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Abstract Background Periodontitis is the sixth-most common disease worldwide. The oral microbiome composition and its association with Periodontal disease (PD) have been largely explored; however, limited studies have explored the microbial profiles of both oral and toothbrushes in patients with PD. Thus, this study aimed to ascertain the oral and toothbrushes microbial composition in high-altitude populations, hypothesizing that their correlation with periodontal health would differ from those at lower altitudes, potentially indicating links between environmental factors, microbial colonization patterns, and periodontal health in distinct geographic contexts. Methods In the present study, we enrolled 35 individuals including 21 healthy and 14 diagnosed with PD from the Lhasa region of Tibet, China. Saliva and toothbrush samples were collected from each participant to assess the association between toothbrush usage and oral microbiome with PD using 16 S rRNA gene-specific V3-V4 regions sequencing. To assess the oral and toothbrush microbiome composition and diversity and its possible link to PD. Results Significantly higher Alpha diversity (Shannon index) was observed between the PD group and PD toothbrushes (p = 0.00021) and between the PD group and Healthy toothbrushes (p = 0.00041). The predominant species were Proteobacteria, Bacteroidota, Firmicutes, Actinobacteria, and Fusobacteria, with genera Pseudomonas, Veillonella, Neisseria, Acinetobacter, and Haemophilus. In addition, PICRUST2 analysis unveiled 44 significant pathways differentiating the disease and healthy groups, along with 29 pathways showing significant differences between their respective toothbrush microbial profiles. The distinct oral and toothbrush microbial composition among high-altitude populations suggests potential adaptations to the challenges of high-altitude environments. Conclusion This study emphasizes the importance of tailored dental care strategies, accounting for altitude and racial factors, to effectively manage periodontal health in these communities. Further research is warranted to investigate the specific microbial mechanisms and develop targeted interventions for optimizing oral health in populations across varying altitudes.

Abstract Mesenchymal stem cells (MSCs) therapy is a highly researched treatment that has the potential to promote immunomodulation and anti-inflammatory, anti-apoptotic, and antimicrobial activities. It is thought that it can enhance internal organ function, reverse tissue remodeling, and achieve significant organ repair and regeneration. However, the limited infusion, survival, and engraftment of transplanted MSCs diminish the effectiveness of MSCs-based therapy. Consequently, various preconditioning methods have emerged as strategies for enhancing the therapeutic effects of MSCs and achieving better clinical outcomes. In particular, the use of natural small molecule compounds (NSMs) as a pretreatment strategy is discussed in this narrative review, with a focus on their roles in regulating MSCs for injury repair in vital internal organs. Additionally, the discussion focuses on the future directions and challenges of transforming mesenchymal stem cell research into clinical applications.

Abstract The illegal water injection into meat not only breaks the market equity, but also deteriorates the meat quality and produces harmful substances. In this work, we proposed a fiber Bragg grating (FBG) sensor that enabled fast, quantitative, and in-situ detection of the moisture content of water-injected meat. The FBG was written in the erbium-ytterbium (Er/Yb) co-doped fiber, which could perform the self-photothermal effect by injecting the near infrared laser into the fiber. As the heated fiber sensor probe was inserted into the meat sample, the temperature decreased due to the heat dissipation mediated by moisture. The intracore Bragg grating could monitor the temperature loss by recording the Bragg wavelength shift, which reflected the water content quantitatively. The results revealed that the sensor could complete the detection within 15 s. The sensor’s sensitivity to detect changes in the pork water content was theoretically calculated to be 0.090847%. The proposed sensor is expected to provide a novel approach for examination of the meat moisture.

Cinnamyl alcohol dehydrogenase (CAD) plays a crucial role in lignin biosynthesis, and the gene family encoding various CAD isozymes has been cloned and characterized in numerous plant species. However, limited information regarding the CAD gene family in tobacco is currently available. In this study, we identified 10 CAD genes in Nicotiana tabacum, four in N. tomentosiformis, and six in N. sylvestris. The nucleotide and amino acid sequences of these tobacco CADs demonstrate high levels of similarity, whereas the putative protein sequences conservatively possessed two Zn2+ binding motifs and an NADP(H) cofactor binding motif. Both NtCAD1 and NtCAD2 had conservative substrate binding sites, similar to those possessed by bona fide CADs, and evidence from phylogenetic analysis as well as expression profiling supported their role as bona fide CADs involved in lignin biosynthesis. NtCAD1 has two paralogous genes, NtCAD1–1 and NtCAD1–2. Enzyme activity analysis revealed that NtCAD1–1 and NtCAD1–2 had a high affinity to coniferyl aldehyde, p-coumaryl aldehyde, and sinapyl aldehyde, whereas NtCAD2 preferred coniferyl aldehyde and p-coumaryl aldehyde as substrates. The kinetic parameter assay revealed that NtCAD1–2 functions as the most efficient enzyme. Downregulation of both NtCAD1–1 and NtCAD1–2 resulted in reddish-brown stems without significant changes in lignin content. Furthermore, NtCAD1–1, NtCAD1–2, and NtCAD2 showed distinct expression patterns in response to biotic and abiotic stresses, as well as different phytohormones. Our findings suggest that NtCAD1–1 and NtCAD1–2 are involved in lignin biosynthesis, with NtCAD1–2 also participating in both biological and abiotic stresses, whereas NtCAD2 plays a distinct role mainly in responding to biological and abiotic stresses in tobacco.

The blood-brain Barrier (BBB), combined with immune clearance, contributes to the low efficacy of drug delivery and suboptimal treatment outcomes in glioma. Here, we propose a novel approach that combines the self-assembly of mouse bone marrow-derived macrophage membrane with a targeted positive charge polymer (An-PEI), along with low-frequency ultrasound (LFU) irradiation, to achieve efficient and safe therapy for glioma. Our findings demonstrate the efficacy of a charge-induced self-assembly strategy, resulting in a stable co-delivery nanosystem with a high drug loading efficiency of 44.2 %. Moreover, this structure triggers a significant release of temozolomide in the acidic environment of the tumor microenvironment. Additionally, the macrophage membrane coating expresses Spyproteins, which increase the amount of An-BMP-TMZ that can evade the immune system by 40 %, while LFU irradiation treatment facilitates the opening of the BBB, allowing for enormously increased entry of An-BMP-TMZ (approximately 400 %) into the brain. Furthermore, after crossing the BBB, the Angiopep-2 peptide-modified An-BMP-TMZ exhibits the ability to selectively target glioma cells. These advantages result in an obvious tumor inhibition effect in animal experiments and significantly improve the survival of glioma-bearing mice. These results suggest that combining the macrophage membrane-coated drug delivery system with LFU irradiation offers a feasible approach for the accurate, efficient and safe treatment of brain disease.

This is an article in the field of ceramics and composites. With the growth of lithium smelting scale in China, the production of lithium slag increases year by year, the need for its resource utilization is becoming more and more obvious. To explore the physical and chemical properties of lithium slag and its potential as a cementitious material to prepare artificial aggregate, the composition and properties of lithium mica lithium slag in Yichun, China and lithium slag from spodumene in Australia were characterized, and their effects on alkali excitation performance were analyzed. Secondly, two kinds of lithium slag artificial aggregates were prepared by disk cold granulation method with sodium hydroxide as alkali activator, and their compressive strength was tested. Finally, the environmental risks of artificial aggregates were demonstrated by glass electrode method, inductively coupled plasma mass spectrometry, ion chromatography and spectrophotometry. The results show that the physical and chemical properties of lithium mica lithium slag are more suitable for the preparation of artificial aggregates by alkali excitation than lithium pyroxene lithium slag, and the resulting artificial aggregates are stronger and the liquid leachate is not environmentally hazardous.

