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Abstract This article delves into Alzheimer’s disease (AD), a prevalent neurodegenerative condition primarily affecting the elderly. It is characterized by progressive memory and cognitive impairments, severely disrupting daily life. Recent research highlights the potential involvement of microRNAs in the pathogenesis of AD. MicroRNAs (MiRNAs), short non-coding RNAs comprising 20–24 nucleotides, significantly influence gene regulation by hindering translation or promoting degradation of target genes. This review explores the role of specific miRNAs in AD progression, focusing on their impact on β-amyloid (Aβ) peptide accumulation, intracellular aggregation of hyperphosphorylated tau proteins, mitochondrial dysfunction, neuroinflammation, oxidative stress, and the expression of the APOE4 gene. Our insights contribute to understanding AD’s pathology, offering new avenues for identifying diagnostic markers and developing novel therapeutic targets.

This is an article in the field of metallurgical engineering. For the vanadium precipitation waste liquid of a waste catalyst in a zinc smelter in Shaanxi, the vanadium in the vanadium precipitation waste liquid was recovered by solvent extraction method. The effects of N235 volume fraction, extraction ratio, extraction time and extraction stage on the vanadium extraction rate were investigated. The results showed that the extraction system with 30%N235+5%TBP+65% sulfonated kerosene was used for four-stage countercurrent extraction, the extraction ratio of VO/VA= 2∶1, the extraction time was t=5 min, and the extraction rate of vanadium was 95.68%. The volume fraction of Na2CO3 was 5%, the extraction ratio of V'o/V'A =4∶1, the extraction time was t=4 min, and the extraction rate of vanadium was 98.25% after three-stage counter-current extraction.

Abstract Small extracellular vesicles (sEV) derived from diverse natural killer (NK) cell lines have proven their exceptional antitumor activities. However, sEV from human primary NK cells, especially memory-like NK cells, are rarely utilized for cancer treatment. In this study, we obtained sEV from IL-12, IL-15 and IL-18 cultured human memory-like NK cells (mNK-sEV) that showed strong cytokine-secretory ability. It was uncovered that mNK-sEV entered cancer cells via macropinocytosis and induced cell apoptosis via caspase-dependent pathway. Compared to sEV from conventionally cultured NK cells (conNK-sEV), mNK-sEV inhibited tumor growth to a greater extent. Concomitantly, pharmacokinetics and biodistribution results validated a higher accumulation of mNK-sEV than conNK-sEV in tumors of xenografted murine models. Notably, elevated containment of granulysin (GNLY) within mNK-sEV, at least in part, may contribute to the enhanced therapeutic effect. Herein our results present that mNK-sEV can be a novel class of therapeutic reagent for effective cancer treatment. Graphical Abstract

Abstract Background Increasing evidence suggests that leptin is involved in the pathology of autism spectrum disorder (ASD). In this study, our objective was to investigate the levels of leptin in the blood of children with ASD and to examine the overall profile of adipokine markers in ASD through meta-analysis. Methods Leptin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) kit, while adipokine profiling, including leptin, was performed via meta-analysis. Original reports that included measurements of peripheral adipokines in ASD patients and healthy controls (HCs) were collected from databases such as Web of Science, PubMed, and Cochrane Library. These studies were collected from September 2022 to September 2023 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Standardized mean differences were calculated using a random effects model for the meta-analysis. Additionally, we performed meta-regression and explored heterogeneity among studies. Results Our findings revealed a significant increase in leptin levels in children with ASD compared to HCs (p = 0.0319). This result was consistent with the findings obtained from the meta-analysis (p

IntroductionSiraitia grosvenorii (Swingle) C. Jeffrey, is an edible and traditional medicine widely used in China. Mogroside V (MGV) and mogrol (MG) are its main active ingredients, which have been found to be effective in the treatment of neurodegenerative diseases recently. However, whether they can effectively treat Parkinson’s disease (PD) and their underlying mechanisms have not been sufficiently explored. In this study, we investigated the neuroprotective and metabolic regulatory effects of MGV and MG on PD.Materials and methodsUsing SH-SY5Y cell models and an MPTP-induced mouse model of PD, we evaluated the compounds’ efficacy in mitigating MPP+-induced neurotoxicity and ameliorating motor deficits and dopaminergic neuron loss. Employing widely targeted metabolomics and bioinformatics analysis to investigate the Metabolic imbalance rectification caused by MGV and MG treatment. The vivo experimental protocol encompassed a 14-day drug administration regimen with mice randomly allocated into six groups (n = 9) receiving distinct compound dosages including a control group, a model group, MGV-H (30 mg/kg/day), MGV-L (10 mg/kg/day), MG-H (15 mg/kg/day), and MG-L (3 mg/kg/day).ResultsOur findings revealed that pre-treatment with MGV and MG significantly enhanced cell viability in SH-SY5Y cells exposed to MPP+, demonstrating a potent protective effect against neurotoxicity. In the MPTP mouse model, MGV-H, MGV-L, and MG-H significantly enhanced motor coordination as assessed by the rotarod test (p < 0.05); MGV-L and MG-H evidently inhibited dopaminergic neuronal loss in the substantia nigra pars compacta (p < 0.05). Furthermore, metabolomic analysis of the substantia nigra highlighted the restoration of metabolic balance, with MGV-L and MG-H impacting 160 differential metabolites and modulating key pathways disrupted in PD, including sphingolipid metabolism, fatty acid metabolism, and amino acid metabolism. Notably, treatment with MGV-L and MG-H led to the regulation of 106 metabolites, showing a recovery trend towards normal levels, which constitutes approximately 17.5% of the identified metabolites. Key metabolites such as n-acetyl-l-glutamate, hexadecanoic acid, and 9-octadecenal were significantly altered (p < 0.05), underscoring their broad-spectrum metabolic regulatory capacity.ConclusionThis study underscores the potential of natural compounds in developing comprehensive treatment strategies for neurodegenerative diseases, paving the way for future clinical research to validate the therapeutic efficacy of mogrosides in PD.

Objectives Circular RNAs (circRNAs) serve a crucial regulatory role in ovarian cancer (OC). Circular RNA ArfGAP with FG repeats 1 (circAGFG1) has been shown to be involved in promoting the progression of several cancers, containing triple-negative breast cancer, esophageal cancer and colorectal cancer. However, the function of circAGFG1 in OC is unclear. Methods Quantitative real-time reverse transcription PCR (RT-qPCR) was conducted to determine the expression levels of circAGFG1 and miR-409-3p. The proliferation and metastasis of cells were determined by colony formation assays, EdU assays, transwell assays and wound healing assays. In addition, a dual-luciferase reporter assay was performed to validate the mechanism between circAGFG1, miR-409-3p, and ZEB1. Results Our data suggested that circAGFG1 was significantly overexpressed in OC tissues compared to normal ovarian epithelial tissues. Overexpression of circAGFG1 was correlated with intraperitoneal metastasis, tumor recurrence and advanced stage. Additionally, circAGFG1 overexpression revealed a poor prognosis in OC patients. Knockdown of circAGFG1 suppressed the proliferation, invasion and migration of OC cells. Mechanistically, circAGFG1 acted as a sponge of miR-409-3p to enhance the expression level of zinc finger E-box binding homeobox 1 (ZEB1), thereby conferring OC cell proliferation, invasion and migration. Importantly, re-expression of ZEB1 effectively reversed the effects of circAGFG1 knockdown on OC cells. Conclusions In summary, our study indicated that circAGFG1 may act as a prognostic biomarker and potential therapeutic target for patients with OC.

