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Abstract Background This study aims to assess the associations of admission systolic blood pressure (SBP) level with spontaneous reperfusion (SR) and long-term prognosis in ST-elevation myocardial infarction (STEMI) patients. Methods Data from 3809 STEMI patients who underwent primary percutaneous coronary intervention within 24 h, as recorded in the Chinese STEMI PPCI Registry (NCT04996901), were analyzed. The primary endpoint was SR, defined as thrombolysis in myocardial infarction grade 2–3 flow of IRA according to emergency angiography. The second endpoint was 2-year all-cause mortality. The association between admission BP and outcomes was evaluated using Logistic regression or Cox proportional hazards models with restricted cubic splines, adjusting for clinical characteristics. Results Admission SBP rather than diastolic BP was associated with SR after adjustment. Notably, this relationship exhibits a nonlinear pattern. Below 120mmHg, There existed a significant positive correlation between admission SBP and the incidence of SR (adjusted OR per 10-mmHg decrease for SBP ≤ 120 mm Hg: 0.800; 95% CI: 0.706–0.907; p120 mm Hg: 1.019; 95% CI: 0.958–1.084, p = 0.552). In the analysis of the endpoint event of mortality, patients admitted with SBP ranging from 121 to 150 mmHg exhibited the lowest mortality compared with those SBP ≤ 120mmHg (adjusted HR: 0.653; 95% CI: 0.495–0.862; p = 0.003). In addition, subgroups analysis with Killip class I-II showed SBP ≤ 120mmHg was still associated with increased risk of mortality. Conclusion The present study revealed admission SBP above 120 mmHg was associated with higher SR,30-d and 2-y survival rate in STEMI patients. The admission SBP could be a marker to provide clinical assessment and treatment. Trial registration ClinicalTrials.gov (NCT04996901), 07/27/2021.

Abstract Background Pig organ xenotransplantation is a potential solution for the severe organ shortage in clinic, while immunogenic genes need to be eliminated to improve the immune compatibility between humans and pigs. Current knockout strategies are mainly aimed at the genes causing hyperacute immune rejection (HAR) that occurs in the first few hours while adaptive immune reactions orchestrated by CD4 T cell thereafter also cause graft failure, in which process the MHC II molecule plays critical roles. Methods Thus, we generate a 4‐gene (GGTA1, CMAH, β4GalNT2, and CIITA) knockout pig by CRISPR/Cas9 and somatic cell nuclear transfer to compromise HAR and CD4 T cell reactions simultaneously. Results We successfully obtained 4KO piglets with deficiency in all alleles of genes, and at cellular and tissue levels. Additionally, the safety of our animals after gene editing was verified by using whole‐genome sequencing and karyotyping. Piglets have survived for more than one year in the barrier, and also survived for more than 3 months in the conventional environment, suggesting that the piglets without MHC II can be raised in the barrier and then gradually mated in the conventional environment. Conclusions 4KO piglets have lower immunogenicity, are safe in genomic level, and are easier to breed than the model with both MHC I and II deletion.

Abstract Cancer is an evolutionary process shaped by selective pressure from the microenvironments. However, recent studies reveal that certain tumors undergo neutral evolution where there is no detectable fitness difference amongst the cells following malignant transformation. Here, through computational modeling, we demonstrate that negative frequency-dependent selection (or NFDS), where the immune response against cancer cells depends on the clonality of neoantigens, can lead to an immunogenic landscape that is highly similar to neutral evolution. Crucially, NFDS promotes high antigenic heterogeneity and early immune evasion in hypermutable tumors, leading to poor responses to immune checkpoint blockade (ICB) therapy. Our model also reveals that NFDS is characterized by a negative association between average clonality and total burden of neoantigens. Indeed, this unique feature of NFDS is common in the whole-exome sequencing (WES) datasets (357 tumor samples from 275 patients) from four melanoma cohorts with ICB therapy and a non-small cell lung cancer (NSCLC) WES dataset (327 tumor samples from 100 patients). Altogether, our study provides quantitative evidence supporting the theory of NFDS in cancer, explaining the high prevalence of neutral-looking tumors. These findings also highlight the critical role of frequency-dependent selection in devising more efficient and predictive immunotherapies.

Abstract Despite recent technological advancements in cell tumor DNA (ctDNA) mutation detection, challenges persist in identifying low-frequency mutations due to inadequate sensitivity and coverage of current procedures. Herein, we introduce a super-sensitivity and specificity technique for detecting ctDNA mutations, named HiCASE. The method utilizes PCR-based CRISPR, coupled with the restriction enzyme. In this work, HiCASE focuses on testing a series of EGFR mutations to provide enhanced detection technology for non–small cell lung cancer (NSCLC), enabling a detection sensitivity of 0.01% with 40 ng cell free DNA standard. When applied to a panel of 140 plasma samples from 120 NSCLC patients, HiCASE exhibits 88.1% clinical sensitivity and 100% specificity with 40 μL of plasma, higher than ddPCR and Super-ARMS assay. In addition, HiCASE can also clearly distinguish T790M/C797S mutations in different positions at a 1% variant allele frequency, offering valuable guidance for drug utilization. Indeed, the established HiCASE assay shows potential for clinical applications.

Abstract The recent discovery of nickelate superconductivity represents an important step toward understanding the four‐decade mastery of unconventional high‐temperature superconductivity. However, the synthesis of the infinite‐layer nickelate superconductors shows great challenges. Particularly, surface capping layers are usually unitized to facilitate the sample synthesis. This leads to an important question whether nickelate superconductors with d9 configuration and ultralow valence of Ni1+ are in metastable state and whether nickelate superconductivity can be robust? In this work, a series of redox cycling experiments are performed across the phase transition between perovskite Nd0.8Sr0.2NiO3 and infinite‐layer Nd0.8Sr0.2NiO2. The infinite‐layer Nd0.8Sr0.2NiO2 is quite robust in the redox environment and can survive the cycling experiments with unchanged crystallographic quality. However, as the cycling number goes on, the perovskite Nd0.8Sr0.2NiO3 shows structural degradation, suggesting stability of nickelate superconductivity is not restricted by the ultralow valence of Ni1+, but by the quality of its perovskite precursor. The observed robustness of infinite‐layer Nd0.8Sr0.2NiO2 up to ten redox cycles further indicates that if an ideal high‐quality perovskite precursor can be obtained, infinite‐layer nickelate superconductivity can be very stable and sustainable under environmental conditions. This work provides important implications for potential device applications for nickelate superconductors.

