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Abstract Background Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, lacks targeted therapies, posing a substantial challenge for treatment. Therefore, investigating its pathogenesis is a crucial research focus. FOXA1 and miR-634 are involved in tumorigenesis. However, the molecular mechanisms underlying the aberrant upregulation of FOXA1 expression in TNBC remain unclear. Therefore, we explore the role of miR-634 in the FOXA1-positive TNBC subtype. Methods Quantitative reverse transcription polymerase chain reaction was used to detect miR-634 expression in breast cancer tissues and cell lines. Aberrantly activated signaling pathways and related genes in TNBC were analyzed using The Cancer Genome Atlas. The potential target of miR-634 was predicted by TargetScan, the TNBC cell proliferation rate was detected using an MTT assay, the in vitro metastatic capacity was determined by transwell assay and the cell cycle distribution was tested using flow cytometry. Western blotting was performed to measure the expression of proteins involved in the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Results The expression of miR-634 was significantly down-regulated in both TNBC tissues and cells, compared with adjacent non-cancerous tissues and MCF10A, respectively. Ectopic expression of miR-634 inhibits breast cancer cell proliferation and in vitro metastasis. The TCGA-based expression profile analysis of TNBC revealed that aberrantly activated PI3K/AKT signaling may contribute to its malignant phenotype. FOXA1, the top hit of aberrantly upregulated genes in TNBC, was a direct target of miR-643. Moreover, forced expression of miR-643 drastically suppressed FOXA1 expression by the inactivation PI3K/AKT signaling. Conclusion MiR-634 suppresses FOXA1 to inhibit the proliferation and metastasis of TNBC cells by inactivating the PI3K/AKT signaling pathway.

Abstract Background Gastric cancer (GC) is a common upper gastrointestinal tumor. However, the evaluation of prognosis and treatment response in patients with gastric cancer remains a challenge. Programmed cell death (PCD) is one of the important terminal paths for the cells of metazoans, and is involved in a variety of biological events that include morphogenesis, maintenance of tissue homeostasis, and elimination of harmful cells. The objective of this project is to investigate the predictive significance of cell death pathways and create prognostic signatures associated to cell death, with the purpose of forecasting prognosis and providing guidance for the treatment of gastric cancer. Methods Gene transcription profiles and corresponding clinical data of gastric cancer patients were collected from The Cancer Genome Atlas (TCGA-STAD, n = 448) and the Gene Expression Comprehensive Database (GSE84437, n = 483). Thirteen types of cell death-related genes, including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, cuprotosis, parthanatos, entotic cell death, netotic cell death, lysosome-dependent cell death, alkaliptosis, oxeiptosis, and disulfidptosis, were analysed. Cell death-related genes associated with prognosis were identified in the TCGA-STAD training cohort using Lasso-Cox regression to generate a risk score. Patients were categorized into high and low-risk groups based on the median risk score for survival difference analysis. Cell death-related genes associated with prognosis were identified in the TCGA-STAD training cohort using Lasso-Cox regression to generate a risk score. Additionally, the response to immunotherapy in the high-risk and low-risk groups was calculated using the oncoPredict algorithm. Futhermore, the model genes were validated in the GEO validation set. Results A total of 324 differential programmed cell death (PCD)-related genes were identified, and 65 were selected through single-factor Cox analysis. Six PCD-related genes were ultimately identified by Lasso regression to construct a prognostic risk score model. The log-rank test revealed that patients in the high-risk group had inferior survival time compared with those in the low-risk group. The area under the ROC curve (AUC) for the training group at years 1, 3, and 5 were 0.684, 0.713, 0.743, respectively, while the AUC for the validation cohort at years 1, 3, and 5 were 0.695, 0.704, and 0.707, respectively. Unsupervised clustering identified potential subtypes included in the model, and a survival difference was also observed between the two subgroups. Multifactor Cox results, combined with clinical information, demonstrated that the prognostic risk score can serve as an independent prognostic factor, irrespective of other clinical features. Conclusion By comprehensively analyzing multiple cell death patterns, we have established a novel model that accurately forecasts the clinical prognosis and drug sensitivity of gastric cancer. It was found that all 12 representative drugs may not be suitable for patients in high-risk groups.

Abstract Immune-mediated liver injury is a common characteristic of various liver diseases, including autoimmune and viral hepatitis. Here, we investigated the role of DEAD-box helicase 3, X-linked (DDX3X) in immune-mediated liver injury. Liver injury was induced in C57BL/6J mice via concanavalin A (Con A). DDX3X hepatocyte-specific knockout (DDX3XΔHep) mice and control (DDX3Xfl/fl) mice were utilized to investigate the role of DDX3X in liver injury. Primary hepatocytes were treated with tunicamycin (TM) to induce ER stress in vitro. The expression of DDX3X in patients with various liver diseases was evaluated. Hepatic DDX3X expression increased, and DDX3X translocated from the cytoplasm to the nucleus during Con A-induced liver injury. DDX3X deficiency ameliorated mouse liver injury and reduced ER stress in liver tissue. The inhibition of ER stress with 4-PBA significantly attenuated liver injury while decreasing DDX3X levels in liver tissue. However, the upregulation of hepatic DDX3X expression reversed Con A-induced liver injury and negated the protective effect of 4-PBA. Mechanistically, the nuclear translocation of DDX3X promoted ER stress-induced apoptosis through the transcriptional induction of CHOP. Moreover, DDX3X was elevated and translocated into the nucleus in patients with HBV-LF and AIH. Additionally, serum DDX3X levels markedly increased in patients with HBV-LF, and a consistent decrease in DDX3X was associated with a good prognosis. The cytoplasmic-to-nuclear translocation of DDX3X promotes ER stress-induced apoptosis, which is an obligatory step that drives hepatic necrosis and tissue damage. Notably, DDX3X is a potential therapeutic target for immune-mediated liver injury.

With the aggravation of energy shortage and ecological deterioration, it becomes more and more essential for China to improve energy efficiency and realize the targets of energy conservation and emission reduction. This paper focuses on the measurement of the total factor energy efficiency (TFEE), the potentials of energy conservation and emission reduction, and the influencing factors of TFEE in China. Firstly, the model of Gray Weight Slack-Based Measure (GW-SBM) is established, with the weights of the indicators obtained via the grey relational analysis method, to calculate the TFEE of thirty provinces and six regions in China from 2009 to 2019. Then, the potentials of energy conservation and emission reduction are analyzed on the basis of TFEE measurements. Finally, the influencing factors of TFEE are identified via the truncated bootstrap model. The findings show that the TFEE values of 30 provinces fluctuate in the range of 0.20 and 1.0, varying significantly among provinces. Energy conservation potential reached 8.7490 million tons of standard coal (potential 39.06%), which means that more than one-third of energy consumption is inefficient. The top two factors in the TFEE measurement identified by the truncated bootstrap model, are energy consumption structure and environmental protection expenditure. Based on the research conclusions, this paper puts forward some countermeasures and suggestions.

