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Abstract MicroRNAs (miRNAs) have been demonstrated to be closely related to human diseases. Studying the potential associations between miRNAs and diseases contributes to our understanding of disease pathogenic mechanisms. As traditional biological experiments are costly and time-consuming, computational models can be considered as effective complementary tools. In this study, we propose a novel model of robust orthogonal non-negative matrix tri-factorization (NMTF) with self-paced learning and dual hypergraph regularization, named SPLHRNMTF, to predict miRNA-disease associations. More specifically, SPLHRNMTF first uses a non-linear fusion method to obtain miRNA and disease comprehensive similarity. Subsequently, the improved miRNA-disease association matrix is reformulated based on weighted k-nearest neighbor profiles to correct false-negative associations. In addition, we utilize $$L_{2,1}$$ L 2 , 1 norm to replace Frobenius norm to calculate residual error, alleviating the impact of noise and outliers on prediction performance. Then, we integrate self-paced learning into NMTF to alleviate the model from falling into bad local optimal solutions by gradually including samples from easy to complex. Finally, hypergraph regularization is introduced to capture high-order complex relations from hypergraphs related to miRNAs and diseases. In 5-fold cross-validation five times experiments, SPLHRNMTF obtains higher average AUC values than other baseline models. Moreover, the case studies on breast neoplasms and lung neoplasms further demonstrate the accuracy of SPLHRNMTF. Meanwhile, the potential associations discovered are of biological significance.

Abstract Background Sterigmatocystin (STE) is a mycotoxin widely found in contaminated food and foodstuffs, and excessive long-term exposure to STE is associated with several health issues, including infertility. However, there is little information available regarding the effects of STE toxin on the female reproductive system, particularly concerning oocyte maturation. Methods In the present study, we investigated the toxic effects of STE on mouse oocyte maturation. We also used Western blot, immunofluorescence, and image quantification analyses to assess the impact of STE exposure on the oocyte maturation progression, mitochondrial distribution, oxidative stress, DNA damages, oocyte ferroptosis and asymmetric division defects. Results Our results revealed that STE exposure disrupted mouse oocyte maturation progression. When we examined the cellular changes following 100 µM STE treatment, we found that STE adversely affected polar body extrusion and induced asymmetric division defects in oocytes. RNA-sequencing data showed that STE exposure affects the expression of several pathway-correlated genes during oocyte meiosis in mice, suggesting its toxicity to oocytes. Based on the RNA-seq data, we showed that STE exposure induced oxidative stress and caused DNA damage in oocytes. Besides, ferroptosis and α-tubulin acetylation were also found in STE-exposed oocytes. Moreover, we determined that STE exposure resulted in reduced RAF1 protein expression in mouse oocytes, and inhibition of RAF1 activity also causes defects in asymmetric division of mouse oocytes. Conclusions Collectively, our research provides novel insights into the molecular mechanisms whereby STE contributes to abnormal meiosis.

Introduction: Polymyxin B is widely used to treat infections caused by multidrug-resistant Gram-negative bacteria. However, the pharmacokinetic study data of PB in the elderly are scarce. Herein, a simple method to measure the concentration of PB in human plasma was developed and validated by high performance liquid chromatography—tandem mass spectrometry, and it was applied to a PK study in the elderly.Methods: PB was extracted from human plasma by a rapid protein-precipitation method using 0.1% formic acid in methanol and then separated on an ultimate AQ-C18 column using linear gradient elution with a 0.5-mL/min flow rate. Subsequently, PB was detected using a mass spectrometer operated in positive-ion and multiple-reaction-monitoring modes.Results: The lower limits of quantification of the method for Polymyxin B1 and Polymyxin B2 were 1.00 and 0.10 μg/mL, respectively. The linear ranges for PB1 and PB2 were 1.00–20.02 and 0.10–2.04 μg/mL, respectively. Patients receiving a 75-mg maintenance dose every 12h had AUCss, 24 h, and Css, av values of 117.70 ± 37.03 μg h/mL and 4.14 ± 1.74 μg/mL, respectively. For patients receiving a 100 mg maintenance dose, these values were 152.73 ± 70.09 μg h/mL and 5.43 ± 2.85 μg/mL, respectively.Conclusion: The validated HPLC–MS/MS method was successfully applied to a study on the pharmacokinetics of PB in elderly patients infected with multidrug-resistant Gram-negative bacteria. Both two dose strategies in this study would have a excessive PB exposure in the elderly patients then the therapeutic window recommended by guidelines.