Abstract The computational pathology has been demonstrated to effectively uncover tumor-related genomic alterations and transcriptomic patterns. Although proteomics has indeed shown great potential in the field of precision medicine, few studies have focused on the computational prediction of protein levels from pathology images. In this paper, we assume that deep learning-based pathological features imply the protein levels of tumor biomarkers that are indicative of prognosis and drug response. For this purpose, we propose wsi2rppa, a weakly supervised contrastive learning framework to infer the protein levels of tumor biomarkers from whole slide images (WSIs) in breast cancer. We first conducted contrastive learning-based pre-training on tessellated tiles to extract pathological features, which are then aggregated by attention pooling and adapted to downstream tasks. We conducted extensive evaluation experiments on the TCGA-BRCA cohort (1978 WSIs of 1093 patients with protein levels of 223 biomarkers) and the CPTAC-BRCA cohort (642 WSIs of 134 patients). The results showed that our method achieved state-of-the-art performance in tumor diagnostic tasks, and also performed well in predicting clinically relevant protein levels and drug response. To show the model interpretability, we spatially visualized the WSIs colored the tiles by their attention scores, and found that the regions with high scores were highly consistent with the tumor and necrotic regions annotated by a 10-year experienced pathologist. Moreover, spatial transcriptomic data further verified that the heatmap generated by attention scores agrees greatly with the spatial expression landscape of two typical tumor biomarker genes. In predicting the response to drug trastuzumab treatment, our method achieved a 0.79 AUC value which is much higher than the previous study reported 0.68. These findings showed the remarkable potential of computational pathology in the prediction of clinically relevant protein levels, drug response, and clinical outcomes.

Abstract Background Metabolic disorders were a health problem for many adults with congenital heart disease, however, the differences in metabolic syndrome-related metabolite levels in adults with congenital heart disease compared to the healthy population were unknown. Methods We collected 18 studies reporting metabolic syndrome-associated metabolite levels in patients with congenital heart disease. Data from different studies were combined under a random-effects model using Cohen’s d values. Results The results found that the levels of total cholesterol (Cohen’s d -0.68, 95% CI: -0.91 to -0.45), high-density lipoprotein cholesterol (Cohen’s d -0.63, 95% CI: -0.89 to -0.37), and low-density lipoprotein cholesterol (Cohen’s d -0.32, 95% CI: -0.54 to -0.10) were significantly lower in congenital heart disease patients compared with controls. Congenital heart disease patients also had a lower body mass index (Cohen’s d -0.27, 95% CI: -0.42 to -0.12) compared with controls. On the contrary, congenital heart disease patients had higher levels of hemoglobin A1c (Cohen’s d 0.93, 95% CI: 0.17 to 1.70) than controls. Meanwhile, there were no significant differences in triglyceride (Cohen’s d 0.07, 95% CI: -0.09 to 0.23), blood glucose (Cohen’s d -0.12, 95% CI: -0.94 to 0.70) levels, systolic (Cohen’s d 0.07, 95% CI: -0.30 to 0.45) and diastolic blood pressure (Cohen’s d -0.10, 95% CI: -0.39 to 0.19) between congenital heart disease patients and controls. Conclusions The lipid levels in patients with congenital heart disease were significantly lower than those in the control group. These data will help in the health management of patients with congenital heart disease and guide clinicians. PROSPERO registration number CRD42022228156.

The aging timescale of particles is a key parameter in determining their impacts on air quality, human health, and climate. In this study, a one-year simulation of the age distributions of the primary and secondary inorganic fine particulate matter (PM2.5) components was conducted over China using an age-resolved Community Multiscale Air Quality (CMAQ) model. The results indicate that primary PM2.5 (PPM) and ammonium mainly originate from fresh local emissions, with approximately 60%–80% concentrated in 0–24 h age bins in most of China throughout the year. The average age is about 15–25 h in most regions in summer, but increases to 40–50 h in southern region of China and the Sichuan Basin (SCB) in winter. Sulfate is more aged than PPM, indicating an enhanced contribution from regional transport. Aged sulfate with atmospheric age > 48 h account for 30%–50% of total sulfate in most regions and seasons, and the concentrations in the > 96 h age bin can reach up to 15 µg·m−3 in SCB during winter. Dramatic seasonal variations occur in the Yangtze River Delta, Pearl River Delta, and SCB, with highest average age of 60–70 h in winter and lowest of 40–45 h in summer. The average age of nitrate is 20–30 h in summer and increases to 40–50 h in winter. The enhanced deposition rate of nitric acid vapor combined with the faster chemical reaction rate of nitrogen oxides leads to a lower atmospheric age in summer. Additionally, on pollution days, the contributions of old age bins (> 24 h) increase notably for both PPM and secondary inorganic aerosols in most cities and seasons, suggesting that regional transport plays a vital role during haze events. The age information of PM2.5, provided by the age-resolved CMAQ model, can help policymakers design effective emergent emission control measures to eliminate severe haze episodes.

(1) Background: Sophora subprostrate, is the dried root and rhizome of Sophora tonkinensis Gagnep. Sophora subprostrate polysaccharide (SSP1) was extracted from Sophora subprostrate, which has shown good anti-inflammatory and antioxidant effects. Previous studies showed SSP1 could modulate inflammatory damage induced by porcine circovirus type 2 (PCV2) in murine splenic lymphocytes, but the specific regulatory mechanism is unclear. (2) Methods: Whole transcriptome analysis was used to characterize the differentially expressed mRNA, lncRNA, and miRNA in PCV2-infected cells and SSP1-treated infected cells. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and other analyses were used to screen for key inflammation-related differentially expressed genes. The sequencing results were verified by RT-qPCR, and western blot was used to verify the key protein in main enriched signal pathways. (3) Results: SSP1 can regulate inflammation-related gene changes induced by PCV2, and its interventional mechanism is mainly involved in the key differential miRNA including miR-7032-y, miR-328-y, and miR-484-z. These inflammation-related genes were mainly enriched in the TNF signal pathway and NF-κB signal pathway, and SSP1 could significantly inhibit the protein expression levels of p-IκB, p-p65, TNF-α, IRF1, GBP2 and p-SAMHD1 to alleviate inflammatory damage. (4) Conclusions: The mechanism of SSP1 regulating PCV2-induced murine splenic lymphocyte inflammation was explored from a whole transcriptome perspective, which provides a theoretical basis for the practical application of SSP1.

Abstract Background Maize has many kernel colors, from white to dark black. However, research on the color and nutritional quality of the different varieties is limited. The color of the maize grain is an important characteristic. Colored maize is rich in nutrients, which have received attention for their role in diet-related chronic diseases and have different degrees of anti-stress protection for animal and human health. Methods A comprehensive metabolome (LC-MS/MS) and transcriptome analysis was performed in this study to compare different colored maize varieties from the perspective of multiple recombination in order to study the nutritional value of maize with different colors and the molecular mechanism of color formation. Results Maize kernels with diverse colors contain different types of health-promoting compounds, highlighting that different maize varieties can be used as functional foods according to human needs. Among them, red-purple and purple-black maize contain more flavonoids than white and yellow kernels. Purple-black kernels have a high content of amino acids and nucleotides, while red-purple kernels significantly accumulate sugar alcohols and lipids. Conclusion Our study can provide insights for improving people’s diets and provide a theoretical basis for the study of food structure for chronic diseases.

Abstract Cyclin D1 (CCND1), a crucial mediator of cell cycle progression, possesses many mutation types with different mutation frequencies in human cancers. The G870A mutation is the most common mutation in CCND1, which produces two isoforms: full-length CCND1a and divergent C-terminal CCND1b. The dysregulation of the CCND1 isoforms is associated with multiple human cancers. Exploring the molecular mechanism of CCND1 isoforms has offer new insight for cancer treatment. On this basis, the alterations of CCND1 gene are described, including amplification, overexpression, and mutation, especially the G870A mutation. Subsequently, we review the characteristics of CCND1 isoforms caused by G870A mutation. Additionally, we summarize cis-regulatory elements, trans-acting factors, and the splice mutation involved in splicing regulation of CCND1. Furthermore, we highlight the function of CCND1 isoforms in cell cycle, invasion, and metastasis in cancers. Importantly, the clinical role of CCND1 isoforms is also discussed, particularly concerning prognosis, chemotherapy, and radiotherapy. Last, emphasis is given to the corrective strategies that modulate the cancerous CCND1 isoforms. Thus, it is highlighting significance of aberrant isoforms of CCND1 as targets for cancer therapy.