Abstract Solid tumors are complex ecosystems with heterogeneous 3D structures, but the spatial intra-tumor heterogeneity (sITH) at the macroscopic (i.e., whole tumor) level is under-explored. Using a phylogeographic approach, we sequence genomes and transcriptomes from 235 spatially informed sectors across 13 hepatocellular carcinomas (HCC), generating one of the largest datasets for studying sITH. We find that tumor heterogeneity in HCC segregates into spatially variegated blocks with large genotypic and phenotypic differences. By dissecting the transcriptomic heterogeneity, we discover that 30% of patients had a “spatially competing distribution” (SCD), where different spatial blocks have distinct transcriptomic subtypes co-existing within a tumor, capturing the critical transition period in disease progression. Interestingly, the tumor regions with more advanced transcriptomic subtypes (e.g., higher cell cycle) often take clonal dominance with a wider geographic range, rejecting neutral evolution for SCD patients. Extending the statistical tests for detecting natural selection to many non-SCD patients reveal varying levels of selective signal across different tumors, implying that many evolutionary forces including natural selection and geographic isolation can influence the overall pattern of sITH. Taken together, tumor phylogeography unravels a dynamic landscape of sITH, pinpointing important evolutionary and clinical consequences of spatial heterogeneity in cancer.

Soybean (Glycine max) stands as a globally significant agricultural crop, and the comprehensive assembly of its genome is of paramount importance for unraveling its biological characteristics and evolutionary history. Nevertheless, previous soybean genome assemblies have harbored gaps and incompleteness, which have constrained in-depth investigations into soybean. Here, we present Telomere-to-Telomere (T2T) assembly of the Chinese soybean cultivar Zhonghuang 13 (ZH13) genome, termed ZH13-T2T, utilizing PacBio Hifi and ONT ultralong reads. We employed a multi-assembler approach, integrating Hifiasm, NextDenovo, and Canu, to minimize biases and enhance assembly accuracy. The assembly spans 1,015,024,879 bp, effectively resolving all 393 gaps that previously plagued the reference genome. Our annotation efforts identified 50,564 high-confidence protein-coding genes, 707 of which are novel. ZH13-T2T revealed longer chromosomes, 421 not-aligned regions (NARs), 112 structure variations (SVs), and a substantial expansion of repetitive element compared to earlier assemblies. Specifically, we identified 25.67 Mb of tandem repeats, an enrichment of 5S and 48S rDNAs, and characterized their genotypic diversity. In summary, we deliver the first complete Chinese soybean cultivar T2T genome. The comprehensive annotation, along with precise centromere and telomere characterization, as well as insights into structural variations, further enhance our understanding of soybean genetics and evolution.

Ovarian cancer (OC) is the deadliest malignancy of the female reproductive system. The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Despite these treatments, there remains a high rate of tumor recurrence and resistance to platinum. Recent studies have highlighted the potential anti-tumor properties of metformin (met), a traditional diabetes drug. In our study, we investigated the impact of met on the anticancer activities of cisplatin (cDDP) both in vitro and in vivo. Our findings revealed that combining met with cisplatin significantly reduced apoptosis in OC cells, decreased DNA damage, and induced resistance to cDDP. Furthermore, our mechanistic study indicated that the resistance induced by met is primarily driven by the inhibition of the ATM/CHK2 pathway and the upregulation of the Rad51 protein. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP.

Delivering high areal capacitance (CA) at high rates is crucial but challenging for flexible supercapacitors. CA is the product of areal loading mass (MA) and gravimetric capacitance (CW). Finding and understanding the balance between MA and CW of supercapacitor materials is significant for designing high-CA electrodes. Herein, we have systematically studied the correlation between MA and CW of the nanosheet arrays of NiCo−layered double hydroxide (NiCo−LDH), which were electrodeposited on carbon cloth with different heights to adjust the MA, accompanied by the interlayer distance regulation to improve the CW. The optimal CW performance is achieved at the best charge transfer kinetics for each of MA series. The NiCo−LDH electrode with the suitable MA (2.58 ​mg ​cm−2) and the relatively high CW (1918 F ​g−1 ​at 5 ​A ​g−1 and 400 ​F ​g−1 ​at 150 ​A ​g−1) present a high CA of 4948 ​mF ​cm−2 ​at 12.9 ​mA ​cm−2 and a record-high 1032 ​mF ​cm−2 among LDHs-based flexible electrodes at an ultrahigh current density of 387 ​mA ​cm−2. The corresponding flexible supercapacitor coupled with activated carbon delivers a high energy density of 0.28 ​mWh cm−2 ​at an ultrahigh power density of 712 ​mW ​cm−2, showing great potential applications.

Concrete, as a composite material, is subject to heterogeneity in its mechanical properties and damage characteristics responding to load. In this paper, a numerical approach for analyzing the heterogeneous characteristics and the mechanical behavior of concrete specimens in tensile splitting tests using DIP techniques is introduced. The experiment involves the preparation of three types of concrete specimens with different strengths and performances of the tensile splitting test. The contour and position information of the different components in the split surface of a concrete specimen are reflected in the numerical model using the DIP techniques and the fracture of the split surface is realized by three types of cohesive elements in the finite element software ABAQUS. The results of the proposed numerical model are highly consistent with the experimental results with a maximum error of 4.77%, whereby the evolution of the splitting process is discussed. The simulation shows that the concrete fracture develops from the periphery towards the center of the concrete and the ITZ region splits first at similar strain levels, followed by the mortar region and finally the aggregate region. In addition, a simplified modeling scheme with faster computational efficiency and higher accuracy is proposed, which indicates that the shape of the heterogeneous components in concrete has a low effect on mechanical strength. The proposed model can accurately reflect the splitting fracture process of concrete which is instantaneous in the actual process, contributing to the understanding of the mechanism of the splitting fracture process and proposing a new methodology for simulating the fracture process of heterogeneous materials (e.g., concrete, rock). This work contributes to the understanding of the effect of material heterogeneity on concrete’s mechanical behavior and fracturing process and provides valuable hints for the research on the non-destructive prediction of concrete strength.

Abstract Hyperhomocysteinemia (HHcy) is closely associated with thrombotic diseases such as myocardial infarction and stroke. Enhanced platelet activation was observed in animals and humans with HHcy. However, the influence of HHcy on thrombopoiesis remains largely unknown. Here, we reported increased platelet count (PLT) in mice and zebrafish with HHcy. In hypertensive patients (n = 11,189), higher serum level of total Hcy was observed in participants with PLT ≥ 291 × 109/L (full adjusted β, 0.59; 95% CI 0.14, 1.04). We used single-cell RNA sequencing (scRNA-seq) to characterize the impact of Hcy on transcriptome, cellular heterogeneity, and developmental trajectories of megakaryopoiesis from human umbilical cord blood (hUCB) CD34+ cells. Together with in vitro and in vivo analysis, we demonstrated that Hcy promoted megakaryocytes (MKs) differentiation via growth hormone (GH)-PI3K-Akt axis. Moreover, the effect of Hcy on thrombopoiesis is independent of thrombopoietin (TPO) because administration of Hcy also led to a significant increase of PLT in homozygous TPO receptor (Mpl) mutant mice and zebrafish. Administration of melatonin effectively reversed Hcy-induced thrombopoiesis in mice. ScRNA-seq showed that melatonin abolished Hcy-facilitated MK differentiation and maturation, inhibited the activation of GH-PI3K-Akt signaling. Our work reveals a previously unrecognized role of HHcy in thrombopoiesis and provides new insight into the mechanisms by which HHcy confers an increased thrombotic risk. Trial Registration clinicaltrials.gov Identifier: NCT00794885.

