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Abstract Nipah virus infection, one of the top priority diseases recognized by the World Health Organization, underscores the urgent need to develop effective countermeasures against potential epidemics and pandemics. Here, we identify a fully human single-domain antibody that targets a highly conserved cryptic epitope situated at the dimeric interface of the Nipah virus G protein (receptor binding protein, RBP), as elucidated through structures by high-resolution cryo-electron microscopy (cryo-EM). This unique binding mode disrupts the tetramerization of the G protein, consequently obstructing the activation of the F protein and inhibiting viral membrane fusion. Furthermore, our investigations reveal that this compact antibody displays enhanced permeability across the blood-brain barrier (BBB) and demonstrates superior efficacy in eliminating pseudovirus within the brain in a murine model of Nipah virus infection, particularly compared to the well-characterized antibody m102.4 in an IgG1 format. Consequently, this single-domain antibody holds promise as a therapeutic candidate to prevent Nipah virus infections and has potential implications for vaccine development.

Dermal fibroblasts play a crucial role in the formation of granulation tissue in skin wounds. Consequently, the differentiation, migration, and proliferation of dermal fibroblasts are considered key factors in the skin wound healing process. However, in patients with diabetic foot ulcers, the proliferation and migration of fibroblasts are impaired by reactive oxygen species and inflammatory factors impair. Therefore, a novel magnetic gelatin-hesperidin microrobots drug delivery system was developed using microfluidics. The morphology, motility characteristics, and drug release of the microrobot were assessed, along with its impact on the proliferation and migration of human dermal fibroblasts under high-glucose conditions. Subjected to a rotating magnetic field, the microrobots exhibit precise, controllable, and flexible autonomous motion, achieving a maximum speed of 9.237 μm/s. In vitro drug release experiments revealed that approximately 78% of the drug was released within 30 min. It was demonstrated through cellular experiments that the proliferation of human dermal fibroblasts was actively promoted by the nanorobot, the migration ability of fibroblasts in a high-glucose state was enhanced, and good biocompatibility was exhibited. Hence, our study may provide a novel drug delivery system with significant potential for promoting the healing of diabetic foot wounds.

IntroductionCyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are first-line treatments for hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. With their increasing clinical use, infection-related adverse events (AEs) associated with CDK4/6 inhibitors have been widely reported in recent years. This study aimed to analyze the occurrence of infections associated with the CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) based on the real-world data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.MethodsData were extracted from the FAERS database between 2015Q1 and 2022Q3. The clinical characteristics of patients with primary suspected infection-related AEs were analyzed. A disproportionality analysis was performed to investigate the potential association between AEs and CDK4/6 inhibitors. The influencing factors were evaluated using Pearson’s chi-square test.ResultsReports of infection-related AEs associated with ribociclib accounted for 8.58% of the total reports of AEs associated with ribociclib, followed by palbociclib (2.72%) and abemaciclib (1.24%). Ribociclib (67.65%) was associated with more serious outcome events than palbociclib (30%) or abemaciclib (48.08%). The sex and age were not associated with outcome severity. Disproportionality analysis showed that fourteen, sixteen and two infection-related preferred terms were detected for palbociclib, ribociclib and abemaciclib, respectively.ConclusionInfection-related AEs were highly associated with three CDK4/6 inhibitors, especially palbociclib and ribociclib, based on the real-world data from the FAERS database. However, further causality assessment is required.

Recent years have witnessed a surge in the application of microrobots within the medical sector, with hydrogel microrobots standing out due to their distinctive advantages. These microrobots, characterized by their exceptional biocompatibility, adjustable physico-mechanical attributes, and acute sensitivity to biological environments, have emerged as pivotal tools in advancing medical applications such as targeted drug delivery, wound healing enhancement, bio-imaging, and precise surgical interventions. The capability of hydrogel microrobots to navigate and perform tasks within complex biological systems significantly enhances the precision, efficiency, and safety of therapeutic procedures. Firstly, this paper delves into the material classification and properties of hydrogel microrobots and compares the advantages of different hydrogel materials. Furthermore, it offers a comprehensive review of the principal categories and recent innovations in the synthesis, actuation mechanisms, and biomedical application of hydrogel-based microrobots. Finally, the manuscript identifies prevailing obstacles and future directions in hydrogel microrobot research, aiming to furnish insights that could propel advancements in this field.