Background: Aortic surgery successfully improves the prognosis of patients with type A aortic dissection. However, total arch replacement and reconstruction remain challenging. This study presents a new surgical modality, the in-situ stent-graft fenestration (ISSF) technique, for simplifying aortic arch reconstruction and assesses its short-term efficacy and safety in patients with type A aortic dissection. Methods: Data from 177 patients with type A aortic dissection who underwent aortic arch reconstruction were retrospectively analyzed. Sun's procedure was performed in 90 patients and ISSF was performed in the other 87. Results: The in-hospital mortality rate was 7.8% in the Sun's procedure group and 3.4% in the ISSF group (p = 0.357). Compared to the Sun's procedure group, the ISSF group had significantly shorter surgical duration, cardiopulmonary bypass time, circulatory arrest time, mechanical ventilation time, and aortic cross-clamp time (p

Driven by the intricacy of the illness and the need for individualized treatments, targeted therapy and biomarker research in thyroid cancer represent an important frontier in oncology. The variety of genetic changes associated with thyroid cancer demand more investigation to elucidate molecular details. This research is clinically significant since it can be used to develop customized treatment plans. A more focused approach is provided by targeted therapies, which target certain molecular targets such as mutant BRAF or RET proteins. This strategy minimizes collateral harm to healthy tissues and may also reduce adverse effects. Simultaneously, patient categorization based on molecular profiles is made possible by biomarker exploration, which allows for customized therapy regimens and maximizes therapeutic results. The benefits of targeted therapy and biomarker research go beyond their immediate clinical impact to encompass the whole cancer landscape. Comprehending the genetic underpinnings of thyroid cancer facilitates the creation of novel treatments that specifically target aberrant molecules. This advances the treatment of thyroid cancer and advances precision medicine, paving the way for the treatment of other cancers. Taken simply, more study on thyroid cancer is promising for better patient care. The concepts discovered during this investigation have the potential to completely transform the way that care is provided, bringing in a new era of personalized, precision medicine. This paradigm shift could improve the prognosis and quality of life for individuals with thyroid cancer and act as an inspiration for advances in other cancer types.

Objective: We here explored whether perinatal nonylphenol (NP) exposure causes myocardial fibrosis (MF) during adulthood in offspring rats and determined the role of the TGF-β1/LIMK1 signaling pathway in NP-induced fibrosis in cardiac fibroblasts (CFs). Methods and results: Histopathology revealed increased collagen deposition and altered fiber arrangement in the NP and isoproterenol hydrochloride (ISO) groups compared with the blank group. Systolic and diastolic functions were impaired. Western blotting and qRT-PCR demonstrated that the expression of central myofibrosis-related proteins (collagens Ι and ΙΙΙ, MMP2, MMP9, TGF-β1, α-SMA, IL-1β, and TGF-β1) and genes (Collagen Ι, Collagen ΙΙΙ, TGF-β1, and α-SMA mRNA) was upregulated in the NP and ISO groups compared with the blank group. The mRNA-seq analysis indicated differential expression of TGF-β1 signaling pathway-associated genes and proteins. Fibrosis-related protein and gene expression increased in the CFs stimulated with the recombinant human TGF-β1 and NP, which was consistent with the results of animal experiments. According to the immunofluorescence analysis and western blotting, NP exposure activated the TGF-β1/LIMK1 signaling pathway whose action mechanism in NP-induced CFs was further validated using the LIMK1 inhibitor (BMS-5). The inhibitor modulated the TGF-β1/LIMK1 signaling pathway and suppressed the NP-induced increase in fibrosis-related protein expression in the CFs. Thus, the aforementioned pathway is involved in NP-induced fibrosis. Conclusion: We here provide the first evidence that perinatal NP exposure causes myocardial fibrosis in growing male rat pups and reveal the molecular mechanism and functional role of the TGF-β1/LIMK1 signaling pathway in this process.

Alcoholic liver disease (ALD) is a globally prevalent form of liver disease for which there is no effective treatment. Recent studies have found that a significant decrease in butyrate was closely associated with ALD development. Given the low compliance and delivery efficiency associated with oral-route butyrate administration, a highly effective butyrate-yielding dietary supplement, butyrylated high-amylose maize starch (HAMSB), is a good alternative approach. Here, we synthesized HAMSB, evaluated the effect of HAMSB on acute ALD in mice, compared its effect with that of oral administration of butyrate, and further studied the potential mechanism of action. The results showed HAMSB alleviated acute ALD in mice, as evidenced by the inhibition of hepatic-function impairment and the improvement in liver steatosis and lipid metabolism; in these respects, HAMSB supplementation was superior to oral sodium butyrate administration. These improvements can be attributed to the reduction of oxidative stress though the regulation of Nrf2-mediated antioxidant signaling in the liver and the improvement in the composition and function of microbiota in the intestine. In conclusion, HAMSB is a safe and effective dietary supplement for preventing acute ALD that could be useful as a disease-modifying functional food or candidate medicine.

Background & aims: Although ferroptosis holds promise as a new strategy for treating hepatocellular carcinoma (HCC), there are several obstacles that need to be overcome. One major challenge is the lack of understanding about the mechanisms underlying ferroptosis. Additionally, while the m6A modification has been shown to regulate various forms of cell death, its role in regulating ferroptosis in HCC has been largely overlooked. Bridging this knowledge gap, our study aimed to elucidate the regulatory influence of m6A modification on HCC ferroptosis. Materials: Dot blot and EpiQuik m6A RNA Methylation Quantitative kit detected changes in overall m6A modification level during ferroptosis in HCC. MeRIP-qPCR and RIP-qPCR identified that the m6A modification of ATG5 mRNA was significant changed. BALB/c nude mice were used to construct xenograft tumor models to verify the phenotypes upon YTHDC2 silencing. In addition, patient-derived organoid models were used to demonstrate that induction of ferroptosis was an effective strategy against HCC. Results: Our study has shown that inducing ferroptosis is a promising strategy for combatting HCC. Specifically, we have found a significant correlation between ferroptosis and high levels of m6A modification in HCC. Notably, we discovered that the elevation of ATG5 mRNA m6A modification mediated by WTAP is dependent on the reading protein YTHDC2. Importantly, inhibition of either WTAP or YTHDC2 effectively prevented ferroptosis and suppressed HCC development in both in vitro and in vivo models. Conclusion: Our study revealed that WTAP upregulates ATG5 expression post-transcriptionally in an m6A-YTHDC2-dependent manner, thereby promoting the translation of ATG5 mRNA during ferroptosis in HCC. These findings have significant implications for the development of innovative and effective therapeutic approaches for HCC treatment.