Abstract Remdesivir (GS-5734; VEKLURY) is a single diastereomer monophosphoramidate prodrug of an adenosine analog (GS-441524). Remdesivir is taken up by target cells and metabolized in multiple steps to form the active nucleoside triphosphate (GS-443902), which acts as a potent inhibitor of viral RNA-dependent RNA polymerases. Remdesivir and GS-441524 have antiviral activity against multiple RNA viruses. Here, we expand the evaluation of remdesivir’s antiviral activity to members of the families Flaviviridae, Picornaviridae, Filoviridae, Orthomyxoviridae, and Hepadnaviridae. Using cell-based assays, we show that remdesivir can inhibit infection of flaviviruses (such as dengue 1–4, West Nile, yellow fever, Zika viruses), picornaviruses (such as enterovirus and rhinovirus), and filoviruses (such as various Ebola, Marburg, and Sudan virus isolates, including novel geographic isolates), but is ineffective or is significantly less effective against orthomyxoviruses (influenza A and B viruses), or hepadnaviruses B, D, and E. In addition, remdesivir shows no antagonistic effect when combined with favipiravir, another broadly acting antiviral nucleoside analog, and has minimal interaction with a panel of concomitant medications. Our data further support remdesivir as a broad-spectrum antiviral agent that has the potential to address multiple unmet medical needs, including those related to antiviral pandemic preparedness.

Abstract TP53, a crucial tumor suppressor gene, is the most commonly mutated gene in human cancers. Aside from losing its tumor suppressor function, mutant p53 (mutp53) often acquires inherent, novel oncogenic functions, which is termed “gain-of-function”. Emerging evidence suggests that mutp53 is highly associated with advanced malignancies and poor prognosis, which makes it a target for development of novel cancer therapies. Herein, we provide a summary of our knowledge of the mutp53 types and mutp53 spectrum in cancers. The mechanisms of mutp53 accumulation and gain-of-function are also summarized. Furthermore, we discuss the gain-of-function of mutp53 in cancers: genetic instability, ferroptosis, microenvironment, and stemness. Importantly, the role of mutp53 in the clinic is also discussed, particularly with regard to chemotherapy and radiotherapy. Last, emphasis is given to emerging strategies on how to target mutp53 for tumor therapy. Thus, this review will contribute to better understanding of the significance of mutp53 as a target for therapeutic strategies.

Abstract The war against cancer traces back to the signature event half-a-century ago when the US National Cancer Act was signed into law. The cancer crusade costs trillions with disappointing returns, teasing the possibility of a new breakthrough. Cure for cancer post-metastases still seems tantalisingly out of reach. Once metastasized, cancer-related death is extremely difficult, if not impossible, to be reversed. Here we present cancer pre-metastasis chemoprevention strategy that can prevent circulating tumour cells (CTCs) from initiating metastases safely and effectively, and is disparate from the traditional cancer chemotherapy and cancer chemoprevention. Deep learning of the biology of CTCs and their disseminating organotropism, complexity of their adhesion to endothelial niche reveals that if the adhesion of CTCs to their metastasis niche (the first and the most important part in cancer metastatic cascade) can be pharmaceutically interrupted, the lethal metastatic cascade could be prevented from getting initiated. We analyse the key inflammatory and adhesive factors contributing to CTC adhesion/germination, provide pharmacological fundamentals for abortifacients to intervene CTC adhesion to the distant metastasis sites. The adhesion/inhibition ratio (AIR) is defined for selecting the best cancer metastasis chemopreventive candidates. The successful development of such new therapeutic modalities for cancer metastasis chemoprevention has great potential to revolutionise the current ineffective post-metastasis treatments.

The emergence of a vaccine against hepatitis B has proven to be an important milestone in the prevention of this disease; however, 5%–10% of vaccinated individuals do not generate an immune response to the vaccine, and its molecular mechanism has not been clarified. In this study, single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from three volunteers with a high immune response (HR) and three with no immune response (NR) to the hepatitis B vaccine. We found that the antigen-presenting activity scores of various antigen-presenting cells, the mitogen-activated protein kinase (MAPK) pathway activity scores of naive B cells, and the cell activity scores of three types of effector T cells were significantly decreased, whereas the cytotoxicity scores of CD3highCD16lowKLRG1high natural killer T (NKT) cells were significantly increased in the NR group compared with those in the HR group. Additionally, the expression levels of some classical molecules associated with distinct signaling pathways—including HLA-B, HLA-DRB5, BLNK, BLK, IL4R, SCIMP, JUN, CEBPB, NDFIP1, and TXNIP—were significantly reduced in corresponding subsets of PBMCs from the NR group relative to those of the HR group. Furthermore, the expression of several cytotoxicity-related effector molecules, such as GNLY, NKG7, GZMB, GZMM, KLRC1, KLRD1, PRF1, CST7, and CTSW, was significantly higher in CD3highCD16lowKLRG1high NKT cells derived from non-responders. Our study provides a molecular basis for the lack of response to the hepatitis B vaccine, including defective antigen presentation, decreased T cell activity, and reduced IL-4 secretion, as well as novel insight into the role of NKT cells in the immune response to the hepatitis B vaccine.

Background: Centrosomal Protein 55 (CEP55) was initially described as a main participant in the final stage of cytokinesis. Further research identified CEP55 as a cancer-testis antigen (CTA) that is aberrantly expressed in different malignancies and a cancer vaccination candidate. The current study aimed to disclose the complete expression of CEP55, its effect on various malignancy prognoses, and its role in the tumor microenvironment.Methods: Transcriptional information regarding tumor and normal tissues, as well as externally validated and protein expression data were gathered from the Cancer Genome Atlas, Genotype-Tissue Expression project, Gene Expression Omnibus, and Human Protein Atlas. We examined the effect of CEP55 on tumor prognosis using Kaplan-Meier (KM) and univariate Cox regression analyses. In addition, we investigated the connections between CEP55 expression and hallmark cancer pathways, immune cell infiltration, and immune regulator expression across malignancies. We constructed and validated a CEP55-related risk model for hepatocellular carcinoma (HCC) and explored the correlations between CEP55 expression and HCC molecular subtypes. Finally, we investigated putative small-molecule drugs targeting CEP55 using a connectivity map (CMap) database and validated them using molecular docking analysis.Findings: CEP55 was aberrantly expressed in most cancers and revealed a prognostic value for several malignancies. Cancers with high CEP55 expression showed significantly enhanced cell cycle, proliferation, and immune-related pathways. For most malignancies, elevated CEP55 expression was associated with the infiltration of myeloid-derived suppressor cells (MDSCs) and Th2 cells. In addition, CEP55 expression was linked to immunomodulators and the potential prediction of immune checkpoint inhibitor (ICI) responses, and strongly associated with distinct molecular HCC subtypes, whereby the CEP55-based nomogram performed well in predicting short- and long-term HCC survival. Finally, we used connectivity map (CMap) and molecular docking analyses to discover three candidate small-molecule drugs that could directly bind to CEP55.Conclusion: CEP55 affected the occurrence and development of various cancers and possibly the regulation of the tumor immune microenvironment. Our findings suggest that CEP55 is a potential biomarker for prognosis and a powerful biomarker for ICI efficacy prediction.

Acylglycerols in natural oils includes monoacylglycerols (MAG), diacylglycerols (DAG) and triacylglycerols (TAG). Each acylglycerol possesses different isomers, which results in variation in physicochemical and nutritional properties that can be used in various applications. Acyl migration is a spontaneous reaction involving the transition of acylglycerols into more stable isomers. Inhibition of acyl migration is beneficial for the application of different acylglycerol isomers. Whilst, the promotion of acyl migration positively impacts the synthesis of acylglycerols, altering the properties and improving the stability of the lipid system. Few studies have been performed recently on the synthesis of various acylglycerol isomers and the approach to control the acyl migration of acylglycerols. This paper discusses the preparation of acylglycerols isomers, the factors influencing acyl migration and the application of the isomers of acylglycerols, which is important for expanding the use of different isomeric acylglycerols as functional foods.