BackgroundAs a severe hematological malignancy in adults, acute myeloid leukemia (AML) is characterized by high heterogeneity and complexity. Emerging evidence highlights the importance of the tumor immune microenvironment and lipid metabolism in cancer progression. In this study, we comprehensively evaluated the expression profiles of genes related to lipid metabolism and immune modifications to develop a prognostic risk signature for AML.MethodsFirst, we extracted the mRNA expression profiles of bone marrow samples from an AML cohort from The Cancer Genome Atlas database and employed Cox regression analysis to select prognostic hub genes associated with lipid metabolism and immunity. We then constructed a prognostic signature with hub genes significantly related to survival and validated the stability and robustness of the prognostic signature using three external datasets. Gene Set Enrichment Analysis was implemented to explore the underlying biological pathways related to the risk signature. Finally, the correlation between signature, immunity, and drug sensitivity was explored.ResultsEight genes were identified from the analysis and verified in the clinical samples, including APOBEC3C, MSMO1, ATP13A2, SMPDL3B, PLA2G4A, TNFSF15, IL2RA, and HGF, to develop a risk-scoring model that effectively stratified patients with AML into low- and high-risk groups, demonstrating significant differences in survival time. The risk signature was negatively related to immune cell infiltration. Samples with AML in the low-risk group, as defined by the risk signature, were more likely to be responsive to immunotherapy, whereas those at high risk responded better to specific targeted drugs.ConclusionsThis study reveals the significant role of lipid metabolism- and immune-related genes in prognosis and demonstrated the utility of these signature genes as reliable bioinformatic indicators for predicting survival in patients with AML. The risk-scoring model based on these prognostic signature genes holds promise as a valuable tool for individualized treatment decision-making, providing valuable insights for improving patient prognosis and treatment outcomes in AML.

Three rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered “undruggable”, recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-small-cell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer. Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.

Copper (Cu) is an essential trace element in the brain and serves as an important cofactor for numerous enzymes involved in a wide range of biochemical processes including neurobehavioral, mitochondrial respiration, and antioxidant effects. Recent studies have demonstrated that copper dyshomeostasis is tightly associated with the development of depression by inducing oxidative stress and inflammatory responses. However, these findings have remained controversial so far. Cumulative studies have shown a positive association, while some other studies showed no association and even a negative association between serum/plasma copper level and depression. Based on these conflicted results, the association was speculated to be due to the clinical features of the population, stages of the disease, severity of copper excess, and types of specimens detected in these studies. In addition, there was an inverse association between dietary copper intake and depression. Furthermore, increasing copper intake could influence dietary zinc and iron intake to prevent and treat depression. Thus, copper supplementation may be a good measure to manage depression. This review provided a deeper understanding of the potential applicability of copper in the prevention and treatment of depression.

In the fight against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), monoclonal antibodies (mAbs) serve as key strategies for the rapid prevention and treatment of COVID-19. However, analysis to fully characterize functional SARS-CoV-2 mAbs is still needed. In this study, by interrogating 1,695 published or patented mAbs of human origin and validated SARS-CoV-2-binding potency, we found a highly preferential usage of IGHV3-53/3-66 germline genes that was then revealed as a distinct selectivity of SARS-CoV-2-induced humoral immunity across other coronaviruses. Moreover, among the rare somatic hypermutations, we identified a novel mutation signature of F27 to I, L, or V with high frequency, which was located in the CDR1 region of the heavy chain among IGHV3-53/3-66-encoded antibodies. This convergent mutation contributed to improving SARS-CoV-2 binding affinity and may advance our knowledge of the humoral immunity to SARS-CoV-2.