Addressing the urgent need for innovative depression treatments, this study heralds a breakthrough in major depressive disorder (MDD) therapy by intertwining clinical observations with neurobiological advancements. We analyzed brain-derived neurotrophic factor (BDNF) levels in serum exosomes from a diverse group of 60 individuals, including first-episode, drug-free MDD patients, medicated MDD patients, and healthy controls. Our results revealed a significant decrease in BDNF levels within MDD patients’ exosomes, which notably increased post-medication, highlighting BDNF’s potential as a biomarker for both MDD diagnosis and treatment efficacy. Advancing these clinical findings, we developed RVG-modified exosomes engineered to overexpress BDNF (RVG-BDNF-Exos), designed to directly target neuronal cells. Our findings demonstrate that these engineered exosomes can successfully traverse the blood–brain barrier, targeting neurons in the hippocampus and prefrontal cortex. In our mouse model of depression induced by lipopolysaccharide, RVG-BDNF-Exos treatment led to a significant increase of BDNF in these key brain regions, crucial for mood regulation and neurogenesis. This intervention modulated the BDNF/TrkB/AKT signaling pathway, central to neural plasticity and implicated in depression’s pathogenesis. Behavioral assessments exhibited substantial improvements in depressive-like behaviors in mice treated with RVG-BDNF-Exos, including reduced immobility in Tail Suspension and Forced Swim Tests. Additionally, our treatment effectively decreased neuroinflammation, as evidenced by the reduction in microglia and astrocyte numbers. Moreover, RVG-BDNF-Exos treatment enhanced neurogenesis and regulated synaptic plasticity, as indicated by the increased expression of neuronal markers MAP2 and DCX, and synaptic proteins PSD95 and Syn-1. In conclusion, this study not only underscores the clinical potential of serum exosomal BDNF as a diagnostic and therapeutic marker for MDD but also demonstrates the efficacy of RVG-BDNF-Exos in alleviating depressive symptoms. Our findings pave the way for future targeted, personalized psychiatric treatments, offering a promising direction in MDD therapy.

As the genome is organized into a three-dimensional structure in intracellular space, epigenomic information also has a complex spatial arrangement. However, most epigenetic studies describe locations of methylation marks, chromatin accessibility regions, and histone modifications in the horizontal dimension. Proper spatial epigenomic information has rarely been obtained. In this study, we designed spatial chromatin accessibility sequencing (SCA-seq) to resolve the genome conformation by capturing the epigenetic information in single-molecular resolution while simultaneously resolving the genome conformation. Using SCA-seq, we are able to examine the spatial interaction of chromatin accessibility (e.g. enhancer–promoter contacts), CpG island methylation, and spatial insulating functions of the CCCTC-binding factor. We demonstrate that SCA-seq paves the way to explore the mechanism of epigenetic interactions and extends our knowledge in 3D packaging of DNA in the nucleus.

Abstract. Background:. Immunotherapies such as adoptive immune cell infusion and immune-modulating agents are widely used for cancer treatment, and the concomitant symptoms, including cytokine release syndrome (CRS) or immune-related adverse events (irAEs), are frequently reported. However, clinical manifestations induced by mismatched donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell (GPBMC) infusion in patients receiving microtransplant (MST) have not yet been well depicted. Methods:. We analyzed 88 cycles of mismatched GPBMC infusion in patients with acute myeloid leukemia receiving MST and 54 cycles of chemotherapy without GPBMC infusion as a comparison. Clinical symptoms and their correlation with clinical features, laboratory findings, and clinical response were explored. Results:. Fever (58.0% [51/88]) and chills (43.2% [38/88]) were the significant early-onset symptoms after GPBMC infusion. Patients possessing less human leukocyte antigen-matching loci with the donor or those with unrelated donors experienced more chills (3 [2–5] loci vs. 5 [3–5] loci, P = 0.043 and 66.7% [12/18] vs. 37.1% [26/70], P = 0.024). On the other hand, those with decreased CD4+/CD8+ T-cell ratio developed more fever (0.8 [0.7–1.2] vs. 1.4 [1.1–2.2], P = 0.007). Multivariable analysis demonstrated that younger patients experienced more fever (odds ratio [OR] = 0.963, 95% confidence interval [CI]: 0.932–0.995, P = 0.022), while patients with younger donors experienced more chills (OR = 0.915, 95% CI: 0.859–0.975, P = 0.006). Elevated ultra-sensitive C-reactive protein levels in the absence of cytokine storm were observed following GPBMC infusion, which indicated mild and transient inflammatory response. Although no predictive value of infusion-related syndrome to leukemia burden change was found, the proportion of host pre-treatment activated T cells was positively correlated with leukemia control. Conclusions:. Mismatched GPBMC infusion in MST induced unique infusion-related symptoms and laboratory changes, which were associated with donor- or recipient-derived risk factors, with less safety and tolerance concerns than reported CRS or irAEs.

Abstract Epigenetic modifications of histones are associated with development and pathogenesis of disease. Existing approaches cannot provide insights into long-range interactions and represent the average chromatin state. Here we describe BIND&MODIFY, a method using long-read sequencing for profiling histone modifications and transcription factors on individual DNA fibers. We use recombinant fused protein A-M.EcoGII to tether methyltransferase M.EcoGII to protein binding sites to label neighboring regions by methylation. Aggregated BIND&MODIFY signal matches bulk ChIP-seq and CUT&TAG. BIND&MODIFY can simultaneously measure histone modification status, transcription factor binding, and CpG 5mC methylation at single-molecule resolution and also quantifies correlation between local and distal elements.

Glucose metabolic disorders (GMD) can promote insulin resistance (IR) and diabetes, and damage liver and kidney. Gynostemma pentaphyllum is commonly used in the clinical treatment of diabetes, but the research on its main active constituents and GMD has not been reported yet. This study explores the therapeutic potential of gypenosides of heat-processed Gynostemma pentaphyllum (HGyp) on high-fat diet-induced GMD in mice. HGyp was administered at different doses for 12 weeks. The investigation encompassed an array of parameters, including body weight, blood lipids, blood glucose, and liver tissue components. Metabolomic and network analyses were conducted to uncover potential targets and pathways associated with HGyp treatment. The results revealed that HGyp alleviated GMD by reducing body weight, blood glucose, and improving blood lipids levels, while increasing liver glycogen and antioxidant enzyme levels. Additionally, HGyp exhibited protective effects on liver and kidney health by reducing tissue damage. Fourteen blood components were detected by LC-MS. Metabolomic and network analyses indicated the potential engagement of the AGE-RAGE signaling pathway in the therapeutic effects of HGyp.Furthermore, Western blot and ELISA assays confirmed that HGyp upregulated GLO1 and GLUT4 while down-regulating AGEs and RAGE expression in liver tissue. In light of these findings, HGyp demonstrates promise as a potential therapeutic candidate for combating GMD, warranting further exploration in the development of therapeutic strategies or functional products.

An effective fluorescent quencher with high quenching efficiency and good stability is of great significance for fluorescence sensing of biomolecules, such as nucleic acid. Here, a porphyrin-based covalent organic polymer (PCOP) was fabricated by a coupling reaction between 1,3,5-triethynylbenzene and 5,10,15,20-tetrakis(4′-bromophenyl) porphyrin. A stable water dispersed PCOP with a porous sphere-like morphology around 50 nm and a zeta potential of −24.6 mV was obtained by using the sonication method. The PCOP showed a superb quenching efficiency and fast quenching dynamics to fluorescent dye due to the high specific surface area of PCOP, which enables the π–π stacking of fluorescent dye to the conjugated porphyrin surface of PCOP, leading to a static quenching effect. The excellent property of PCOP as a fluorescent quencher is comparable with graphene oxide, which is widely utilized in biomolecule detection. Thus, a sensing platform of PCOP for the rapid fluorescence detection of DNA from influenza A virus was constructed with high sensitivity and selectivity. The detection range was found from 1 to 30 nM for the target DNA with a detection limit of 0.38 nM. The effective and stable dispersed nano-quencher reported here highlighted the importance of covalent organic polymers for their sensing application.