Solid-liquid phase-change materials (PCMs) offer exciting prospects for thermal energy conservation, whose performance is greatly affected by the carrier materials. Using expanded vermiculite (EV) as frameworks, carbon nanotube arrays (CNTs) were grown between EV layers by chemical vapor deposition (CVD). Then, the paraffin (PA) was loaded on the EV@CNTs composite by vacuum impregnation to prepare composite PCMs (PA/EV@CNTs), where the PA is organic carrier and the EV@CNTs acts as porous supports with high structural strength. The loading capacity of PA is further regulated by the hydrotropism of CNTs which effectively prevents the leakage of molten PA. The in-situ grown CNTs significantly improves the thermal conductivity of PCMs, improving the efficiency of energy conversion. With maximum PA loading capacity of 95 wt%, the thermal conductivity of PA/EV@CNTs-95% reaching 0.7176 W/mK, which was 1.73 and 2.96 times higher than that of pristine EV and PA. The phase change latent heat of PA/EV@CNTs-95% was measured to be 168.54 J/g, which is 1.48 times higher than that of PA/EV. After 100 cycles, the PA/EV@CNTs still maintains excellent thermal stability, and the enthalpy retention rate is 98.73%. The incorporation of high thermal conductivity amphipathicity CNTs in these PCMs makes them promising candidate for various applications such as energy-efficient buildings, thermal management in electronic devices, and self-cleaning materials.

BackgroundObservational studies have shown that oxidative stress (OS) is associated with Parkinson’s disease (PD). However, whether such observations reflect cause–effect remains largely unknown. To test this, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to investigate the causal-effects between OS biomarkers and PD.MethodsWe selected summary statistics data for single-nucleotide polymorphisms (SNPs) associated with catalase (n = 13), glutathione peroxidases (n = 12), superoxide dismutase (n = 13), vitamin A (n = 7), vitamin C (n = 10), vitamin E (n = 12), vitamin B12 (n = 8), folate (n = 14), copper (n = 6), Zinc (n = 7), and iron (n = 23) levels, and the corresponding data for PD from the International Parkinson Disease Genomics Consortium (IPDGC, 33,674 cases and 449,056 controls). Inverse-variance weighted (IVW) MR analyses were conducted to estimate associations of OS with PD. Reverse MR analysis was further performed to predict the causal effects of PD on the above OS biomarkers.ResultsAs for PD, the IVW method suggested that the Zinc (Zn) levels was significantly associated with PD (OR = 1.107, 95% CI 1.013–1.211; p = 0.025), which is consistent with results from the weighted median analyses. Moreover, the results remained consistent and robust in the sensitivity analysis. However, there were no significant associations of catalase, glutathione peroxidases, superoxide dismutase, vitamin A, vitamin C, vitamin E, vitamin B12, folate, copper, or iron with PD. As for OS, our reverse MR analysis also did not support a causal effect of liability to PD on OS.ConclusionThe MR study supported the causal effect of Zn on PD. These findings may inform prevention strategies and interventions directed toward OS and PD.

Background/Purpose: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is capable of causing serious community and hospital-acquired infections. However, currently, the identification of CRKP is complex and inefficient. Hence, this study aimed to develop methods for the early and effective identification of CRKP to allow reasonable antimicrobial therapy in a timely manner. Methods: K. pneumoniae (KP)-, K. pneumoniae carbapenemase (KPC)- and New Delhi metallo-β-lactamase (NDM)- specific CRISPR RNAs (crRNAs), polymerase chain reaction (PCR) primers and recombinase-aided amplification (RAA) primers were designed and screened in conserved sequence regions. We established fluorescence and lateral flow strip assays based on CRISPR/Cas13a combined with PCR and RAA, respectively, to assist in the detection of CRKP. Sixty-one clinical strains (including 51 CRKP strains and 10 carbapenem-sensitive strains) were collected for clinical validation. Results: Using the PCR-CRISPR assay, the limit of detection (LOD) for KP and the blaKPC and blaNDM genes reached 1 copy/μL with the fluorescence signal readout. Using the RAA-CRISPR assay, the LOD could reach 101 copies/μL with both the fluorescence signal readout and the lateral flow strip readout. Additionally, the positivity rates of CRKP-positive samples detected by the PCR/RAA-CRISPR fluorescence and RAA-CRISPR lateral flow strip methods was 92.16% (47/51). The sensitivity and specificity reached 100% for KP and blaKPC and blaNDM gene detection. For detection in a simulated environmental sample, 1 CFU/cm2 KP could be detected. Conclusion: We established PCR/RAA-CRISPR assays for the detection of blaKPC and blaNDM carbapenemase genes, as well as KP, to facilitate the detection of CRKP.

BackgroundGonadotrophin-releasing hormone (GnRH) administration significantly decreases the pregnancy rate of recipient ewes after embryo transfer, possibly because GnRH affects endometrial epithelial cell function. Therefore, this study investigated the effect of GnRH on endometrial epithelial cells.MethodsTranscriptome sequencing was used to determine the regulatory effect of GnRH on the ewe endometrium, and the S100A4 gene, which showed altered transcription, was screened as a candidate regulator of this effect. Endometrial epithelial cells were further isolated, the S100A4 protein was immunoprecipitated, and host proteins that interacted with S100A4 were identified by mass spectrometry. We further verified the effects of S100A4 and GNAI2 on the proliferation of endometrial epithelial cells via overexpression/knockdown experiments and subsequent CCK-8 and EdU assays. The effect of S100A4 deletion in endometrial cells on reproduction was verified in mice with S100A4 knockout.ResultsOur results showed that S100A4 gene transcription in endometrial cells was significantly inhibited after GnRH administration. GNAI2 was identified as a downstream interacting protein of S100A4, and S100A4 was confirmed to activate the MAPK signaling pathway to promote cell proliferation by targeting GNAI2.ConclusionGnRH can suppress the expression of S100A4 in the endometrium, consequently inhibiting the proliferation of endometrial cells through the S100A4/GNAI2/MAPK signaling pathway. These findings suggest a potential explanation for the limited efficacy of GnRH in promoting embryo implantation.

BackgroundAcute liver injury (ALI), which is a type of inflammation-mediated hepatocellular injury, is a clinical syndrome that results from hepatocellular apoptosis and hemorrhagic necrosis. Apoptosis stimulating protein of p53-2 (ASPP2) is a proapoptotic member of the p53 binding protein family. However, the role of ASPP2 in the pathogenesis of ALI and its regulatory mechanisms remain unclear.MethodsThe expression of ASPP2 were compared between liver biopsies derived from patients with CHB, patients with ALI, and normal controls. Acute liver injury was modelled in mice by administration of D-GalN/LPS. Liver injury was demonstrated by serum transaminases and histological assessment of liver sections. ASPP2-knockdown mice (ASPP2+/−) were used to determine its role in acute liver injury. Mouse bone marrow macrophages (BMMs) were isolated from wildtype and ASPP2+/- mice and stimulated with LPS, and the supernatant was collected to incubate with the primary hepatocytes. Quantitative real-time PCR and western blot were used to analyze the expression level of target.ResultsThe expression of ASPP2 was significantly upregulated in the liver tissue of ALI patients and acute liver injury mice. ASPP2+/- mice significantly relieved liver injury through reducing liver inflammation and decreasing hepatocyte apoptosis. Moreover, the conditioned medium (CM) of ASPP2+/- bone marrow-derived macrophages (BMMs) protected hepatocytes against apoptosis. Mechanistically, we revealed that ASPP2 deficiency in BMMs specifically upregulated IL-6 through autophagy activation, which decreased the level of TNF-α to reduce hepatocytes apoptosis. Furthermore, up-regulation of ASPP2 sensitizes hepatocytes to TNF-α-induced apoptosis.ConclusionOur novel findings show the critical role of ASPP2 in inflammatory immunoregulatory mechanism of ALI and provide a rationale to target ASPP2 as a refined therapeutic strategy to ameliorate acute liver injury.