Abstract To increase the efficiency and robustness of stability-based transition prediction in flow simulations, simplified methods are introduced to substitute direct stability analyses for rapid disturbance growth prediction. For low-speed boundary layers, these methods are mainly established based on self-similar assumptions, which are not applicable to non-similar boundary layers in hypersonic flows. The objective of this article is to investigate the application of surrogate models to stability analysis of non-similar flows over blunt cones, focused on parameterization of boundary-layer (BL) profiles. Firstly, correlations between BL edge and profile parameters are analyzed, along with self-similar flow parameters and discrete points on BL profiles, which present four groups of BL characteristic parameters. Secondly, using these parameters as inputs, surrogate models are built for disturbance growth prediction over an MF-1 blunt cone. Results show that, surrogate models using four BL edge parameters and a BL shape factor {U e , T e , ρ e , η e , H 12} for stability analysis can achieve comparable accuracy with those using 16 discrete BL profile parameters, which are more precise than those using merely self-similar parameters or BL edge parameters. Thirdly, the established surrogate models are validated by stability analysis and transition prediction over the MF-1 blunt cone in flight experiments at the instants of t = 17 s ~ 22 s. Compared with direct linear stability analyses, the mean relative error of predicted disturbance growth rates by surrogate models is 8.0% and the maximum relative error of N factor envelopes is 6.6%, which indicates feasible applications of surrogate models to stability analysis and transition prediction of non-similar boundary layers in hypersonic flows.

Chemoresistance is a main limitation for the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, the authors show that an antibody drug conjugate-like compound targeting both EGFR and HER2 overcomes gemcitabine resistance in PDAC preclinical models by mechanisms involving the tumour suppressor SMAD4.

Space debris is considered an increasingly serious threat to on‐orbit spacecrafts. There are several potential solutions to this problem, including active debris removal. Flexible robots have shown promising adaptability and dexterity in soft manipulation owing to their inherent compliance. This compliance allows them to interact safely and efficiently during space missions such as active debris removal. Herein, inspired by the bistable structure and energy‐release mechanism of the Venus flytrap, a bistable origami‐based gripper is developed. The flexible gripper, which can rapidly achieve stable state switching, is in the form of a biomimetic flytrap leaf curvature and is actuated using a shape memory alloy actuator. Subsequently, a flytrap bristle‐like locking structure is used to ensure locking via the action of a dielectric elastomer actuator to alleviate the vibration instability of the flexible robot under rapid actuation. The experimental results showed that the flexible gripper can achieve effective capture within approximately 300 ms. In addition, it exhibits good adaptability and mechanical robustness with targets having complex shapes and sizes, indicating its potential applications in the space capture and sampling fields.

Most existing aerodynamic shape optimization (ASO) studies do not take the balanced pitching moment into account and thus the optimized configuration has to be trimmed to ensure zero pitching moment, which causes additional drag and reduces the benefit of ASO remarkably. This article proposes an efficient global ASO method that directly enforces a zero pitching moment constraint. A free-form deformation (FFD) parameterization combing Laplacian smoothing method is implemented to parameterize a full aircraft configuration and ensure sufficiently smooth aerodynamic shapes. Reynolds-averaged Navier–Stokes (RANS) equations are solved to simulate transonic viscous flows. A surrogate-based multi-round optimization strategy is used to drive ASO towards the global optimum. To verify the effectiveness of the proposed method, we adopt two design optimization strategies for the NASA Common Research Model (CRM) wing–body–tail configuration. The first strategy is to optimize the configuration without considering balance of pitching moment, and then manually trim the optimized configuration by deflecting the horizontal tail. The second one is to directly enforce the zero pitching moment constraint in the optimization model and take the deflection angle of the horizontal tail as an additional design variable. Results show that: (1) for the first strategy, about 4-count drag-reducing benefits would be lost when manually trimming the optimal configuration; (2) the second strategy can achieve 3.2-count more drag-reducing benefits than the first strategy; (3) compared with gradient-based optimization (GBO), surrogate-based optimization (SBO) is more efficient than GBO for ASO problems with around 80 design variables, and the benefit of ASO achieved by SBO is comparable to that obtained by GBO.

Abstract The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19.