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment.

To systematically evaluate the problems of insufficient load capacity，mass over limit， low stability caused by the application of traditional gear transmission in aero-engine high-power extraction transmission system， the central transmission of aero-engine based on face gear transmission is designed， the LTCA is performed， and the contact area ratio and stress are calculated. It is concluded that the central transmission based on face gear transmission has the advantages of high load capacity， light weight and good running stability， face gear transmission can provide a new transmission design route for the existing aero-engine transmission system.

In order to definite the molecular structure and allergic characteristics of cashew nuts, the main allergic proteins were isolated and purified by organic solvent defatting, salting out, dialysis and Sephadex G-150 gel. The allergenic proteins were definitely by UV, BCA kit, SDS-PAGE and Western-Blotting. The amino acid sequence and the DNA sequence of cashew allergic protein were obtained by using the NCBI database and protein mass spectrum sequencing. The structure of cashew allergic protein was predicted by DNAstar bio-information software and circular dichroism (CD). The results showed that the Ana o 2 and Ana o 3 were the main cashew allergenic proteins with molecular weight of 33 and 17 kD. The results of CD and Protean program in DNAstar predicted that there were α-helical, β-folded regions and corner regions which was a hydrophilic protein with strong sensitization because of the β-corners and random curls were found in 54% in Ana o 2. The secondary structure had only a small amount of β-folded region and corner region, accounted for 12%, but had mainly α-helix and random coil structure. It was also hydrophilic allergic protein, and the formation of allergenic epitopes was relatively weak. This study would provide reference for further clarifying the structure of the main allergens of natural cashew nuts and exploring the sensitization mechanism of cashew nuts.

In order to improve the structural performance of the aero-engine gearbox housing and reduce the adverse effects of the engine bad working conditions on the supporting components， the topology optimization theory based on variable density method is adopted， and the minimum flexibility index and weighted average transverse eigenvalue are taken as the target number， and the coupling of thermal-elastohydrodynamic-lubrication effects of the supporting components are considered. Taking the maximum deformation less than 0.15 mm and the equivalent stress less than the material stress as the constraint conditions， the topology optimization design of the aero-engine gearbox housing is carried out. According to the topology optimization results， the geometric reconstruction of the housing structure is carried out， and the strength， stiffness and mass of the shell structure before and after optimization are compared and analyzed. The results show that， after optimization， the housing mass is reduced from 5.53 kg to 5.107 kg， the weight is reduced by 7.6%， the maximum deflection of the housing is reduced from 0.173 1 mm to 0.127 mm， the deformation is reduced by 26.6%， the maximum equivalent stress of the housing is reduced from 124 MPa to 116.9 MPa， the stress is reduced by 5.7%.The maximum deformation and equivalent stress of the housing are effectively reduced， and the strength and stiffness of the housing are significantly improved. It is of great significance to improve the reliability and service life of aero-engine central transmission shell.

IntroductionCalcium sensor calcineurin B-like proteins (CBLs) and their interacting partners, CBL-interacting protein kinases (CIPKs), have emerged as a complex network in response to abiotic and biotic stress perception. However, little is known about how CBL-CIPK complexes function in potatoes.MethodsIn this study, we identified the components of one potato signaling complex, StCBL4–StCIPK2, and characterized its function in defense against Rhizoctonia solani causing stem canker in potato.ResultsExpressions of both StCBL4 and StCIPK2 from potato were coordinately induced upon R. solani infection and following exposure to the defense genes. Furthermore, transient overexpression of StCBL4 and StCIPK2 individually and synergistically increased the tolerance of potato plants to R. solani in Nicotiana benthamiana. Additionally, the transgenic potato has also been shown to enhance resistance significantly. In contrast, susceptibility to R. solani was exhibited in N. benthamiana following virus-induced gene silencing of NbCBL and NbCIPK2. Evidence revealed that StCBL4 could interact in yeast and in planta with StCIPK2. StCBL4 and StCIPK2 transcription was induced upon R. solani infection and this expression in response to the pathogen was enhanced in StCBL4- and StCIPK2-transgenic potato. Moreover, accumulated expression of pathogenesis-related (PR) genes and reactive oxygen species (ROS) was significantly upregulated and enhanced in both StCBL4- and StCIPK2- transgenic potato.DiscussionAccordingly, StCBL4 and StCIPK2 were involved in regulating the immune response to defend the potato plant against R. solani. Together, our data demonstrate that StCBL4 functions in concert with StCIPK2, as positive regulators of immunity, contributing to combating stem canker disease in potato.

Gypenosides (GYP) exerted anticancer activity against various cancers. However, the mechanism of GYP against lung cancer (LC) in vivo remains unclear. This study aims to reveal the potential mechanism of GYP against LC and enhancing cisplatin efficacy using a comprehensive analysis of metabolomics, network analysis. Pharmacodynamic results showed that GYP inhibited tumor growth, reduced tumor volume and tumor weight, and alleviated pathological symptoms in Lewis tumor-bearing mice, and GYP could enhance the anti-LC effects of cisplatin. Using serum metabolomics methods, 53 metabolites were found to be significantly altered in the model group, and the levels of 23 biomarkers were significantly restored after GYP treatment. GYP-related metabolic pathways involved six pathways, including alpha-linolenic acid metabolism, glutathione metabolism, sphingolipid metabolism, glycerophospholipid metabolism, tryptophan metabolism, and primary bile acid biosynthesis. 57 genes associated with differential metabolites of GYP recovery and 7 genes of 11 saponins of GYP against LC were screened by network analysis, the STRING database was used to find the association between 57 genes and 7 genes, and a compound-intersection gene-metabolite related gene-metabolite-pathway network was constructed, and STAT3, MAPK14, EGFR and TYMS might be the crucial targets of GYP against LC. Western blot results showed that GYP restored the levels of STA3, MAPK14, EGFR, and TYMS in the model group, and GYP also restored the levels of STAT3 and MAPK14 in the cisplatin group, indicating that GYP might exert anti-LC effects and enhance the pharmacological effects of cisplatin through MAPK14/STAT3 signaling pathway. Our method revealed the effect and mechanism of GYP on LC and the pharmacological effects of GYP-enhanced chemotherapeutic agent cisplatin, which provided some reference for the development of anti-cancer drugs.