Abstract Background Human papillomavirus (HPV) has been proposed as a potential pathogenetic organism involved in prostate cancer (PCa), but the association between HPV infection and relevant genomic changes in PCa is poorly understood. Methods To evaluate the relationship between HPV genotypes and genomic alterations in PCa, HPV capture sequencing of DNA isolated from 59 Han Chinese PCa patients was performed using an Illumina HiSeq2500. Additionally, whole-exome sequencing of DNA from these 59 PCa tissue samples and matched normal tissues was carried out using the BGI DNBSEQ platform. HPV infection status and genotyping were determined, and the genetic disparities between HPV-positive and HPV-negative PCa were evaluated. Results The presence of the high-risk HPV genome was identified in 16.9% of our cohort, and HPV16 was the most frequent genotype detected. The overall mutational burden in HPV-positive and HPV-negative PCa was similar, with an average of 2.68/Mb versus 2.58/Mb, respectively, in the targeted whole-exome region. HPV-negative tumors showed a mutational spectrum concordant with published PCa analyses with enrichment for mutations in SPOP, FOXA1, and MED12. HPV-positive tumors showed more mutations in KMT2C, KMT2D and ERCC2. Copy number alterations per sample were comparable between the two groups. However, the significantly amplified or deleted regions of the two groups only partially overlapped. We identified amplifications in oncogenes, including FCGR2B and CCND1, and deletions of tumor suppressors, such as CCNC and RB1, only in HPV-negative tumors. HPV-positive tumors showed unique deletions of tumor suppressors such as NTRK1 and JAK1. Conclusions The genomic mutational landscape of PCa differs based on HPV infection status. This work adds evidence for the direct involvement of HPV in PCa etiology. Different genomic features render HPV-positive PCa a unique subpopulation that might benefit from virus-targeted therapy.

Abstract Background Cisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy. Results We performed whole exome sequencing (WES) of 156 cervical cancer tissues to assess genomic features related to platinum-based chemoresistance. By using WES, we identified a frequently mutated locus SETD8 (7%), which was associated with drug sensitivity. Cell functional assays, in vivo xenografts tumor growth experiments, and survival analysis were used to investigate the functional significance and mechanism of chemosensitization after SETD8 downregulation. Knockdown of SETD8 increased the responsiveness of cervical cancer cells to cisplatin treatment. The mechanism is exerted by reduced binding of 53BP1 to DNA breaks and inhibition of the non-homologous end joining (NHEJ) repair pathway. In addition, SETD8 expression was positively correlated with resistance to cisplatin and negatively associated with the prognosis of cervical cancer patients. Further, UNC0379 as a small molecule inhibitor of SETD8 was found to enhance cisplatin sensitivity both in vitro and in vivo. Conclusions SETD8 was a promising therapeutic target to ameliorate cisplatin resistance and improve the efficacy of chemotherapy.

Introduction: Reported confirmed cases represent a small portion of overall true cases for many infectious diseases. The undercounting of true cases can be considerable when a significant portion of infected individuals are asymptomatic or minimally symptomatic, as is the case with COVID-19. Seroprevalence studies are an efficient way to assess the extent to which true cases are undercounted during a large-scale outbreak and can inform efforts to improve case identification and reporting. Methods: A longitudinal seroprevalence study of active duty U.S. military members was conducted from May 2020 through June 2021. A random selection of service member serum samples submitted to the Department of Defense Serum Repository was analyzed for the presence of antibodies reactive to SARS-CoV-2. The monthly seroprevalence rates were compared with those of cumulative confirmed cases reported during the study period. Results: Seroprevalence was 2.3% in May 2020 and increased to 74.0% by June 2021. The estimated true case count based on seroprevalence was 9.3 times greater than monthly reported cases at the beginning of the study period and fell to 1.7 by the end of the study. Conclusions: In our sample, confirmed case counts significantly underestimated true cases of COVID-19. The increased availability of testing over the study period and enhanced efforts to detect asymptomatic and minimally symptomatic cases likely contributed to the fall in the seroprevalence to reported case ratio.

Summary: Here, we present a protocol for generating LtCas12a protein recognizing distinct TTNA (N represented A, T, C, G) protospacer adjacent motif sequence. We describe steps for transforming and harvesting bacterial cells and protein purification including nickel affinity chromatography and dialysis. We then detail procedures for verification of LtCas12a with cis- and trans-cleavage activities.For complete details on the use and execution of this protocol, please refer to Chen et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Introduction: Hypertension is a well-known risk factor for aneurysms, as high blood pressure can worsen the development and rupture of aneurysms. Ginsenoside, derived from ginseng and widely used in traditional herbal medicine, is believed to have antihypertensive properties. Recent research has also shown a connection between gut microbiota and various diseases, including hypertension. However, the relationship between ginsenosides, gut microbiota, blood pressure, and intracranial aneurysms needs further exploration.Methods: In this study, a rat model was used to investigate the effects of ginsenosides on both blood pressure and intracranial arteries. Comparative analysis was conducted, and 16S rRNA sequencing was employed to identify marker genera within the gut microbiota. Metabolites were also analyzed to uncover potential mediators of blood pressure regulation.Results and Discussion: The results of this study revealed that ginsenosides, particularly ginsenoside Rb1, demonstrated positive effects in reducing both blood pressure and the development of intracranial aneurysms in rats. Furthermore, the analysis of gut microbiota showed that certain genera, including Clostridium, Roseburia, Ruminococcus, and Treponema, were significantly influenced by ginsenoside treatment. Several metabolites, such as behenic acid, N-Acetylserotonin, Prostaglandin F2a, and Vitamin D2, were also detected, all of which play a role in regulating blood pressure. These findings provide valuable insights into the potential benefits of ginsenosides in hypertension and atheroma development. Furthermore, they suggest a possible link between ginsenosides, gut microbiota, and blood pressure regulation. Further research is needed to fully understand the mechanisms underlying these effects and to determine the clinical implications for treating hypertension and reducing the risk of aneurysm development.

