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Abstract Background Mounting evidence shows that tumor-derived extracellular vesicles (EVs) are critical constituents in the tumor microenvironment. The composition and function of EVs often change during cancer progression. However, it remains less clear how cancer cells modulate their own EV biogenesis to promote tumor development. The release of EVs is closely linked to the endolysosome system residing within the cell. The current study aims to decipher the role of endosomal protein DENND10 in cancer development. Results Bioinformatics data mining showed that DENND10 expression is significantly associated with poor prognosis in multiple cancer types and up-regulated in metastatic breast cancer cell lines. DENND10 knockout (DENND10-KO) in breast cancer cells led to defective EV biogenesis due to impaired endolysosomal trafficking. Intriguingly, DENND10-KO cells exhibited reductions in cell spreading, migration, invasion, and metastatic potential in vivo. These deficiencies in cell motility were associated with compromised cytoskeleton organization. Importantly, wild-type conditioned medium or EVs restored the migratory ability and cytoskeletal organization of DENND10-KO cells. Global proteomic profiling revealed that DENND10 depletion led to a distinct EV compositional landscape with remodeled profiles of extracellular matrix (ECM) and adhesion molecules. Consistently, exogenous application of ECM molecules rescued the spreading and migration of DENND10-KO cells. Conclusions In summary, our study unveiled DENND10 as an intrinsic regulator of cell migration that modifies the tumor microenvironment through autocrine EV release, which could be exploited for developing targeted therapies for tumor metastasis.

Abstract Objective This retrospective study aimed to investigate the factors influencing the occurrence of neutropenia in patients with endometrial cancer (EC) following adjuvant chemoradiotherapy (CRT). Methods Retrospective analysis of EC patients who underwent adjuvant CRT from January 2012 to June 2023 in the Department of Gynecology and Oncology of the First Affiliated Hospital of Shandong First Medical University. Neutropenia was defined as an Absolute Neutrophil Count (ANC) of peripheral blood neutrophils below 2 × 109/L. Factors affecting neutropenia in EC patients treated with CRT using Generalized Estimating Equation (GEE), and Logistic regression was used to further analyze the effect of adding radiotherapy to different chemotherapy cycles on neutropenia, so that patients receive optimal adjuvant CRT while the risk of neutropenia is appropriately controlled. Results A total of 144 patients met the inclusion criteria. They underwent 330 cycles of adjuvant chemotherapy, of whom 96 (66.7%) developed neutropenia, which occurred 140 times. The results of one-way GEE analysis showed that before CRT, White Blood Cell (WBC) (OR = 0.827; 95%CI, 0.701–0.976), ANC (OR = 0.749; 95%CI, 0.586–0.957), Absolute Monocyte Count (AMC) (OR = 0.047; 95%CI, 0.008–0.283), Blood Urea Nitrogen (BUN) (OR = 0.857; 95%CI, 0.741–0.991), platinum and docetaxel (platinum/docetaxel) dosing regimen (OR = 2.284; 95%CI, 1.130–4.618) were associated with neutropenia with adjuvant CRT for EC (p

Abstract Background Rose is recognized as an important ornamental plant worldwide, and it is also one of the most widely used flowers in gardens. At present, the improvement of rose traits is still difficult and uncertain, and molecular breeding can provide new ideas for the improvement of modern rose varieties. Somatic embryos are quite good receptors for genetic transformation. However, little is known about the molecular mechanisms underlying during the regeneration process of rose somatic embryos. To elucidate the molecular regulation mechanism of somatic embryo plantlet regeneration, the relationship between the differences in traits of the two different regenerated materials and the significantly differentially expressed genes (DEGs) related to phytohormone pathways in the process of regeneration were be investigated. Results These representative two regenerated samples from single-piece cotyledonary somatic embryo (SPC) culture of Rosa hybrida ‘John F. Kennedy’, were harvested for transcriptome analysis, with the SPC explants at the initial culture (Day 0) as the control. The differentially expressed genes (DEGs) in the materials from two different types for regeneration approach (SBF type: the regeneration approach type of single bud formed from SPC explants; MBF type: the regeneration approach type of multiple buds formed from SPC explants) were be screened by means of the transcriptome sequencing technology. In this study, a total of about 396.24 million clean reads were obtained, of which 78.95–82.92% were localized to the reference genome, compared with the initial material (CK sample), there were 5594 specific genes in the material of SBF type and 6142 specific genes in the MBF type. The DEGs from the SBF type material were mainly concentrated in the biological processes of GO terms such as phytohormones, substance transport, cell differentiation, and redox reaction. The KEGG enrichment analysis revealed these DEGs were more active in ubiquinone and other terpenoid-quinone biosynthesis, fatty acid elongation, steroid biosynthesis, and glycosphingolipid biosynthesis-globo and isoglobo series. In contrast, the DEGs induced by the MBF type material were mainly associated with the biological processes such as phytohormones, phosphorylation, photosynthesis and signal transduction. According to KEGG analysis, these DEGs of MBF type were significantly enriched in the porphyrin and chlorophyll metabolism, brassinosteroid biosynthesis, carotenoid biosynthesis, and peroxisome. Furthermore, the results from the phytohormone pathways analysis showed that the auxin-responsive factor SAUR and the cell wall modifying enzyme gene XTH were upregulated for expression but the protein phosphatase gene PP2C was downregulated for expression in SBF type; the higher expression of the ethylene receptor ETR, the ethylene transduction genes EBF1/2, the transcription factor EIN3, and the ethylene-responsive transcription factor ERF1/2 were induced by MBF type. Conclusions According to the GO and KEGG analysis, it indicated the DEGs between two different regenerated materials from somatic embryos were significantly different which might be causing morphological differences. That was somatic embryos from Rosa hybrida ‘John F. Kennedy’ could regenerate plantlet via both classic somatic embryogenesis (seed-like germination) and organogenesis, cotyledonary somatic embryos should be considered as one kind of intermediate materials similiar to callus, rather than the indicator materials for somatic embryogenesis.

ObjectivePost-stroke dysphagia (PSD) is a common complication of stroke. Acupuncture as one of the traditional therapies in traditional Chinese medicine (TCM), can change the excitability of cerebral cortical nerve cells, and promote the recovery of neurological and swallowing functions. Several clinical primary studies (including RCTs, cohort studies, etc.) and systematic reviews have demonstrated its efficacy and safety in patients with PSD. The positive effects of acupuncture on PSD are also mentioned in international clinical and treatment guidelines, while there is no synthesis of this evidence. This scoping review aims to summarize the evidence from clinical primary studies, reviews, systematic reviews, and guidelines on acupuncture for the treatment of PSD and explore the breadth of this evidence, provide an overview of the range and characteristics of existing evidence, research gaps, and future research priorities in treating PSD with acupuncture.MethodPubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, SinoMed, Wan Fang Data, and VIP databases were searched from inception until June 12, 2024. The relevant data were presented through bubble diagrams, line graphs, and structured tables along with descriptive statistics and analysis. This scoping review was conducted based on the PRISMA-ScR Checklist.ResultsA total of 1,130 studies were included. Most of the studies were conducted in China, with the number increasing over time. The studies included 254 reviews, 815 clinical studies (678 RCTs,107 nRCTs, 12 case reports, 14 cohort studies, and four case series), 51 systematic reviews, and 10 guidelines. Acupuncture interventions included manual acupuncture (MA), electroacupuncture (EA), and MA/EA combined with acupuncture-related methods (such as scalp acupuncture, auricular acupuncture, warm acupuncture, etc.). The most frequently used acupoint was RN23. Acupuncture is often applied in combination with other treatments, such as herbal medicine, Western medicine, rehabilitation training, swallowing training, or catheter balloon dilatation. Effective rates and WTS were the most frequently used outcomes. Most studies reported significant efficacy and only a few studies explicitly reported adverse events. Acupuncture received positive recommendations in nine guidelines for the treatment of PSD.ConclusionAs a convenient and safe traditional Chinese medicine therapy with its characteristics, acupuncture can improve different stages and types of dysphagia without causing serious adverse reactions. In the future, more standardized international cooperative clinical research is needed to identify the influence of different acupuncture intervention times on the curative effect and dose-effect relationship of acupuncture; standardize the clinical acupoint selection scheme of acupuncture; develop a COS with TCM characteristics to improve the quality of outcome reporting, This will enable different research data to be summarized and compared, reduce resource waste, and provide more high-quality evidence.