Objectives: Killer cell lectin like receptor G1 (KLRG1) is identified as a co-inhibitory receptor for NK cells and antigen-experienced T cells. The role of KLRG1 in immune regulation in patients with non-small cell lung cancer (NSCLC) remains poorly understood. Materials and Methods: We measured the proportion and immune function of KLRG1+CD8+ T cells derived from peripheral blood in patients with NSCLC by flow cytometry. Besides, using data from the gene expression profiles and single-cell sequencing, we explored the expression and immune role of KLRG1 in tumor tissues of patients with NSCLC. We further determined the prognostic value of KLRG1 in terms of overall survival (OS) in NSCLC patients. Results: We found that the proportion of KLRG1+CD8+T cells in peripheral blood significantly increased in patients with NSCLC as compared to those with benign pulmonary nodules and healthy donors. Peripheral KLRG1+CD8+T cell proportion was increased in elder subjects compared to that in younger ones, implying an immunosenescence phenotype. Moreover, the KLRG1+CD8+T cell levels were positively correlated with tumor size and TNM stage in the NSCLC cohort. In vitro stimulation experiments demonstrated that the KLRG1+CD8+T cells from peripheral blood expressed higher levels of Granzyme B and perforin than the KLRG1−CD8+ T cells. However, single-cell RNA sequencing data revealed that the KLRG1+CD8+ T cells were less infiltrated in tumor microenvironment and exhibited impaired cytotoxicity. The KLRG1 gene expression levels were significantly lower in tumor tissues than that in normal lung tissues, and were inversely correlated with CDH1 expression levels. Moreover, higher expression of CDH1 in tumor tissues predicted worse overall survival only in patients with KLRG1-high expression, but not in the KLRG1-low subset. Conclusion: This study demonstrates that KLRG1+CD8+T cells were associated with tumor immune evasion in NSCLC and suggests KLRG1 as a potential immunotherapy target.

Small-scale pedestrian detection is a challenge. The main issues are as follows: 1) Troubled by their small scale, it is difficult to extract features effectively; 2) During the detection process, it is easily disturbed by background noise such as inter-class occlusion and intra-class occlusion, leading to missed or false detection; 3) The current widely used IoU measurement method is very sensitive to the position deviation of small objects, which seriously reduces the detection performance. To address these problems, we improve YOLOv5 structure by integrating Non-Local and Convolution structures, building a new feature extraction module called ResNet-Conv&NonL, combined with the ResNet structure. This module was then integrated into the backbone of YOLOv5 for better image feature extraction. In addition, we developed a novel model to measure the similarity between bounding boxes, which are embedded in the loss function of the YOLOv5 structure to replace the normal IoU measurement. Experiments on a self-made dataset and a combined dataset from Caltech and CityPersons show the feasibility of the proposed network structure. Results demonstrate the feasibility of the improved network structure is superior to the original method because it increases average precision by 6.0% compared to the original one.

Aims: Astragalus polysaccharide (APS) participates in various processes, such as the enhancement of immunity and inhibition of tumours. APS can affect osteoporosis (OP) by regulating the osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs). This study was designed to elucidate the mechanism of APS in hBMSC proliferation and osteoblast differentiation. Methods: Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting were performed to determine the expression of microRNA (miR)-760 and ankyrin repeat and FYVE domain containing 1 (ANKFY1) in OP tissues and hBMSCs. Cell viability was measured using the Cell Counting Kit-8 assay. The expression of cyclin D1 and osteogenic marker genes (osteocalcin (OCN), alkaline phosphatase (ALP), and runt-related transcription factor 2 (RUNX2)) was evaluated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Mineral deposits were detected through Alizarin Red S staining. In addition, Western blotting was performed to detect the ANKFY1 protein levels following the regulation of miR-760. The relationship between miR-760 and ANKFY1 was determined using a luciferase reporter assay. Results: The expression of miR-760 was upregulated in OP tissues, whereas ANKFY1 expression was downregulated. APS stimulated the differentiation and proliferation of hBMSCs by: increasing their viability; upregulating the expression levels of cyclin D1, ALP, OCN, and RUNX2; and inducing osteoblast mineralization. Moreover, APS downregulated the expression of miR-760. Overexpression of miR-760 was found to inhibit the promotive effect of APS on hBMSC differentiation and proliferation, while knockdown of miR-760 had the opposite effect. ANKFY1 was found to be the direct target of miR-760. Additionally, ANKFY1 participated in the APS-mediated regulation of miR-760 function in hBMSCs. Conclusion: APS promotes the osteogenic differentiation and proliferation of hBMSCs. Moreover, APS alleviates the effects of OP by downregulating miR-760 and upregulating ANKFY1 expression. Cite this article: Bone Joint Res 2023;12(8):476–485.

Introduction: Elderly patients are more prone to develop acute kidney injury during infections and polymyxin B (PMB)-associated nephrotoxicity than young patients. The differential response to PMB between the elderly and young critically ill patients is unknown. We aimed to assess PMB exposure in elderly patients compared with young critically ill patients, and to determine the covariates of PMB pharmacokinetics in critically ill patients.Methods: Seventeen elderly patients (age ≥ 65 years) and six young critically ill patients (age < 65 years) were enrolled. Six to eight blood samples were collected during the 12 h intervals after at least six doses of intravenous PMB in each patient. PMB plasma concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry. The primary outcome was PMB exposure as assessed by the area under the concentration-time curve over 24 h at steady state (AUCss, 0–24 h).Results and Discussion: The elderly group had lower total body weight (TBW) and higher Charlson comorbidity scores than young group. Neither AUCss, 0–24 h nor normalized AUCss, 0–24 h (adjusting AUC for the daily dose in mg/kg of TBW) was significantly different between the elderly group and young group. The half-life time was longer in the elderly patients than in young patients (11.21 vs 6.56 h respectively, p = 0.003). Age and TBW were the covariates of half-life time (r = 0.415, p = 0.049 and r = −0.489, p = 0.018, respectively). TBW was the covariate of clearance (r = 0.527, p = 0.010) and AUCss, 0–24 h (r = −0.414, p = 0.049). Patients with AUCss, 0–24 h ≥ 100 mg·h/L had higher baseline serum creatinine levels and lower TBW than patients with AUCss, 0–24 h < 50 mg·h/L or patients with AUCss, 0–24 h 50–100 mg·h/L. The PMB exposures were comparable in elderly and young critically ill patients. High baseline serum creatinine levels and low TBW was associated with PMB overdose.Trial registration: ChiCTR2300073896 retrospectively registered on 25 July 2023.