Abstract Lithium niobate on insulator (LNOI) is widely recognized as an essential optoelectronic integration platform due to its unique ferroelectric properties and photorefractive effect. However, the wide bandgap and weak absorption of lithium niobate limit its further application in integrated photodetection field. To address this issue, encapsulating silver nanoparticles within the LNOI structure are proposed to manipulate the light field distribution of modified lithium niobate through the localized surface plasmon resonance (LSPR) effect and utilize the modified lithium niobate thin film as a functional substrate to tailor the optoelectronic properties of surface SnSe2 nanosheets, significantly enhancing their photodetection capabilities. The photocurrent of the SnSe2 photodetector based on LNOI with embedded Ag nanoparticles is enhanced by up to 1912 times compared to that on the original LNOI under the same conditions, which represents the highest reported plasmonic‐induced photodetection enhancement. This work deepens the basic research on plasmonic‐modified 2D materials and ferroelectric materials, which promotes the development of on‐chip photodetectors and the realization of fully functional photonic circuits that integrate all essential components on a single chip.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Background/Aims: To investigate the autoantibody against fumarate hydratase (FH), which is a specific liver failure-associated antigen (LFAA) and determine whether it can be used as a biomarker to evaluate the prognosis of acute-on-chronic liver failure (ACLF). Methods: An immunoproteomic approach was applied to screen specific LFAAs related to differential prognosis of ACLF (n=60). Enzyme-linked immunosorbent assay (ELISA) technology was employed for the validation of the frequency and titer of autoantibodies against FH in ACLF patients with different prognoses (n=82). Moreover, we clarified the expression of autoantibodies against FH in patients with chronic hepatitis B (n=60) and hepatitis B virus-related liver cirrhosis (n=60). The dynamic changes in the titers of autoantibodies against FH were analyzed by sample collection at multiple time points during the clinical course of eight ACLF patients with different prognoses. Results: Ultimately, 15 LFAAs were screened and identified by the immunoproteomic approach. Based on ELISA-based verification, anti-FH/Fumarate hydratase protein autoantibody was chosen to verify its expression in ACLF patients. ACLF patients had a much higher anti-FH autoantibody frequency (76.8%) than patients with liver cirrhosis (10%, p=0.000), patients with chronic hepatitis B (6.7%, p=0.022), and normal humans (0%, p=0.000). More importantly, the frequency and titer of anti-FH protein autoantibodies in the serum of ACLF patients with a good prognosis were much higher than that of patients with a poor prognosis (83.9% vs 61.5%, p=0.019; 1.41±0.85 vs 0.94±0.56, p=0.017, respectively). The titer of anti-FH autoantibodies showed dynamic changes in the clinical course of ACLF. Conclusions: The anti-FH autoantibody in serum may be a potential biomarker for predicting the prognosis of ACLF.

Tumors represent a significant threat to human health, underscoring the critical need for effective treatment strategies. However, conventional drug therapies are hampered by imprecise delivery, potentially leading to inadequate efficacy and severe side effects. The strategic development of nanomedicines is believed to harbor enormous potential for enhancing drug safety and efficacy, especially for precise, tumor-targeted therapies. Nevertheless, the fate of these nanomedicines within the human body is intricately governed by various physiological barriers and complex environments, posing challenges to predicting their behaviors. Near-infrared II (NIR-II, 1000–1700 nm) fluorescence imaging technology serves as a non-invasive, real-time monitoring method that can be applied for the precise evaluation of nanomedicine delivery in cancer therapy due to its numerous advantages, including high tissue penetration depth, high spatiotemporal resolution, and high signal-to-noise ratio. In this review, we comprehensively summarize the pivotal role of NIR-II fluorescence imaging in guiding the intratumoral precise delivery of nanomedicines and shed light on its current applications, challenges, and promising prospects in this field.

Abstract Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance.

Abstract Background Structural maintenance of chromosomes protein 1 A (SMC1A) is a crucial subunit of the cohesion protein complex and plays a vital role in cell cycle regulation, genomic stability maintenance, chromosome dynamics. Recent studies demonstrated that SMC1A participates in tumorigenesis. This reseach aims to explore the role and the underlying mechanisms of SMC1A in gastric cancer (GC). Materials and methods RT-qPCR and western blot were used to examine the expression levels of SMC1A in GC tissues and cell lines. The role of SMC1A on GC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) were analyzed. Furthermore,the mechanism of SMC1A action was investigated. Results SMC1A was highly expressed in GC tissues and cell lines. The high expression of SMC1A indicated the poor overall survival of GC patients from Kaplan-Meier Plotter. Enhancing the expression of SMC1A in AGS cells remarkably promoted cell proliferation in vitro and in vivo, migration and invasion, Conversely, knockdown of SMC1A in HGC27 cells inhibited cell proliferation, migration and invasion. Moreover, it’s observed that SMC1A promoted EMT and malignant cell behaviors via regulating SNAIL. Conclusion Our study revealed that SMC1A promotes EMT process by upregulating SNAIL, which contributes to gastric cancer cell proliferation, migration and invasion. Therefore, targeting SMC1A may be a potential strategy to improve GC therapy.

The most important thing for wetlands as terrestrial ecosystems is carbon, which is an important way to slow down the rise of dihydride carbon content in the global atmosphere and global warming. At present, most studies focus on carbon storage and carbon density in natural wetlands. However, there are relatively few studies on carbon density and its changes in coal mining collapse wetlands. Based on the investigation of carbon content and influencing factors in water bodies and sediments of coal mining subsidence wetlands, this paper studies the carbon exchange fluxes of different forms at the sediment-water interface of coal mining subsidence wetlands, evaluates the source/sink characteristics of sediments for carbon in overlying water, and discusses the changes of the exchange fluxes of various forms of carbon at the sediment-water interface under the single and interactive interaction of different environmental factors. The sediment and overlying water were collected in December 2020, April 2021 and August 2021, respectively, to analyze the occurrence characteristics of carbon in the sediment and water and the key factors affecting carbon content in the coal mining collapse wetland of Jiuli Lake. The dissolved carbon exchange fluxes at the sediment-water interface were studied through laboratory simulation experiments, and the effects of major environmental factors on dissolved carbon exchange fluxes were discussed. Finally, a regression model of dissolved carbon exchange flux at the sediment-water interface was constructed based on the response surface method to predict the minimum release conditions of dissolved carbon in coal mining subsidence wetlands and estimate the total amount of dissolved carbon release in coal mining subsidence wetlands. The results are as follows: temperature increase leads to the increase of dissolved carbon exchange flux, while pH has little effect on it; The exchange fluxes of dissolved organic carbon (DOC) and dissolved inorganic carbon (DIC) were relatively high under high oxygen (9.0 mg/L) and low oxygen (3.0 mg/L) conditions, and relatively small under medium oxygen (6.0 mg/L) conditions. The optimal conditions under the interaction of environmental factors are obtained. When the temperature is 5.69 ℃, the pH is 7.18, and the DO is 6.38 mg/L the minimum exchange flux region of DOC and DIC is 2.32 and 3.54 mg/(m2·h), respectively. It was estimated that the total amount of DOC and DIC released in wetland sediments in August was the highest, which was 1.75 t and 5.76 t respectively. The total release of DOC and DIC was the lowest in December, which were 0.98 t and 2.01 t, respectively. The results showed that the environmental factors had different degrees of influence on the exchange fluxes of DOC and DIC, and the exchange fluxes of DOC and DIC increased with the increase of temperature by changing the adsorption capacity and biological activity. pH affects the solubility of carbonate in the sediment, so DIC does not increase significantly in alkaline environment, but has little effect on DOC exchange flux. The variation law of total release of DOC and DIC is consistent. The high temperature in summer and strong microbial activity in sediments promote the release of DOC and DIC in the upward overlying water, while the low temperature in winter significantly reduces the release effect. Only temperature, pH and DO are considered for dissolved carbon exchange fluxes at the sediment-water interface. However, factors affecting the migration and transformation of substances at the sediment-water interface include the characteristics of sediments themselves, bioturbation and heavy metals, etc. For wetlands formed by coal mining, the release of dissolved carbon by metal ions in sediments should be paid more attention. In the following research, microorganisms can be used as the starting point to explore the critical conditions for the conversion of sediment carbon “source” and “sink”.