ABSTRACT HIV-1 replication is tightly regulated in host cells, and various restriction factors have important roles in inhibiting viral replication. SAMHD1, a well-known restriction factor, suppresses HIV-1 replication by hydrolyzing intracellular dNTPs, thereby limiting the synthesis of viral cDNA in quiescent cells. In this study, we revealed an additional and distinct mechanism of SAMHD1 inhibition during the postviral cDNA synthesis stage. Using immunoprecipitation and mass spectrometry analysis, we demonstrated the interaction between SAMHD1 and MX2/MxB, an interferon-induced antiviral factor that inhibits HIV-1 cDNA nuclear import. The disruption of endogenous MX2 expression significantly weakened the ability of SAMHD1 to inhibit HIV-1. The crucial region within SAMHD1 that binds to MX2 has been identified. Notably, we found that SAMHD1 can act as a sensor that recognizes and binds to the incoming HIV-1 core, subsequently delivering it to the molecular trap formed by MX2, thereby blocking the nuclear entry of the HIV-1 core structure. SAMHD1 mutants unable to recognize the HIV-1 core showed a substantial decrease in antiviral activity. Certain mutations in HIV-1 capsids confer resistance to MX2 inhibition while maintaining susceptibility to suppression by the SAMHD1-MX2 axis. Overall, our study identifies an intriguing antiviral pattern wherein two distinct restriction factors, SAMHD1 and MX2, collaborate to establish an alternative mechanism deviating from their actions. These findings provide valuable insight into the complex immune defense networks against exogenous viral infections and have implications for the development of targeted anti-HIV therapeutics.IMPORTANCEIn contrast to most restriction factors that directly bind to viral components to exert their antiviral effects, SAMHD1, the only known deoxynucleotide triphosphate (dNTP) hydrolase in eukaryotes, indirectly inhibits viral replication in quiescent cells by reducing the pool of dNTP substrates available for viral cDNA synthesis. Our study provides a novel perspective on the antiviral functions of SAMHD1. In addition to its role in dNTP hydrolysis, SAMHD1 cooperates with MX2 to inhibit HIV-1 nuclear import. In this process, SAMHD1 acts as a sensor for incoming HIV-1 cores, detecting and binding to them, before subsequently delivering the complex to the molecular trap formed by MX2, thereby immobilizing the virus. This study not only reveals a new antiviral pathway for SAMHD1 but also identifies a unique collaboration and interaction between two distinct restriction factors, establishing a novel line of defense against HIV-1 infection, which challenges the traditional view of restriction factors acting independently. Overall, our findings further indicate the intricate complexity of the host immune defense network and provide potential targets for promoting host antiviral immune defense.

After 20 years of service, multiple web shear cracks were observed in 20 m-span prestressed concrete hollow slab beams. Shear enhancement is required to improve structural safety. To evaluate the strengthening effect of the new material on the hollow slab beam structure, fiber-reinforced cementitious composites (FRCC) were used to fill the cavities at the beam ends, and a comprehensive field load test was carried out on the shear-resistant performance of the actual bridge. The web principal stresses changed before and after strengthening under various working conditions, which were analyzed and compared with the performance of the traditional channel steel technique. The findings show that the web principal stresses are significantly reduced by more than 50 % after filling with FRCC, notably superior to the channel steel technique. In addition, both methods can reduce mid-span deflections by 10–20 %. The channel steel technique specifically enhances transverse connection capabilities. Furthermore, strain responses in the beam end sections were reduced by about 30–45 %. Finally, finite element simulations of single beam strengthening were also conducted to complement the experimental analysis. The simulation results show that the shear span ratio (λ), FRCC length and strand prestress loss remarkably impact the strengthening effect. The ultimate load capacity of the strengthened specimens decreases with the increase of λ and prestress loss and increases with the increase of FRCC length. In conclusion, the utilization of FRCC presents a superior alternative for shear enhancement in prestressed concrete hollow slab beams, offering substantial reductions in web principal stresses and enhanced structural performance compared to the traditional strengthening method.

Abstract Background Acute pancreatitis (AP) is a severe disorder that leads to high morbidity and mortality. Appropriate reference genes are important for gene analysis in AP. This study sought to study the expression stability of several reference genes in the golden Syrian hamster, a model of AP. Methods AP was induced in golden Syrian hamster by intraperitoneal injection of ethanol (1.35 g/kg) and palmitoleic acid (2 mg/kg). The expression of candidate genes, including Actb, Gapdh, Eef2, Ywhaz, Rps18, Hprt1, Tubb, Rpl13a, Nono, and B2m, in hamster pancreas at different time points (1, 3, 6, 9, and 24 h) posttreatment was analyzed using quantitative polymerase chain reaction. The expression stability of these genes was calculated using BestKeeper, Comprehensive Delta CT, NormFinder, and geNorm algorithms and RefFinder software. Results Our results show that the expression of these reference genes fluctuated during AP, of which Ywhaz and Gapdh were the most stable genes, whereas Tubb, Eef2, and Actb were the least stable genes. Furthermore, these genes were used to normalize the expression of TNF‐α messenger ribonucleic acid in inflamed pancreas. Conclusions In conclusion, Ywhaz and Gapdh were suitable reference genes for gene expression analysis in AP induced in Syrian hamster.

Refueling decisions of liner ships are facing challenges from both fuel price fluctuations and carbon emission constraints. This paper proposes a multistage stochastic programming model to tackle the refueling problem for dual-fuel ships under carbon intensity indicator (CII) rating limit and carbon tax costs. The model also takes into account various factors, including fuel consumption of main and auxiliary engines, fuel availability at ports of call, and fuel price fluctuations. The proposed model is solved using scenario size selection and moment matching methods, and a greedy heuristic algorithm is adopted to speed up the process. Managerial insights are obtained from multinomial logistic regression and sensitivity analyses. Our numerical results reveal that low sulfur fuel oil (LSFO) refueling decisions are closely linked to the difference of LSFO and liquefied natural gas (LNG) fuel prices and that LSFO becomes more attractive when the variance of LSFO fuel price or the LNG availability decreases. Besides, carbon emission costs are found to become a true consideration when carbon taxes exceed a certain threshold. These insights can help practitioners better understand the coupling influence of carbon emissions and fuel price fluctuations on the ship refueling problem.