During deep-sea mining, heavy metal pollutants can cause contamination in the marine environment. In this paper, the multiphasic coupling model is established to describe the heavy metal migration process during deep-sea mining, which takes the effects of the convection–diffusion, adsorption–desorption, and sedimentation–resuspension of heavy metals in the aquatic environment into full consideration. Due to the advantages of the Lattice Boltzmann method, it is adopted to numerically solve the multiphasic coupling model and achieve the simulation of the heavy metal migration process during deep-sea mining. In addition, taking cadmium as an example, the concentration variations are discussed and analyzed in detail. Based on the established model and Lattice Boltzmann method, the concentration distribution of heavy metals can be accurately described to provide the reasonable bases for the evaluation of marine environmental protection.

Thermal runaway (TR) of lithium-ion batteries has always been a topic of concern, and the safety of batteries is closely related to the operating temperature. An overheated battery can significantly impact the surrounding batteries, increasing the risk of fire and explosion. To improve the safety of battery modules and prevent TR, we focus on the characteristics of temperature distribution and thermal spread of battery modules under overheating conditions. The heat transfer characteristics of battery modules under different battery thermal management systems (BTMSs) are assessed. In addition, the effects of abnormal heat generation rate, abnormal heat generation location, and ambient temperature on the temperature distribution and thermal spread of battery modules are also studied. The results indicate that the BTMS consisting of flat heat pipes (FHPs) and bottom and side liquid cooling plates can effectively suppress thermal spread and improve the safety of the battery module.

Plants are widely grown around the world and have high economic benefits. plant leaf diseases not only negatively affect the healthy growth and development of plants, but also have a negative impact on the environment. While traditional manual methods of identifying plant pests and diseases are costly, inefficient and inaccurate, computer vision technologies can avoid these drawbacks and also achieve shorter control times and associated cost reductions. The focusing mechanism of Transformer-based models(such as Visual Transformer) improves image interpretability and enhances the achievements of convolutional neural network (CNN) in image recognition, but Visual Transformer(ViT) performs poorly on small and medium-sized datasets. Therefore, in this paper, we propose a new hybrid architecture named FOTCA, which uses Transformer architecture based on adaptive Fourier Neural Operators(AFNO) to extract the global features in advance, and further down sampling by convolutional kernel to extract local features in a hybrid manner. To avoid the poor performance of Transformer-based architecture on small datasets, we adopt the idea of migration learning to make the model have good scientific generalization on OOD (Out-of-Distribution) samples to improve the model’s overall understanding of images. In further experiments, Focal loss and hybrid architecture can greatly improve the convergence speed and recognition accuracy of the model in ablation experiments compared with traditional models. The model proposed in this paper has the best performance with an average recognition accuracy of 99.8% and an F1-score of 0.9931. It is sufficient for deployment in plant leaf disease image recognition.

Summary: Oncogenic KRAS mutations are a key driver for initiation and progression in non-small cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity remain largely unclear. Here, we show that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysines 182 and 184. SETD7-mediated methylation of KRAS leads to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, is recruited and promotes KRAS degradation in a K182/K184 methylation-dependent manner. Notably, SETD7 is inversely correlated with KRAS at the protein level in clinical NSCLC tissues. Low SETD7 or RABGEF1 expression is associated with poor prognosis in lung adenocarcinoma patients. Altogether, our results define a tumor-suppressive function of SETD7 that operates via modulating KRAS methylation and degradation.

Abstract As a highly conserved and ubiquitously expressed serine/threonine kinase, p21-activated kinase 2 (PAK2) participates in diverse biologic events. However, its roles in mouse oocyte meiotic maturation remain unclear. The present study revealed that mouse oocytes depleted of Pak2 were unable to completely progress through meiosis and that a majority were arrested at metaphase I. Pak2 depletion thus prompted MI arrest and induced meiotic chromosome alignment defects in mouse oocytes, in part due to a reduction in polo-like kinase (PLK1). We demonstrated that PAK2’s interaction with PLK1 protected it from degradation by APC/CCdh1, and that it promoted meiotic progression and bipolar spindle formation. Our data collectively display critical functions for PAK2 in meiotic progression and chromosome alignment in mouse oocytes.