Chronic pancreatitis (CP) is a precancerous illness linked to pancreatic ductal adenocarcinoma (PDAC), although the evolutionary mechanism is uncertain. CP is distinguished by severe fibrosis caused by the activation of pancreatic stellate cells (PSCs). The current clinical therapeutic protocol for CP lacks specific therapeutic medicines for the prevention and suppression of inflammation and fibrosis aggravating in CP. More research on specifically targeting PSCs would help facilitate the development of novel therapies for pancreatic fibrosis. Notably, using natural compounds from medicinal plants as new antifibrotic agents has become a focus of recent research and is widely employed as an alternative and complementary approach. Our goal was to shed light on the role of PSCs in the development of CP and provide a focused update on the new potential therapeutic strategies against PSCs in CP models. Future studies can refer to these possible strategies for drug design, bioavailability, pharmacokinetics, and other issues to obtain better clinical outcomes for treating CP.

Abstract Background Although extrachromosomal DNA (ecDNA) has been intensively studied for several decades, the mechanisms underlying its tumorigenic effects have been revealed only recently. In most conventional sequencing studies, the high-throughput short-read sequencing largely ignores the epigenetic status of most ecDNA regions except for the junctional areas. Methods Here, we developed a method of sequencing enzyme-accessible chromatin in circular DNA (CCDA-seq) based on the use of methylase to label open chromatin without fragmentation and exonuclease to enrich ecDNA sequencing depth, followed by long-read nanopore sequencing. Results Using CCDA-seq, we observed significantly different patterns in nucleosome/regulator binding to ecDNA at a single-molecule resolution. Conclusions These results deepen the understanding of ecDNA regulatory mechanisms.

Permeable pipe piles are set in the soft soil foundation to accelerate the dissipation rate of excess pore water pressure induced by pile driving and then to accelerate the consolidation of soil around the pile. At present, there are many studies, including model tests and numerical simulation, on the bearing capacity and permeability performance of permeable pipe piles. However, few field tests have been conducted to deeply study the time effect of bearing capacity and load transfer law of permeable pipe piles. Based on the fiber Bragg grating (FBG) technology, the static load tests were carried out to study the strain distribution and internal force transfer of the permeable pipe pile in soft soil foundation. Meanwhile, the relationship between the variation of excess pore water pressure of the pile?soil interface with time at different positions of the pile shaft and the time effect of bearing capacity of the permeable pipe pile was analyzed. The test results showed that at the early stage of pile driving, the growth rate of bearing capacity of a single permeable pipe pile under increased vertical loads was higher, and then gradually decreased with time. Under the test site conditions, the improvement of the bearing capacity of the permeable pipe pile within 10 days was mainly attributed to the pile side friction, whereas the pile tip resistance made more contribution to the improvement of bearing capacity within 10-24 days. The excess pore water pressure of the pile?soil interface increased along with the depth of the pile. With the rapid dissipation of excess pore water pressure near the pile tip, the effective stress of soil gradually increased, and the pile side friction and pile tip resistance also increased. This study provides an improved insight into the design and construction of permeable pipe piles in soft soil foundation.

Ulcerative colitis (UC) is an inflammatory bowel disease that is persistent and nonspecific. There are several medications available for the treatment of UC. However, conventional UC medications have substantial adverse effects, low clinical effectiveness, and a high recurrence rate. Therefore, it is critical to discover new medicines that are both safe and effective for UC patients. Natural polysaccharides offer a wide range of pharmacological benefits, including anti-inflammatory, anti-virus, anti-tumor, anti-aging, immune enhancement, and gut flora regulation. In the therapy of UC, natural polysaccharides can modulate inflammatory factors, the immune system, and intestinal flora, and preserve the intestinal mucosa. It demonstrates a good curative effect and is of safety to use, thereby being a potential treatment for UC patients. This paper covers the structure, the pharmacological effects on UC, and the mechanisms of natural polysaccharides. Finally, limitations, challenges, and perspectives are discussed. It is hoped that the findings of this publication will inspire more natural polysaccharides research and provide a theoretical foundation for the creation of new UC medications.

In this paper, based on the axisymmetric consolidation theory of unsaturated soil and equal-strain assumption, an analytical solution using the homogenization of boundary conditions and eigenfunction method is proposed to three-dimensional consolidation of unsaturated soil enhanced by vertical drains under instantaneous loading, in which the continuous permeable boundary conditions are properly introduced. Then, the proposed solution is verified by the special cases of double drainage boundary conditions. Finally, the solution is analyzed using examples and the results show that the proposed solution can be used to simulate the arbitrary distribution of permeability of the top and bottom boundary by setting reasonable interface parameters, which makes up for the problem that the permeability of the top and bottom boundary is between pervious and impervious condition or follows an asymmetric distribution. In addition, with a proper ratio of influence radius to drainage well radius and appropriate depth of vertical drain, the influence of vertical flows on the dissipation of excess pore pressures is small when the ratio of radial to vertical permeability coefficient is greater than two. Last but not the least, the above influence of excess pore pressures is more obvious with the enhancement of the permeability of the top and bottom boundary considering the vertical flows.

Abstract Severely immunosuppressed AIDS patients with recurrent opportunistic infections (OIs) represent an unmet medical need even in the era of antiretroviral therapy (ART). Here we report the development of a human leukocyte antigen (HLA)-mismatched allogeneic adaptive immune therapy (AAIT) for severely immunosuppressed AIDS patients. Twelve severely immunosuppressed AIDS patients with severe OIs were enrolled in this single-arm study. Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4–5 days to stimulate hematopoiesis. Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients. Clinical, immunological, and virological parameters were monitored during a 12-month follow-up period. We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients. Improvements in clinical symptoms were evident throughout the study period. All patients exhibited a steady increase of peripheral CD4+ T cells from a median 10.5 to 207.5 cells/μl. Rapid increase in peripheral CD8+ T-cell count from a median 416.5 to 1206.5 cells/μl was found in the first 90 days since initiation of AAIT. In addition, their inflammatory cytokine levels and HIV RNA viral load decreased. A short-term microchimerism with donor cells was found. There were no adverse events associated with graft-versus-host disease throughout the study period. Overall, AAIT treatment was safe, and might help severely immunosuppressed AIDS patients to achieve a better immune restoration. A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.

In order to correctly evaluate the gear strength calculation results in different standards， the difference between Chinese aviation industry standard （HB） and international standardization organization standard （ISO） in calculating the load capacity of bevel gear tooth surface contact fatigue is analyzed and compared. Through the two ways of comparison of calculation methods and examples， the differences of the two standard calculation formulas， the types of correction coefficients， the differences in values and their effects on the calculation results are found out. The results show that the ISO standard considers more influence factors than the HB standard， and the range is wider. Especially， there is a great difference in the calculation of dynamic load coefficient， which makes the basic value of contact stress calculated by ISO standard smaller， the calculated contact stress equivalent， and the allowable contact stress larger.

Abstract WHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. In this study, we revealed how WHSC1 regulates tumorigenesis and chemosensitivity of colorectal cancer (CRC). Our data showed that WHSC1 as well as H3K36me2 were highly expressed in clinical CRC samples, and high WHSC1 expression is associated with poorer prognosis in OS patients. WHSC1 reduction promoted colon cancer cell apoptosis both in vivo and in vitro. We found that B cell lymphoma-2 (BCL2) expression, an anti-apoptotic protein, is markedly decreased in after WHSC1 depletion. Mechanistic characterization indicated that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level. What’s more, our study indicated that WHSC1 depletion promotes chemosensitivity in CRC cells. Together, our results suggested that WHSC1 and H3K36me2 modification might be optimal therapeutic targets to disrupt CRC progression and WHSC1-targeted therapy might potentially overcome the resistance of chemotherapeutic agents.