Abstract Background Progressive familial intrahepatic cholestasis (PFIC) is a group of rapidly progressive autosomal recessive disorders characterized by intrahepatic cholestasis. PFIC-3 is caused by mutations in the ATP-binding cassette subfamily B member 4 gene (ABCB4), which encodes multidrug resistance protein 3 (MDR3/ABCB4). Patients are usually in infancy or childhood, but cirrhosis and portal hypertension may be the first manifestation in older children or young adults. Case presentation A 25-year-old young woman with recurrent abnormal hepatic function was mainly characterized by increased gamma glutamyl transpeptidase (GGT) and bile acid with cryptogenic cirrhosis. After 7 months of treatment with ursodeoxycholic acid (UDCA), her hepatic pathology suggested there were also obvious widening and venous fibrosis around the portal vein, and slight bile duct hyperplasia at the edge of the portal area. Infiltration of inflammatory cells around the portal vein and hepatocyte ABCB4/MDR3 protein was basically normal. Sequencing indicated the patient had heterozygous mutations in the ABCB4 gene: c.2696C > G and wes [hg19]7q21.12(87032513–87033422) × 1. Through SWISS-MODEL Predict for protein structures, the missense mutation results in protein side chain missing a methyl group (-CH3), and the deletion mutation results in the serious damage to the structure of MDR3 protein which lead to phosphatidylcholine deficiency of bile in the capillary bile ducts. The toxic effect of bile salts then damages the bile ducts, causing cholestasis and cholangitis, which can then develop into biliary cirrhosis. Through the analysis of pathogenicity prediction software, the mutations led to PFIC3. After treatment of UDCA for 29 months, her cirrhosis was improved, hepatic function was close to normal. Conclusion Novel heterozygous mutations are the molecular pathological cause of PFIC3 in this patient. All young adult patients with occult cirrhosis should be tested for ABCB4. Early diagnosis of PFIC3 and continued treatment with UDCA are key to improving prognosis and delaying the onset of end-stage liver disease.

Background & Aims Hepatitis delta virus (HDV) infection accelerates the progression of chronic hepatitis B virus (HBV) infection, posing a large economic and health burden to patients. At present, there remains a lack of accurate and portable detection methods for HDV RNA. Here, we aim to establish a convenient, rapid, highly sensitive and specific method to detect HDV RNA using CRISPR–Cas13a technology.Methods We established fluorescence (F) and lateral flow strip (L) assays based on CRISPR–Cas13a combined with RT–PCR and RT-RAA for HDV RNA detection, respectively. we conducted a cohort study of 144 patients with HDV-IgG positive to evaluate the CRISPR–Cas13a diagnostic performance for identifying HDV in clinical samples, compared to RT–qPCR and RT-ddPCR.Results For synthetic HDV RNA plasmids, the sensitivity of RT–PCR-CRISPR-based fluorescence assays was 1 copy/μL, higher than that of RT–qPCR (10 copies/μL) and RT-ddPCR (10 copies/μL); for HDV RNA-positive samples, the sensitivity of RT-RAA-CRISPR-based fluorescence and lateral flow strip assays was 10 copies/μL, as low as that of RT–qPCR and RT-ddPCR, and the assay took only approximately 85 min. Additionally, the positivity rates of anti-HDV IgG-positive samples detected by the RT–qPCR, RT-ddPCR, RT–PCR-CRISPR fluorescence and RT-RAA-CRISPR lateral flow strip methods were 66.7% (96/144), 76.4% (110/144), 81.9% (118/144), and 72.2% (104/144), respectively.Conclusions We developed a highly sensitive and specific, as well as a portable and easy CRISPR-based assay for the detection of HDV RNA, which could be a prospective measure for monitoring the development of HDV infection and evaluating the therapeutic effect.

ABSTRACTBackground & Aims The WHO declared to eliminate hepatitis B virus (HBV) by 2030. However, an increasing number of patients are presenting with low-level viremia (LLV) with the widespread use of antiviral medications. The diagnostic efficiency and coverage area of HBV infection are low. Hence, this study intended to drive the HBV infection detection to effectively adaptable for any small to medium-sized laboratory or field survey.Methods We established, optimized, and evaluated a colloidal gold test strip for detection of HBV DNA based on CRISPR/Cas13a combined with recombinase-aided amplification (RAA) technology. Furthermore, 180 HBV-infected patients (including patients with different viral loads, LLV patients and dynamic plasma samples of patients on antiviral therapy) were enrolled for clinical validation.Results The strip detection of HBV DNA was established based on RAA-CRISPR-Cas13a technology with a sensitivity of 101 copies/μL and a specificity of 100%. HBV DNA gradient concentration plasmids and clinical samples were effectively identified by this approach. The positive coincidence rate for LLV patients was 87%, while the negative coincidence rate was 100%. The positive coincidence rate reached 100% in LLV patients (viral loading >100 IU/mL). The sensitivity, specificity, positive predictive agreement (PPA) and negative predictive agreement (NPA) values of dynamic plasma detection in patients on antiviral therapy were 100%, 92.15%, 93.75%, and 100%, respectively.Conclusions We develop rapid and portable RAA-CRISPR/Cas13a-based strip of HBV DNA detection for LLV patients. This study provides a visual and faster alternative to current PCR-based diagnosis for HBV infection.

Abstract Background Newcastle disease virus (NDV) is an oncolytic virus that can inhibit cancer cell proliferation and kill cancer cells. The NDV nonstructural V protein can regulate viral replication; however, whether the V protein contributes to NDV oncolysis is unclear. Results This study revealed that NDV inhibited tumor cell proliferation and that V protein expression promoted the proliferation of HepG2 cells, as determined at the single-cell level. In addition, to identify the regulatory mechanism of the V protein in HepG2 cells, transcriptome sequencing was performed and indicated that the expression/activation of multiple cell proliferation-related genes/signaling pathways were changed in cells overexpressing the V protein. Hence, the MAPK and WNT signaling pathways were selected for verification, and after blocking these two signaling pathways with inhibitors, the V protein promotion of cell proliferation was found to be attenuated. Conclusions The results showed that the V protein regulated the proliferation of cancer cells through multiple signaling pathways, providing valuable references for future studies on the mechanism by which the V protein regulates cancer cell proliferation.