ObjectiveThis study aimed to investigate the role of spectral detector computed tomography (SDCT) quantitative parameters and their derived quantitative parameters combined with lesion morphological information in the differential diagnosis of solid SPNs.MethodsThis retrospective study included basic clinical data and SDCT images of 132 patients with pathologically confirmed SPNs (102 and 30 patients in the malignant and benign groups, respectively). The morphological signs of SPNs were evaluated and the region of interest (ROI) was delineated from the lesion to extract and calculate the relevant SDCT quantitative parameters, and standardise the process. Differences in qualitative and quantitative parameters between the groups were statistically analysed. A receiver operating characteristic (ROC) curve was constructed to evaluate the efficacy of the corresponding parameters in the diagnosis of benign and malignant SPNs. Statistically significant clinical data, CT signs and SDCT quantitative parameters were analysed using multivariate logistic regression to determine the independent risk factors for predicting benign and malignant SPNs, and the best multi-parameter regression model was established. Inter-observer repeatability was assessed using the intraclass correlation coefficient (ICC) and Bland–Altman plots.ResultsMalignant SPNs differed from benign SPNs in terms of size, lesion morphology, short spicule sign, and vascular enrichment sign (P< 0.05). The SDCT quantitative parameters and their derived quantitative parameters of malignant SPNs (SAR40keV, SAR70keV, Δ40keV, Δ70keV, CER40keV, CER70keV, NEF40keV, NEF70keV, λ, NIC, NZeff) were significantly higher than those of benign SPNs (P< 0.05). In the subgroup analysis, most parameters could distinguish between benign and adenocarcinoma groups (SAR40keV, SAR70keV, Δ40keV, Δ70keV, CER40keV, CER70keV, NEF40keV, NEF70keV, λ, NIC, and NZeff), and between benign and squamous cell carcinoma groups (SAR40keV, SAR70keV, Δ40keV, Δ70keV, NEF40keV, NEF70keV, λ, and NIC). However, there were no significant differences between the parameters in the adenocarcinoma and squamous cell carcinoma groups. ROC curve analysis indicated that NIC, NEF70keV, and NEF40keV had higher diagnostic efficacy for differentiating benign and malignant SPNs (area under the curve [AUC]:0.869, 0.854, and 0.853, respectively), and NIC was the highest. Multivariate logistic regression analysis showed that size (OR=1.138, 95% CI 1.022-1.267, P=0.019), Δ70keV (OR=1.060, 95% CI 1.002-1.122, P=0.043), and NIC (OR=7.758, 95% CI 1.966-30.612, P=0.003) were independent risk factors for the prediction of benign and malignant SPNs. ROC curve analysis showed that the AUC of size, Δ70keV, NIC, and a combination of the three for differential diagnosis of benign and malignant SPNs were 0.636, 0.846, 0.869, and 0.903, respectively. The AUC for the combined parameters was the largest, and the sensitivity, specificity, and accuracy were 88.2%, 83.3% and 86.4%, respectively. The SDCT quantitative parameters and their derived quantitative parameters in this study exhibited satisfactory inter-observer repeatability (ICC: 0.811-0.997).ConclusionSDCT quantitative parameters and their derivatives can be helpful in the differential diagnosis of benign and malignant solid SPNs. The quantitative parameter, NIC, is superior to the other relevant quantitative parameters and when NIC is combined with lesion size and Δ70keV value for comprehensive diagnosis, the efficacy could be further improved.

Background: Locally advanced cervical cancer (LACC) is frequently treated with neoadjuvant chemotherapy (NACT), which includes paclitaxel and platinum. However, the development of severe chemotherapy toxicity is a barrier to successful NACT. Phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT) pathway is related to the occurrence of chemotherapeutic toxicity. In this research work, we employ a random forest (RF) machine learning model to forecast NACT toxicity (neurological, gastrointestinal, and hematological reactions). Materials and Methods: Twenty-four single nucleotide polymorphisms (SNPs) in the PI3K/AKT pathway from 259 LACC patients were used to construct a dataset. Following the data preprocessing, the RF model was trained. The Mean Decrease in Impurity approach was adopted to evaluate the relevance of 70 selected genotypes' importance by comparing chemotherapy toxicity grades 1–2 vs. 3. Results: In the Mean Decrease in Impurity analysis, neurological toxicity was much more likely to occur in LACC patients with homozygous AA in Akt2 rs7259541 than in those with AG or GG genotypes. The CT genotype of PTEN rs532678 and the CT genotype of Akt1 rs2494739 increased the risk of neurological toxicity. The top three loci were rs4558508, rs17431184, and rs1130233, which were attributed to an elevated risk of gastrointestinal toxicity. LACC patients who had heterozygous AG in Akt2 rs7259541 exhibited an obviously greater risk of hematological toxicity than those who had AA or GG genotypes. And the CT genotype for Akt1 rs2494739 and the CC genotype in PTEN rs926091 showed a tendency to increase the risk of suffering from hematological toxicity. Conclusion: Akt2 rs7259541 and rs4558508, Akt1 rs2494739 and rs1130233, PTEN rs532678, rs17431184, and rs926091 polymorphisms are associated with different toxic effects during the chemotherapy treatment of LACC.

Background: The PI3K/Akt pathway involves in regulating resistance to platinum-based neoadjuvant chemotherapy (NACT) in locally advanced cervical cancer (LACC) patients. Single nucleotide polymorphisms (SNPs) reflect the basic genetic variation between individuals. Random forest (RF) is one of the machine-learning models that can predict drug sensitivity with high accuracy. We applied the RF model for genomic prediction of NACT sensitivity in LACC patients. Materials and Methods: A total of 259 LACC patients were separated to two groups (i) effective and (ii) ineffective NACT group, depending on the NACT response. The 24 SNPs in four genes (PTEN, PIK3CA, Akt1, and Akt2) were genotyped by the Sequenom MassArray system in these patients. We implemented the SNPs as the feature to train the RF model, calculated the feature importance using mean decreases in impurity based on the model, and further analyzed the importance of each SNP. Results: The importance analysis indicated that the top three SNPs (rs4558508, rs1130233, and rs7259541) and the last six loci (rs892120, rs62107593, rs34716810, rs10416620, rs41275748, and rs41275746) were all located in Akt. The patients carrying heterozygous GA in Akt2 rs4558508 had a considerably higher risk of chemoresistance than those carrying GG or AA genotype. Conclusion: The RF model could accurately predict the response to platinum-based NACT of LACC patients. The variables of Akt2 rs4558508 and rs7259541, and Akt1 rs1130233 were major polymorphic loci for NACT inefficiency. The LACC patients carrying heterozygous GA of Akt2 rs4558508 had a significantly increased risk of chemoresistance. Akt was an important gene in PI3K/Akt pathway that could predict the response of platinum-based NACT. The study applied the basis for an individualized approach to LACC patient therapy.

Abstract Diabetic retinopathy attracts considerable research interest due to the number of diabetic patients increasing rapidly in recent years. Diabetic retinopathy is a common symptom of retinopathy, which damages the patient's eyesight and even causes the patient to lose sight. The authors propose a novel attention mechanism named block attention mechanism to actively explore the role of attention mechanisms in recognizing retinopathy features. Specifically, the block attention mechanism contributions are as follows: (1) The relationship between the blocks in the entire feature map is explored, and the corresponding coefficients are assigned to different blocks to highlight the importance of blocks. (2) Furthermore, the relationship between the edge elements of the feature map and the edge elements is explored, and corresponding coefficients are assigned to the elements at different positions on the feature map to highlight the importance of the elements in the feature map. Experimental results show that the proposed framework outperforms the existing popular attention‐based baselines on two public retina datasets, OCT2017 and SD‐OCT, achieving a 99.64% and 96.54% accuracy rate, respectively.