Objectives This study aimed to clarify the relationship between white blood cell (WBC) and adverse pregnancy outcomes.Design A total of 25 270 pregnant women underwent peripheral blood white blood cell count tests in the first, second and third trimesters. Adverse pregnancy outcomes were gestational hypertension, pre-eclampsia, gestational diabetes mellitus, preterm birth, low birth weight, caesarean delivery, macrosomia and fetal distress. Due to acute infectious disease or other diseases, 1127 were excluded.Setting Minhang Hospital, China.Participants A total of 24 143 pregnant women were included in this study.Primary and secondary outcome measures The primary outcome was the adverse pregnancy outcomes.Results For the 24 143 participants, we calculated adjusted ORs for adverse pregnancy outcomes associated with an increased WBC count. For gestational hypertension, the ORs were 1.18 (95% CI, 1.05 to 1.24) in the first trimester and 1.10 (1.06 to 1.13) in the second trimester; for pre-eclampsia, ORs were 1.14 (95% CI, 1.47 to 1.64) in the first trimester and 1.10 (1.05 to 1.16) in the second trimester; for gestational diabetes mellitus, ORs were 1.06 (95% CI, 1.00 to 1.13) in the first trimester and 1.10 (1.04 to 1.16) in the second trimester; for preterm birth, ORs were 1.12 (95% CI, 1.06 to 1.18) in the first trimester, 1.10 (1.06 to 1.13) in the second trimester and 1.12 (1.09 to 1.15) in the third trimester; for low birth weight, ORs were 1.09 (95% CI, 1.02 to 1.17) in the first trimester, 1.03 (0.99 to 1.08) in the second trimester and 1.12 (1.08 to 1.16) in the third trimester. Significant associations were not observed obviously for caesarean delivery, macrosomia and fetal distress.Conclusions Our results indicate strong, continuous associations of maternal WBC count with increased risks of adverse pregnancy outcomes.

Background: Semantic segmentation is crucial in medical image diagnosis. Traditional deep convolutional neural networks excel in image classification and object detection but fall short in segmentation tasks. Enhancing the accuracy and efficiency of detecting high-level cervical lesions and invasive cancer poses a primary challenge in segmentation model development. Methods: Between 2018 and 2022, we retrospectively studied a total of 777 patients, comprising 339 patients with high-level cervical lesions and 313 patients with microinvasive or invasive cervical cancer. Overall, 1554 colposcopic images were put into the DeepLabv3+ model for learning. Accuracy, Precision, Specificity, and mIoU were employed to evaluate the performance of the model in the prediction of cervical high-level lesions and cancer. Results: Experiments showed that our segmentation model had better diagnosis efficiency than colposcopic experts and other artificial intelligence models, and reached Accuracy of 93.29 %, Precision of 87.2 %, Specificity of 90.1 %, and mIoU of 80.27 %, respectively. Conclution: The DeepLabv3+ model had good performance in the segmentation of cervical lesions in colposcopic post-acetic-acid images and can better assist colposcopists in improving the diagnosis.

Abstract With the rapid development of cloud computing technology, how to achieve secure access to cloud data has become a current research hotspot. Attribute-based encryption technology provides the feasibility to achieve the above goal. However, most of the existing solutions have high computational and trust costs. Furthermore, the fairness of access authorization and the security of data search can be difficult to guarantee. To address these issues, we propose a novel access control scheme based on blockchain and attribute-based searchable encryption in cloud environment. The proposed scheme achieves fine-grained access control with low computation consumption by implementing proxy encryption and decryption, while supporting policy hiding and attribute revocation. The encrypted file is stored in the IPFS and the metadata ciphertext is stored on the blockchain, which ensures data integrity and confidentiality. Simultaneously, the scheme enables the secure search of ciphertext keyword in an open and transparent blockchain environment. Additionally, an audit contract is designed to constrain user access behavior to dynamically manage access authorization. Security analysis proves that our scheme is resistant to chosen-plaintext attacks and keyword-guessing attacks. Theoretical analysis and experimental results show that our scheme has high computational and storage efficiency, which is more advantageous than other schemes.

GRIN2A is associated with epilepsy (EP); however, its regulatory mechanism involving upstream miRNA (miR-30b-5p) has been overlooked. In this study, we aimed to identify the regulatory mechanism of the miR-30b-5p/GRIN2A axis in EP. Hippocampal neurons isolated from mice were incubated in magnesium-free medium for 48 h to establish an in vitro EP model. An in vivo model of EP was constructed by the intraperitoneal injection of atropine into mice. Nissl staining and hematoxylin and eosin staining were used to evaluate pathological injuries in the hippocampal CA1 regions of mice. The CCK8 assay confirmed that miR-30b-5p overexpression restored the suppressed proliferative capacity of hippocampal neurons exposed to magnesium-free conditions. Caspase-3 activity assay revealed that miR-30b-5p overexpression abrogated the increased apoptosis of hippocampal neurons under magnesium-free conditions. In an in vivo model of EP, miR-30b-5p overexpression reversed pathological injuries in the hippocampal CA1 regions of mice and abrogated the increased apoptosis in the EP mouse model. Luciferase assays and western blotting confirmed that miR-30b-5p targeted GRIN2A, thereby inhibiting GRIN2A expression. Overall, miR-30b-5p can protect against cell proliferation and attenuate apoptosis in hippocampal neurons under magnesium-free conditions by targeting GRIN2A.

Key points TLR9 is not only a prognostic biomarker but also a potential target for B-ALL therapy. C-MYC-mediated BAX activation leads to CpG 685-induced apoptosis in B-ALL.

The intricacies of foundation pit engineering often result in alterations to the surrounding environment, posing potential threats to the safe operation of nearby buildings and pile foundations. This study employs finite element numerical simulation to scrutinize the influence of vacuum preloading pressure, preloading duration, excavation slope ratio, excavation duration, and retaining pile wall depth on the stress and deformation of existing plain concrete pile foundations. The findings reveal that the impacts of excavation are primarily absorbed by both proximal and distal piles in relation to the pit. Moreover, elevating vacuum preloading pressure and extending the preloading duration during dewatering can lead to increased internal forces and displacement of the piles. Changes in excavation slope ratio exhibit minimal effects, while prolonged excavation duration can shift internal forces from predominantly positive to negative, with negligible impact on horizontal displacement. Importantly, augmenting the depth of the retaining pile wall embedding effectively mitigates the effects of pit excavation.

Hematological malignancy is a disease arisen by complicate reasons that seriously endangers human health. The research on its pathogenesis and therapies depends on the usage of animal models. Conventional animal model cannot faithfully mirror some characteristics of human features due to the evolutionary divergence, whereas the mouse models hosting human hematological malignancy are more and more applied in basic as well as translational investigations in recent years. According to the construction methods, they can be divided into different types (e.g. cell-derived xenograft (CDX) and patient-derived xenograft model (PDX) model) that have diverse characteristics and application values. In addition, a variety of strategies have been developed to improve human hematological malignant cell engraftment and differentiation in vivo. Moreover, the humanized mouse model with both functional human immune system and autologous human hematological malignancy provides a unique tool for the evaluation of the efficacy of novel immunotherapeutic drugs/approaches. Herein, we first review the evolution of the mouse model of human hematological malignancy; Then, we analyze the characteristics of different types of models and summarize the ways to improve the models; Finally, the way and value of humanized mouse model of human immune system in the immunotherapy of human hematological malignancy are discussed.