Abstract Background Accumulating evidence suggests a strong association between polycystic ovary syndrome (PCOS) and ovarian cancer (OC), but the potential molecular mechanism remains unclear. In this study, we identified previously unrecognized genes that are significantly correlated with PCOS and OC via bioinformatics. Materials and methods Multiple bioinformatic analyses, such as differential expression analysis, univariate Cox analysis, functional and pathway enrichment analysis, protein–protein interaction (PPI) network construction, survival analysis, and immune infiltration analysis, were utilized. We further evaluated the effect of OGN on FSHR expression via immunofluorescence. Results TCGA-OC, GSE140082 (for OC) and GSE34526 (for PCOS) datasets were downloaded. Twelve genes, including RNF144B, LPAR3, CRISPLD2, JCHAIN, OR7E14P, IL27RA, PTPRD, STAT1, NR4A1, OGN, GALNT6 and CXCL11, were identified as signature genes. Drug sensitivity analysis showed that OGN might represent a hub gene in the progression of PCOS and OC. Experimental analysis found that OGN could increase FSHR expression, indicating that OGN could regulate the hormonal response in PCOS and OC. Furthermore, correlation analysis indicated that OGN function might be closely related to m6A and ferroptosis. Conclusions Our study identified a 12-gene signature that might be involved in the prognostic significance of OC. Furthermore, the hub gene OGN represent a significant gene involved in OC and PCOS progression by regulating the hormonal response.

Abstract Background The quality of the early embryo is vital to embryonic development and implantation. As a highly conserved serine/threonine kinase, p21-activated kinase 2 (Pak2) participates in diverse biologic processes, especially in cytoskeleton remodeling and cell apoptosis. In mice, Pak2 knock out and endothelial depletion of Pak2 showed embryonic lethality. However, the role of Pak2 in preimplantation embryos remains unelucidated. Methods In the present work, Pak2 was reduced using a specific small interfering RNA in early mouse embryos, validating the unique roles of Pak2 in spindle assembly and DNA repair during mice early embryonic development. We also employed immunoblotting, immunostaining, in vitro fertilization (IVF) and image quantification analyses to test the Pak2 knockdown on the embryonic development progression, spindle assembly, chromosome alignment, oxidative stress, DNA lesions and blastocyst cell apoptosis. Areas in chromatin with γH2AX were detected by immunofluorescence microscopy and serve as a biomarker of DNA damages. Results We found that Pak2 knockdown significantly reduced blastocyst formation of early embryos. In addition, Pak2 reduction led to dramatically increased abnormal spindle assembly and chromosomal aberrations in the embryos. We noted the overproduction of reactive oxygen species (ROS) with Pak2 knockdown in embryos. In response to DNA double strand breaks (DSBs), the histone protein H2AX is specifically phosphorylated at serine139 to generate γH2AX, which is used to quantitative DSBs. In this research, Pak2 knockdown also resulted in the accumulation of phosphorylated γH2AX, indicative of increased embryonic DNA damage. Commensurate with this, a significantly augmented rate of blastocyst cell apoptosis was detected in Pak2-KD embryos compared to their controls. Conclusions Collectively, our data suggest that Pak2 may serve as an important regulator of spindle assembly and DNA repair, and thus participate in the development of early mouse embryos.

Pancreatic cancer is the deadliest malignancy of the digestive system and is the seventh most common cause of cancer-related deaths worldwide. The incidence and mortality of pancreatic cancer continue to increase, and its 5-year survival rate remains the lowest among all cancers. N6-methyladenine (m6A) is the most abundant reversible RNA modification in various eukaryotic messenger and long noncoding RNAs and plays crucial roles in the occurrence and development of cancers. However, the role of m6A in pancreatic cancer remains unclear. The present study aimed to explore the role of m6A and its regulators in pancreatic cancer and assess its underlying molecular mechanism associated with pancreatic cancer cell proliferation, invasion, and metastasis. Reduced expression of the m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. Altogether, this study describes new, potential molecular therapeutic targets for pancreatic cancer that could pave the way to improve patient outcome.

Abstract As wind‐borne migration of insects is strongly influenced by atmospheric circulation and weather systems, the relationships between insect population abundance and meteorological conditions are substantial. The brown planthopper (BPH), Nilaparvata lugens (Stål), is one of the major wind‐borne insects hampering rice production in Asia, and its migration is significantly influenced by the Asian monsoon, a main component of the Asian climate system. However, the degree and mechanisms of the effects of monsoon on BPH migration have been little studied. In this paper, the effect of the Asian monsoon on the northward migration of BPH from the Indochina Peninsula to northern South China (NSC) was investigated based on the BPH light‐trap data and meteorological data for 39 years. The results show that the level of BPH migration in May could indicate the degree of annual pest outbreaks in NSC and that the southeast monsoon was more critical in this northward migration than the previously recognized southwest monsoon. The significance of the southeast monsoon stemmed from the strong effect of South China Sea subtropical high on BPH migration under a unique weather system distribution, the Polar low–Continental low–West Pacific subtropical high pattern. Furthermore, based on the key areas of migration obtained from the composite analysis, the multivariable linear regression prediction model could effectively predict the occurrence of BPH in NSC. These results indicate the importance of interactions between monsoons during BPH northward migration, which reflects the complex relationship between BPH migration and atmospheric motion.

A large-capacity prismatic lithium-ion battery thermal management system (BTMS) combining composite phase change material (CPCM), a flat heat pipe (FHP), and liquid cooling is proposed. The three conventional configurations analyzed in this study are the BTMSs using only CPCM, CPCM with aluminum thermal diffusion plates, and CPCM with FHPs. In addition, a CPCM–FHP assisted with liquid cooling at the lateral sides is established to enhance the thermal performance of large-capacity batteries. Moreover, the influences of coolant temperature, the number of FHPs and cooling pipes, and the coolant direction on the temperature field of a BTMS are discussed. Finally, the orthogonal design method is used for the multi-level analysis of multiple factors to improve the light weight of the system. The optimal parameter combination is obtained to achieve the best thermal performance of the BTMS, with the maximum temperature and the temperature difference at 43.17 °C and 3.36 °C, respectively, under a maximum discharge rate of 2C and a high-temperature environment of 37 °C. The optimal scheme is further analyzed and affirmed through the comprehensive balance method.