Abstract Background SHARPIN (SHANK‐associated RH domain interactor) is a component of the linear ubiquitination complex that regulates the NF‐κB signaling pathway. To better understand the function of SHARPIN, we sought to establish a novel genetically engineered Syrian hamster with SHARPIN disruption using the CRISPR/Cas9 system. Methods A single‐guide ribonucleic acid targeting exon 1 of SHARPIN gene was designed and constructed. The zygotes generated by cytoplasmic injection of the Cas9/gRNA ribonucleoprotein were transferred into pseudopregnant hamsters. Neonatal mutants were identified by genotyping. SHARPIN protein expression was detected using Western blotting assay. Splenic, mesenteric lymph nodes (MLNs), and thymic weights were measured, and organ coefficients were calculated. Histopathological examination of the spleen, liver, lung, small intestine, and esophagus was performed independently by a pathologist. The expression of lymphocytic markers and cytokines was evaluated using reverse transcriptase‐quantitative polymerase chain reaction. Results All the offspring harbored germline‐transmitted SHARPIN mutations. Compared with wild‐type hamsters, SHARPIN protein was undetectable in SHARPIN−/− hamsters. Spleen enlargement and splenic coefficient elevation were spotted in SHARPIN−/− hamsters, with the descent of MLNs and thymuses. Further, eosinophil infiltration and structural alteration in spleens, livers, lungs, small intestines, and esophagi were obvious after the deletion of SHARPIN. Notably, the expression of CD94 and CD22 was downregulated in the spleens of knockout (KO) animals. Nonetheless, the expression of CCR3, CCL11, Il4, and Il13 was upregulated in the esophagi. The expression of NF‐κB and phosphorylation of NF‐κB and IκB protein significantly diminished in SHARPIN−/− animals. Conclusions A novel SHARPIN KO hamster was successfully established using the CRISPR/Cas9 system. Abnormal development of secondary lymphoid organs and eosinophil infiltration in multiple organs reveal its potential in delineating SHARPIN function and chronic inflammation.

CD19-targeted chimeric antigen receptor-modified T (CD19 CAR-T) cell therapy has been demonstrated as one of the most promising therapeutic strategies for treating B cell malignancies. However, it has shown limited treatment efficacy for diffuse large B cell lymphoma (DLBCL). This is, in part, due to the tumor heterogeneity and the hostile tumor microenvironment. Human interleukin-12 (IL-12), as a potent antitumor cytokine, has delivered encouraging outcomes in preclinical studies of DLBCL. However, potentially lethal toxicity associated with systemic administration precludes its clinical application. Here, an armed CD19 CAR expressing hypoxia-regulated IL-12 was developed (CAR19/hIL12ODD). In this vector, IL-12 secretion was restricted to hypoxic microenvironments within the tumor site by fusion of IL-12 with the oxygen degradation domain (ODD) of HIF1α. In vitro, CAR19/hIL12ODD-T cells could only secrete bioactive IL-12 under hypoxic conditions, accompanied by enhanced proliferation, robust IFN-γ secretion, increased abundance of CD4+, and central memory T cell phenotype. In vivo, adoptive transfer of CAR19/hIL12ODD-T cells significantly enhanced regression of large, established DLBCL xenografts in a novel immunodeficient Syrian hamster model. Notably, this targeted and controlled IL-12 treatment was without toxicity in this model. Taken together, our results suggest that armed CD19 CARs with hypoxia-controlled IL-12 (CAR19/hIL12ODD) might be a promising and safer approach for treating DLBCL.

AgBi3S5 is a new n-type thermoelectric material that is environmentally friendly and composed of elements of earth-abundant, non-toxic and high performance-cost ratio. This compound features an intrinsically low thermal conductivity derived from its complex monoclinic structure. However, the terrible electrical transport properties greatly limited the improvement of thermoelectric performance. Most previous studies considered that carrier concentration is the main reason for low electrical conductivity and focused on improving carrier concentration by aliovalent ion doping. In this work, we found that the critical parameter that restricts the electric transport performance of AgBi3S5 was the extremely low carrier mobility instead of the carrier concentration. According to the Pisarenko relationships and density functional theory calculations, Nb doping can sharpen the conduction band of AgBi3S5, which contributes to reducing the effective mass and improving the carrier mobility. With a further increase of the Nb doping content, the conduction band convergence can enlarge the effective mass and preserve the carrier mobility. Combined with the decrease in lattice thermal conductivity due to the intensive phone scattering, a maximum ZT value of ∼0.50 at 773 K was achieved in Ag0.97Nb0.03Bi3S5, which was ∼109.6% higher than that of pure AgBi3S5. This work will stimulate the new exploration of high-performance thermoelectric materials in ternary metal sulfides.

To investigate the effects of long-term prestress loss on concrete box girders strengthened with external prestressing, a large-span box girder, in service for over 20 years and strengthened with external prestressing, was monitored for four months. Prestress loss in the longitudinal, vertical, and transverse directions of the box girder was calculated according to Chinese code requirements. Magnetic flux rope force transducers were used to monitor the prestress loss in the external prestressing cables. Fiber Bragg Grating (FBG) sensors were used to monitor deflection changes at the mid-span of the bridge. Finally, the effect of prestress loss in the longitudinal, vertical, and transverse tendons on mid-span deflection was investigated through simulations using ABAQUS software. The results show that instantaneous prestress loss accounts for most of the total loss compared to long-term loss, and that longitudinal prestress loss has the most significant effect on mid-span deflection. The impact of longitudinal prestress loss on deflection before and after strengthening was also compared. The downward deflection and up-ward arch caused by longitudinal tendon prestress loss were reduced after strengthening, con-firming the effectiveness of the external prestressing method.

Summary: Aberrant long interspersed element 1 (LINE-1 or L1) activity can cause insertional mutagenesis and chromosomal rearrangements and has been detected in several types of cancers. Here, we show that neddylation, a post-translational modification process, is essential for L1 transposition. The antineoplastic drug MLN4924 is an L1 inhibitor that suppresses NEDD8-activating enzyme activity. Neddylation inhibition by MLN4924 selectively impairs ORF2p-mediated L1 reverse transcription and blocks the generation of L1 cDNA. Consistent with these results, MLN4924 treatment suppresses the retrotransposition activity of the non-autonomous retrotransposons short interspersed nuclear element R/variable number of tandem repeat/Alu and Alu, which rely on the reverse transcription activity of L1 ORF2p. The E2 enzyme UBE2M in the neddylation pathway, rather than UBE2F, is required for L1 ORF2p and retrotransposition. Interference with the functions of certain neddylation-dependent Cullin-really interesting new gene E3 ligases disrupts L1 reverse transcription and transposition activity. Our findings provide insights into the regulation of L1 retrotransposition and the identification of therapeutic targets for L1 dysfunctions.

Considering that structured light depth imagers are difficult to use for precision measurements due to their limited measurement accuracy, we propose an innovative method for correcting structural parameters of structured light depth imagers to reduce the depth measurement error caused by structural parameter errors. For the structured light depth imager, the analytical imaging model is established, and the model of depth error caused by structural parameter errors is established based on the analysis of the depth measurement error analysis. Then, structural parameters are corrected according to the depth measurement error analysis and processing based on experimental depth imaging data of the standard reference plane at the maximum depth. As a result, the corrected analytical imaging model and corrected depth measurement values are obtained. Experimental results have demonstrated the success of this proposed method and its simplicity and convenience.

Abstract Keratinocytes are closely associated with innate immunity and inflammatory responses, and are dysregulated during the development of psoriasis, but the underlying mechanisms are not yet fully understood. This work aims to reveal the effects of long non-coding RNA (lncRNA) UCA1 in psoriatic keratinocytes. UCA1 was identified as a psoriasis-related lncRNA that highly expressed in psoriatic lesions. The transcriptome and proteome data of keratinocyte cell line HaCaT showed that UCA1 could positively regulate inflammatory functions, such as response to cytokine. Furthermore, UCA1 silencing decreased inflammatory cytokine secretion and innate immunity gene expression in HaCaT, its culture supernatant also decreased the migration and tube formation ability of vascular endothelial cells (HUVECs). Mechanistically, UCA1 activated the NF-κB signaling pathway, which is regulated by HIF-1α and STAT3. We also observed a direct interaction between UCA1 and N6-methyladenosine (m6A) methyltransferase METTL14. Knocking down METTL14 counteracted the effects of UCA1 silencing, indicating that it can suppress inflammation. In addition, the levels of m6A-modified HIF-1α were decreased in psoriatic lesions, indicating that HIF-1α is a potential target of METTL14. Taken together, this work indicates that UCA1 positively regulates keratinocyte-driven inflammation and psoriasis development by binding to METTL14, and activating HIF-1α and NF-κB signaling pathway. Our findings provide new insights into the molecular mechanisms of keratinocyte-driven inflammation in psoriasis.