Abstract Dogs with X-linked hereditary nephropathy (XLHN) are an animal model for Alport syndrome in humans and progressive chronic kidney disease (CKD). Using mRNA sequencing (mRNA-seq), we have characterized the gene expression profile affecting the progression of XLHN; however, the microRNA (miRNA, miR) expression remains unknown. With small RNA-seq and quantitative RT-PCR (qRT-PCR), we used 3 small RNA-seq analysis tools (QIAGEN OmicSoft Studio, miRDeep2, and CPSS 2.0) to profile differentially expressed renal miRNAs, top-ranked miRNA target genes, and enriched biological processes and pathways in CKD progression. Twenty-three kidney biopsies were collected from 5 dogs with XLHN and 4 age-matched, unaffected littermates at 3 clinical time points (T1: onset of proteinuria, T2: onset of azotemia, and T3: advanced azotemia). We identified up to 23 differentially expressed miRNAs at each clinical time point. Five miRNAs (miR-21, miR-146b, miR-802, miR-142, miR-147) were consistently upregulated in affected dogs. We identified miR-186 and miR-26b as effective reference miRNAs for qRT-PCR. This study applied small RNA-seq to identify differentially expressed miRNAs that might regulate critical pathways contributing to CKD progression in dogs with XLHN.

ABSTRACT Hepatitis B virus (HBV) infection is a serious global health issue with more than 250 million chronic carriers. It causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Persistent suppression of the HBV surface antigen (HBsAg) is necessary for a functional cure of chronic hepatitis B (CHB) virus infection. However, this can hardly be achieved with currently approved drugs. Antibody treatment against HBsAg has shown promise in restoring HBV-specific immune responses and promoting HBV cure. To achieve long-lasting HBsAg suppression, we used an advanced mRNA drug to encode the genes of three anti-HBsAg antibodies, G12-scFv, G12-scFv-Fc, and G12-IgG. Antibody-encoding mRNA-lipid nanoparticles (LNPs), mL (G12-scFv-Fc) and mL (G12-IgG), substantially reduced serum HBsAg levels in treated mice within 30 days after a single dose. In contrast, exogenous antibodies lost effect on reducing HBsAg or HBV DNA levels 9 days postadministration. The high affinity of anti-HBsAg antibodies and the adjuvant activity of mRNA-LNPs resulted in long-term HBsAg seroclearance, which could contribute to the reestablishment of the immune system in HBV carriers. These findings highlight the great potential of antibody-encoding mRNA molecules against CHB infection. IMPORTANCE It is the first time that mRNA-LNPs have been used to express anti-HBsAg antibodies (G12-scFv, G12-scFv-Fc, and G12-IgG). G12-scFv-Fc- and G12-IgG-encoding mRNA-LNPs exerted a sustained effect on HBsAg serum clearance in the adeno-associated virus (AAV)/HBV mouse model with persistent HBsAg expression. These findings may provide a new design of combination therapy for functional cure of HBV. For example, this strategy could provide an alternative for antibodies in “sandwich” therapy and further enhance the immunization properties of the therapy. Overall, mRNA therapeutics are promising for treatment of infectious diseases because of their rapid development, economic value, and simplicity.

BackgroundAcute myeloid leukemia (AML) is a highly aggressive hematological malignancy characterized by extensive genetic abnormalities that might affect the prognosis and provide potential drug targets for treatment. Reprogramming of lipid metabolism plays important roles in tumorigenesis and progression and has been newly recognized a new hallmark of malignancy, and some related molecules in the signal pathways could be prognostic biomarkers and potential therapeutic targets for cancer treatment. However, the clinical value of lipid metabolism reprogramming in AML has not been systematically explored. In this study, we aim to explore the clinical value of lipid metabolism reprogramming and develop a prognostic risk signature for AML.MethodsWe implemented univariate Cox regression analysis to identify the prognosis-related lipid metabolism genes, and then performed LASSO analysis to develop the risk signature with six lipid metabolism-related genes (LDLRAP1, PNPLA6, DGKA, PLA2G4A, CBR1, and EBP). The risk scores of samples were calculated and divided into low- and high-risk groups by the median risk score.ResultsSurvival analysis showed the high-risk group hold the significantly poorer outcomes than the low-risk group. The signature was validated in the GEO datasets and displayed a robust prognostic value in the stratification analysis. Multivariate analysis revealed the signature was an independent prognostic factor for AML patients and could serve as a potential prognostic biomarker in clinical evaluation. Furthermore, the risk signature was also found to be closely related to immune landscape and immunotherapy response in AML.ConclusionsOverall, we conducted a comprehensive analysis of lipid metabolism in AML and constructed a risk signature with six genes related to lipid metabolism for the malignancy, prognosis, and immune landscape of AML, and our study might contribute to better understanding in the use of metabolites and metabolic pathways as the potential prognostic biomarkers and therapeutic targets for AML.