Abstract Background Pancreatic cancer is a fatal malignancy of the digestive system and the 5-year survival rate remains low. Therefore, new molecular therapeutic targets are required to improve treatments, prognosis, and the survival of patients. N6-methyladenosine (m6A) is the most prevalent reversible methylation in mammalian messenger RNA (mRNA) and has critical roles in the tumorigenesis and metastasis of various malignancies. However, the role of m6A in pancreatic cancer is still unclear. Exploring genetic alterations and functional networks of m6A regulators in pancreatic cancer may provide new strategies for its treatment. Methods In this study, we used data from the Cancer Genome Atlas (TCGA) database and other public databases through cBioPortal, LinkedOmics, UALCAN, GEPIA, STRING, and the database for annotation, visualization, and integrated discovery (DAVID) to systematically analyze the molecular alterations and functions of 20 main m6A regulators in pancreatic cancer. Results We found that m6A regulators had widespread genetic alterations, and that their expression levels were significantly correlated with pancreatic cancer malignancy. Moreover, m6A regulators were associated with the prognosis of pancreatic cancer patients. Conclusions m6A regulators play a crucial part in the occurrence and development of pancreatic cancer. Our study will guide further studies of m6A RNA modification in pancreatic cancer and could potentially provide new strategies for pancreatic cancer treatment.

Abstract Background Cell‐free messenger RNA (cf‐mRNA) and long non‐coding RNA (cf‐lncRNA) are becoming increasingly important in liquid biopsy by providing biomarkers for disease prediction, diagnosis and prognosis, but the simultaneous characterization of coding and non‐coding RNAs in human biofluids remains challenging. Methods Here, we developed polyadenylation ligation‐mediated sequencing (PALM‐Seq), an RNA sequencing strategy employing treatment of RNA with T4 polynucleotide kinase to generate cell‐free RNA (cfRNA) fragments with 5′ phosphate and 3′ hydroxyl and RNase H to deplete abundant RNAs, achieving simultaneous quantification and characterization of cfRNAs. Results Using PALM‐Seq, we successfully identified well‐known differentially abundant mRNA, lncRNA and microRNA in the blood plasma of pregnant women. We further characterized cfRNAs in blood plasma, saliva, urine, seminal plasma and amniotic fluid and found that the detected numbers of different RNA biotypes varied with body fluids. The profiles of cf‐mRNA reflected the function of originated tissues, and immune cells significantly contributed RNA to blood plasma and saliva. Short fragments (

Batteries with high energy density are packed into compact groups to solve the range anxiety of new-energy vehicles, which brings greater workload and insecurity, risking thermal runaway in harsh conditions. To improve the battery thermal performance under high ambient temperature and discharge rate, a battery thermal management system (BTMS) based on honeycomb-structured liquid cooling and phase change materials (PCM) is innovatively proposed. In this paper, the thermal characteristics of INR18650/25P battery are studied theoretically and experimentally. Moreover, the influence of structure, material and operating parameters are studied based on verifying the simplified BTMS model. The results show that the counterflow, honeycomb structure of six cooling tubes and fins, 12% expanded graphite mass fraction and 25 mm battery spacing give a better battery thermal performance with high group efficiency. The maximum temperature and temperature difference in the battery in the optimal BTMS are 45.71 °C and 4.4 °C at the 40 °C environment/coolant, as against 30.4 °C and 4.97 °C at the 23.6 °C environment/coolant, respectively. Precooling the coolant can further reduce the maximum battery temperature in high temperature environments, and the precooling temperature difference within 5 °C could meet the uniformity requirements. Furthermore, this study can provide guidance for the design and optimization of BTMS under harsh conditions.

Reactivation of γ-globin expression is a promising therapeutic approach for β-hemoglobinopathies. Here, we propose a novel Cas9/AAV6-mediated genome editing strategy for the treatment of β-thalassemia: Natural HPFH mutations −113A > G, −114C > T, −117G>A, −175T > C, −195C > G, and −198T > C were introduced by homologous recombination following disruption of BCL11A binding sites in HBG1/HBG2 promoters. Precise on-target editing and significantly increased γ-globin expression during erythroid differentiation were observed in both HUDEP-2 cells and primary HSPCs from β-thalassemia major patients. Moreover, edited HSPCs maintained the capacity for long-term hematopoietic reconstitution in B-NDG hTHPO mice. This study provides evidence of the effectiveness of introducing naturally occurring HPFH mutations as a genetic therapy for β-thalassemia.