The cell structure and compressive properties of extruded polyethylene terephthalate (PET) foam with different densities were studied. The die of the PET foaming extruder is a special multi-hole breaker plate, which results in a honeycomb-shaped foam block. The SEM analysis showed that the aspect ratio and cell wall thickness of the strand border is greater than that of the strand body. The cells are elongated and stronger in the extruding direction, and the foam anisotropy of the structure and compressive properties decrease with increasing density. The compression results show typical stress–strain curves even though the extruded PET foam is composed of multiple foamed strands. The compression properties of PET foam vary in each of the three directions, with the best performing direction (i.e., extrusion direction) showing stretch-dominated structures, while the other two directions show bending-dominated structures. Foam mechanics models based on both rectangular and elongated Kelvin cell geometries were considered to predict the compressive properties of PET foams in terms of relative density, structure anisotropy, and the properties of the raw polymer. The results show that the modulus and strength anisotropy of PET foam can be reasonably predicted by the rectangular cell model, but more accurate predictions were obtained with an appropriately assumed elongated Kelvin model.

The performance of plasma-facing materials (PFMs) is one of the key factors that significantly impact the stability of operation in fusion reactors. Herein, a new CrMoTaWV/W (high entropy alloy (HEA)/W) multilayer structure is designed as PFM to investigate its resistance to He plasma irradiation. It was observed that the introduction of the interfaces effectively absorbed plenty of He atoms, preventing them from diffusing into the material and delaying the formation of fuzz incubation zone, therefore, enhancing the resistance to plasma irradiation. The thickness transformed to fuzz in the HEA/W multilayer films was observed to be about two-thirds of those in the CrMoTaWV (HEA) film. Additionally, the fuzz growth rates in HEA/W multilayer films are lower than the average growth rate of bulk W and HEA films combined. These findings highlight a promising new avenue for the exploration of high-performance PFMs.

The properties of basalt fiber reinforced polypropylene composites (BF/PP) were improved by ultrasonic treatment of resin building pressure to assist melt impregnation. Combined with the study of ultrasonic pressure building theory, the mechanical properties of the modified composites were analyzed using the characterization of tensile, flexural and impact strengths in response to porosity and fracture rate. The effects of ultrasonic power, frequency and distance of action on resin building pressure and composite properties were investigated. The results showed that the best effect was achieved when the ultrasonic frequency was 25 kHz, the ultrasonic power was 300 W, and the action distance was 4 mm, at which time the porosity of the prepreg was reduced to 2.99%, the fracture rate was 3.36%, and the tensile, flexural, and impact strengths were 108.73 MPa, 116.81 MPa, and 51.59 KJ.m ^−2 .

Background and Aims: It is urgent need to develop new-effective and well-tolerable medical treatment for endometriosis, but normal drug development is tedious, costly and time-consuming. Artificial intelligence (AI) is a powerful tool to drive discovery of novel druggable targets. Here we aim to use AI to identify novel therapeutic targets for endometriosis treatment. Method: Targets associated with endometriosis were prioritized by PandaOmics (a well-established AI-driven target identification platform). Expression levels of druggable targets were tested in human endometriotic lesions. Functional characterizations of the targets were performed by in-vitro and in-vivo endometriosis models. Viability, proliferation and apoptosis were examined. Results: Analysis of 11 public endometriosis bulk transcriptomics databases revealed 2 lists of high confidence and novel druggable targets. Tow novel targets ENDO01 and ENDO02 were selected based on ranking in PandaOmics, consistency of significant dysregulated expression across comparisons, as well as literature evidence relevant to disease-driving mechanisms. Differential expressions were confirmed in human endometriosis tissues. siRNA targeting ENDO01 and ENDO02 significantly reduced cell viability and proliferation, as well as enhanced apoptosis in endometriotic cells in-vitro; and significantly decreased lesion volume and weight with reduced proliferative and enhanced apoptosis in-vivo. Conclusion: Two novel targets for endometriosis were identified with AI and validated by in-vitro and in-vivo experiments within a short period. The study demonstrated how AI could speed up the novel target discovery process from years to months. For diseases remaining incurable or with high morbidity, the application of AI in target discovery could be a new therapeutic regimen that benefits patients.

Abstract Hepatocellular carcinoma (HCC) is a common digestive malignant tumor with high morbidity and mortality worldwide, however, the treatment of HCC and prognosis of patients are not optimistic, finding more effective treatments are imperative. Taraxacum officinale (L.) Weber ex F.H.Wigg is a perennial herb of compositae, and our study has demonstrated that Taraxacum officinale polysaccharide has certain anti-tumor effect on HCC cells. Taraxasterol (TS) is a natural product extracted from Taraxacum officinale with strong physiological, pharmacological and biological activities, but the effect of TS on HCC is yet to be determined. Therefore, the aim of this study is to explore the effect of dandelion sterol on HCC in vivo and in vitro. The results showed that TS significantly inhibited the proliferation, induced apoptosis and blocked cell cycle in HCC cell lines HepG2 and Huh7 cells in vitro. TS inhibited the tumor growth of H22 bearing mice and the expression of Ki67 in vivo. More importantly, TS regulated the immunity of H22 bearing mice by elevating the ratio of CD4+ T cells in spleen, and increasing the number of T cell infiltration in tumor tissue. Except immunomodulation, the mechanism of tumor growth inhibition may be related to the regulation of apoptosis related proteins and IL-6/STAT3 pathway. TS significantly inhibited the growth of HCC cells both in vitro and in vivo. The study would provide a theoretical basis for the new application of TS and the adjuvant treatment of malignant tumor with traditional Chinese medicine.

Background and Aims Coinfection of hepatitis delta virus (HDV) with hepatitis B virus (HBV) causes the most severe form of viral hepatitis, and the global prevalence of HDV infection is underestimated. Although serological testing of anti-HDV antibodies is widely used in the diagnosis of HDV, its diagnostic efficacy remains unclear. This study aimed to evaluate the diagnostic efficacy of HDV serological tests, the results of which may assist in the diagnosis of HDV. Methods Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. The PubMed, Web of Science and Cochrane Library databases were searched from the beginning to 31 May 2023. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. STATA SE was used for the meta-analysis of the sensitivity, specificity, positive likelihood ratio and negative likelihood ratio. Results Among a total of 1376 initially identified studies, only 12 articles met the final inclusion criteria. The pooled sensitivity and specificity were 1.00 (95% CI: 0.00–1.00) and 0.71 (95% CI: 0.50–0.78) for HDV total antibodies, 0.96 (95% CI: 0.83–0.99) and 0.98 (95% CI: 0.82–1.00) for anti-HDV IgM and 0.95 (95% CI: 0.86–0.98) and 0.96 (95% CI: 0.67–1.00) for anti-HDV IgG. The pooled sensitivity and specificity for HDV serological tests were 0.99 (95% CI: 0.96–1.00) and 0.90 (95% CI: 0.79–0.96). Conclusions This meta-analysis suggests that serological tests have high diagnostic performance in detecting antibodies against HDV, especially in HDV IgM and IgG. However, this conclusion is based on studies of a limited number and quality, and the development of new diagnostic tools with higher precision and reliability is still necessary.