BackgroundAscending to high altitude can induce a range of physiological and molecular alterations, rendering a proportion of lowlanders unacclimatized. The prediction of acute mountain sickness (AMS) prior to ascent to high altitude remains elusive.MethodsA total of 40 participants were enrolled for our study in the discovery cohort, and plasma samples were collected from all individuals. The subjects were divided into severe AMS-susceptible (sAMS) group, moderate AMS-susceptible (mAMS) group and non-AMS group based on the Lake Louise Score (LLS) at both 5000m and 3700m. Proteomic analysis was conducted on a cohort of 40 individuals to elucidate differentially expressed proteins (DEPs) and associated pathways between AMS-susceptible group and AMS-resistant group at low altitude (1400m) and middle high-altitude (3700m). Subsequently, a validation cohort consisting of 118 individuals was enrolled. The plasma concentration of selected DEPs were quantified using ELISA. Comparative analyses of DEPs among different groups in validation cohort were performed, followed by Receiver Operating Characteristic (ROC) analysis to evaluate the predictive efficiency of DEPs for the occurrence of AMS.ResultsThe occurrence of the AMS symptoms and LLS differed significantly among the three groups in the discovery cohort (p

Summary: Fractional CO2 laser, as a typical ablative laser, has been used to assist in the treatment of many skin diseases, such as photoaging, atrophic scar, hypertrophic scar, superficial pigmentation, vitiligo, and so on. However, the dynamic changes in skin function after fractional CO2 laser treatment are still unclear. This study explored the changes in local skin function and possible regulatory mechanisms after fractional CO2 laser treatment for 1, 3, 5, and 7 days through transcriptome high-throughput sequencing. The results showed that fractional CO2 laser tended to transform the “lesions” into “normal skin”, regulate the skin barrier, coordinate the rearrangement of collagen, enhance the local microvascular circulation, activate the immune system to secrete a large number of cytokines, and act as an auxiliary tool to assist drug transport. In conclusion, according to the basic principle of destruction before reconstruction, fractional CO2 laser plays a key role of balancer in skin reconstruction.

Ship fouling has significant adverse effects on vessel performance and environmental sustainability. Therefore, this research study develops a bi-level programming model to simultaneously optimize cleaning equipment deployment by cleaning service providers in the upper level and cleaning decisions by shipping companies in the lower level. To address the interaction within the bi-level problem, the model is transformed into a single-level formulation using the big-M method. This transformation greatly simplifies the complexity of the computation and reduces computation time. Numerical experiments are conducted using real-world data to evaluate the performance of the proposed models. In addition, sensitivity analyses are performed to investigate the influence of key parameters. The results indicate that cleaning service providers primarily purchase equipment in the first year based on the demand distribution. To maximize profit, they may choose to forgo a portion of the demand. The sensitivity analysis reveals that sacrificing part of the demand can lead to an additional USD 27 million in profits compared with satisfying all demand. Moreover, increasing the cleaning price reduces both demand and equipment purchases but increases total profits. Conversely, increasing purchase costs reduces profits and the total amount of equipment purchased. When service providers can no longer generate profits, they are likely to exit the market. These findings offer valuable insights for service providers and shipping companies in the practical deployment of cleaning equipment and foul cleaning decisions, respectively.

Immunotherapies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor-T (CAR-T) cells, are only efficient in a small proportion of tumor patients. One of the major reasons for this is the lack of immune cell infiltration and activation in the tumor microenvironment (TME). Recent research reported that abundant bystander CD8+ T cells targeting viral antigens exist in tumor infiltrates and that virus-specific memory T cells could be recalled to kill tumor cells. Therefore, virus-specific memory T cells may be effective candidates for tumor immunotherapy. In this study, we established subcutaneous tumor mice models that were pre-immunized with Vaccinia virus (VV) and confirmed that tumor cells with ectopic expression of the viral B8R protein could be recognized and killed by memory T cells. To create a therapeutic delivery system, we designed a recombinant adeno-associated virus (rAAV) with a modified tumor-specific promoter and used it to deliver VV B8R to tumor cells. We observed that rAAV gene therapy can retard tumor growth in VV pre-immunized mice. In summary, our study demonstrates that rAAV containing a tumor-specific promoter to restrict VV B8R gene expression to tumor cells is a potential therapeutic agent for cancer treatment in VV pre-immunized or VV-treated mice bearing tumors.

Hyperspectral image (HSI) classification, due to its characteristic combination of images and spectra, has important applications in various fields through pixel-level image classification. The fusion of spatial–spectral features is a topic of great interest in the context of hyperspectral image classification, which typically requires selecting a larger spatial neighborhood window, potentially leading to overlaps between training and testing samples. Vision Transformer (ViTs), with their powerful global modeling abilities, have had a significant impact in the field of computer vision through various variants. In this study, an ensemble learning framework for HSI classification is proposed by integrating multiple variants of ViTs, achieving high-precision pixel-level classification. Firstly, the spatial shuffle operation was introduced to preprocess the training samples for HSI classification. By randomly shuffling operations using smaller spatial neighborhood windows, a greater potential spatial distribution of pixels can be described. Then, the training samples were transformed from a 3D cube to a 2D image, and a learning framework was built by integrating seven ViT variants. Finally, a two-level ensemble strategy was employed to achieve pixel-level classification based on the results of multiple ViT variants. Our experimental results demonstrate that the proposed ensemble learning framework achieves stable and significantly high classification accuracy on multiple publicly available HSI datasets. The proposed method also shows notable classification performance with varying numbers of training samples. Moreover, herein, it is proven that the spatial shuffle operation plays a crucial role in improving classification accuracy. By introducing superior individual classifiers, the proposed ensemble framework is expected to achieve even better classification performance.

Fault localization, a critical process of software debugging, can be implemented by ranking program statements according to their suspiciousness of being faulty, which, in turn, is calculated based on the execution behaviors of test cases. The performance of fault localization will deteriorate if the actual faulty statement is ranked low in suspiciousness. Intuitively speaking, the quality of the used test cases affects the suspiciousness ranking and thus the efficacy of fault localization. As such, it is necessary to generate test cases with “better” quality to improve the chance of faulty statements being ranked as highly suspicious. In this paper, we propose a software fault localization approach based on feedback ranking information, namely FLFR, according to an improved genetic algorithm. The starting point of the new method is the execution of a set of test cases, which gives a preliminary suspiciousness ranking of program statements. The improved genetic algorithm is iteratively applied to generate new test cases. The new method is evaluated through a series of experiments on four C programs and two Java programs. The experimental results show that the test cases automatically generated by the method can improve the suspiciousness ranking of the faulty statement, and thus enhance the performance of fault localization.