In this study, we propose a highly efficient robot platform for pollutant adsorption. This robot system consists of a flapping-wing micro aircraft (FWMA) for long-distance transportation and delivery and cost-effective multifunctional Janus microrobots for pollutant purification. The flapping-wing micro air vehicle can hover for 11.3 km with a flapping frequency of approximately 15 Hz, fly forward up to 31.6 km/h, and drop microrobots to a targeted destination. The Janus microrobot, which is composed of a silica microsphere, nickel layer, and hydrophobic layer, is used to absorb the oil and process organic pollutants. These Janus microrobots can be propelled fast up to 9.6 body lengths per second, and on-demand speed regulation and remote navigation are manageable. These Janus microrobots can continuously carry oil droplets in aqueous environments under the control of a uniform rotating magnetic field. Because of the fluid dynamics induced by the Janus microrobots, a highly efficient removal of Rhodamine B is accomplished. This smart robot system may open a door for pollutant purification.

Abstract The excellent performance of geometric positioning of a newly launched satellite will greatly broaden its application field. Launched on January 15, 2020, the Hongqi-1-H9 wide-range satellite is the largest sub-meter-level satellite worldwide and the first ton-level commercial remote sensing satellite in China, with a resolution of less than 1 m and a swath width of 136 km. This study was aimed at assessing the geometric positioning accuracy of this newly launched satellite considering three aspects, namely, the circle error accuracy, rational polynomial coefficient-based direct geometric positioning accuracy and ground control point-based absolute positioning accuracy under urban, plain, and mountainous areas, with different topographies. The results of the conducted experimental investigation indicated that the Hongqi-1-H9 satellite could exhibit a high positioning accuracy in planar and vertical directions for different terrains. In particular, for our experimental areas with a low topography and few surface structures, the geometric positioning accuracy of the Hongqi-1-H9 satellite imagery was less than 4m and 2 m in the planimetry and elevation directions, respectively. These characteristics can promote the application of the Hongqi-1-H9 satellite images in agricultural surveys, target detection, and land surveys, among other domains.

Accumulating evidence has showed that sushi-repeat-containing protein X-linked 2 (SRPX2) is an abnormal expression in a variety of cancers and involved in cancer carcinogenesis, chemosensitivity, and prognosis, which mainly promote cancer cell metastasis, invasion, and migration by regulating the uPAR/integrins/FAK signaling pathway, epithelial-mesenchymal transition (EMT), angiogenesis, and glycosylation. Inflammation has been regarded as a key role in regulating cancer initiation, progression, EMT, and therapeutics. Furthermore, SRPX2 exhibited excellent antifibrosis effect via the TGFβR1/SMAD3/SRPX2/AP1/SMAD7 signaling pathway. Therefore, this review provides compelling evidence that SRPX2 might be a therapeutic target for inflammation and cancer-related inflammation for future cancer therapeutics.

Mycoplasma pneumoniae (MP) can infect both the upper and lower respiratory tracts related diseases and a common cause of community-acquired pneumonia, mostly in young children and adolescents. Zingiber zerumbet (L.) belongs to the family of Zingiberaceae and it is a perennial and aromatic plant that cultivates in subtropical and tropical countries. This plant is traditionally found throughout Southeast Asia and the Pacific region, where it is commonly used in foods, and beverages purposes. Zingiber zerumbet is a valuable foundation of diverse classes of bioactive major compounds that fit to a varied diversity of chemical metabolites, including polyphenols, alkaloids and terpenes. The numerous studies of Z. zerumbet have shown the enormous pharmacological potential of this plant and its derived bioactive compounds in the treatment of various immune-related diseases like inflammation and other chronic diseases. Based on the previous scientific reports, there are no scientific investigations that claim the antipneumonial activity of the Z. zerumbet based silver nanoparticle. Therefore, the aim of the present study was designed and evaluated the anti-pneumonial potential of biosynthesized with Z. zerumbet based silver nanoparticles in mycoplasmal pneumonia in experimental rats.