In order to simulate the target echo laser signal, we designed a novel laser target simulator with high precision and high attenuation rate used for sensitivity test, function test or tracking mode test of laser receiving equipment, such as Lidar and Laser Range Finder. Regarding the laser receiving equipment on the motion platform, the model of target echo power was established based on the characteristics of laser atmospheric transmissions in the application environment. The simulation shows the model is consistent with the test data. Additionally, the MEMS ESVOA (Micro-Electro Mechanical Systems Electro-Static Variable Optical Attenuator) device was used in the overall solution of the laser target simulator to realize the target echo signal simulation with miniaturization, high attenuation rate and high precision. Finally, a laser target simulator test system was built and its high rate of attenuation, high precision and stability of laser power tested. The test results show that the change rate of target echo signal energy is more than 7 × 104 dB/s, the power simulation accuracy is better than 0.1 dB and the laser pulse power stability is better than 0.61%.

ObjectiveEnteral feeding after intestinal atresia has always been a concern for clinicians. But the present studies mainly focused on single factors. This research aimed to comprehensively analyze the multiple factors on complete enteral nutrition after primary anastomosis, and establish the convenient prediction model.MethodsWe retrospectively collected reliable information in neonates with intestinal atresia form January 2010 to June 2022. The cox regression analysis was performed to select independent risk factors and develop nomogram. Subsequently, ROC curve, calibration curve and decision curve were drawn to thoroughly evaluate the accuracy and applicability of the model.ResultsThe predictors finally included in the model were gestational age, meconium peritonitis, distance from the anastomosis to the ileocecal region, diameter ratio of proximal to distal bowels, and time of initial feeding. The nomogram of predicting the probability of week 2, week 3 and week 4 was drawn and their area under the curve were 0.765, 0.785 and 0.747, respectively. Similarly, calibration and decision curve indicated that the prediction model had a great prediction performance.ConclusionThe clinical value of predictive models can be recognized. The hope is that the predictive model can help pediatricians reduce hospital costs and parental anxiety.

Background: s: Hyperhomocysteinemia (HHcy) is one of risk factors for vascular cognitive impairment (VCI). GTP cyclohydrolase 1 (GCH1) deficiency is critical to oxidative stress in vascular dysfunction. The aim of this study was designed to examine whether HHcy induces VCI through GCH1 S-nitrosylation, a redox-related post-translational modification of cysteine. Methods: The VCI model was induced by feeding mice homocysteine thiolactone (HTL) for 16 consecutive weeks. The cognitive functions were evaluated by step-down avoidance test, passive avoidance step-through task test, and Morris water maze (MWM) test. Protein S-nitrosylation was assayed using a biotin-switch method. Results: In cell-free system, nitric oxide (NO) donor induced GCH1 protein S-nitrosylation and decreased GCH1 activity. In endothelial cells, HTL increased GCH1 S-nitrosylation, reduced tetrahydrobiopterin, and induced oxidative stress, which were attenuated by N-acetyl-cysteine, L-N6-1-Iminoethyl-lysine, mutant of GCH1 cysteine 141 to alanine (MT-GCH1) or gene deletion of inducible NO synthase (iNOS). Further, HTL incubation or iNOS overexpression promoted endothelial cellular senescence, but abolished by exogenous expression of MT-GCH1 or pharmacological approaches including N-acetyl-cysteine, L-sepiapterin, and tempol. In wildtype mice, long-term administration of HTL induced GCH1 S-nitrosylation and vascular stiffness, decreased cerebral blood flow, and damaged the cognitive functions. However, these abnormalities induced by HTL administration were rescued by enforced expression of MT-GCH1 or gene knockout of iNOS. In human subjects, GCH1 S-nitrosylation was increased and cognitive functions were impaired in patients with HHcy. Conclusion: The iNOS-mediated nitrosative stress induced by HTL drives GCH1 S-nitrosylation to induce cerebral vascular stiffness and cognitive impairments.

Abstract Background Oxidation-specific epitopes (OSEs) are rich in atherosclerotic plaques. Innate and adaptive immune responses to OSEs play an important role in atherosclerosis. The purpose of this study was to develop novel human single-chain variable fragment (scFv) antibody specific to OSEs to image and inhibit atherosclerosis. Results Here, we screened a novel scFv antibody, named as ASA6, from phage-displayed human scFv library. ASA6 can bind to oxidized LDL (Ox-LDL) and atherosclerotic plaques. Meanwhile, ASA6 can also inhibit the uptake of Ox-LDL into macrophage to reduce macrophage apoptosis. The atherosclerotic lesion area of ApoE −/− mice administrated with ASA6 antibody was significantly reduced. Transcriptome analysis reveals the anti-atherosclerosis effect of ASA6 is related to the regulation of fatty acid metabolism and inhibition of M1 macrophage polarization. Moreover, we conjugated ASA6 antibody to NaNdF4@NaGdF4 nanoparticles for noninvasive imaging of atherosclerotic plaques by magnetic resonance (MR) and near-infrared window II (NIR-II) imaging. Conclusions Together, these data demonstrate the potential of ASA6 antibody in targeted therapy and noninvasive imaging for atherosclerosis. Graphic abstract

BackgroundHepatitis delta virus (HDV) is a satellite RNA virus that relies on hepatitis B virus (HBV) for transmission. HIV/HBV/HDV coinfection or triple infection is common and has a worse prognosis than monoinfection. ObjectiveWe aimed to reveal the epidemiological characteristics of HIV/HBV/HDV triple infection in the global population. MethodsA systematic literature search in PubMed, Embase, and the Cochrane Library was performed for studies of the prevalence of HIV/HBV/HDV triple infection published from January 1, 1990, to May 31, 2021. The Der Simonian-Laird random effects model was used to calculate the pooled prevalence. ResultsWe included 14 studies with 11,852 participants. The pooled triple infection rate in the global population was 7.4% (877/11,852; 95% CI 0.73%-29.59%). The results of the subgroup analysis showed that the prevalence of triple infection was significantly higher in the Asian population (214/986, 21.4%; 95% CI 7.1%-35.8%), in men (212/5579, 3.8%; 95% CI 2.5%-5.2%), and in men who have sex with men (216/2734, 7.9%; 95% CI 4.3%-11.4%). In addition, compared with people living with HIV, the HIV/HBV/HDV triple infection rate was higher in people with hepatitis B. ConclusionsThis meta-analysis suggests that the prevalence of HIV/HBV/HDV triple infection in the global population is underestimated, and we should focus more effort on the prevention and control of HIV/HBV/HDV triple infection. Trial RegistrationPROSPERO CRD42021273949; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=273949

Plasmon‐based devices have founded numerous applications in photonics based on optically excited strong near‐field effect at nanoscale. So far, the large‐area fabrication of periodic plasmonic nanostructures is still challenging due to a small write‐field limitation of lithography‐based techniques, especially for metallic substrates. A novel strategy is proposed to fabricate millimeter‐sized patterns of periodic plasmonic nanostructures inside dielectric materials (glass) through a femtosecond laser direct‐write plasmonic nanolithography approach. Noble metal nanoparticles are formed by the ion implantation in glass and reshaped into a nanowire‐like nanoparticles’ assembly by direct writing with femtosecond laser harnessing plasmonic interaction. As‐designed patterns at nanoscale are inscribed by this type of plasmonic lithography to form wires composed of nanoparticles. Examples for applications, the linear dichroism response, and structural color have been achieved by the plasmonic nanogratings buried inside glass (i.e., at subsurface regions). The work opens a new avenue to manipulate metallic nanoparticles in solids by direct plasmonic nanolithography and offers a reliable implementation of large‐area fabrication of plasmonic nanostructures for diverse range of photonic applications.