Summary: Cisplatin resistance remains a major obstacle limiting the effectiveness of chemotherapy in cervical cancer. However, the underlying mechanism of cisplatin resistance is still unclear. In this study, we demonstrate that vacuolar protein sorting 13 homolog C (VPS13C) deficiency promotes cisplatin resistance in cervical cancer. Moreover, through an RNA sequencing screen, VPS13C deficiency was identified as negatively correlated with the high expression of glutathione S-transferase pi gene (GSTP1). Mechanistically, loss of VPS13C contributes to cisplatin resistance by influencing the expression of GSTP1 and inhibiting the downstream c-Jun N-terminal kinase (JNK) pathway. In addition, targeting GSTP1 with the inhibitor NBDHEX effectively rescued the cisplatin resistance induced by VPS13C deficiency. Overall, our findings provide insights into the underlying mechanisms of VPS13C in cisplatin resistance and identify VPS13C as a promising candidate for the treatment of chemoresistance in cervical cancer.

G2/M arrest of epithelial cells leads to fibrosis with unclear mechanisms. This study identifies a protein-encoding circRNA, circBNC2, which inhibits epithelial cells G2/M arrest to prevent fibrotic maladaptive repair in damaged kidney and liver, revealing a potential intervention target for fibrosis.

Rice bean is an underexploited legume crop that has many desirable properties against bio and abiotic stresses. Here, the authors report the genome assembly of this species, conduct population genetics studies and reveal the genetic variations associated with adaptation and yield traits.

Natural soil in geotechnical engineering is commonly in the anisotropic stress state, but the effect of stress anisotropy on soil suffusion remains unclear. In this study, the coupled computational fluid dynamics–discrete element method was utilised to simulate the complete suffusion process of gap-graded soils by introducing a vertical seepage flow through the soil assembly. The mechanical consequences of suffusion on gap-graded soils were evaluated by comparing the triaxial shear responses of soil specimens before and after suffusion. The results indicated that the specimens with greater stress anisotropy are more vulnerable to suffusion, particularly those with the principal stress that is coincident with the principal flow direction. Compared with the isotropically consolidated specimens, the specimens with greater stress anisotropy exhibited more pronounced reduction in shear strength and secant stiffness after suffusion. The effects of stress anisotropy on the suffusion and mechanical properties of gap-graded soils were also evaluated from a microcosmic perspective in terms of force chain, coordination number, and fabric tensor.

To improve the biosafety of the nanodelivery system, this study developed novel monodisperse spherical aluminum nanoparticles (Al NPs) and evaluated their cytotoxicity in vitro and distribution and biotoxicity in vivo. Compared with gold nanoparticles of the same size, Al NPs not only had low cytotoxicity in vitro but also did not cause accumulation in major organs in vivo after intravenous injections. No significant abnormalities were observed in the serum biochemical indices of mice injected with Al NPs. Additionally, no substantial changes occurred in the histopathology of major organs, and no apparent biological toxicity was measured after consecutive injections of Al NPs. These results indicate that Al NPs have a good biological safety and provide a new method for developing low-toxicity nanomedicine.

A genome editing tool targeting the high-risk human papillomavirus (HPV) oncogene is a promising therapeutic strategy to treat HPV-related cervical cancer. To improve gene knockout efficiency, we developed a gene knockout chain reaction (GKCR) method for continually generating mutagenic disruptions and used this method to disrupt the HPV18 E6 and E7 genes. We verified that the GKCR Cas9/guide RNA (gRNA) cassettes could integrated into the targeted loci via homology-independent targeted insertion (HITI). The qPCR results revealed that the GKCR method enabled a relatively higher Cas9/gRNA cassette insertion rate than a control method (the common CRISPR-Cas9 strategy). Tracking of Indels by DEcomposition (TIDE) assay results showed that the GKCR method produced a significantly higher percentage of insertions or deletions (indels) in the HPV18 E6 and E7 genes. Furthermore, by targeting the HPV18 E6/E7 oncogenes, we found that the GKCR method significantly upregulated the P53/RB proteins and inhibited the proliferation and motility of HeLa cells. The GKCR method significantly improved the gene knockout efficiency of the HPV18 E6/E7 oncogenes, which might provide new insights into treatment of HPV infection and related cervical cancer.

Abstract Background Graft-versus-host disease (GVHD) is a common fatal complication of hematopoietic stem cell transplantation (HSCT), where steroids are used as a treatment option. However, there are currently no second-line treatments for patients that develop steroid-resistance (SR). Mesenchymal stem cells (MSCs) have immunomodulatory functions and can exert immunosuppressive effects on the inflammatory microenvironment. A large number of in vitro experiments have confirmed that MSCs can significantly inhibit the proliferation or activation of innate and adaptive immune cells. In a mouse model of GVHD, MSCs improved weight loss and increased survival rate. Therefore, there is great promise for the clinical translation of MSCs for the prevention or treatment of GVHD, and several clinical trials have already been conducted to date. Main body In this study, we searched multiple databases and found 79 clinical trials involving the use of MSCs to prevent or treat GVHD and summarized the characteristics of these clinical trials, including study design, phase, status, and locations. We analyzed the results of these clinical trials, including the response and survival rates, to enable researchers to obtain a comprehensive understanding of the field’s progress, challenges, limitations, and future development trends. Additionally, factors that might result in inconsistencies in clinical trial results were discussed. Conclusion In this study, we attempted to analyze the clinical trials for MSCs in GVHD, identify the most suitable group of patients for MSC therapy, and provide a new perspective for the design of such trials in the future.

Abstract Background Mice with humanized livers are important models to study drug toxicology testing, development of hepatitis virus treatments, and hepatocyte transplantation therapy. However, the huge difference between mouse and human in size and anatomy limited the application of humanized mice in investigating human diseases. Therefore, it is urgent to construct humanized livers in pigs to precisely investigate hepatocyte regeneration and human hepatocyte therapy. CRISPR/Cas9 system and somatic cell cloning technology were used to generate two pig models with FAH deficiency and exhibiting severe immunodeficiency (FAH/RAG1 and FAH/RAG1/IL2RG deficiency). Human primary hepatocytes were then successfully transplanted into the FG pig model and constructed two pigs with human liver. Results The constructed FAH/RAG1/IL2RG triple-knockout pig models were characterized by chronic liver injury and severe immunodeficiency. Importantly, the FG pigs transplanted with primary human hepatocytes produced human albumin in a time dependent manner as early as 1 week after transplantation. Furthermore, the colonization of human hepatocytes was confirmed by immunochemistry staining. Conclusions We successfully generated pig models with severe immunodeficiency that could construct human liver tissues.

Gene editing tools have tremendous potential for biomedical and basic research. Here the authors report a Cas9 from Faecalibaculum rodentium (FrCas9) that achieves efficient and specific gene editing in human cells with a NNTA palindrome PAMs for targeting optimal sites at TATA-boxes to enhance CRISPRa/i screening.