Abstract Background Mesenchymal stem cells (MSC) hold great promise for treating cardiovascular disease. Recently, we genetically modified MSCs with high mobility group box 1 (HMGB1), and these cells demonstrated high mobility by efficient migrating and homing to target neointima. The possible mechanism was investigated in the current study. Methods Rat MSCs were transfected with lentivirus containing HMGB1 cDNA to yield MSC-H cell line stably overexpressing HMGB1. The MSC-C cells which were transfected with empty lentivirus served as negative control, and the differentially expressed genes were analyzed by microarray. The cell mobility was determined by transwell migration assay. Intracellular free calcium and the expression of Cav3.2 T-type calcium channel (CACNA1H) were assayed to analyze activity of CACNA1H-mediated calcium influx. H2S production and γ-cystathionase expression were examined to assess the activity of γ-cystathionase/H2S signaling. The interaction of HMGB1 with γ-cystathionase in MSC-H cells was analyzed by co-immunoprecipitation. Luciferase reporter assay was performed to determine whether the promoter activity of γ-cystathionase was regulated by interaction of β-catenin and TCF/LEF binding site. Intercellular cAMP, PKA activity, phosphorylation of β-catenin, and GSK3β were investigated to reveal cAMP/PKA mediated β-catenin activation. Result Microarray analysis revealed that differentially expressed genes were enriched in cAMP signaling and calcium signaling. CACNA1H was upregulated to increase intracellular free calcium and MSC-H cell migration. Blockage of CACNA1H by ABT-639 significantly reduced intracellular free calcium and cell migration. The γ-cystathionase/H2S signaling was responsible for CACNA1H activation. H2S production was increased with high expression of γ-cystathionase in MSC-H cells, which was blocked by γ-cystathionase inhibitor DL-propargylglycine. Upregulation of γ-cystathionase was not attributed to interaction with HMGB1 overexpressed in MSC-H cells although γ-cystathionase was suggested to co-immunoprecipitate with oxidized HMGB1. Bioinformatics analysis identified a conserved TCF/LEF binding site in the promoter of γ-cystathionase gene. Luciferase reporter assay confirmed that the promoter had positive response to β-catenin which was activated in MSC-H cells. Finally, cAMP/PKA was activated to phosphorylate β-catenin at Ser657 and GSK3β, enabling persisting activation of Wnt/β-catenin signaling in MSC-H cells. Conclusion Our study revealed that modification of MSCs with HMGB1 promoted CACNA1H-mediated calcium influx via PKA/β-catenin/γ-cystathionase pathway. This was a plausible mechanism for high mobility of MSC-H cell line.

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 bp with low or no protein-coding ability, which play essential roles in various biological processes in plants. Tobacco is an ideal model plant for studying nicotine biosynthesis and metabolism, and there is little research on lncRNAs in this field. Therefore, how to take advantage of the mature tobacco system to profoundly investigate the lncRNAs involved in the nicotine pathway is intriguing. By exploiting 549 public RNA-Seq datasets of tobacco, 30,212 lncRNA candidates were identified, including 24,084 large intervening non-coding RNAs (lincRNAs), 5,778 natural antisense transcripts (NATs) and 350 intronic non-coding RNAs (incRNAs). Compared with protein-coding genes, lncRNAs have distinct properties in terms of exon number, sequence length, A/U content, and tissue-specific expression pattern. lincRNAs showed an asymmetric evolutionary pattern, with a higher proportion (68.71%) expressed from the Nicotiana sylvestris (S) subgenome. We predicted the potential cis/trans-regulatory effects on protein-coding genes. One hundred four lncRNAs were detected as precursors of 30 known microRNA (miRNA) family members, and 110 lncRNAs were expected to be the potential endogenous target mimics for 39 miRNAs. By combining the results of weighted gene co-expression network analysis with the differentially expressed gene analysis of topping RNA-seq data, we constructed a sub-network containing eight lncRNAs and 25 nicotine-related coding genes. We confirmed that the expression of seven lncRNAs could be affected by MeJA treatment and may be controlled by the transcription factor NtMYC2 using a quantitative PCR assay and gene editing. The results suggested that lncRNAs are involved in the nicotine pathway. Our findings further deepened the understanding of the features and functions of lncRNAs and provided new candidates for regulating nicotine biosynthesis in tobacco.

Carboxylesterases (CXE) are a class of hydrolytic enzymes with α/β-folding domains that play a vital role in plant growth, development, stress response, and activation of herbicide-active substances. In this study, 49 Nicotiana tabacum L. CXE genes (NtCXEs) were identified using a sequence homology search. The basic characteristics, phylogenetic evolution, gene structure, subcellular location, promoter cis-elements, and gene expression patterns of the CXE family were systematically analyzed. RNA-seq data and quantitative real-time PCR showed that the expression level of CXEs was associated with various stressors and hormones; gene expression levels were significantly different among the eight tissues examined and at different developmental periods. As a new class of hormones, strigolactones (SLs) are released from the roots of plants and can control the germination of axillary buds.NtCXE7, NtCXE9, NtCXE22, and NtCXE24 were homologous to Arabidopsis SLs hydrolase AtCXE15, and changes in their expression levels were induced by topping and by GR24 (a synthetic analogue of strigolactone). Further examination revealed that NtCXE22-mutant (ntcxe22) plants generated by CRISPR-Cas9 technology had shorter bud outgrowth with lower SLs content. Validation of NtCXE22 was also performed in NtCCD8-OE plants (with fewer axillary buds) and in ntccd8 mutant plants (with more axillary buds). The results suggest that NtCXE22 may act as an efficient SLs hydrolase and affects axillary bud development, thereby providing a feasible method for manipulating endogenous SLs in crops and ornamental plants.

Abstract To examine the feasibility of quantitative dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) in the early assessment of the therapeutic response to concurrent chemoradiotherapy (CRT) in esophageal cancer (EC) patients and to determine its value in predicting HIF‐1α expression. EC patients underwent DCE‐MRI 1 week pre‐CRT and 3 weeks post‐CRT (3w‐CRT). According to tumor regression post‐treatment, patients were divided into sensitive group (SG) and resistant group (RG). HIF‐1α expression was assessed by immunohistochemistry (IHC). Quantitative parameters (ktrans, kep, and ve) were compared between the SG and RG groups, as well as between the HIF‐1α(+) and HIF‐1α(−) groups. Receiver operating characteristic (ROC) curve analysis was performed to detect the best predictor of the above parameters in the therapeutic response and in predicting HIF‐1α expression. Totally 34 and 5 patients were included in the SG and RG, respectively. Pre‐ktrans and pre‐kep were decreased significantly in the SG at 3w‐CRT (p

Projecting future air pollution and related health burdens remains challenging because of the complex interactions among future emissions, population, and climate change. In this study, we estimated the premature deaths attributed to ambient fine particulate matter (PM2.5) and ozone (O3) from 2015 to 2100 under four socioeconomic climate scenarios based on an age-stratified assessment method. We found that PM2.5 will decrease in all shared socioeconomic pathway (SSP) scenarios and O3 will decrease in the SSP1-2.6 and SSP2-4.5 scenarios, contributing to a decrease in premature mortality together with the declining total population in China. However, the benefits of a decline in population size and PM2.5 and O3 concentrations over time will be largely offset by population aging, and premature death caused by PM2.5 and O3 will continue to rise till 2060–2080. This impact was greater for the O3-related deaths than those for PM2.5. Our study highlights the importance of future prevention strategies that must jointly improve air quality and susceptibility to aging.

The treatment of complex cerebrovascular diseases (CCVDs) at the skull base, such as complex intracranial aneurysms, carotid-cavernous sinus fistulas, and intracranial artery traumatic injuries, is a difficult clinical problem despite advances in endovascular and surgical therapies. Covered stents or stent graft insertion is a new concept for endovascular treatment that focuses on arterial wall defect reconstruction, differing from endovascular lesion embolization or flow diverter therapies. In recent years, covered stents specifically designed for cerebrovascular treatment have been applied in the clinical setting, allowing thousands of patients with CCVDs to undergo intraluminal reconstruction treatment and achieving positive results, even in the era of flow diverters. Since there is no unified reference standard for the application of covered stents for treating CCVDs, it is necessary to further standardize and guide the clinical application of this technique. Thus, we organized authoritative experts in the field of neurointervention in China to write an expert consensus, which aims to summarize the results of covered stent insertion in the treatment of CCVDs and propose suitable standards for its application in the clinical setting. Based on the contents of this consensus, clinicians can use individualized intraluminal reconstruction treatment techniques for patients with CCVDs.