Abstract Wearable self-powered systems integrated with energy conversion and storage devices such as solar-charging power units arouse widespread concerns in scientific and industrial realms. However, their applications are hampered by the restrictions of unbefitting size matching between integrated modules, limited tolerance to the variation of input current, reliability, and safety issues. Herein, flexible solar-charging self-powered units based on printed Zn-ion hybrid micro-capacitor as the energy storage module is developed. Unique 3D micro-/nano-architecture of the biomass kelp-carbon combined with multivalent ion (Zn2+) storage endows the aqueous Zn-ion hybrid capacitor with high specific capacity (196.7 mAh g−1 at 0.1 A g−1). By employing an in-plane asymmetric printing technique, the fabricated quasi-solid-state Zn-ion hybrid micro-capacitors exhibit high rate, long life and energy density up to 8.2 μWh cm−2. After integrating the micro-capacitor with organic solar cells, the derived self-powered system presents outstanding energy conversion/storage efficiency (η overall = 17.8%), solar-charging cyclic stability (95% after 100 cycles), wide current tolerance, and good mechanical flexibility. Such portable, wearable, and green integrated units offer new insights into design of advanced self-powered systems toward the goal of developing highly safe, economic, stable, and long-life smart wearable electronics.

Formative assessment (FA) has been used to facilitate EFL learning and teaching. However, due to factors such as task complexity and time constraints, FA implementation faces a variety of challenges, especially in countries with an exam-oriented education system. Drawing on the case of EFL teachers from Chinese public secondary schools, this study examines the features of FA practice and explains their underlying aspects in an EFL exam-oriented context from a social psychology perspective. It adopts a mixed-methods research approach. Guided by the theory of planned behavior, 10 English teachers from Guangdong province in China were interviewed to establish an item pool for a structured questionnaire. A total of 161 English teachers from four cities in Guangdong province took part in the subsequent survey. The results revealed that the participating teachers have an implicit understanding of FA, based primarily on its literal meaning and their own teaching experience. They know and follow FA methods but lack confidence about their own practice. Regional differences were significant. Possible reasons for the perceptions and practices of Chinese EFL teachers from public secondary schools are the teachers’ own attitudes, the influence of other stakeholders, and the limitations of the FA methods. The study elucidates the features of FA practice and its mechanism in an EFL exam-oriented context.

Recently, research on detecting SNP interactions has attracted considerable attention, which is of great significance for exploring complex diseases. The formulation of effective swarm intelligence optimization algorithms is a primary resolution to this issue. To achieve this goal, an important problem needs to be solved in advance; that is, designing and selecting lightweight scoring criteria that can be calculated in O(m) time and can accurately estimate the degree of association between SNP combinations and disease status. In this study, we propose a high-accuracy scoring criterion (HSICCR) by measuring the degree of causality dedicated to assessing the degree. First, we approximate two kinds of dependencies according to the structural equation of the causal relationship between epistasis SNP combination and disease status. Then, inspired by these dependencies, we put forward this scoring criterion that integrates a widely used method of measuring statistical dependencies based on kernel functions (HSIC). However, the computing time complexity of HSIC is O(m2), which is too costly to be an integral part of the scoring criterion. Since the sizes of the sample space of the disease status, SNP loci and SNP combination are small enough, we propose an efficient method of computing HSIC for variables with a small sample in O(m) time. Eventually, HSICCR can be computed in O(m) time in practice. Finally, we compared HSICCR with five representative high-accuracy scoring criteria that detect SNP interactions for 49 simulation disease models. The experimental results show that the accuracy of our proposed scoring criterion is, overall, state-of-the-art.

Hemophilia A (HA), is a X-linked recessive congenital bleeding disorder, caused by deficiency of the coagulation factor VIII (FVIII) which is encoded by coagulation factor 8 (F8). HA affects 1 of every 5,000 males worldwide. The intron 22 inversion (Inv22) mutation of F8 causes about 45% of severe HA cases. Here, we generated induced pluripotent stem cells (iPSCs) from a HA patient with Inv22 mutation by electroporation of urine-derived cells (UCs) with episomal plasmids under feeder-free, virus-free, serum-free condition and without oncogene c-MYC. This iPSCs line could facilitate future applications of human iPSCs by provide a valuable cell model.

Background The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX, which are important in the development of various tissues and organs in mammals. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as key tumor suppressors and oncogenes for many cancers. However, the expression levels and distinctive prognostic values of the NFI family remain poorly explored in most cancers. Materials and Methods In the present study, the differences in mRNA expression of the NFI family in various cancers were investigated using the Oncomine and TCGA databases, and the mRNA expression, genetic alteration and DNA methylation of the NFI family members in various cancers were examined using cBioPortal for Cancer Genomics. In addition, the prognostic significance of the NFI family was assessed in multiple cancers using the Kaplan–Meier plotter (KM plotter) and SurvExpress databases. Results The mRNA expression levels in the NFI family were significantly downregulated in most cancers compared with normal tissues and DNA hypermethylation might downregulate the NFI family expression. Although NFIX expression was not downregulated in kidney, colorectal and prostate cancers. Furthermore, NFIB expression was upregulated in gastric cancer. Further survival analyses based on the KM plotter and SurvExpress databases showed dysregulations of the NFI genes were significantly correlated with survival outcomes in breast, lung, and head and neck cancers. Decreased expression levels of NFIA, NFIB and NFIC were associated with poor overall survival (OS) in head and neck cancer. Low mRNA expression of NFIA and NFIB was significantly associated with OS and first progression in lung adenocarcinoma, but not in lung squamous cell carcinoma. In addition, potential correlations between NFI family members and survival outcomes were also observed in liver, esophageal, kidney and cervical cancer. Conclusion The results from the present study indicated certain members of the NFI family could be promising therapeutic targets and novel prognostic biomarkers for human cancers.