The pathological process involves a range of intrinsic biochemical markers. The detection of multiple biological parameters is imperative for providing precise diagnostic information on diseases. In vivo multichannel fluorescence biosensing facilitates the acquisition of biochemical information at different levels, such as tissue, cellular, and molecular, with rapid feedback, high sensitivity, and high spatiotemporal resolution. Notably, fluorescence imaging in the near-infrared-II (NIR-II) window (950–1700 nm) promises deeper optical penetration depth and diminished interferential autofluorescence compared with imaging in the visible (400–700 nm) and near-infrared-I (NIR-I, 700–950 nm) regions, making it a promising option for in vivo multichannel biosensing toward clinical practice. Furthermore, the use of advanced NIR-II fluorophores supports the development of biosensing with spectra-domain, lifetime-domain, and fluorescence-lifetime modes. This review summarizes the versatile designs and functions of NIR-II fluorophores for in vivo multichannel biosensing in various scenarios, including biological process monitoring, cellular tracking, and pathological analysis. Additionally, the review briefly discusses desirable traits required for the clinical translation of NIR-II fluorophores such as safety, long-wavelength emission, and clear components.

ObjectiveThe purpose of this study was to establish a predictive model of postoperative fever in children with acute appendicitis through retrospective analysis, and the prediction ability of the model is demonstrated by model evaluation and external validation.MethodsMedical records information on children undergoing surgery for acute appendicitis within 2 years were retrospectively collected, prospective collection was performed for external validation in the next 3 months. The patients were divided into two groups according to whether the postoperative body temperature exceeded 38.5°C. Multivariate logistic regression analysis was used to determine independent risk factors and develop regression equations and nomogram. ROC curve, calibration curve and decision curve were made for model evaluation. Finally, the clinical implication of the prediction model was clarified by associating postoperative fever with prognosis.ResultsHigh risk factors of postoperative fever included in the prediction model were onset time (X1), preoperative temperature (X2), leukocyte count (X3), C-reactive protein (X4) and operation time (X5). The regression equation is logit (P) = 0.005X1+0.166X2+0.056X3+0.004X4+0.005X5-9.042. ROC curve showed that the area under the curve (AUC) of the training set was 0.660 (0.621, 0.699), and the AUC of the verification set was 0.712 (0.639, 0.784). The calibration curve suggested that the prediction probability was close to the actual probability. Decision curve analysis (DCA) showed that patients could benefit from clinician’s judgment. Furthermore, prognostic analysis showed children presenting with postoperative fever had the more duration of postoperative fever, hospitalization stays and cost, except for rehospitalization.ConclusionAll the results revealed that the model had good predictive ability. Pediatricians can calculate the probability of postoperative fever and make timely interventions to reduce pain for children and parents.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with ill-defined pathogenesis, calling for urgent developments of new therapeutic regimens. Herein, we applied PandaOmics, an AI-driven target discovery platform, to analyze the expression profiles of central nervous system (CNS) samples (237 cases; 91 controls) from public datasets, and direct iPSC-derived motor neurons (diMNs) (135 cases; 31 controls) from Answer ALS. Seventeen high-confidence and eleven novel therapeutic targets were identified and will be released onto ALS.AI (http://als.ai/). Among the proposed targets screened in the c9ALS Drosophila model, we verified 8 unreported genes (KCNB2, KCNS3, ADRA2B, NR3C1, P2RY14, PPP3CB, PTPRC, and RARA) whose suppression strongly rescues eye neurodegeneration. Dysregulated pathways identified from CNS and diMN data characterize different stages of disease development. Altogether, our study provides new insights into ALS pathophysiology and demonstrates how AI speeds up the target discovery process, and opens up new opportunities for therapeutic interventions.

The serious mismatch between industrialization and urbanization has led to the emergence of ghost cities. Industry-and-city integration aims to agglomerate industries and the population simultaneously by coordinating the planning and construction, and by mixing different functional areas including industry, office, living, and commercial functions. Based on the population spatial vector database of Jimei District in Xiamen in 2020, this paper empirically analyzes the effects of spatial patterns between industry and city, in terms of residential location and job accessibility, on the housing occupancy rate in new towns and cities. The findings demonstrate that: (1) The attraction of residential location to population varies among three different urban expansion models. The housing occupancy rate of residential areas that meet the concentric circle model is the highest, followed by the sector model, and the multiple nuclei model is the lowest; (2) The jobs–housing relationship has a stable and positive impact on the occupancy rate of commercial housing in the new town, which verifies that job accessibility is the basic demand for families’ residential location choice; (3) There is a significant pattern difference in the influence of job accessibility on the occupancy rate. The occupancy rate of the sector model residential area is highly dependent on job accessibility: the higher the job accessibility, the lower the occupancy rate of the concentric residential area, while job accessibility has a weak impact on the occupancy rate of the multiple nuclei residential area. The conclusions suggest that the spatial planning of new towns should include a clear population absorbing strategy, and the residential location should follow the expansion law of the urban residential functional area, balance the relationship between industrial agglomeration and the job–housing relationship, and allocate life factors in a targeted manner according to the actual impact of job accessibility.

There were rare clinical reports on clear cell tumor of the lung (CCTL). The clinical characteristics and underlying genetic mutation status of CCTL are poorly understood. From 2012 to 2017, patients pathologically diagnosed with CCTL in our hospital were investigated and analyzed based on clinical manifestations, pathological characteristics, prognosis and full gene mutation status through next generation sequencing (NGS) technology. During a 6-year period, four eligible patients were diagnosed with CCTL through surgical resection and were included in this study. All patients showed solitary nodules or lumps located in the left lung. The average maximum diameter of lesions was 2.5 ± 1.1 cm. Computed tomography (CT) imaging characteristics of these nodules/lumps demonstrated the features of benign tumors. The hematoxylin-eosin (HE) morphology and immunohistochemistry were consistent with the histopathological features of benign CCTL. Subsequent NGS analysis showed frame shift mutations of F2421/E2419, K1466E mutation, and p. 1450_1456 deletion mutation in mTOR gene in two of four patient samples and amplifications of MCL1 were observed in three of four samples. CCTL is a rare type of primary pulmonary mesenchymal tumor with good prognosis. Preliminary diagnosis on CT is usually sclerosing pneumocytoma. It is still unclear whether the occurrence and development of the disease are related to specific gene mutation. In this study, the genomic findings of frame shift mutation of mTOR genes and amplification of MCL1 gene in CCTL suggest that these mutations might play a role in proliferation of CCTL.

BackgroundMother-to-child transmission (MTCT) is the most common propagation mode of hepatitis B virus (HBV) transmission. Exploring the mechanisms of HBV MTCT is the key to protect infant from infection. In this study, we aim to clarify the important role of autophagy complicated in HBV MTCT.MethodsA total of 169 placental samples were collected in this study, includes 144 HBV positive pregnant women and 25 normal pregnant women. In vitro, JEG-3 cells were treated with serum contained different HBV viral loads. Electron microscope was used to observed the number of autophagosome. RT-qPCR and western blotting were used to measure the expression level of autophagy relative genes and proteins respectively. Immunofluorescence was used to analyzed the expression of LC-3 of the frozen section of placental tissue.ResultsAccording to the number of autophagosomes and the expression level of autophagic genes mRNA and protein, autophagy was increased in HBV maternal placenta. Among the control, low viral load, medium viral load and high viral load groups, autophagy was significantly up-regulated with the increase of HBV viral loads. Also, autophagy was increased in the HBeAg positive pregnant women compared with their HBeAg negative counterparts. Also, autophagy in infant-infected group was up-regulated compared with infant-uninfected group. In vitro, choriocarcinoma JEG-3 cells were treated with the different HBV viral loads or different time incubation, the mRNA and protein of autophagy related genes was maximum expression in the medium viral load or treatment in a short period, but decreased in the high viral load treatment or with long-term HBV exposure.ConclusionOur study determines the high levels of viremia could be the cause of both increase autophagy activities and MTCT. Autophagy was significantly up-regulated in pregnant women with high viral load or HBeAg positive, which plays an important part in the HBV MTCT.