This study aimed to present evidence that miR-7 inhibited the metastasis of breast cancer stem cells (BCSCs) and elucidated the mechanisms that have remained unknown. The samples collected from miR-7 agomir-treated, BCSC-driven tumors were subjected to a protein array to analyze the protein expression profiles. A dual-luciferase reporter and chromatin immunoprecipitation-PCR were used to validate and evaluate the molecular expressions of interest in the collected breast cancer tissues and cell lines. miR-7 overexpression affecting metastasis of BCSCs was further evaluated in mice. The endothelial cell-selective adhesion molecule (ESAM) was highly expressed in breast cancer tissues and in BCSC-driven xenografts. Results of the dual-luciferase reporter and chromatin immunoprecipitation-PCR indicated that the miR-7 mimic reduced RELA expression by directly targeting the 3′ UTR of RELA to inhibit ESAM expression in MDA-MB-231 cells. Moreover, the expression levels of RELA, CD44, and ESAM were significantly decreased in lentivirus (Lenti)-miR-7-BCSC-driven xenografts compared with the control xenografts, accompanied with an increase in E-cadherin and a decrease in vimentin expression, as well as reduction in tumor growth and metastasis to lungs. Our data demonstrated that miR-7 overexpression reduced the metastasis of BCSCs via inhibiting ESAM, suggesting that ESAM could be a potential target for breast cancer therapy.

Abstract Background Breast cancer stem cells (BCSCs) are typically seed cells of breast tumor that initiate and maintain tumor growth. MiR-7, as a cancer inhibitor, decreases the BCSC subset and inhibits tumor progression through mechanisms that remain unknown. Methods We examined miR-7 expression in breast cancer and developed a BCSC-driven xenograft mouse model, to evaluate the effects of miR-7 overexpression on the decrease of the BCSC subset in vitro and in vivo. In addition, we determined how miR-7 decreased the BCSC subset by using the ALDEFLUOR, lentivirus infection, dual-luciferase reporter, and chromatin immunoprecipitation-PCR assays. Results MiR-7 was expressed at low levels in breast cancer tissues compared with normal tissues, and overexpression of miR-7 directly inhibited lncRNA XIST, which mediates the transcriptional silencing of genes on the X chromosome, and reduced epithelium-specific antigen (ESA) expression by increasing miR-92b and inhibiting slug. Moreover, miR-7 suppressed CD44 and ESA by directly inhibiting the NF-κB subunit RELA and slug in breast cancer cell lines and in BCSC-driven xenografts, which confirmed the antitumor activity in mice injected with miR-7 agomir or stably infected with lenti-miR-7. Conclusions The findings from this study uncover the molecular mechanisms by which miR-7 inhibits XIST, modulates the miR-92b/Slug/ESA axis, and decreases the RELA and CD44 expression, resulting in a reduced BCSC subset and breast cancer growth inhibition. These findings suggest a potentially targeted treatment approach to breast cancer.

Flexible zinc batteries have great potential in wearable electronic devices due to their high safety, low cost, and environmental friendliness. In the past few years, a great deal of work on flexible zinc batteries has been reported, with exciting results. Therefore, many solutions have been proposed in electrode design and electrolyte preparation to ensure the desired flexibility without sacrificing the capacity. This paper reviews the recent progress of flexible zinc batteries. We discuss the differences between various anode materials, cathode materials, and electrolytes, introduce the differences of electrode preparation methods of active materials on flexible substrates and their influence on the performance of the battery. Finally, the challenges and future research trends of flexible zinc batteries in capacity and mechanical properties are pointed out.

Rheum tanguticum (R. tanguticum) has been widely used for the treatment of inflammatory diseases in clinical. However, limited research exist on the quality evaluation of various R. tanguticum locations, which has certain drawbacks. In this study, Fourier-transform infrared spectroscopy (FTIR) and high-performance liquid chromatography (HPLC) were used to comparative study on the chemical contents of R. tanguticum, to clarify the relationship between the chemical contents and the spatial distribution of R. tanguticum. First of all, the FTIR spectra of 18 batches of R. tanguticum were examined. Following the cluster analysis, the FTIR spectra of various production locations differed. To some extent, establishing the double index analysis sequence of common and variation peaks may differentiate distinct production locations of medicinal materials. The HPLC fingerprint of R. tanguticum was constructed to further explore the link between components and their origin. PCA of common peaks of 18 batches of R. tanguticum indicated that R. tanguticum grown in Gannan and Qinghai had a tendency to separate t[2], however this trend was not noticeable. Then, OPLS-DA model was established, and the key differential components of R. tanguticum produced in Gannan and Qinghai were discovered to be R16, R37, R46, and R47 (Aloe emodin) (VIP ≥ 1 and P < 0.05). At last, Pearson's test was used to examine the relationship between longitude, latitude, altitude, and composition. Longitude was significantly positively correlated with R28 and R30 (P < 0.05), and a very significantly positively correlated with R35, R36, R37, R46, and R47 (P < 0.01). Latitude was significantly negatively correlated with R34, R35, and R40 (P < 0.05), and extremely significantly negatively correlated with R28, R30, R36, R37, R46, and R47 (P < 0.01). Altitude was significantly positive correlation with R36 and R37 (P < 0.01). The results of our study can provide insights into R. tanguticum quality control and aid in establishing a natural medication traceability system.

The calibration of response spectra is an important issue that needs further research in engineering earthquake resistance. This paper proposes an improved calibration method for site-related response spectra. The seismic acceleration response spectra are statistically analyzed in the random period bands in the form of regression analysis, and the fitting indices in each frequency band under 11 different functions are given. Accordingly, the best fitting function for each period band is determined. Combined with a genetic algorithm, the control parameters of the seismic acceleration response spectrum are calibrated according to the determined new design spectral shape. After comparing the calibration results with the proposed piecewise results, a new calibration model of the three-section curve expression is proposed by improving the piecewise standard until the calibration results are identical to the proposed period point. The accuracy of the proposed calibration method is validated against the other four available methods using Qian’a earthquake records and actual engineering examples. The research results show that the site-related response spectrum calibration method given in this paper objectively reflects the spectrum characteristics of the site-related response spectrum. The proposed method may have a certain reference value for the calibration of the site-related response spectrum.

The fourth basic circuit component, the memristor, has been proposed for a long time, but it is not mentioned in the experiment teaching system of Electrical and Electronic Technology. In this paper, an RC bridge oscillation chaotic circuit based on memristor is designed to solve this problem. The dynamical behavior of the circuit system is analyzed using Lyapunov exponents spectrum, bifurcation diagram, phase portrait and Poincaré map. A series of complex dynamical behaviors such as symmetric single-scroll coexistence, asymmetrical single-scroll coexistence, symmetric double-scroll coexistence and asymmetrical limit–cycle coexistence exist in the circuit system. This research plays a critical role in enriching students’ knowledge and improving the experiment teaching system of Electrical and Electronic Technology.