Abstract Background Activation of c-Met, a receptor tyrosine kinase, induces radiation therapy resistance in non-small cell lung cancer (NSCLC). The activated residual of c-Met is located in lipid rafts (Duhon et al. Mol Carcinog 49:739-49, 2010). Therefore, we hypothesized that disturbing the integrity of lipid rafts would restrain the activation of the c-Met protein and reverse radiation resistance in NSCLC. In this study, a series of experiments was performed to test this hypothesis. Methods NSCLC A549 and H1993 cells were incubated with methyl-β-cyclodextrin (MβCD), a lipid raft inhibitor, at different concentrations for 1 h before the cells were X-ray irradiated. The following methods were used: clonogenic (colony-forming) survival assays, flow cytometry (for cell cycle and apoptosis analyses), immunofluorescence microscopy (to show the distribution of proteins in lipid rafts), Western blotting, and biochemical lipid raft isolation (purifying lipid rafts to show the distribution of proteins in lipid rafts). Results Our results showed that X-ray irradiation induced the aggregation of lipid rafts in A549 cells, activated c-Met and c-Src, and induced c-Met and c-Src clustering to lipid rafts. More importantly, MβCD suppressed the proliferation of A549 and H1993 cells, and the combination of MβCD and radiation resulted in additive increases in A549 and H1993 cell apoptosis. Destroying the integrity of lipid rafts inhibited the aggregation of c-Met and c-Src to lipid rafts and reduced the expression of phosphorylated c-Met and phosphorylated c-Src in lipid rafts. Conclusions X-ray irradiation induced the aggregation of lipid rafts and the clustering of c-Met and c-Src to lipid rafts through both lipid raft-dependent and lipid raft-independent mechanisms. The lipid raft-dependent activation of c-Met and its downstream pathways played an important role in the development of radiation resistance in NSCLC cells mediated by c-Met. Further studies are still required to explore the molecular mechanisms of the activation of c-Met and c-Src in lipid rafts induced by radiation.

The Chinese paifang is an essential constituent element for Chinese or many other oriental architectures. In this paper, a new method for detection and analysis of the reflection symmetry of the paifang based on 3D point clouds is proposed. The method invokes a new model to simultaneously fit two vertical planes of symmetry to the 3D point cloud of a paifang to support further symmetry analysis. Several simulated datasets were used to verify the proposed method. The results indicated that the proposed method was able to quantity the symmetry of a paifang in terms of the RMSE obtained from the ICP algorithm, with resistance to the presence of some random noise added to the simulated measurements. For real datasets, three old Chinese paifangs (with ages from 90 to 500 years) were scanned as point clouds to input into the proposed method. The method quantified the degree of symmetry for the three Chinese paifangs in terms of the RMSE, which ranged from 20 to 61 mm. One of the paifangs with apparent asymmetry had the highest RMSE (61 mm). Other than the quantification of the symmetry of the paifangs, the proposed method could also locate which portion of the paifang was relatively more symmetric. The proposed method can potentially be used for structural health inspection and cultural studies of the Chinese paifangs and some other similar architecture.

Faster-than-Nyquist (FTN) signaling can improve the system effectiveness without reducing the system reliability,but the fierce inter-symbol interference (ISI) introduced by it may cause that the complexity of the optimal receiver is intolerable.An effective low-complexity FTN receiver is iterative block decision feedback equalizer (IBDFE),which can achieve performance close to the optimal receiver with much lower complexity,but its complexity can be further reduced.Therefore,a reduced-complexity IBDFE (RC-IBDFE) was proposed for FTN communication systems,which was based on IBDFE,but introduced a simplified method to design the feedforward and feedback filters.When packing factor is τ={0.8,0.7},numerical results and analysis indicate that,compared with IBDFE,RC-IBDFE has stronger robustness,its complexity is reduced by {45.7%,25%},and its performance gain is {0.605 4,0.193 6} dB when the bit error rate (BER) is 10-5.Compared with the existing low-complexity IBDFE (LC-IBDFE),RC-IBDFE has stronger robustness,its complexity is reduced by {13.6%,-25.8%},and its performance gain is {0.289 7,0.531 2} dB when the BER is 10-5.

A secure OFDM transmission scheme based on two-stage chaos mapping was introduced, which were cha-oticphase rotation and sub-carrier chaos mapping. The characteristics of pseudo-random and sensitivity to initial condi-tions of chaos sequences were employed. Numerical results and analysis show that the scheme canensure secure informa-tion transmission,and improve the pseudo-randomness of transmitted signals. The eavesdropper cannot estimate the mes-sage from statistic characteristics of received signals, which guarantees the communication security. Compared with tra-ditional methods like advanced encryption standard, randomization of MIMO transmission coefficients, the scheme shows favorable computation security.