Background: Acute myeloid leukemia (AML) remains the most common type of hematopoietic malignancy in adults and has an unfavorable outcome. Herein, we aimed to construct an N6-methylandenosine (m6A)-related long noncoding RNAs (lncRNAs) signature to accurately predict the prognosis of patients with AML using the data downloaded from The Cancer Genome Atlas (TCGA) database.Methods: The RNA-seq and clinical data were obtained from the TCGA AML cohort. First, Pearson correlation analysis was performed to identify the m6A-related lncRNAs. Next, univariate Cox regression analysis was used to determine the candidate lncRNAs with prognostic value. Then, feature selection was carried out by Least absolute shrinkage and selection operator (LASSO) analysis, and seven eligible m6A-related lncRNAs were included to construct the prognostic risk signature. Kaplan–Meier and receiver operating characteristic (ROC) curve analyses were performed to evaluate the predictive capacity of the risk signature both in the training and testing datasets. A nomogram was used to predict 1-year, 2-year, and 3-year overall survival (OS) of AML patients. Next, the expression levels of lncRNAs in the signature were validated in AML samples by qRT-PCR. Functional enrichment analyses were carried out to identify probable biological processes and cellular pathways. The ceRNA network was developed to explore the downstream targets and mechanisms of m6A-related lncRNAs in AML.Results: Seven m6A-related lncRNAs were identified as a prognostic signature. The low-risk group hold significantly prolonged OS. The nomogram showed excellent accuracy of the signature for predicting 1-year, 2-year and 3-year OS (AUC = 0.769, 0.820, and 0.800, respectively). Moreover, the risk scores were significantly correlated with enrichment in cancer hallmark- and malignancy-related pathways and immunotherapy response in AML patients.Conclusion: We developed and validated a novel risk signature with m6A-related lncRNAs which could predict prognosis accurately and reflect the immunotherapy response in AML patients.

Background: Bladder cancer (BLCA) ranks 10th in incidence among malignant tumors and 6th in incidence among malignant tumors in males. With the application of immune therapy, the overall survival (OS) rate of BLCA patients has greatly improved, but the 5-year survival rate of BLCA patients is still low. Furthermore, not every BLCA patient benefits from immunotherapy, and there are a limited number of biomarkers for predicting the immunotherapy response. Therefore, novel biomarkers for predicting the immunotherapy response and prognosis of BLCA are urgently needed.Methods: The RNA sequencing (RNA-seq) data, clinical data and gene annotation files for The Cancer Genome Atlas (TCGA) BLCA cohort were extracted from the University of California, Santa Cruz (UCSC) Xena Browser. The BLCA datasets GSE31684 and GSE32894 from the Gene Expression Omnibus (GEO) database were extracted for external validation. Immune-related genes were extracted from InnateDB. Significant differentially expressed genes (DEGs) were identified using the R package “limma,” and Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for the DEGs were performed using R package “clusterProfiler.” Least absolute shrinkage and selection operator (LASSO) regression analysis were used to construct the signature model. The infiltration level of each immune cell type was estimated using the single-sample gene set enrichment analysis (ssGSEA) algorithm. The performance of the model was evaluated with receiver operating characteristic (ROC) curves and calibration curves.Results: In total, 1,040 immune-related DEGs were identified, and eight signature genes were selected to construct a model using LASSO regression analysis. The risk score of BLCA patients based on the signature model was negatively correlated with OS and the immunotherapy response. The ROC curve for OS revealed that the model had good accuracy. The calibration curve showed good agreement between the predictions and actual observations.Conclusions: Herein, we constructed an immune-related eight-gene signature that could be a potential biomarker to predict the immunotherapy response and prognosis of BLCA patients.