Motor imagery brain–computer interface (MI-based BCIs) have demonstrated great potential in various applications. However, to well generalize classifiers to new subjects, a time-consuming calibration process is necessary due to high inter-subject variabilities of EEG signals. This process is costly and tedious, hindering the further expansion of MI-based BCIs outside of the laboratory. To reduce the calibration time of MI-based BCIs, we propose a novel domain adaptation framework that adapts multiple source subjects’ labeled data to the unseen trials of target subjects. Firstly, we train one Subject Separation Network(SSN) for each of the source subjects in the dataset. Based on adversarial domain adaptation, a shared encoder is constructed to learn similar representations for both domains. Secondly, to model the factors that cause subject variabilities and eliminate the correlated noise existing in common feature space, private feature spaces orthogonal to the shared counterpart are learned for each subject. We use a shared decoder to validate that the model is actually learning from task-relevant neurophysiological information. At last, an ensemble classifier is built by the integration of the SSNs using the information extracted from each subject’s task-relevant characteristics. To quantify the efficacy of the framework, we analyze the accuracy–calibration cost trade-off in MI-based BCIs, and theoretically guarantee a generalization bound on the target error. Visualizations of the transformed features illustrate the effectiveness of domain adaptation. The experimental results on the BCI Competition IV-IIa dataset prove the effectiveness of the proposed framework compared with multiple classification methods. We infer from our results that users could learn to control MI-based BCIs without a heavy calibration process. Our study further shows how to design and train Neural Networks to decode task-related information from different subjects and highlights the potential of deep learning methods for inter-subject EEG decoding.

Abstract Background Spontaneous formation of urinoma is a rare condition, especially for pregnant women. We report a patient in the third trimester of pregnancy with a spontaneous renal rupture who then develops a urinoma from urine leaking into the perinephric space. Case presentation A 23-year-old primagravida was diagnosed with a spontaneous renal rupture and acute left loin pain accompanied by hematuria when she was 35 weeks pregnant. A sub-capsular perinephric cyst then developed to a size of 319 × 175 × 253 mm, and because of discomfort to the patient, we performed Cesarean section. After a healthy male newborn was delivered, fluid was suctioned from a large perirenal cyst that had an estimated size of 300 × 200 × 300 mm. A percutaneous nephrostomy tube was left in the cyst until CT showed no remaining fluid. In the six-month follow-up, the patient showed no perirenal extravasation according to an ultrasound scan, and the urine analysis and renal function tests were normal. Conclusion Close follow-up should be recommended for the patient who has renal rupture after conservative therapy, especially for pregnant woman. CT or MRI should be considered in addition to utilizing ultrasound in the management of pregnant women who present with urinomas. Percutaneous nephrostomy is suggested as an appropriate treatment for large urinomas.

Splines are irreplaceable in high-speed aviation fields due to their simplicity, reliability, and high specific power. Aviation splines are not only subjected to severe operating mechanical loads, but also sometimes operate under grease-lubricated and non-lubricated environments. All of this results in aviation splines suffering widespread failures. Since the 1960s, many researchers have carried out much research on aviation splines. The wide range of research topics demonstrates the technical challenges of understanding aviation spline. This paper reviews the research of aviation spline from the aspects of failure form, fatigue strength, surface contact stress, effects of lubrication, and misalignment on wear, as well as experiments. Relevant research shows crowned splines can mitigate the spline wear process induced by angular misalignment, and oil-lubricating splines experience almost no wear. This paper also looks forward to the future development directions of aviation splines.

BackgroundAgenesis of the dorsal pancreas (ADP) is a rare disease, the pathogenic mechanism of which is partially related to variants of hepatocyte nuclear factor 1B (HNF1B) gene.Case PresentationWe report a case of ADP, which presented with acute ketoacidosis, hyperuricemia, and liver dysfunction. In this case, the HNF1B score was estimated as 16 and a heterozygous variant of HNF1B in exon 2 (c.513G>A-p.W171X) was identified through gene sequencing.ConclusionsA good understanding of the clinical comorbidities of ADP is essential for avoiding missed diagnosis to a great extent. Moreover, estimation of HNF1B score is recommended before genetic testing.

Virtual reality (VR) technology provides highly immersive depth perception experiences; nevertheless, stereoscopic visual fatigue (SVF) has become an important factor currently hindering the development of VR applications. However, there is scant research on the underlying neural mechanism of SVF, especially those induced by VR displays, which need further research. In this paper, a Go/NoGo paradigm based on disparity variations is proposed to induce SVF associated with depth perception, and the underlying neural mechanism of SVF in a VR environment was investigated. The effects of disparity variations as well as SVF on the temporal characteristics of visual evoked potentials (VEPs) were explored. Point-by-point permutation statistical with repeated measures ANOVA results revealed that the amplitudes and latencies of the posterior VEP component P2 were modulated by disparities, and posterior P2 amplitudes were modulated differently by SVF in different depth perception situations. Cortical source localization analysis was performed to explore the original cortex areas related to certain fatigue levels and disparities, and the results showed that posterior P2 generated from the precuneus could represent depth perception in binocular vision, and therefore could be performed to distinguish SVF induced by disparity variations. Our findings could help to extend an understanding of the neural mechanisms underlying depth perception and SVF as well as providing beneficial information for improving the visual experience in VR applications.

Abstract Background During human pregnancy, placental trophectoderm cells release extracellular vesicles (EVs) into maternal circulation. Trophoblasts also give rise to cell-free DNA (cfDNA) in maternal blood, and has been used for noninvasive prenatal screening for chromosomal aneuploidy. We intended to prove the existence of DNA in the EVs (evDNA) of maternal blood, and compared evDNA with plasma cfDNA in terms of genome distribution, fragment length, and the possibility of detecting genetic diseases. Methods Maternal blood from 20 euploid pregnancies, 9 T21 pregnancies, 3 T18 pregnancies, 1 T13 pregnancy, and 2 pregnancies with FGFR3 mutations were obtained. EVs were separated from maternal plasma, and confirmed by transmission electronic microscopy (TEM), western blotting, and flow cytometry (FACS). evDNA was extracted and its fetal origin was confirmed by quantitative PCR (qPCR). Pair-end (PE) whole genome sequencing was performed to characterize evDNA, and the results were compared with that of cfDNA. The fetal risk of aneuploidy and monogenic diseases was analyzed using the evDNA sequencing data. Results EVs separated from maternal plasma were confirmed with morphology by TEM, and protein markers of CD9, CD63, CD81 as well as the placental specific protein placental alkaline phosphatase (PLAP) were confirmed by western blotting or flow cytometry. EvDNA could be successfully extracted for qPCR and sequencing from the plasma EVs. Sequencing data showed that evDNA span on all 23 pairs of chromosomes and mitochondria, sharing a similar distribution pattern and higher GC content comparing with cfDNA. EvDNA showed shorter fragments yet lower fetal fraction than cfDNA. EvDNA could be used to correctly determine fetal gender, trisomies, and de novo FGFR3 mutations. Conclusions We proved that fetal DNA could be detected in EVs separated from maternal plasma. EvDNA shared some similar features to plasma cfDNA, and could potentially be used to detect genetic diseases in fetus.