The Faraday rotation originates from the mechanism by which the time‐reversal symmetry in the material is broken by the external magnetic field. It is the basis for the development of some magneto‐optical devices, such as optical isolators. In integrated optics and telecommunications, nonreciprocal photonic devices with high transmittance and strong Faraday rotation are desired for low‐cost, compact optical systems. Localized surface plasmon resonance (LSPR) from the metallic nanoparticles in dielectrics allows the light localization in subwavelength scales, boosting the interaction between nanoparticles and materials, which results in a number of plasmon‐enhanced effects. Herein, the strong Faraday rotation in BK7 glass by embedded metallic nanoparticles through LSPR is reported. It is elucidated that the mechanism of Faraday rotation is the near‐field enhancement of spin–photon coupling effect in the presence of an external magnetic field. The Verdet constant of the thin‐layer BK7 glass with embedded Au nanoparticles is determined as high as 5059.7 rad T−1 m−1 at 532 nm, exhibiting excellent magneto‐optical features. This work opens a new avenue to develop the subwavelength magneto‐optical devices with embedded metallic nanoparticles.

Many patients with major depressive disorder (MDD) suffer from residual symptoms. Rumination is a specific known risk factor for the onset, severity, prolongation, and relapse of MDD. This study aimed to examine the efficacy and EEG substrates of mindfulness-based cognitive therapy (MBCT) in alleviating depression and rumination in an MDD population with residual symptoms. We recruited 26 recurrent MDD individuals who had residual symptoms with their current antidepressants to participate in the 8-week MBCT intervention. We evaluated the efficacy and changes in the dynamics of resting-state theta rhythm after the intervention, as well as the associations between theta alterations and improvements in depression and rumination. The participants showed reduced depression, enhanced adaptive reflective rumination, and increased theta power and phase synchronization after MBCT. The increased theta-band phase synchronizations between the right occipital regions and the right prefrontal, central, and parietal regions were associated with reduced depression, while the increase in theta power in the left parietal region was associated with improvements in reflective rumination. MBCT could alleviate depression and enhance adaptive, reflective rumination in recurrent MDD individuals with residual symptoms through the modulation of theta dynamics in specific brain regions.

Trastuzumab is a humanized mAb used to treat HER2-overexpressing breast cancer; however its mechanisms remain to be fully elucidated. Previous studies suggest a role for immunity in mediating trastuzumab-specific antitumor effects. This study evaluated the role(s) of trastuzumab and other antibodies on macrophage activation and Ab-dependent cell-mediated phagocytosis (ADCP) of HER2+ breast cancer cells in vitro and in vivo. We employed orthotopic implantation of HER2+ murine breast cancer (BC) cells in immunocompetent mouse models, a human HER2+ BC xenograft in an immune humanized mouse model, and human PDXs involving adoptive transfer of autologous macrophages to simulate an endogenous mammary tumor-immune microenvironment. Our study demonstrated that trastuzumab greatly and consistently increased macrophage frequency and tumor-cell phagocytosis, and that concurrent knockdown of B7-H4 by a neutralizing antibody increased immune cell infiltration and promoted an antitumor phenotype. Furthermore, neoadjuvant trastuzumab therapy significantly upregulated B7-H4 in the cancer-infiltrating macrophages of HER2+ BC patients, which predicted poor trastuzumab response. We suggest that strategies to specifically enhance ADCP activity might be critical to overcoming resistance to HER2 mAb therapies by inhibiting tumor growth and potentially enhance antigen presentation. Furthermore, these results advance the understanding of macrophage plasticity by uncovering a dual role for ADCP in macrophages involving elimination of tumors by engulfing cancer cells while causing a concomitant undesired effect by upregulating immunosuppressive checkpoints.

Abstract Background Preoperative imatinib mesylate therapy for gastrointestinal stromal tumors (GISTs) is controversial. This study aimed to explore the clinical efficacy and optimal duration of preoperative imatinib mesylate (IM) therapy in patients with locally advanced and recurrent/metastatic GISTs. Methods We retrospectively examined patients who received preoperative imatinib mesylate therapy from January 2013 to December 2018 at Xiangya Hospital, Central South University and the Second Xiangya Hospital of Central South University, China. Clinical data, including the results of tests for mutations in KIT and PDGFR, findings from regularly conducted re-examinations, abdominal-enhanced computed tomography/magnetic resonance imaging data, responses to imatinib, progression-free survival, and overall cancer-specific survival, were recorded. Results A total of 25 patients were enrolled in our study, including 18 with a locally advanced GIST and 7 with recurrent or metastatic GISTs. Their ages ranged from 22 to 70 years (M:F = 1.6:0.9), with a mean age of 50.48 ± 12.51 years. The tumor locations included the stomach (56.0%), rectum (16.0%), enterocoelic/retroperitoneal sites (12.0%), and the small intestine (12.0%). Based on testing for mutations in KIT and PDGFR, 22 patients received 400 mg/day KIT, and 3 patients received 600 mg/day PDGFR. The median duration of preoperative IM therapy was 8.96 ± 4.81 months, ranging from 3 to 26 months. According to the Choi criteria, 24 patients achieved a partial response (PR), and 1 patient had stable disease (SD). All patients underwent surgery after preoperative IM therapy, and no postoperative complications appeared. The 2-year PFS and 5-year PFS were 92% and 60%, respectively, and the total 5-year cancer-specific survival (CSS) was 92%. Conclusion Preoperative imatinib therapy is feasible for locally advanced and recurrent/metastatic GISTs and can effectively shrink the tumor size, allow organ sparing, and avoid extensive organ resection. Moreover, the optimal duration of preoperative IM therapy in patients with locally advanced and recurrent/metastatic GISTs was 8.96 ± 4.81 months, ranging from 3 to 26 months, and gastric GISTs had a better response to preoperative IM therapy than did non-gastric GISTs.

For the spiral blade of the concrete mixing tank of concrete mixer truck, in order to satisfy the stirring and discharging performance, the installation angle and helix angle of the blade should be assigned according to their segmentation function. Due to the different helix angles and the installation tilt angles, a junction gap of blade is formed at the joint, resulting in the severe silting of discharge or the uneven agitation. We put forward a more reasonable solution by using the MFG (method of fitting gradient) to solve the gap connection of spiral blades. The MFG that can reduce the discharging residual rate of the mixing material has been verified by experiments and applied to actual mass production. We also make the coupling simulation of Multi-Physics Field based on simulation software 17-STARCCM+® to visually verify the scientificity of design and study the complex stresses distribution inside the actual mixing tank. Finally, we provide an up-to-date reference for the design of spiral logarithmic blade, solving the problem of the gap at the traditional spiral-blade connection.