Background: Bladder cancer (BLCA) is a common malignant tumor of the genitourinary system, and there is a lack of specific, reliable, and non-invasive tumor biomarker tests for diagnosis and prognosis evaluation. Homeobox genes play a vital role in BLCA tumorigenesis and development, but few studies have focused on the prognostic value of homeobox genes in BLCA. In this study, we aim to develop a prognostic signature associated with the homeobox gene family for BLCA.Methods: The RNA sequencing data, clinical data, and probe annotation files of BLCA patients were downloaded from the Gene Expression Omnibus database and the University of California, Santa Cruz (UCSC), Xena Browser. First, differentially expressed homeobox gene screening between tumor and normal samples was performed using the “limma” and robust rank aggregation (RRA) methods. The mutation data were obtained with the “TCGAmutation” package and visualized with the “maftools” package. Kaplan–Meier curves were plotted with the “survminer” package. Then, a signature was constructed by logistic regression analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using “clusterProfiler.” Furthermore, the infiltration level of each immune cell type was estimated using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Finally, the performance of the signature was evaluated by receiver-operating characteristic (ROC) curve and calibration curve analyses.Results: Six genes were selected to construct this prognostic model: TSHZ3, ZFHX4, ZEB2, MEIS1, ISL1, and HOXC4. We divided the BLCA cohort into high- and low-risk groups based on the median risk score calculated with the novel signature. The overall survival (OS) rate of the high-risk group was significantly lower than that of the low-risk group. The infiltration levels of almost all immune cells were significantly higher in the high-risk group than in the low-risk group. The average risk score for the group that responded to immunotherapy was significantly lower than that of the group that did not.Conclusion: We constructed a risk prediction signature with six homeobox genes, which showed good accuracy and consistency in predicting the patient’s prognosis and response to immunotherapy. Therefore, this signature can be a potential biomarker and treatment target for BLCA patients.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a refractory malignant tumor with poor prognosis, limited chemotherapeutic efficacy, and only about 5% of 5‐year survival rate. We generated a dual‐targeting ligand‐based lidamycin (DTLL) to investigate its efficacy against pancreatic cancer after preparing its precursor, DTLP. DTLP was shown specifically binding to EGFR and HER2 on cell surface, followed by endocytosis into cytoplasm of pancreatic cancer cells. DTLL significantly promoted apoptosis and cell cycle arrest at G2/M stages and inhibited cell proliferation. Pancreatic tumors of either MIA‐paca‐2 cell line‐derived (CDX) or patient‐derived xenograft (PDX) mouse models were significantly regressed in response to DTLL. It suggested that DTLL might be a highly potent bispecific antibody‐drug conjugate (ADC)‐like agent for pancreatic cancer therapy. LDM is known to function as an antitumor cytotoxic agent by its induction of DNA damage in cancer cells, therefore, DTLL, as its derivative, also showed similar cytotoxicity. However, we found that DTLL might reverse the AKT/mTOR feedback activation induced by LDM at the first time. The results from both in vitro and in vivo experiments suggested that DTLL enhanced DNA damage via EGFR/HER2‐dependent blockage of PI3K/AKT/mTOR and PD‐L1 signaling pathways in cancer cells, leading to the inhibition of cell proliferation and immunosurveillance escape from pancreatic tumor. Our studies on DTLL functional characterization revealed its novel mechanisms on internal enhancement of DNA damage and implied that DTLL might provide a promising targeted therapeutic strategy for pancreatic cancer.

Understanding the mechanisms of trim and flight stability in birds is critical to guide the design of bionic micro air vehicles. The complex movements (plunging, sweeping, twisting) and morphing of wings always keeps the flapping flight of birds in dynamic equilibrium, which makes it difficult to determine the critical factors of trim and stability. Hence, a model has been developed that takes real complex movement and the calculation of unsteady aerodynamics into consideration. Two trim methods, including wash-out and forward-sweep, have been used to achieve equilibrium in the longitudinal direction. It is interesting to find that these two methods are both important to realize a larger take-off weight, lower power consumption, and stronger longitudinal stability. This implies that the seagull probably uses both of them to obtain the requirement of equilibrium and stability, which further inspires the design of seagull-inspired micro air vehicles.