Amino acids are vital nitrogen (N) sources for plant growth, development, and yield. The uptake and translocation of amino acids are mediated by amino acid transporters (AATs). The AATs family including lysine-histidine transporters (LHTs), amino acid permeases (AAPs), and proline transporters (ProTs) subfamilies have been identified in various plants. However, little is known about these genes in tobacco. In this study, we identified 23 LHT genes, the important members of AATs, in the tobacco genome. The gene structure, phylogenetic tree, transmembrane helices, chromosomal distribution, cis-regulatory elements, and expression profiles of NtLHT genes were systematically analyzed. Phylogenetic analysis divided the 23 NtLHT genes into two conserved subgroups. Expression profiles confirmed that the NtLHT genes were differentially expressed in various tissues, indicating their potential roles in tobacco growth and development. Cis-elements analysis of promoters and expression patterns after stress treatments suggested that NtLHT genes probable participate in abiotic stress responses of tobacco. In addition, Knock out and overexpression of NtLHT22 changed the amino acids homeostasis in the transgenic plants, the contents of amino acids were significantly decreased in NtLHT22 overexpression plants than wild-type. The results from this study provide important information for further studies on the molecular functions of the NtLHT genes.

Metastasis is the leading cause of cancer-related death and a critical challenge in improving cancer treatment today. Circulating tumor cells (CTCs) adhesion to and across the vascular endothelium are critical steps in the establishment of micrometastatic foci away from the primary tumor. Therefore, we believe that interrupting CTCs adhesion to endothelium and transendothelial migration may efficiently prevent cancer metastasis. Fucoxanthin (Fx) is an algal carotenoid widely distributed in brown algae, macroalgae, and diatoms. Previous studies have found that Fx has various pharmacological activities, including antidiabetic, antioxidant, anti-inflammatory, anti-obesity, antimalarial, anticancer, and so on. However, it remains unclear whether Fx has a preventive effect on cancer metastasis. Here, we found that Fx interrupts breast cancer cells MCF-7 adhesion to endothelium and transendothelial migration, thus inhibiting CTCs-based pulmonary metastasis in vivo. The hetero-adhesion assay showed that Fx significantly inhibited the expression of inflammatory factor-induced cell adhesion molecules (CAMs) and the resulting adhesion between MCF-7 cells and endothelial cells. The wound-healing and transwell assays showed that Fx significantly inhibited the motility, invasion, and transendothelial migration abilities of MCF-7 cells. However, the same concentration of Fx did not significantly alter the cell viability, cell cycle, apoptosis, and ROS of breast cancer cells, thus excluding the possibility that Fx inhibits MCF-7 cell adhesion and transendothelial migration through cytotoxicity. Mechanistically, Fx inhibits the expression of CAMs on endothelial cells by inhibiting the NF-кB signaling pathway by down-regulating the phosphorylation level of IKK-α/β, IкB-α, and NF-кB p65. Fx inhibits transendothelial migration of MCF-7 cells by inhibiting Epithelial-to-mesenchymal transition (EMT), PI3K/AKT, and FAK/Paxillin signaling pathways. Moreover, we demonstrated that Fx significantly inhibits the formation of lung micrometastatic foci in immunocompetent syngeneic mouse breast cancer metastasis models. We also showed that Fx enhances antitumor immune responses by substantially increasing the subsets of cytotoxic T lymphocytes in the peripheral immune system. This new finding provides a basis for the application of Fx in cancer metastatic chemoprevention and suggests that interruption of the CTCs adhesion to endothelium and transendothelial migration may serve as a new avenue for cancer metastatic chemoprevention.

This paper addresses the problem of coherence, i.e., whether the internal and external dimensions of li (礼 rituals, rites, and the observance of them) are compatible. This problem stems mainly from Mencius’ seemingly conflicting statements. On the one hand, he emphasized the goodness of xing (性 human nature) in terms of the goodness of the heart-mind. On the other hand, he defended the act of following li regardless of one’s heart-mind. This paper argues that Mencius held coherent moral reasons internalism, asserting that moral reasons are embedded in people’s universal and potential instinct to do morally good things. Consequently, he distinguished morality from non-moral normativity and claimed that the former takes precedence over the latter. The concept of li is thus divided into moral li and non-moral li, with moral li taking precedence over non-moral li. Therefore, the act of “following li regardless of one’s heart-mind” refers to following non-moral li, as long as it does not conflict with moral li. Based on the fact that Mencius’ concept of li is a kind of coherent moral reasons internalism, this paper further responds to some challenges from moral reasons externalism. It does so by clarifying the meaning of “seeking the cause within oneself” (反求诸己 fan qiu zhu ji), showing that Mencius believed every individual could establish rational inner guidance and be motivated to lead a reflective and autonomous moral life.

Around 11% of all known gene lesions causing human genetic diseases are nonsense mutations that introduce a premature stop codon (PTC) into the protein-coding gene sequence. Drug-induced PTC readthrough is a promising therapeutic strategy for treating hereditary diseases caused by nonsense mutations. To date, it has been found that more than 50 small-molecular compounds can promote PTC readthrough, known as translational readthrough-inducing drugs (TRIDs), and can be divided into two major categories: aminoglycosides and non-aminoglycosides. This review summarizes the pharmacodynamics and clinical application potential of the main TRIDs discovered so far, especially some newly discovered TRIDs in the past decade. The discovery of these TRIDs brings hope for treating nonsense mutations in various genetic diseases. Further research is still needed to deeply understand the mechanism of eukaryotic cell termination and drug-induced PTC readthrough so that patients can achieve the greatest benefit from the various TRID treatments.

Abstract RNA-binding motif protein 39 (RBM39), as a key factor in tumor-targeted mRNA and protein expression, not only plays a vital role in tumorigenesis, but also has broad development prospects in clinical treatment and drug research. Moreover, since RBM39 was identified as a target of sulfonamides, it has played a key role in the emerging field of molecule drug development. Hence, it is of great significance to study the interaction between RBM39 and tumors and the clinical application of drug-targeted therapy. In this paper, we describe the possible multi-level regulation of RBM39, including gene transcription, protein translation, and alternative splicing. Importantly, the molecular function of RBM39 as an important splicing factor in most common tumors is systematically outlined. Furthermore, we briefly introduce RBM39’s tumor-targeted drug research and its clinical application, hoping to give reference significance for the molecular mechanism of RBM39 in tumors, and provide reliable ideas for in-depth research for future therapeutic strategies.

TiFe0.5Ni0.5Sb-based half-Heusler compounds have the intrinsic low lattice thermal conductivity and the adjustable band structure. Inspired by the previously reports to achieve both p- and n-type components by tuning the ratio of Fe and Ni based on the same parent TiFe0.5Ni0.5Sb, we selected Co as the amphoteric dopants to prepare both n-type and p-type pseudo-ternary Ti(Fe, Co, Ni)Sb-based half-Heusler alloys. The carrier concentration, as well as the density of states effective mass was significantly increased by Co doping, contributing to the enhanced power factor of 1.80 mW m−1 K−2 for n-type TiFe0.3Co0.2Ni0.5Sb and 2.21 mW m−1 K−2 for p-type TiFe0.5Co0.15Ni0.35Sb at 973 K. Combined with the further decreased lattice thermal conductivity due to the strain field and mass fluctuation scattering induced by alloying Hf on the Ti site, peak ZTs of 0.65 in n-type Ti0.8Hf0.2Fe0.3Co0.2Ni0.5Sb and 0.85 in p-type Ti0.8Hf0.2Fe0.5Co0.15Ni0.35Sb were achieved at 973 K, which is of great significance for the thermoelectric power generation applications.