Abstract Background Activating transcription factor-2 (ATF2) is a member of the basic leucine zipper family of DNA-binding proteins, which exhibits both oncogenic and tumor suppression activity in different tumors. However, the molecular mechanism of its dual function in cancer chemotherapy especially in gastric cancer has still not been elucidated. Methods The protein expression and location of ATF2 in gastric cancer tissues was detected with immunohistochemistry assay, and the clinical significance was analyzed using TCGA and GEO database. The activation and impact of ATF2 in cisplatin treated cells were evaluated with western blot, incucyte live cell analysis, clone formation and tumor xenografts assays. Interaction between ATF2 and p53 was confirmed with immunoprecipitation and GST-pull down. Potential molecular mechanism of ATF2 in different p53 status cells was analyzed with RNA sequencing and real-time quantitative PCR. Results ATF2 mainly located in the nucleus of cancer cells, higher ATF2 level was associated with poor five-year survival of gastric patients, especially in those undergone chemotherapy treatment. Cisplatin treatment significantly activated ATF2 in p53 mutant cells. ATF2 could interact with the trans-activation domain of p53 and enhance cisplatin sensitivity in p53 wild type cell lines, while promoted cell survival in mutant p53 cancer cells by affecting ERK1/2 pathway. Conclusions This study confirmed the effect of ATF2 on cisplatin sensitivity was associated with the functional status of p53 in gastric cancer cells. Integrated analysis of ATF2 expression and P53 status could be used to evaluate the chemotherapy sensitivity and prognosis of gastric cancer patients.

Enterovirus D68 (EV-D68) is a globally re-emerging respiratory pathogen implicated in outbreaks of severe respiratory illnesses and associated with acute flaccid myelitis. However, effective vaccines or treatments for EV-D68 infections remain scarce. We demonstrated that the active constituent of blueberries, pterostilbene (Pte), and its major metabolite, pinostilbene (Pin), facilitated innate immune responses in EV-D68-infected human respiratory cells. Pte and Pin treatment clearly relieved EV-D68-triggered cytopathic effects. Importantly, both Pte and Pin disrupted viral RNA replication (EC50 rank from 1.336 to 4.997 µM) and infectious virion production in a dose-dependent manner, without cytotoxicity at virucidal concentrations. Pte- or Pin-treated respiratory cells did not show any influences on EV-D68 entry but showed substantially decreased viral RNA replication and protein synthesis. Finally, we showed that Pte and Pin broadly suppressed the replication capacity of circulating EV-D68 strains isolated from recent pandemics. In summary, our results suggest that Pte and its derivative, Pin, enhance host immune recognition of EV-D68 and suppress EV-D68 replication, which represents a promising strategy for antiviral drug development.

BackgroundThe COVID-19 pandemic has impacted many facets of life. This study focuses on undergraduate and postgraduate students in China to explore how the pandemic has affected health status, daily life, learning situations, graduation-related situations, and their studies or work planning.MethodsThis study sent online questionnaires to 2,395 participants to investigate the extent to which they were affected by the epidemic in the various aspects mentioned above and to understand what help they tend to get in the face of these effects.ResultsA total of 2,000 valid questionnaires were collected. The physical health of 82.90% of the respondents was affected to varying degrees, with male students, non-medical students, and graduates being more affected than female students, students with medical majors, and non-graduates, respectively. The proportion of students affected by mental health, the total amount of physical exercise, emotional life, and interpersonal communication was 86.35, 88.65, 80.15, and 90.15%, respectively. Compared with medical students and non-graduates, non-medical students and graduates were more affected. In addition, students’ learning and graduation conditions have also been affected to a certain extent: 13.07% of students may not be able to graduate on time, and the proportion of postgraduate students’ graduations affected was higher than that of undergraduate students.ConclusionThe COVID-19 pandemic has affected the health status of students, their daily lives, learning situations, and so on to varying degrees. We need to pay attention to the issues, provide practical solutions, and provide a basis for better responses to similar epidemics in the future.

Psoriasis is a common inflammatory skin disease that seriously affects the patient's quality of life. The diagnosis of psoriasis is mainly based on clinical and pathological features, and the assessment depends on the psoriasis area and severity index (PASI). However, there are few reliable and accurate evaluation methods to assess lesion severity and therapeutic effects. This work identified 17 model genes from GEO datasets and established 6 psoriasis evaluation models by LASSO regression, linear regression, and random forest separately. Models were trained and evaluated in different GEO datasets. All 6 models accurately classified psoriatic lesions and non-lesional skin in training and testing data, and showed good AUC. In biologics-treated samples, the model scores were positively correlated with the severity of lesions and negatively correlated with treatment length. Thus, models have the potential to assess the therapeutic effects. In addition, the expression of model genes was examined in keratinocytes, skin of IMQ-induced psoriatic mice, and lesions of psoriasis patients. The RNA and protein levels of model genes increased in cytokine-stimulated keratinocytes and psoriatic lesions as expected. This work provides new methods to assess the lesion severity and therapeutic effects of biologics in psoriasis.

It is well known that the air-gap magnetic field of the permanent magnet synchronous generator (PMSG) is difficult to adjust. To overcome this challenge while maintaining the brushless feature of PMSGs, a hybrid excitation synchronous generator (HESG) based on inherent third harmonic field induction is proposed in this paper. The HESG adds a set of third harmonic windings with a pitch of 1/3 of the armature winding in the stator core and a set of harmonic windings with the same pitch as the third harmonic winding in the rotor core. Due to electromagnetic induction, the third harmonic field established by third harmonic windings in the stator induces the harmonic electromotive force (EMF) of six times the frequency in the rotor harmonic winding. This harmonic EMF is directly provided to the rotor excitation winding after rectifying by the diode rotating rectifier. The HESG has armature windings and third harmonic windings in the stator, and excitation windings, harmonic windings and permanent magnets in the rotor. In this article, the mechanism of stator third harmonic winding EMF, rotor harmonic EMF, and the brushless excitation are elaborated. The experimental results of adjustable armature winding voltages with controlling the stator third harmonic winding current have proven the feasibility of the proposed brushless excitation principle based on the third harmonic.

Infrared dim and small target detection is a key technology for various detection tasks. However, due to the lack of shape, texture, and other information, it is a challenging task to detect dim and small targets. Recently, since many traditional algorithms ignore the global information of infrared images, they generate some false alarms in complicated environments. To address this problem, in this paper, a coarse-to-fine deep learning-based method was proposed to detect dim and small targets. Firstly, a coarse-to-fine detection framework integrating deep learning and background prediction was applied for detecting targets. The framework contains a coarse detection module and a fine detection module. In the coarse detection stage, Region Proposal Network (RPN) is employed to generate masks in target candidate regions. Then, to further optimize the result, inpainting is utilized to predict the background using the global semantics of images. In this paper, an inpainting algorithm with a mask-aware dynamic filtering module was incorporated into the fine detection stage to estimate the background of the candidate targets. Finally, compared with existing algorithms, the experimental results indicate that the proposed framework has effective detection capability and robustness for complex surroundings.

Fiber fault detection is crucial for maintaining the quality of optical communication, especially in well-established optical access networks with extended distances and a growing number of subscribers. However, the increasing insertion loss in fiber links presents challenges for traditional fault-detection methods in capturing fault echoes. To overcome these limitations, we propose a modulation-enhanced external-cavity-resonant-frequency method that utilizes a laser for fault echo reception, providing improved sensitivity compared to traditional photodetector-based methods. Our previous work focused on analyzing key parameters, such as sensitivity and spatial resolution, but did not consider practical aspects of selecting optimal modulation parameters. In this study, we develop a model based on Lang–Kobayashi rate equations for current-modulated optical feedback lasers and validate it through experimental investigations. Our findings reveal that optimal detection performance is achieved with a modulation depth of 0.048, a frequency sweeping range of 0.6 times the laser relaxation oscillation frequency, and a frequency sweeping step of 0.1 times the external cavity resonant frequency.