Sonodynamic therapy (SDT) induces reactive oxygen species (ROS) to kill tumor cells. Heme oxygenase-1 (HO-1), as an important antioxidant enzyme, resists killing by scavenging ROS. Zinc protoporphyrin (ZnPP) not only effectively inhibits HO-1 activity, but also becomes a potential sonosensitizer. However, its poor water solubility limits its applications. Herein, we developed an improved water-soluble method. It was proved that pegylated zinc protoporphyrin-mediated SDT (PEG-ZnPP-SDT) could significantly enhance ROS production by destroying the HO-1 antioxidant system in ovarian cancer. Increased ROS could cause mitochondrial membrane potential collapse, release cytochrome c from mitochondria to the cytoplasm, and trigger the mitochondrial–caspase apoptotic pathway. In conclusion, our results demonstrated that PEG-ZnPP-SDT, as a novel sonosensitizer, could improve the antitumor effects by destroying the HO-1 antioxidant system. It provided a new therapeutic strategy for SDT to treat cancers, especially those with higher HO-1 expression.

Plant-derived preservatives exhibit excellent antifungal effects. However, their antifungal active ingredients can easily leach out. A properly designed functional response system can help realize the responsive release of preservatives and reduce leaching. Herein, the pH-responsive preservatives delivery system was designed and synthesized. The preservative (Forsythia) was encapsulated with hollow mesoporous organosilica nanoparticles (HMONs), and carbon quantum dots (CQDs) were employed as mesoporous plugging agents. Forsythia’s release was achieved by grafting pH-sensitive chemical bonds on the surface of the carrier. X-ray photoelectron spectroscopy and antifungal results showed that the pH-responsive switch was successfully broken. After 12 weeks of soil-jar incubation, the weight loss rate of treated wood was 2 % ± 0.5 %. The leaching of Forsythia–HMON–CQDs was lower than that of Forsythia under the same concentration. The design of the system reduced the leaching of Forsythia and extended the service life of wood. In addition, the system was also applicable to ammoniacal copper quat (ACQ). Forsythia–HMON–CQDs showed an outstanding fixation effect and antifungal ability, and its fluorescence can be used to track distribution in wood. This system can be extensively employed in protecting antifungal active ingredients and demonstrates an effective strategy for developing potential bio-based wood preservatives.

Zinc-finger nucleases (ZFNs), transcription activator-like endonucleases (TALENs), and CRISPR-associated Cas9 endonucleases are three major generations of genome editing tools. However, no parallel comparison about the efficiencies and off-target activity of the three nucleases has been reported, which is critical for the final clinical decision. We for the first time developed the genome-wide unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) method in ZFNs and TALENs with novel bioinformatics algorithms to evaluate the off-targets. By targeting human papillomavirus 16 (HPV16), we compared the performance of ZFNs, TALENs, and SpCas9 in vivo. Our data showed that ZFNs with similar targets could generate distinct massive off-targets (287–1,856), and the specificity could be reversely correlated with the counts of middle “G” in zinc finger proteins (ZFPs). We also compared the TALENs with different N-terminal domains (wild-type [WT]/αN/βN) and G recognition modules (NN/NH) and found the design (αN or NN) to improve the efficiency of TALEN inevitably increased off-targets. Finally, our results showed that SpCas9 was more efficient and specific than ZFNs and TALENs. Specifically, SpCas9 had fewer off-target counts in URR (SpCas9, n = 0; TALEN, n = 1; ZFN, n = 287), E6 (SpCas9, n = 0; TALEN, n = 7), and E7 (SpCas9, n = 4; TALEN, n = 36). Taken together, we suggest that for HPV gene therapies, SpCas9 is a more efficient and safer genome editing tool. Our off-target data could be used to improve the design of ZFNs and TALENs, and the universal in vivo off-target detection pipeline for three generations of artificial nucleases provided useful tools for genome engineering-based gene therapy.

Abstract Background UCA1 is frequently upregulated in a variety of cancers, including CRC, and it can play an oncogenic role by various mechanisms. However, how UCA1 is regulated in cancer is largely unknown. In this study, we aimed to determine whether RNA methylation at N6-methyladenosine (m6A) can impact UCA1 expression in colorectal cancer (CRC). Methods qRT-PCR was performed to detect the level of UCA1 and IGF2BP2 in CRC samples. CRISPR/Cas9 was employed to knockout (KO) UCA1, METTL3 and WTAP in DLD-1 and HCT-116 cells, while rescue experiments were carried out to re-express METTL3 and WTAP in KO cells. Immunoprecipitation using m6A antibody was performed to determine the m6A modification of UCA1. In vivo pulldown assays using S1m tagging combined with site-direct mutagenesis was carried out to confirm the recognition of m6A-modified UCA1 by IGF2BP2. Cell viability was measured by MTT and colony formation assays. The expression of UCA1 and IGF2BP2 in TCGA CRC database was obtained from GEPIA ( http://gepia.cancer-pku.cn ). Results Our results revealed that IGF2BP2 serves as a reader for m6A modified UCA1 and that adenosine at 1038 of UCA1 is critical to the recognition by IGF2BP2. Importantly, we showed that m6A writers, METTL3 and WTAP positively regulate UCA1 expression. Mechanically, IGF2BP2 increases the stability of m6A-modified UCA1. Clinically, IGF2BP2 is upregulated in CRC tissues compared with normal tissues. Conclusion These results suggest that m6A modification is an important factor contributing to upregulation of UCA1 in CRC tissues.

Background: Trimethylamine-N-oxide (TMAO) is an intestinal metabolic toxin, which is produced by gut flora via metabolizing high-choline foods. TMAO is known to increase the risk of atherosclerosis and cardiovascular events in chronic kidney disease (CKD) patients. Objectives: The objective of this study was to explore the role and mechanism of TMAO aggravating kidney injury. Method: We used the five-sixths nephrectomy (5/6 Nx)-induced CKD rats to investigate whether TMAO could aggravate kidney damage and its possible mechanisms. Six weeks after the operation, the two groups of 5/6 Nx rats were subjected to intraperitoneal injection with 2.5% glucose peritoneal dialysis fluid (2.5% PDF) and 2.5% PDF plus TMAO 20 mg/kg/day. Results: In this study, we provided evidence showing TMAO significantly aggravated renal failure as well as inflammatory cell infiltration and in five-sixths nephrectomy-induced CKD rats. We found that TMAO could upregulate inflammatory factors including MCP-1, TNF-α, IL-6, IL-1β, and IL-18 by activating p38 phosphorylation and upregulation of human antigen R. TMAO could aggravate oxidative stress by upregulating NOX4 and downregulating SOD. The result also confirmed that TMAO promoted NLRP3 inflammasome formation as well as cleaved caspase-1 and IL-1β activation in the kidney tissue. Conclusions: Taken together, the present study validates TMAO as a pro-inflammatory factor that causes renal inflammatory injury and renal function impairment. Inhibition of TMAO synthesis or promoting its clearance may be a potential therapeutic approach of CKD in the future.

