radiat. Oncol. Biol. Phys. was both influential and productive. Corresponding authors represented the USA (2610 articles) and China mainland (2060 articles) took part in most publications and articles with corresponding authors from Netherlands were most cited (46.12 citations per paper). Chemoradiotherapy was the hottest research area, and stereotactic body radiotherapy has become a research hotspot since 2006. Radiotherapy plus immunotherapy has been highly focused since 2019.ConclusionsThis bibliometric analysis comprehensively and quantitatively presents the research trends and hotspots based on 9868 relevant articles, and further suggests future research directions. The researchers can benefit in selecting journals and in finding potential collaborators. This study can help researchers gain a comprehensive picture of the research landscape, historical development, and recent hotspots in lung cancer radiotherapy and can provide inspiration for future research.

Tomato (Solanum lycopersicum) is a major vegetable crop cultivated worldwide. The regulation of tomato growth and fruit quality has long been a popular research topic. MYC2 is a key regulator of the interaction between jasmonic acid (JA) signaling and other signaling pathways, and MYC2 can integrate the interaction between JA signaling and other hormone signals to regulate plant growth and development. TOR signaling is also an essential regulator of plant growth and development. However, it is unclear whether MYC2 can integrate JA signaling and TOR signaling during growth and development in tomato. Here, MeJA treatment and SlMYC2 overexpression inhibited the growth and development of tomato seedlings and photosynthesis, but increased the sugar–acid ratio and the contents of lycopene, carotenoid, soluble sugar, total phenol and flavonoids, indicating that JA signaling inhibited the growth of tomato seedlings and altered fruit quality. When TOR signaling was inhibited by RAP, the JA content increased, and the growth and photosynthesis of tomato seedlings decreased, indicating that TOR signaling positively regulated the growth and development of tomato seedlings. Further yeast one-hybrid assays showed that SlMYC2 could bind directly to the SlTOR promoter. Based on GUS staining analysis, SlMYC2 regulated the transcription of SlTOR, indicating that SlMYC2 mediated the interaction between JA and TOR signaling by acting on the promoter of SlTOR. This study provides a new strategy and some theoretical basis for tomato breeding.

The STEAM education involves children’s ability to integrate and apply their knowledge of science, technology, engineering, arts, and mathematics. The application and transfer of interdisciplinary knowledge in practical activities is the structure of STEAM education. This study assesses children’s practical drawing skills and transferable skills based on the global features of their realistic figure drawing. The drawings incorporate the visual information and the multidisciplinary knowledge that children acquire. The assessment variables of the global features are observation perspectives, baseline, and comparison. The results showed that most children present their works through the front view. The children of different age groups show differences in express baseline and comparison features. Boys and girls show some variances in baseline features. Moreover, children are relatively unskilled at applying interdisciplinary knowledge in their drawings.

Abstract LEOPARD syndrome (OMIM #151,100) caused by a germline PTPN11 mutation are characterized as multisystemic anomalies and variable marked phenotypes such as multiple lentigines and cafe´-au-lait spots, electrocardiographic conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness. Phenotype overlap complicates clinical discrimination within RASopathies, making the diagnosis of LEOPARD more confusing and challenging. Besides, LEOPARD patients do not usually present with all these typical clinical features, increasing the possibility of underdiagnosis or misdiagnosis. Herein, we report a case of LEOPARD syndrome in a patient who only presented with pigmented skin spots and was initially diagnosed with multiple acquired melanocytic nevi. Subsequent pathological examination confirmed the diagnosis of multiple lentigines rather than melanocytic nevi. A genetic study showed a germline PTPN11 (Tyr279Cys) mutation and raised the suspicion of LEOPARD syndrome. A subsequent ECG examination detected potential cardiac defects and confirmed the diagnosis of LEOPARD. We considered that the potential damage of other systems underlying the skin multiple lentigines should not be ignored. The diagnosis of LEOPARD syndrome in an early stage before cardiac damage has reached a serious and irreversible stage can be meaningful for patients to fully understand the potential risks, complications and prognosis of the disease and to take appropriate precautions to prevent the potential risk of cardiac damage.

Background and objective Immune checkpoint inhibitor associated pneumonia (CIP) is a serious side effect of immune checkpoint inhibitors. There is a consensus on the treatment of acute phase of CIP, but the treatment of pulmonary interstitial fibrosis after the acute phase is still a clinical problem to be solved. Methods The diagnosis and treatment of a non-small cell lung cancer (NSCLC) patient with immune checkpoint inhibitor associated pneumonia in the Stereotactic Radiotherapy Department of Qingdao Central Hospital were retrospectively analyzed, and literatures were reviewed. Results A 70-year-old male patient was diagnosed with Poorly differentiated squamous cell carcinoma of left lung with mediastinal lymph node metastasis T3N3M0 stage IIIc, EGFR/ALK/ROS1/RAF negative, PD-L1 (22c3) immunohistochemistry negative. After the progression of first-line chemotherapy, the patient was diagnosed as immune checkpoint inhibitor associated pneumonia grade 3 during second-line monotherapy with Nivolumab. After initial high-dose glucocorticoid pulse therapy, the lung computed tomography (CT) imaging and clinical symptoms of the patients were partially relieved, and then pirfenidone (300 mg tid) was given orally for more than 11 months. During the treatment of pirfenidone, the CT imaging and clinical symptoms of the patients were significantly improved, and there were no other adverse reactions except grade 1 nausea. During this period, chemotherapy and Anlotinib was given concurrently with pirfenidone and showed good safety profile. Conclusion This case report is the first report of pirfenidone in the treatment of CIP, which provides a new idea for the clinical practice and research of CIP treatment.