In the current modern power system, extreme load peaks and valleys frequently occur due to the complicated electricity consumption behaviors. This point severely impacts the security, stability, and economy of the power system. Demand response (DR) has been proved to be one of the most effective ways to shift load to relieve the intensity of the power system. Although DR is mainly applied on the commercial and industrial loads traditionally, in recent years, the residential load has gradually attracted attentions of DR researches, especially incentive demand response (IDR) research because of its remarkable stability and flexibility in terms of load shifting. However, the difficulty of measuring the IDR adaptability and potential of a residential user according to the load curve significantly prevents the IDR from being conveniently implemented. And further, the power company is tremendously difficult to efficiently and effectively select the users with high IDR adaptabilities and potentials to participate in IDR. Therefore, to address the aforementioned issues, this paper presents a residential user classification approach based on the graded user portrait with considering the IDR adaptability and potential. Based on the portrait approach, the residential users with high IDR adaptabilities can be preliminarily selected. And then, based on the selected users, the portrait approach to delineate the users with high IDR potentials is further presented. Afterward, the achieved residential users with high adaptabilities and potentials are labeled, which are employed to train the presented variational auto encoder based deep belief network (VAE-DBN) load classification model. The experimental results show the effectiveness of the presented user portrait approaches as well as the presented load classification model. The results suggest that the presented approaches could be potential tools for power company to identify the suitable residential users for participating in the IDR tasks.

IntroductionEndothelial cells play important roles in neurodegenerative diseases caused by diabetes, therefore, we aimed at investigating the mechanisms through which endothelial cells are involved in diabetes development.MethodsSingle cell analysis was performed to identify the major endothelial cell subtypes in cardiovascular tissues that are involved in diabetes development. A cell-cell communication approach was then used to identify ligand-receptor interaction pairs between these cell types. Differential expression analysis between the two experimental groups [standard chow diet group and diabetogenic diet with cholesterol (DDC) group] was used to identify diabetes-related differentially expressed genes (DEGs). The upregulated genes were used to identify candidate ligands or receptors, as well as the corresponding cell types. Cell trajectory inference was performed to identify the stage of cell development and changes in expression of candidate ligands or receptors during cell development. Gene set enrichment analysis (GSEA) was conducted to investigate the biological functions of genes of purpose. Finally, molecular dynamics simulations (MDSs) were used to predict potential drugs with the ability to target the proteins of purpose.ResultsSeven cell types, including five endothelial cell subtypes (EC_1, EC_2, EC_3, EC_4, and EC_EndMT), were identified from endothelial cell-enriched single cell samples from the heart and aorta of mice. Cell-cell communication analysis revealed the potential ligand-receptor interactions between these cell types while five important ligand-receptor-associated genes, including Fn1, Vcam1, Fbn1, Col4a1, and Col4a2, were established by differential expression analysis. Among them, Vcam1 is mainly expressed in EC_EndMT and is involved in interactions between EC_EndMT and other cells. Cell trajectory extrapolation analysis revealed a shift from EC_2/EC_4 to EC_EndMT and a shift from EC_EndMT to EC_3/EC_1 during the progression of diabetes. GSEA analysis revealed that upregulation of VCAM1 may have inhibitory effects on cell growth and energy metabolism.ConclusionEC_EndMT subtypes have a complex role in neurodegenerative diseases caused by diabetes. Through mechanisms involved in cell-cell communication, Vcam1 may play an important role in dysregulation of biological functions of EC_ EndMT. Molecular docking results of the quercetin-VCAM1 complex suggest that quercetin may be an effective drug for targeting this protein.

BackgroundCurrently, only a few studies have examined the link between dental health, cognitive impairment, and physical activity. The current study examined the relationship between denture use and physical activity in elderly patients with different cognitive abilities.MethodsThe study data was sourced from the 2018 China Health and Retirement Longitudinal Study (CHARLS) database, which included information on denture use and amount of daily physical activity undertaken by older persons. Physical activity was categorized into three levels using the International Physical Activity General Questionnaire and the International Physical Activity Scale (IPAQ) rubric. The relationship between denture use and physical activity in middle-aged and older persons with varying degrees of cognitive functioning was studied using logistic regression models.ResultsA total of 5,892 older people with varying cognitive abilities were included. Denture use was linked to physical activity in the cognitively healthy 60 + age group (p = 0.004). Denture use was positively related with moderate physical activity in the population (odds ratio, OR: 1.336, 95% confidence interval: 1.173–1.520, p < 0.001), according to a multivariate logistic regression analysis, a finding that was supported by the calibration curve. Furthermore, the moderate physical activity group was more likely to wear dentures than the mild physical activity group among age-adjusted cognitively unimpaired middle-aged and older persons (OR: 1.213, 95% CI: 1.053–1.397, p < 0.01). In a fully adjusted logistic regression model, moderate physical activity population had increased ORs of 1.163 (95% CI: 1.008–1.341, p < 0.05) of dentures and vigorous physical activity population had not increased ORs of 1.016 (95% CI: 0.853–1.210, p > 0.05), compared with mild physical activity population.ConclusionThis findings revealed that wearing dentures affects physical activity differently in older persons with different cognitive conditions. In cognitively unimpaired older adults, wearing dentures was associated with an active and appropriate physical activity status.

Background: Deoxythymidylate kinase (DTYMK) serves as a pyrimidine metabolic rate-limiting enzyme that catalyzes deoxythymidine monophosphate (dTMP) to generate deoxythymidine diphosphate (dTDP). It remains unclear whether DTYMK expression has the potential to predict outcome and immune cell infiltration in cancers.Methods: DTYMK expression profile was analyzed using Oncomine, TIMER, GEPIA and UALCAN databases. The influence of DTYMK on immune infiltration was examined using TIMER and TISIDB databases. DTYMK interactive gene hub and co-expressing genes were obtained and analyzed by STRING and Linkedomics, respectively. The relationship between DTYMK expression and patient prognosis was validated using GEPIA, Kaplan-Meier plotter, and PrognoScan databases. The functions of DTYMK in cancer cells were also biologically validated in vitro.Results: DTYMK expression was elevated in tumor tissues compared with their control counterparts. DTYMK expression varied in different stages and discriminatorily distributed in different immune and molecular subtypes. Higher expression of DTYMK predicted worse outcome in several cancer types such as liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD). High DTYMK expression was positively or negatively correlated with immune cell infiltration, including B cell, CD8+ cell, CD4+ T cell, macrophage, neutrophil and dendritic cell, depending on the type of cancers. Additionally, DTYMK co-expressing genes participated in pyrimidine metabolism as well as in T helper cell differentiation in LIHC and LUAD. In vitro, knockdown of DTYMK suppressed cell migration of liver and lung cancer cells.Conclusion: DTYMK might be taken as an useful prognostic and immunological marker in cancers and further investigation is warrented.

Autonomous underwater vehicles (AUVs) are important tools for exploring and studying the ocean. To improve the stealthiness of AUV positioning, a new type of inverted ultra-short baseline (i-USBL) positioning system is proposed in this paper. The system uses a surface GPS buoy as a positioning base station to transmit positioning signals to the AUV, which receives the signals through the i-USBL and calculates its own coordinates. In this way, the power consumption of the AUV will be lower, improving its endurance. In addition, azimuth observation is one of the key observation quantities in ultra-short baseline positioning systems. Therefore, this paper derives two phase difference estimation algorithms for azimuth measurement, which are the Least Mean Square (LMS) algorithm and the Discrete Fourier Transform (DFT) algorithm. Simulation results show that when the signal-to-noise ratio (SNR) is less than or equal to 0 dB, the DFT algorithm has higher accuracy; when SNR is greater than or equal to 10 dB, LMS has slightly higher accuracy than DFT; however, DFT is more stable than LMS at all SNRs. When SNR is 20 dB, the maximum azimuth measurement error of LMS and DFT is 0.3301° and 0.2204°, respectively, which can meet the positioning accuracy requirements. The average running times of LMS and DFT are 0.085 s and 0.011 s, respectively, and LMS has a faster running speed. In summary, the LMS algorithm can be used for azimuth observation when the SNR is good, and DFT can be applied when the SNR is poor.