Summary: Background: The role of the IL6 family members in organ fibrosis, including renal interstitial fibrosis (TIF), has been widely explored. However, few studies have ever simultaneously examined them in the same cohort of patients. Besides, the role of leukemia inhibitory factor (LIF) in TIF remains unclear. Methods: RNA-seq data of kidney biopsies from chronic kidney disease (CKD) patients, in both public databases and our assays, were used to analyze transcript levels of IL6 family members. Two TIF mouse models, the unilateral ureteral obstruction (UUO) and the ischemia reperfusion injury (IRI), were employed to validate the finding. To assess the role of LIF in vivo, short hairpin RNA, lenti-GFP-LIF was used to knockdown LIF receptor (LIFR), overexpress LIF, respectively. LIF-neutralizing antibody was used in therapeutic studies. Whether urinary LIF could be used as a promising predictor for CKD progression was investigated in a prospective observation patient cohort. Findings: Among IL6 family members, LIF is the most upregulated one in both human and mouse renal fibrotic lesions. The mRNA level of LIF negatively correlated with eGFR with the strongest correlation and the smallest P value. Baseline urinary concentrations of LIF in CKD patients predict the risk of CKD progression to end-stage kidney disease by Kaplan–Meier analysis. In mouse TIF models, knockdown of LIFR alleviated TIF; conversely, overexpressing LIF exacerbated TIF. Most encouragingly, visible efficacy against TIF was observed by administering LIF-neutralizing antibodies to mice. Mechanistically, LIF–LIFR-EGR1 axis and Sonic Hedgehog signaling formed a vicious cycle between fibroblasts and proximal tubular cells to augment LIF expression and promote the pro-fibrotic response via ERK and STAT3 activation. Interpretation: This study discovered that LIF is a noninvasive biomarker for the progression of CKD and a potential therapeutic target of TIF. Fundings: Stated in the Acknowledgements section of the manuscript.

Chronic kidney disease (CKD) is a global public health problem that shortens lifespan primarily by increasing the risk of cardiovascular diseases. Trimethylamine-N-oxide (TMAO), a gut microbiota-derived toxin produced by metabolizing high-choline or carnitine foods, is associated with cardiovascular events in patients with CKD. Although the deleterious effect of TMAO on CKD-induced cardiac injury has been confirmed by various researches, the mechanisms remain unclear. Here, we tested the hypothesis that TMAO aggravates CKD-induced cardiac injury and explores the potential mechanism. CD1 mice underwent 5/6 nephrectomy to induce CKD, and then fed with a diet supplemented with choline (1.2% total) for 8 weeks. Serum TMAO levels were elevated in CKD mice compared with SHAM group, and higher TMAO levels were found in choline-supplemented CKD mice compared with CKD group. Dietary choline aggravated CKD-induced cardiac dysfunction, and reducing TMAO levels via medicinal charcoal tablets improved cardiac dysfunction. RNA-seq analysis revealed that dietary choline affected cardiac angiogenesis in CKD mice. Reduced cardiac capillary density and expressions of angiogenesis-related genes were observed in choline-treated CKD mice. Furthermore, dietary choline inhibited cardiac Hif-1α protein level in CKD mice, and Hif-1α stabilizer FG-4592 could improve cardiac angiogenesis and dysfunction in CKD mice on a high-choline diet. In conclusion, these data indicate that dietary choline, via gut microbe-generated TMAO, inhibits cardiac angiogenesis by reducing Hif-1α protein level, ultimately aggravates cardiac dysfunction in CKD mice.

Abstract Background Aberrant expression of Aldo-Keto reductase family 1 member B10 (AKR1B10) was associated with tumor size and metastasis of breast cancer in our published preliminary studies. However, little is known about the detailed function and underlying molecular mechanism of AKR1B10 in the pathological process of breast cancer. Methods The relationship between elevated AKR1B10 expression and the overall survival and disease-free survival of breast cancer patients was analyzed by Kaplan–Meier Plotter database. Breast cancer cell lines overexpressing AKR1B10 (MCF-7/AKR1B10) and breast cancer cell lines with knockdown of AKR1B10 (BT-20/shAKR1B10) were constructed to analyze the impact of AKR1B10 expression on cell proliferation and migration of breast cancer. The expression levels of AKR1B10 were detected and compared in the breast cancer cell lines and tissues by RT-qPCR, western blot and immunohistochemistry. The proliferation of breast cancer cells was monitored by CCK8 cell proliferation assay, and the migration and invasion of breast cancer cells was observed by cell scratch test and transwell assay. The proliferation- and EMT-related proteins including cyclinD1, c-myc, Survivin, Twist, SNAI1, SLUG, ZEB1, E-cadherin, PI3K, p-PI3K, AKT, p-AKT, IKBα, p-IKBα, NF-κB p65, p-NF-κB p65 were detected by western blot in breast cancer cells. MCF-7/AKR1B10 cells were treated with LY294002, a PI3K inhibitor, to consider the impact of AKR1B10 overexpression on the PI3K/AKT/NF-κB signal cascade and the presence of NF-κB p65 in nuclear. In vivo tumor xenograft experiments were used to observe the role of AKR1B10 in breast cancer growth in mice. Results AKR1B10 expression was significantly greater in breast cancer tissue compared to paired non-cancerous tissue. The expression of AKR1B10 positively correlated with lymph node metastasis, tumor size, Ki67 expression, and p53 expression, but inversely correlated with overall and disease-free survival rates. Gene Ontology analysis showed that AKR1B10 activity contributes to cell proliferation. Overexpression of AKR1B10 facilitated the proliferation of MCF-7 cells, and induced the migration and invasion of MCF-7 cells in vitro in association with induction of epithelial-mesenchymal transition (EMT). Conversely, knockdown of AKR1B10 inhibited these effects in BT-20 cells. Mechanistically, AKR1B10 activated PI3K, AKT, and NF-κB p65, and induced nuclear translocation of NF-κB p65, and expression of proliferation-related proteins including c-myc, cyclinD1, Survivin, and EMT-related proteins including ZEB1, SLUG, Twist, but downregulated E-cadherin expression in MCF-7 cells. AKR1B10 silencing reduced the phosphorylation of PI3K, AKT, and NF-κB p65, the nuclear translocation of NF-κB p65, and the expression of proliferation- and migration-related proteins in BT-20 cells. LY294002, a PI3K inhibitor, attenuated the phosphorylation of PI3K, AKT, and NF-κB p65, and the nuclear translocation of NF-κB p65. In vivo tumor xenograft experiments confirmed that AKR1B10 promoted breast cancer growth in mice. Conclusions AKR1B10 promotes the proliferation, migration and invasion of breast cancer cells via the PI3K/AKT/NF-κB signaling pathway and represents a novel prognostic indicator as well as a potential therapeutic target in breast cancer.