Abstract Bcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

Particulate nitrate (pNO3) is now becoming the principal component of PM2.5 during severe winter haze episodes in many cities of China. To gain a comprehensive understanding of the key factors controlling pNO3 formation and driving its trends, we reviewed the recent pNO3 modeling studies which mainly focused on the formation mechanism and recent trends of pNO3 as well as its responses to emission controls in China. The results indicate that although recent chemical transport models (CTMs) can reasonably capture the spatial–temporal variations of pNO3, model-observation biases still exist due to large uncertainties in the parameterization of dinitrogen pentoxide (N2O5) uptake and ammonia (NH3) emissions, insufficient heterogeneous reaction mechanism, and the predicted low sulfate concentrations in current CTMs. The heterogeneous hydrolysis of N2O5 dominates nocturnal pNO3 formation, however, the contribution to total pNO3 varies among studies, ranging from 21.0% to 51.6%. Moreover, the continuously increasing PM2.5 pNO3 fraction in recent years is mainly due to the decreased sulfur dioxide emissions, the enhanced atmospheric oxidation capacity (AOC), and the weakened nitrate deposition. Reducing NH3 emissions is found to be the most effective control strategy for mitigating pNO3 pollution in China. This review suggests that more field measurements are needed to constrain the parameterization of heterogeneous N2O5 and nitrogen dioxide (NO2) uptake. Future studies are also needed to quantify the relationships of pNO3 to AOC, O3, NOx, and volatile organic compounds (VOCs) in different regions of China under different meteorological conditions. Research on multiple-pollutant control strategies involving NH3, NOX, and VOCs is required to mitigate pNO3 pollution, especially during severe winter haze events.

Hereditary Spastic Paraplegia (HSP) is considered to be one of the common neurodegenerative diseases with marked genetic heterogeneity. Recently, the mutations in ubiquitin-associated protein 1 (UBAP1) have been described in patients with HSP, known as spastic paraplegias 80 (SPG80). Here, we reported a Chinese HSP family presenting a frameshift mutation in the UBAP1 gene leading to complex HSP. Their clinical features encompassed spastic paraparetic gait, exaggerated patellar tendon reflexes, bilateral Babinski signs, and hyperactive Achilles tendon reflex. The proband also had severe urinary incontinence and a dermoid cyst at the lumbar 4–5 spinal cord, which rarely occurs in HSP patients. Following whole-exome sequencing, a novel heterozygous mutation (c.437dupG, NM_016,525) was identified in the UBAP1 that segregated with the family’s phenotype and resulted in truncating UBAP1 protein (p.Ser146ArgfsTer13). Moreover, we reviewed the genotypes of UBAP1 and the phenotypic variability in 90 HSP patients reported in the literature. We found that the age of onset in UBAP1-related patients was juvenile, and there were population differences in the age of onset. The main complications were lower extremity spasticity, hyperreflexia, and the Babinski sign. Exon 4 of UBAP1 was identified as a mutation hotspot region. Our study expands the knowledge of UBAP1 mutations, which will aid in HSP patient counseling. Further molecular biological research is needed to explore the genotype-phenotype correlations of UBAP1-related HSP.

BackgroundBlood blister aneurysm (BBA) is a complex and rare aneurysm that presents significant treatment challenges. The application of pipeline embolization device (PED)-assisted coiling in the treatment of ruptured BBA remains controversial. This study aimed to report on our experience and assess the safety and efficacy of this strategy.MethodsBetween February 2019 and February 2021, 12 patients with ruptured BBAs underwent PED-assisted coil embolization. We collected detailed data about each patient, including demographic information, aneurysmal data, technical details, antiplatelet strategy, operation-related complications, and follow-up outcomes.ResultsA total of 12 BBA patients were treated with single PED-assisted coil embolization. One patient experienced intraoperative rupture that was controlled by rapid coiling without clinical consequences. All the patients demonstrated complete occlusion on postoperative angiography. A total of three patients had postoperative complications: left hemiparesis, Broca's aphasia, and right hemiplegia due to vasospasm, and transient hemiparesis. Follow-up angiography revealed that all BBAs were completely occluded, except one with neck residue. All patients had favorable outcomes at discharge and the most recent clinical follow-up (mRS score ≤ 2).ConclusionEndovascular treatment of BBAs of the internal carotid artery using PED-assisted coil embolization is a safe and effective strategy. This has contributed to the understanding of BBA therapy and provides a potentially optimal treatment option for this intractable lesion.

This study utilizes the Weather Research and Forecasting model with a higher resolution (36 km × 36 km) to dynamically downscale the Community Earth System Model results forced by the three representative concentration pathways (RCP) scenarios (RCP4.5, RCP6.0, and RCP8.5) over China. The goal was to compare meteorological fields during the present (2006–2015) and future (2046–2055) climatological periods. An appropriate air stagnation judgment index was selected to explore the effect of climate change on air quality-related meteorological conditions. The results show that the occurrence of wintertime air stagnation over China in the middle of this century (2046–2055) will reduce slightly, with the largest reduction projected under the RCP8.5 scenario (−4 times). However, long-lasting air stagnation events (ASE) are projected to increase in the future, and this increasing trend is more obvious under the RCP8.5 scenario. The projected increase in the long-lasting ASE in different regions of China ranges from 3 to 11 times. Among these, Central China has the largest increase, followed by East and Northeast China, while South China has the lowest increase in ASE. Our results indicate that more attention should be dedicated to extreme pollution events that may potentially be caused by long-lasting air stagnation events in the future.

Chemotherapy-induced neutropenia (CIN) is a potentially fatal and common complication in myelosuppressive chemotherapy. The timing and grade of CIN may play prognostic and predictive roles in cancer therapy. CIN is associated with older age, poor functional and nutritional status, the presence of significant comorbidities, the type of cancer, previous chemotherapy cycles, the stage of the disease, specific chemotherapy regimens, and combined therapies. There are many key points and new challenges in the management of CIN in adults including: (1) Genetic risk factors to evaluate the patient’s risk for CIN remain unclear. However, these risk factors urgently need to be identified. (2) Febrile neutropenia (FN) remains one of the most common reasons for oncological emergency. No consensus nomogram for FN risk assessment has been established. (3) Different assessment tools [e.g., Multinational Association for Supportive Care in Cancer (MASCC), the Clinical Index of Stable Febrile Neutropenia (CISNE) score model, and other tools] have been suggested to help stratify the risk of complications in patients with FN. However, current tools have limitations. The CISNE score model is useful to support decision-making, especially for patients with stable FN. (4) There are still some challenges, including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN. In view of the current reports, our group discusses the key points, new challenges, and management of CIN.

Cracks in the skin of jujube fruit reduce freshness and quality; thus, greater understanding of the molecular mechanism that underlies cracking is required to improve fruit production. In this study, we profiled genes that are differentially expressed between cracked and normal jujube fruits through RNA sequencing (RNA‐seq). We selectively confirmed differentially expressed genes (DEGs) using quantitative RT‐PCR. Among 1036 DEGs, 785 genes were up‐regulated and 251 genes were down‐regulated in cracked jujube fruits. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that some of these DEGs encode proteins involved in metabolic processes (including growth hormone and surface wax production) in cracked jujube fruits. In summary, we have identified differentially expressed metabolic genes between cracked and normal jujube fruits, which may serve as the basis for further studies of fruit quality control.

Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). Here, the authors use ratiometrically designed nanoparticles to codeliver the CDK4/6 inhibitor palbociclib and the autophagy inhibitor hydroxychloroquine, and show their synergistic therapeutic effects in mouse model of PDAC.