In this study, high intensity ultrasonication (HIU) was employed as an efficient tool to improve the gel property and in vitro digestibility of marinated egg (ME). The effects of HIU treatment at 100 W and 200 W for a series of time periods (0.5 h, 1 h, and 2 h) on the textural profiles, structural changes, and microstructures were also studied. After HIU treatment, the springiness and gumminess of ME white were enhanced. The water holding capacity reached the highest point (66.6%) when 0.5 h 200 W HIU was used. It was observed that 100 W HIU led to the highest zeta potential (-12.0 mV) and hydrophobicity (175.35 μg) of ME, indicating a high degree of electrostatic repulsion prevented agglomeration. HIU treatment at 100 W affected the dynamic rheological behaviors by boosting non-covalent bonds, which maintains the gel network's homogeneity. Meanwhile, the decreasing formation of α-helix, in contrast to β-turn, altered the aggregation behaviors of egg white gel. The microstructure of the 200 W HIU treated samples had porous colloidal network structures, and the in vitro digestibility (>75%) was increased after HIU. This work demonstrated that HIU could be a green and cost-effective tool for processing the egg product with high quality.

Polymyxin is the “last resort” of antibiotics. The self-induced resistance to polymyxin in Gram-negative bacteria could be mediated by lipopolysaccharide (LPS) modification, which is regulated by the two-component system, PhoP/PhoQ. Yersinia enterocolitica is a common foodborne pathogen. However, PhoP/PhoQ has not been thoroughly studied in Y. enterocolitica. In this study, the functions of PhoP/PhoQ in Y. enterocolitica intrinsic resistance were investigated. The resistance of Y. enterocolitica was found to decrease with the deletion of PhoP/PhoQ. Further, PhoP/PhoQ was found to play an important role in maintaining membrane permeability, intercellular metabolism, and reducing membrane depolarization. Based on subsequent studies, the binding ability of polymyxin to Y. enterocolitica was decreased by the modification of LPS with structures, such as L-Ara4N and palmitate. Analysis of the gene transcription levels revealed that the LPS modification genes, pagP and arn operon, were downregulated with the deletion of PhoP/PhoQ in Y. enterocolitica during exposure to polymyxin. In addition, pmrA, pmrB, and eptA were downregulated in the mutants compared with the wild-type strain. Such findings demonstrate that PhoP/PhoQ contributes to the intrinsic resistance of Y. enterocolitica toward polymyxins. LPS modification with L-Ara4N or palmitate is mainly responsible for the resistance of Y. enterocolitica to polymyxins. The transcription of genes related to LPS modification and PmrA/PmrB can be both affected by PhoP/PhoQ in Y. enterocolitica. This study adds to current knowledge regarding the role of PhoP/PhoQ in intrinsic resistance of Y. enterocolitica to polymyxin.

In the current decade, software systems have been more intensively employed in every aspect of our lives. However, it is disappointing that the quality of software is far from satisfactory. More importantly, the complexity and size of today's software systems are increasing dramatically, which means that the number of required modifications is also increasing exponentially. Therefore, it is necessary to understand how function-level modifications impact the distribution of software bugs. In addition, other factors such as a function's structural characteristics as well as attributes of functions themselves may also serve as informative indicators for software fault prediction. In this paper, we perform statistical methods and logistic regression to analyze the possible factors that are related to the distribution of software bugs. We demonstrate our study from the following five perspectives: 1) the distribution of bugs in time and space; 2) the distribution of function-level modifications in time and space; 3) the relationship between function-level modifications and functions' fault-proneness; 4) the relationship between functional attributes and functions' fault-proneness; and 5) the relationship between software structural characteristics and functions' fault-proneness.

The majority of enterovirus proteins are encoded as polyprotein in one open reading frame. Here, Guo et al. characterize a second open reading frame in human enteroviruses and show that it is important for viral particle release, particularly in epithelial cells, and that it affects mortality in a mouse model.

Enterovirus D68 (EV-D68) is a respiratory viral pathogen that causes severe respiratory diseases and neurologic manifestations. Since the 2014 outbreak, EV-D68 has been reported to cause severe complications worldwide. However, there are currently no approved antiviral agents or vaccines for EV-D68. In this study, we found that zinc ions exerted substantial antiviral activity against EV-D68 infection in vitro. Zinc salt treatment potently suppressed EV-D68 RNA replication, protein synthesis, and infectious virion production and inhibited cytopathic effects without producing significant cytotoxicity at virucidal concentrations (EC50=0.033mM). Zinc chloride (ZnCl2) treatment moderately inhibited EV-D68 attachment. Time-dose analysis of EV-D68 structural protein VP1 synthesis showed stronger suppression of VP1 in the culture medium than that in the cell lysates. Furthermore, a zinc ionophore, pyrrolidine dithiocarbamate, which can transport zinc ions into cells, also enhanced the anti-EV-D68 activity of ZnCl2 treatment. Taken together, our results demonstrated that the enhancement of zinc influx could serve as a powerful strategy for the therapeutic treatment of EV-D68 infections.

Long interspersed element 1 (LINE-1 or L1) is the only active autonomous retrotransposon in the human genome that can serve as an endogenous upstream activator of cytoplasmic nucleic acid sensing pathways to elicit an antiviral immune response. In this study, we investigated the influence of enteroviral infection on L1 mobility. The results showed that infection with different enteroviruses, both EV-D68 and EV-A71, blocked L1 transposition. We screened diverse viral accessory proteins for L1 activity and identified EV-D68 2A, 3A, 3C, and EV-A71 ORF2p proteins as viral L1 inhibitors. EV-D68 2A suppressed L1 mobility by expression suppression of L1 proteins. Viral proteins 3A and 3C restricted ORF2p-mediated L1 reverse transcription in isolated L1 ribonucleoproteins. The newly identified enteroviral protein ORF2p inhibited the expression of L1 ORF1p. Altogether, our findings shed light on the strict modulation of L1 retrotransposons during enterovirus replication.

The accurate identification of Very Fast Transient Overvoltage (VFTO) is the key of overvoltage control in modern smart grids. In order to accurately identify VFTO generated by the operation of a disconnector in Gas Insulated Substation (GIS), a VFTO identification method based on Wavelet Transform (WT) and Singular Value Decomposition (SVD) is proposed. The simulation model of VFTO is established in ATP-EMTP software first, and then wavelet decomposition is used in MATLAB software for VFTO simulation of the waveform from the ATP-EMTP software. Then, the feature matrix is composed of the coefficients of each frequency layer of the wavelet. The SVD is used to decompose the feature matrix, and finally the characteristic parameters of the VFTO are obtained. The simulation results in Matlab software indicate that the characteristic parameters of VFTO have an obvious difference compared with those of power frequency AC voltage, especially in the load-side, which verifies the effectiveness of the VFTO identification method based on WT and SVD proposed in this paper.

Abstract This study was conducted to explore the effects of DNMT1 and DNMT3A polymorphisms on susceptibility to noise-induced hearing loss (NIHL) in Chinese workers. A total of 2689 industrial workers from a single textile factory were recruited. Venous blood was collected, as were questionnaire and pure-tone audiometry (PTA) data by specialist physicians. Four selected SNPs (rs7578575, rs749131, rs1550117, and rs2228611) in DNMT1 and DNMT3A were genotyped in 527 NIHL patients and 527 controls. Then, main effects of the genotypes and their interactions were evaluated. Results revealed that the GG genotype at rs749131 and the AG/GG genotypes at rs1550117 and rs2228611 [odds ratio (OR) = 1.87, 2.57, and 1.98 respectively], as well as the haplotypes AGGG and TGGA (rs7578578-rs749131-rs1550117-rs2228611) (OR = 1.35 and 1.56, respectively) were associated with an increased risk of NIHL in the Chinese population. Multifactor dimensionality reduction analysis indicated that rs7578575, rs749131, and rs2228611 interact and are related to increased NIHL risk (OR = 1.63). The genetic polymorphisms rs749131 G, rs1550117 G, and rs2228611 G within the DNMT1 and DNMT3A genes are associated with an increased risk of NIHL in the Chinese population and have the potential to act as biomarkers for noise-exposed workers.