In utero hematopoietic cell transplantation (IUHCT) is considered a potentially efficient therapeutic approach with relatively few side effects, compared to adult hematopoietic cell transplantation, for various hematological genetic disorders. The principle of IUHCT has been extensively studied in rodent models and in some large animals with close evolutionary similarities to human beings. However, IUHCT has only been used to rebuild human T cell immunity in certain patients with inherent immunodeficiencies. This review will first summarize the animal models utilized for IUHCT investigations and describe the associated outcomes. Recent advances and potential barriers for successful IUHCT are discussed, followed by possible strategies to overcome these barriers experimentally. Lastly, we will outline the progress made towards utilizing IUHCT to treat inherent disorders for patients, list out associated limitations and propose feasible means to promote the efficacy of IUHCT clinically.

Abstract Background The hepatitis B virus (HBV) is one of the main causes of viral hepatitis and liver cancer. HBV integration is one of the key steps in the virus-promoted malignant transformation. Results An attention-based deep learning model, DeepHBV, was developed to predict HBV integration sites. By learning local genomic features automatically, DeepHBV was trained and tested using HBV integration site data from the dsVIS database. Initially, DeepHBV showed an AUROC of 0.6363 and an AUPR of 0.5471 for the dataset. The integration of genomic features of repeat peaks and TCGA Pan-Cancer peaks significantly improved model performance, with AUROCs of 0.8378 and 0.9430 and AUPRs of 0.7535 and 0.9310, respectively. The transcription factor binding sites (TFBS) were significantly enriched near the genomic positions that were considered. The binding sites of the AR-halfsite, Arnt, Atf1, bHLHE40, bHLHE41, BMAL1, CLOCK, c-Myc, COUP-TFII, E2A, EBF1, Erra, and Foxo3 were highlighted by DeepHBV in both the dsVIS and VISDB datasets, revealing a novel integration preference for HBV. Conclusions DeepHBV is a useful tool for predicting HBV integration sites, revealing novel insights into HBV integration-related carcinogenesis.

According to the requirements of the aerospace industry for high strength, high stiffness, and lightweight structural parts, topology optimization has been proved to be an effective product design method. As one of the most conceptual and prospective structural optimization design methods, topology optimization intends to seek the optimal layout of materials in an allowed design region under a given load and boundary conditions. Thus, the object of study in the article is the method of topological optimization of aircraft structures. The goal of this article is to analyze the existing approaches, algorithms, as well as application of the method of topological optimization in the aerospace field in applied problems. The tasks are to describe the existing various approaches methods, features, and research directions of topological optimization as well as to study the possibility of application in the manufacturing process of composite structures. The following results were obtained. The optimization methods are briefly explained and compared, and the advantages and limitations of each approach are discussed. The various ways of simultaneous optimization of fiber orientation and structural topology were described and analyzed. The features of different methods of continuous fiber orientation optimization method were reviewed. The discrete fiber orientation optimization methods were represented. The possibility of multi-scale concurrent topological optimization was described. The combination of topology optimization and additive manufacturing was considered. Finally, the topology optimization of FRC structures which have been resolved in literature are reviewed and the potential research fields requiring more investigation are pointed out. Conclusions. In the article, a comprehensive review of the topology optimization design of FRC structures was presented. The promising way is to combine topology optimization with additive manufacturing techniques. However, these proposed methods may not suitable for other more complex problems, such as bucking stability and natural frequency. Hence, the topology optimization design of complex FRC components under complicated conditions is the main challenge in the future. This can be a new trend in the topology design of FRC structures.

Abstract Lithium‐metal anodes suffer from inadequate rate and cycling performances for practical application mainly due to the harmful dendrite growth, especially at high currents. Herein a facile construction of the porous and robust network with thermally conductive AlN nanowires onto the commercial polypropylene separator by convenient vacuum filtration is reported. The so‐constructed AlN‐network shield provides a uniform thermal distribution to realize homogeneous Li deposition, super electrolyte‐philic channels to enhance Li‐ion transport, and also a physical barrier to resist dendrite piercing as the last fence. Consequently, the symmetric Li|Li cell presents an ultralong lifetime over 8000 h (20 mA cm−2, 3 mAh cm−2) and over 1000 h even at an unprecedented high rate (80 mA cm−2, 80 mAh cm−2), which is far surpassing the corresponding performances reported to date. The corresponding Li|LiFePO4 cell delivers a high specific capacity of 84.3 mAh g−1 at 10 C. This study demonstrates an efficient approach with great application potential toward durable and high‐power Li–metal batteries and even beyond.

Uterine natural killer (uNK) cells are an immune subset located in the uterus. uNK cells have distinct tissue-specific characteristics compared to their counterparts in peripheral blood and lymphoid organs. Based on their location and the pregnancy status of the host, uNK cells are classified as endometrial NK (eNK) cells or decidua NK (dNK) cells. uNK cells are important in protecting the host from pathogen invasion and contribute to a series of physiological processes that affect successful pregnancy, including uterine spiral artery remodeling, fetal development, and immunity tolerance. Abnormal alterations in uNK cell numbers and/or impaired function may cause pregnancy complications, such as recurrent miscarriage, preeclampsia, or even infertility. In this review, we introduce recent advances in human uNK cell research under normal physiological or pathological conditions, and summarize their unique influences on the process of pregnancy complications or uterine diseases. Finally, we propose the potential clinical use of uNK cells as a novel cellular immunotherapeutic approach for reproductive disorders.

Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ injury occurring due to endothelial cell damage and microthrombi formation in small vessels. TMA is primary when a genetic or acquired defect is identified, as in atypical hemolytic uremic syndrome (aHUS) or secondary when occurring in the context of another disease process such as infection, autoimmune disease, malignancy or drugs. Differentiating between a primary complement-mediated process and one triggered by secondary factors is critical to initiate timely treatment but can be challenging for clinicians, especially after a kidney transplant due to presence of multiple confounding factors. Similarly, primary membranous nephropathy is an immune-mediated glomerular disease associated with circulating autoantibodies (directed against the M-type phospholipase A2 receptor (PLA2R) in 70% cases) while secondary membranous nephropathy is associated with infections, drugs, cancer, or other autoimmune diseases. Complement activation has also been proposed as a possible mechanism in the etiopathogenesis of primary membranous nephropathy; however, despite complement being a potentially common link, aHUS and primary membranous nephropathy have not been reported together. Herein we describe a case of aHUS due to a pathogenic mutation in complement factor I that developed after a kidney transplant in a patient with an underlying diagnosis of PLA2R antibody associated-membranous nephropathy. We highlight how a systematic and comprehensive analysis helped to define the etiology of aHUS, establish mechanism of disease, and facilitated timely treatment with eculizumab that led to recovery of his kidney function. Nonetheless, ongoing anti-complement therapy did not prevent recurrence of membranous nephropathy in the allograft. To our knowledge, this is the first report of a patient with primary membranous nephropathy and aHUS after a kidney transplant.