Long non-coding RNAs (lncRNAs) regulate gene expression and are crucial for plant growth and development. However, the mechanisms underlying the effects of activated lncRNAs on axillary bud development remain largely unknown. By lncRNA transcriptomes of axillary buds in topped and untopped tobacco plants, we identified a total of 13,694 lncRNAs. LncRNA analysis indicated that the promoted growth of axillary bud by topping might be partially ascribed to the genes related to hormone signal transduction and glycometabolism, trans-regulated by differentially expressed lncRNAs, such as MSTRG.52498.1, MSTRG.60026.1, MSTRG.17770.1, and MSTRG.32431.1. Metabolite profiling indicated that auxin, abscisic acid and gibberellin were decreased in axillary buds of topped tobacco lines, while cytokinin was increased, consistent with the expression levels of related lncRNAs. MSTRG.52498.1, MSTRG.60026.1, MSTRG.17770.1, and MSTRG.32431.1 were shown to be influenced by hormones and sucrose treatments, and were associated with changes of axillary bud growth in the overexpression of NtCCD8 plants (with reduced axillary buds) and RNA interference of NtTB1 plants (with increased axillary buds). Moreover, MSTRG.28151.1 was identified as the antisense lncRNA of NtTB1. Silencing of MSTRG.28151.1 in tobacco significantly attenuated the expression of NtTB1 and resulted in larger axillary buds, suggesting the vital function of MSTRG.28151.1 axillary bud developmen by NtTB1. Our findings shed light on lncRNA-mRNA interactions and their functional roles in axillary bud growth, which would improve our understanding of lncRNAs as important regulators of axillary bud development and plant architecture.

Oncogenic exosomes can circulate in the blood, but their selective removal has not been possible. Here the authors show that aptamer-functionalised mesoporous silica nanoparticles can find to a specific population of circulating exosomes and eliminate them via the hepatobiliary route.

Introduction: Spinal epidural arteriovenous fistulas (SEDAVFs) are extremely rare and the pathological process still remains unclear. Nevertheless, neurofibromatosis, surgery, as well as trauma have been implicated as causes. Nevertheless, long standing chronic vertebral compression fractures (VCFs) as a cause of SEDAVFs has not been reported in literature. Case presentation: Our cases comprised of a male and female with ages 67 and 62 year respectively. They presented with weakness of bilateral lower extremities and back pain. Their symptoms deteriorated into mild recto-bladder dysfunction as well as hypoesthesia of lower limbs. They both had history of road traffic accidents (RTAs) prior to their symptomatology. In both cases, Magnetic resonance imaging (MRI) revealed VCFs prior to the above symptomatology. Spinal digital subtraction angiography (DSA) was used to confirm SEDAVFs in both cases. We utilized the trans-arterial route with Onyx embolization agent to obliterate both fistulae and their debilitating symptomatology resolved after the embolization because they were caused by the acute SEDAVF. Two-years follow-ups revealed no recurrence of their fistulae. Conclusion: The initial long standing VCFs caused by trauma resulted in perforation of the dorsal somatic branches of the radicular artery leading to the occurrences of SEDAVFs in our cases.

Background: Pipeline Flex embolization device (PLED) is a specific management modality for adults with intracranial aneurysms (IAs). The technical characteristics of the PLED aid in safe as well as extremely efficient usage. We present our experience of attempted and non-attempted resolution of wall malapposition in ICAs and vertebral artery aneurysms with associated cavernous ICA (cICA) tortuosity’s. Methods: We conducted a retrospective study to identify PLED wall malapposition from April 2018 to July 2019. We assessed various degrees of vascular tortuosity’s, aneurysm characteristics, immediate wall apposition, postoperative resolution of wall malapposition, postoperative follow-up of patients with wall malapposition as well as wall malapposition related complications. The patients were put into two category such as attempt resolution and non-attempted resolution (conservative treatments) groups. Results: We treated a total of 118 patients with PLED out of which 22 patients (18.6%) had wall malapposition. All patients were treated with a single PLEDs. Coils were used to obliterate the aneurysms in nine patients. Adequate aneurysm neck coverage was achieved in all cases. Resolution of wall malapposition was attempted in 13 patients while no resolution was attempted in nine patients intraoperatively. Out of the 22 patients with wall malapposition, 14 of them (63.64%) did not resolve in both groups. These 14 patients were put into follow-up sequence category. Conclusion: Attempted resolution may not be suitable for certain aneurysms in very angulated ICAs with associated cICA tortuosity. Interestingly, spontaneous resolution of wall malapposition of PLED didn’t occur as we anticipated in most of our conservative treatment category.

This paper presents a theoretical and experimental study on the flame trajectory of a non-vertical turbulent diffusion flame in still air. A series of propane turbulent flame tests (inner diameter of the burner: d=13 mm) with different initial Froude numbers Fr0 (31.4, 125.5, 282.3, 501.8, and 784.1) and initial flame angles θ0 (60∘, 45∘, 30∘, 15∘, 0∘, −30∘, and −45∘) are performed. The flame motion is physically described based on the Favre-averaged governing equations. The effects of buoyancy and streamline curvature on turbulent mixing are characterized by the mixing length theory. By theoretical derivations, a Richardson number (Ria) is proposed to characterize the flame asymmetry, and a flame trajectory predictive model coupled with the effect of flame asymmetry is established. Experimental results indicate that under the same conditions, the flame curvature first increases and then decreases (eventually tends to be zero) with the continuous increase of Fr0, and increases gradually with the decrease of θ0. A flame intermittency fitting method and a temperature fitting method based on the normal bi-Gaussian distribution are proposed to determine the flame trajectory under different flame asymmetry. These methods are validated by experimental data. It is found that in the near field where the flame is curved, the peak trajectory deviates from the flame midline. In the far field, as the flame recovers to be symmetric, the peak trajectory tends to coincide with the flame midline. Furthermore, experimental data verify that the proposed model can accurately predict the flame trajectory under different flame asymmetry. Finally, results indicate that, under the same conditions, the effect of flame asymmetry on the flame trajectory first increases and then decreases (eventually disappears) with the continuous increase of Fr0, and increases continuously with the decrease of θ0. Comparison between model prediction and experimental data verifies that Ria is the key parameter for the flame asymmetry.

In order to solve the problems of high missed rate and easily damaged seeds in traditional garlic metering devices, an air suction garlic seed metering device was designed. The critical components include a seed tray and a seed disturbing tooth. Seed contour curve fitting and a discrete element method were used to determine the initial parameters. The optimal parameter combinations were obtained through fluid dynamics simulation. With a higher pass seeding rate and a lower missed seeding rate as the goal, the device has been optimized for parameters. The best combination of parameters was obtained: the number of type holes was 9; the diameter of holes was 7.2 mm; the forward speed was 1 km/h; the working negative pressure was −5.5 kPa; the pass seeding rate was 88.54%; and the missed seeding rate was 6.34%. Field trials had shown that the air suction garlic seed metering device designed in this study satisfied the requirements of garlic cultivation. Three tests were conducted and a pass rate of 87.83% and a missed rate of 6.85% were obtained.

Climate changes occurring today require detailed research of the effects of increasing temperatures on photosynthesis in different species and cultivars. Temperature variability is a crucial determinant of the yield and quality of plants, particularly when high-temperature episodes coincide with their growth and fruit development. The effect of high temperature (HT) on higher plants primarily concerns photosynthetic functions, but the sensitivity of photosynthesis to high temperature is not well-understood in kiwifruits. In this study, we designed a new environmental monitoring system to evaluate the effects of environmental factors on the photosynthetic physiology of different kiwifruit species and cultivars. A significant positive correlation was determined between the main photosynthetic indices of kiwifruits, such as transpiration rate and net photosynthetic rate. The net photosynthetic rate of commercial kiwifruit cultivars was strongly inhibited when the temperature exceeded 44.5 °C, and the leaves of kiwifruits were irreversibly damaged when the temperature increased to 52 °C. Kiwifruit cultivars with different ploidy levels (diploid, tetraploid and hexaploid) were found to be sensitive to high temperature, whereas tetraploids had higher HT resistance and hexaploids had the highest net photosynthetic rate. Further research showed that the HT tolerance of kiwifruits existed not only between species but also among cultivars. A. eriantha had the highest net photosynthetic rate at more than 44.7 °C, but those of A. deliciosa and A. arguta declined sharply as the temperature exceeded 43.5 °C. As a result, it was determined that high temperatures have important effects on the photosynthetic activities of kiwifruit plants with different ploidy levels, and that these effects can significantly change their development according to how they differ among different species/cultivars.