Abstract Background Liver fibrosis is a key phase that will progress to further injuries such as liver cirrhosis or carcinoma. This study aimed to investigate whether transplantation of bone marrow mesenchymal stromal cells (BM-MSCs) can attenuate liver fibrosis in mice and the underlying mechanisms based on the regulation of macrophage subtypes. Methods A liver fibrosis model was induced by intraperitoneal (i.p.) injection of CCl4 twice per week for 70 days, and BM-MSCs were intravenously transplanted twice on the 60th and 70th days. Immunohistology and gene expression of liver fibrosis and macrophage subtypes were analyzed. Mouse RAW264.7 cells and JS1 cells (hepatic stellate cell strain) were also used to explore the underlying mechanisms of the effects of BM-MSCs on liver fibrosis. Results After transplantation of BM-MSCs, F4/80+CD206+-activated M2 macrophages and matrix metalloproteinase 13 (MMP 13) expression were significantly increased while F4/80+iNOS+-activated M1 macrophages were inhibited in liver tissue. Gene expression of IL-10 was elevated while IL12b, IFN-γ, TNF-α, and IL-6 gene expression were decreased. ΤGF-β1 and collagen-1 secretions were reduced while caspase-3 was increased in JS1 cells treated with BM-MSC-conditioned media. BM-MSCs effectively suppressed the expression of α-SMA, Sirius red, and collagen-1 in the liver, which are positively correlated with fibrosis and induced by CCl4 injection. Conclusions Taken together, we have provided the first demonstration that BM-MSC transplantation can promote the activation of M2 macrophages expressing MMP13 and inhibition of M1 macrophages to further inhibit hepatic stellate cells (HSCs), which play synergistic roles in attenuating liver fibrosis.

In this paper, a new hybrid method for controlling a wheeled robot is introduced. Model predictive control (MPC) is the main controller and a fuzzy controller is used as a compensator. The wheeled robot is a nonlinear, multi-input–multi-output system that requires new and combined methods for precise control. In order to stabilize the system the appropriate control input is set, and at the same time, attention is paid to the reference signal tracking. In the simulation section, several different scenarios are applied and parameter uncertainties and their effects on the controller’s performance are evaluated. The simulation results show the success and efficiency of the proposed method.

BaMoO4 ceramic was prepared using a conventional solid-sintering method. It was observed that the sample is a pure BaMoO4 with a tetragonal scheelite structure by analyzing X-ray diffraction data. Scanning electron microscopy characterized the dense sample with uniform grains. The phonon modes were analyzed by Raman and Far-infrared reflection spectra, and the phonon characteristics were studied. The intrinsic properties of the sample were calculated by the four-parameter semi-quantum model as well as the Clausius-Mosotti & damping equations, and the results were of εr = 9.388 and tanδ = 4.760 × 10−4, εr = 9.798 and tanδ = 6.445 × 10−4, respectively, which agrees well with the experimental values (εr = 9.84, tanδ = 5.0 × 10−4). The contributions to dielectric properties of each mode were investigated, and the results indicate that the external mode (Eu) yield greatest contribution to intrinsic permittivity and loss. Keywords: Microwave dielectric ceramic, BaMoO4, Crystal structure, Dielectric properties, Phonon characteristics

Background: Patients with acute aortic dissection type A (AADA) often have hypoxemia (partial pressure of oxygen [PaO2]/fraction of inspired oxygen [FiO2]

Colorectal cancer (CRC), initiated and maintained by colorectal cancer stem cells (CCSCs), ranks the third most common cancers and has drawn wide attentions worldwide. Therefore, targeting clearance of CCSCs has become an important strategy of CRC immunotherapy. Mucin1 (MUC1) is a tumor-associated cell surface antigen of CRC, but its role in CCSC vaccine remains unclear. In the study, we demonstrated that MUC1 may be a dominant antigen to exert antitumor immunity in CCSC vaccine. First, CCSCs were enriched from CT26 cell line via a serum-free sphere formation approach, and were identified by detecting expression of CD133, ALDH, and ALCAM. Then, the isolated CCSCs were frozen for 30 min and thawed for 30 min to prepare the cell lysate. The specific anti-MUC1 antibody was added to the cell lysate to neutralize the dominant antigen MUC1. Finally, mice were subcutaneously immunized with the cell lysate, followed by a challenge with CT26 cells at one week after final vaccination. Attractively, CCSC vaccine significantly activated the NK cells, T cells, and B cells, resulting in inhibiting the tumor growth via a target killing of CCSCs as evidenced by a decrease of CD133+cells in tumor compared to CCSC vaccine with specific anti-MUC1 antibody. In addition, CCSC vaccine reduced expression of inflammatory factors in vaccinated mice. As expected, neutralizing antibody against MUC1 significantly impaired the antitumor efficacy of CCSC vaccine. Overall, CCSC vaccine could serve as a potent vaccine for CRC immunotherapy. The surface dominant antigen MUC1 may play a key role in regulating immunogenicity of CCSCs.

Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis inducers, bromodomain-containing protein 7 (BRD7) protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. CRISPR/Cas9-mediated BRD7 knockout conferred resistance to HSC ferroptosis, whereas specific BRD7 plasmid-mediated BRD7 overexpression facilitated HSC ferroptosis. Interestingly, the elevated BRD7 expression exhibited to promote p53 mitochondrial translocation via direct binding with p53 N-terminal transactivation domain (TAD), which may be the underlying mechanisms for BRD7-enhanced HSC ferroptosis. Site-directed mutations of serine 392 completely blocked the binding of BRD7 to p53, and, in turn, prevented p53 mitochondrial translocation and HSC ferroptosis. Importantly, mitochondrial p53 interacted with solute carrier family 25 member 28 (SLC25A28) to form complex and enhanced the activity of SLC25A28, which could lead to the abnormal accumulation of redox-active iron and hyperfunction of electron transfer chain (ETC). SLC25A28 knockdown impaired BRD7-or p53-mediated ferroptotic events. In mice, erastin treatment ameliorated pathological damage of liver fibrosis through inducing HSC ferroptosis. HSC-specific blockade of BRD7-P53-SLC25A28 axis could abrogate erastin-induced HSC ferroptosis. Of note, we analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, BRD7 upregulation, p53 mitochondrial translocation, combination of SLC25A28 and p53, and ferroptosis induction occurred in primary human HSCs. Overall, these findings reveal novel signal transduction and regulatory mechanism of ferroptosis, and also suggest BRD7-P53-SLC25A28 axis as potential targets for liver fibrosis.

Stroke is a disease that occurs due to a sudden interruption of the blood supply to the brain. It is a leading cause of death and disability worldwide. It is well-known that the immune system drives brain injury following an episode of ischemic stroke. The innate system and the adaptive system play distinct but synergistic roles following ischemia. The innate system can be activated by damage-associated molecular patterns (DAMPs), which are released from cells in the ischemic region. Damaged cells also release various other mediators that serve to increase inflammation and compromise the integrity of the blood–brain barrier (BBB). Within 24 h of an ischemic insult, the adaptive immune system is activated. This involves T cell and B cell-mediated inflammatory and humoral effects. These cells also stimulate the release of various interleukins and cytokines, which can modulate the inflammatory response. The adaptive immune system has been shown to contribute to a state of immunodepression following an ischemic episode, and this can increase the risk of infections. However, this phenomenon is equally important in preventing autoimmunity of the body to brain antigens that are released into the peripheral system as a result of BBB compromise. In this review, we highlight the key components of the adaptive immune system that are activated following cerebral ischemia.