Col4a3−/− Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3−/− mouse model with a 129/SvJ background and an intermediate-progressing F1 hybrid mouse model with a mixed genetic background, with angiotensin-converting enzyme inhibitor (ACEi) monotherapy in combination with anti-miR-21 therapy. In the fast-progressing model, the anti miR-21 and ACEi therapies showed an additive effect in the reduction in fibrosis, the decline of proteinuria, the preservation of kidney function and increased survival. In the intermediate-progressing F1 model, the anti-miR-21 and ACEi therapies individually improved kidney pathology. Both also improved kidney function and survival; however, the combination showed a significant additive effect, particularly for survival. RNA sequencing (RNA-seq) gene expression profiling revealed that the anti-miR-21 and ACEi therapies modulate several common pathways. However, anti-miR-21 was particularly effective at normalizing the expression profiles of the genes involved in renal tubulointerstitial injury pathways. In conclusion, significant additive effects were detected for the combination of anti-miR-21 and ACEi therapies on kidney function, pathology and survival in Alport mouse models, as well as a strong differential effect of anti-miR-21 on the renal expression of fibrotic factors. These results support the addition of anti-miR-21 to the current standard of care (ACEi) in ongoing clinical trials in patients with Alport syndrome.

Combined geometric positioning using images with different resolutions and imaging sensors is being increasingly widely utilized in practical engineering applications. In this work, we attempt to perform the combined geometric positioning and performance analysis of multi-resolution optical images from satellite and aerial platforms based on weighted rational function model (RFM) bundle adjustment without using ground control points (GCPs). Firstly, we introduced an integrated image matching method combining least squares and phase correlation. Next, for bundle adjustment, a combined model of the geometric positioning based on weighted RFM bundle adjustment was derived, and a method for weight determination was given to make the weights of all image points variable. Finally, we conducted experiments using a case study in Shanghai with ZiYuan-3 (ZY-3) satellite imagery, GeoEye-1 satellite imagery, and Digital Mapping Camera (DMC) aerial imagery to validate the effectiveness of the proposed weighted method, and to investigate the positioning accuracy by using different combination scenarios of multi-resolution heterogeneous images. The experimental results indicate that the proposed weighted method is effective, and the positioning accuracy of different combination scenarios can give a good reference for the combined geometric positioning of multi-stereo heterogeneous images in future practical engineering applications.

Automatic fine registration of multisensor images plays an essential role in many remote sensing applications. However, it is always a challenging task due to significant radiometric and textural differences. In this paper, an enhanced subpixel phase correlation method is proposed, which embeds phase congruency-based structural representation, L1-norm-based rank-one matrix approximation with adaptive masking, and stable robust model fitting into the conventional calculation framework in the frequency domain. The aim is to improve the accuracy and robustness of subpixel translation estimation in practical cases. In addition, template matching using the enhanced subpixel phase correlation is integrated to realize reliable fine registration, which is able to extract a sufficient number of well-distributed and high-accuracy tie points and reduce the local misalignment for coarsely coregistered multisensor remote sensing images. Experiments undertaken with images from different satellites and sensors were carried out in two parts: tie point matching and fine registration. The results of qualitative analysis and quantitative comparison with the state-of-the-art area-based and feature-based matching methods demonstrate the effectiveness and reliability of the proposed method for multisensor matching and registration.

A new airfoil family, called NPU-MWA (Northwestern Polytechnical University Multi-megawatt Wind-turbine A-series) airfoils, was designed to improve both aerodynamic and structural performance, with the outboard airfoils being designed at high design lift coefficient and high Reynolds number, and the inboard airfoils being designed as flat-back airfoils. This article aims to design a multi-megawatt wind turbine blade in order to demonstrate the advantages of the NPU-MWA airfoils in improving wind energy capturing and structural weight reduction. The distributions of chord length and twist angle for a 5 MW wind turbine blade are optimized by a Kriging surrogate model-based optimizer, with aerodynamic performance being evaluated by blade element-momentum theory. The Reynolds-averaged Navier−Stokes equations solver was used to validate the improvement in aerodynamic performance. Results show that compared with an existing NREL (National Renewable Energy Laboratory) 5 MW blade, the maximum power coefficient of the optimized NPU 5 MW blade is larger, and the chord lengths at all span-wise sections are dramatically smaller, resulting in a significant structural weight reduction (9%). It is shown that the NPU-MWA airfoils feature excellent aerodynamic and structural performance for the design of multi-megawatt wind turbine blades.