Aramid fibers with low density and high strength, modulus, and thermal resistance are widely used in applications such as bulletproof vests and cables. However, owing to their chemical structure, they are sensitive to ultraviolet light, which degrades the fibers’ useful mechanical properties. In this study, titanium dioxide (TiO2) nanoparticles were synthesized both on the aramid III fiber surface and in the interfacial space between the fibrils/microfibrils in supercritical carbon dioxide (scCO2) to improve the UV resistance of aramid fibers. The effects of scCO2 treatment pressure on the TiO2 structure, morphology, surface composition, thermal stability, photostability, and mechanical properties were investigated using Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis, ultraviolet−visible spectroscopy, and single-fiber test. The results show that amorphous TiO2 formed on the fiber surface and the interface between fibrils/microfibrils, and decreased the photodegradation rate of the aramid III fiber. Moreover, this modification can also improve the tensile strength via treatment at low temperature and without the use of a solvent. The simple synthesis process in scCO2, which is scalable, is used for mild modifications with a green solvent, providing a promising technique for synthesizing metal dioxide on polymers.

Positron emission tomography (PET) radioligands targeting the human translocator membrane protein (TSPO) are broadly used for the investigations of neuroinflammatory conditions associated with neurological disorders. Structural information on the mammalian protein homodimers—the suggested functional state of the protein—is limited to a solid-state nuclear magnetic resonance (NMR) study and to a model based on the previously-deposited solution NMR structure of the monomeric mouse protein. Computational studies performed here suggest that the NMR-solved structure in the presence of detergents is not prone to dimer formation and is furthermore unstable in its native membrane environment. We, therefore, propose a new model of the functionally-relevant dimeric form of the mouse protein, based on a prokaryotic homologue. The model, fully consistent with solid-state NMR data, is very different from the previous predictions. Hence, it provides, for the first time, structural insights into this pharmaceutically-important target which are fully consistent with experimental data.

Tau is a microtubule-associated protein implicated in neurodegenerative tauopathies. Six tau isoforms are generated from a single gene through alternative splicing of exons 2, 3 and 10 in human brain. Differential expression of tau isoforms has been detected in different brain areas, during neurodevelopment and in neurodegenerative disorders. However, the biological significance of different tau isoforms is not clear. Here, we investigated the individual effect of six different isoforms of tau on cell proliferation and the possible mechanisms by transient expression of eGFP-labeled tau isoform plasmid in N2a cells. Our study showed the transfection efficiency was comparable between different isoforms of tau by examining GFP expression. Compared with other isoforms, we found expression of 1N3R-tau significantly inhibited cell proliferation by Cell Counting Kit-8 assay and BrdU incorporation. Flow cytometry analysis further showed expression of 1N3R-tau induced S phase arrest. Compared with the longest isoform of tau, expression of 1N3R-tau induced cyclin E translocation from the nuclei to cytoplasm, while it did not change the level of cell cycle checkpoint proteins. These data indicate that 1N3R-tau inhibits cell proliferation through inducing S phase arrest.

Early onset torsion dystonia is a movement disorder inherited as an autosomal dominant syndrome with reduced penetrance. Symptoms appear to result from altered neuronal circuitry within the brain with no evidence of neuronal loss. Most cases are caused by loss of a glutamic acid residue in the AAA+ chaperone protein, torsinA, encoded in the DYT1 gene. In this study, torsinA was found to move in conjunction with vimentin in three cell culture paradigms—recovery from microtubule depolymerization, expression of a dominant-negative form of kinesin light chain and respreading after trypsinization. Co-immune precipitation studies revealed association between vimentin and torsinA in a complex including other cytoskeletal elements, actin and tubulin, as well as two proteins previously shown to interact with torsinA—the motor protein, kinesin light chain 1, and the nuclear envelope protein, LAP1. Morphologic and functional differences related to vimentin were noted in primary fibroblasts from patients carrying this DYT1 mutation as compared with controls, including an increased perinuclear concentration of vimentin and a delayed rate of adhesion to the substratum. Overexpression of mutant torsinA inhibited neurite extension in human neuroblastoma cells, with torsinA and vimentin immunoreactivity enriched in the perinuclear region and in cytoplasmic inclusions. Collectively, these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain.

Alzheimer's disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.

Understanding the complex influencing factors of soil erosion is critical for maintaining regional ecological security. The revised wind erosion equation (RWEQ) and partial least squares regression (PLSR) model were used to reveal the primary factors affecting soil erosion. Based on the results of the RWEQ model, the wind erosion area was 8,439.3 km2 in 2018, accounting for 54.3% of the total planning area, and mild erosion, moderate erosion, intense erosion, very intense erosion, and fierce erosion accounted for 18.22%, 11.43%, 11.78%, 10.16%, and 2.74% of the total planning area, respectively. Based on the results of the PLSR model, the results indicate that the proportion of mining land, meteorological indicators, and mean square deviation of slope difference were positively correlated with the soil erosion area, intensity, and severity, respectively. The proportion of grassland and forest land was negatively correlated with the soil erosion area, intensity, and severity. The mean square deviation of slope difference, the mean square deviation of difference in elevation, and the proportion of urban land use contributed the most to the soil erosion severity index, with variable importance in projection (VIP) scores of 1.55, 1.44 and 1.43, respectively. The mean square deviation of slope difference, the proportion of urban land, and the mean square deviation of difference in elevation contributed the most to the soil erosion area, with VIP scores of 1.53, 1.26 and 1.24, respectively. The results provide new insights into wind erosion and the influences of weather conditions and human influences, which can guide regional soil and water conservation planning in wind erosion regions. [ABSTRACT FROM AUTHOR]