High-risk Human papillomaviruses (HPVs) types are associated with more than 90% of premalignant and malignant squamous lesions of the uterine cervix. The E6 oncoprotein of high-risk HPVs is a key determinant in cell transformation because it induces the degradation of the host pro-apoptotic tumor suppressor p53. E6 recruits the intracellular ubiquitin ligase E6AP and subsequently induces proteasome-dependent p53 degradation. Neither E6 nor E6AP alone interact with p53; however, the precise mechanism of the functional regulation of the E6/E6AP/p53 complex is unclear. Here, we showed that the high-risk HPV E6 proteins are ubiquitinated during E6/E6AP/p53 complex assembly and degraded by the proteasome system. Increasing p53 expression enhanced E6/E6AP/p53 assembly and facilitated E6 ubiquitination and degradation. The dominant negative mutant of p53 R175H, which does not efficiently bind E6, decreased E6 ubiquitination and increased stability. Furthermore, we showed that the ubiquitin ligase E6AP is essential for E6 ubiquitination, and downregulation of E6AP expression increased E6 stability. We also showed that p53 R175H inhibited E6-mediated p53 degradation. Consistently, the host deubiquitinating enzyme USP15 removed ubiquitin chains from E6 proteins and inhibited E6-mediated p53 degradation. Crucially, ectopic expression of either p53 R175H or USP15 promoted p53-triggered apoptosis in human cervical cancer cells. Considering the importance of ubiquitinated E6 on p53 degradation, the disruption of E6 ubiquitination represents an attractive pharmacological intervention against HPV-positive human cervical cancer.ImportanceVirtually 100% of cervical cancers are linked to HPV infection. Commercial HPV vaccines are estimated to prevent up to 90% of HPV-associated cancers, while they do not eliminate persistent HPV infections and have no effect on the progression to malignancy. Hence, the development of novel therapeutic interventions against HPV is urgently required. The HPV oncoprotein E6 binds to the intracellular E3 ubiquitin ligase E6AP and p53 resulting in the degradation of p53. In this study, we demonstrate that HPV E6 is ubiquitinated by E6AP in presence of p53. Crucially, ubiquitination of E6 is important for p53 degradation and blockage of E6 ubiquitination negatively interferes with E6-mediated p53 degradation and enhances the apoptotic effects of p53 and the cytotoxicity of DNA damage in HPV-positive cervical cancer cells. Importantly, our data suggest that the HPV oncogene E6 might be an optimal pharmacologic.

Background: Human cholangiocarcinoma (CCA) is a highly lethal cancer that occurs in the biliary tract. It is characterized by early invasion, poor outcomes, and resistance to current chemotherapies. To date, an effective therapeutic strategy for this devastating and deadly disease is lacking. Pterostilbene, a natural compound found in the extracts of many plants including blueberries, kino tree, or dragon blood tree, has several health benefits. However, its effects on CCA have not been clarified. Here, we investigated the potential application of pterostilbene for the treatment of human CCA in vitro and in vivo.Methods: The effects of pterostilbene on CCA cells were determined by assessing cell viability (CCK), cell proliferation, and colony formation. Cell cycle arrest and apoptosis were measured by flow cytometric analysis, whereas proteins related to autophagy were detected by immunofluorescence and immunoblotting assays. A well-established xenograft mouse model was used to evaluate the effects of pterostilbene on tumor growth in vivo.Results: Pterostilbene induced dose-dependent and time-dependent cytotoxic effects, inhibited proliferation and colony formation, and caused S phase cell cycle arrest in CCA cells. Instead of triggering apoptotic cell death in these cells, pterostilbene was found to exert potent autophagy-inducing effects, and this correlated with p62 downregulation, elevated expression of endogenous Beclin-1, ATG5, and LC3-II, and increases in LC3 puncta. Pretreating cancer cells with the autophagy inhibitor 3-MA suppressed the induction of autophagy and antitumor activity caused by pterostilbene. Finally, we confirmed that pterostilbene inhibited tumor growth in a CCA xenograft mouse model with minimal general toxicity.Conclusion: Taken together, our findings indicate that pterostilbene, through the induction of autophagic flux, acts as an anti-cancer agent against CCA cells.

Infrared thermography has been used as a key means for the identification of overheating defects in power cable accessories. At present, analysis of thermal imaging pictures relies on human visual inspections, which is time-consuming and laborious and requires engineering expertise. In order to realize intelligent, autonomous recognition of infrared images taken from electrical equipment, previous studies reported preliminary work in preprocessing of infrared images and in the extraction of key feature parameters, which were then used to train neural networks. However, the key features required manual selection, and previous reports showed no practical implementations. In this contribution, an autonomous diagnosis method, which is based on the Faster RCNN network and the Mean-Shift algorithm, is proposed. Firstly, the Faster RCNN network is trained to implement the autonomous identification and positioning of the objects to be diagnosed in the infrared images. Then, the Mean-Shift algorithm is used for image segmentation to extract the area of overheating. Next, the parameters determining the temperature of the overheating parts of cable accessories are calculated, based on which the diagnosis are then made by following the relevant cable condition assessment criteria. Case studies are carried out in the paper, and results show that the cable accessories and their overheating regions can be located and assessed at different camera angles and under various background conditions via the autonomous processing and diagnosis methods proposed in the paper.

Abstract Phosphorescent near‐infrared (NIR) organic light‐emitting devices (OLEDs) have drawn increasing attention for their promising applications in the fields such as photodynamic therapy and night‐vision readable displays. Here, three simple phosphorescent Pt(II) complexes are synthesized, and their intermolecular interactions are investigated in crystals and neat films by X‐ray single crystal diffraction and grazing‐incidence wide‐angle X‐ray scattering, respectively. The photophysical properties, molecular aggregation (including Pt–Pt interaction), molecular packing orientation, and electron transport ability are all influenced by the strong intermolecular hydrogen bonds. Consequently, the nondoped OLEDs based on tBu‐Pt and F‐Pt show electroluminescent emissions in NIR region with the highest external quantum efficiencies of 13.9% and 16.7%, respectively.

Enterovirus D68 (EV-D68) has emerged as a significant respiratory pathogen that can cause severe respiratory disease and acute neurologic disease. At present, there are no approved antiviral agents or vaccines for EV-D68. In this study, we demonstrate that andrographolide (ADO), an active component of Andrographis paniculata, exerts substantial antiviral activity against EV-D68 infection. ADO treatment dramatically inhibited EV-D68 RNA replication (EC50 = 3.45 μM) and protein synthesis without producing significant cytotoxicity at virucidal concentrations. ADO-treated cells did not show any changes in host immune activation, EV-D68 attachment, or viral 5′ UTR activity. Using a pH-sensitive fluorescent indicator system for endocytosis in living cells, we found that ADO prevented the acidification of endocytic vesicles after receptor-mediated endocytosis. Finally, we showed that ADO inhibited the viral replication of circulating isolated EV-D68 strains. In summary, our results demonstrate that ADO suppresses EV-D68 replication by targeting the maturation of virus-containing endosomes of EV-D68. This mechanism represents a promising strategy for drug development.

Recent studies have identified human myxovirus resistance protein 2 (MxB or Mx2) as an interferon induced inhibitor of HIV-1 replication. However, whether HIV-1 can overcome MxB restriction without compromise of viral fitness has been undefined. Here, we have discovered that naturally occurring capsid (CA) variants can render HIV-1 resistant to the activity of MxB without losing viral infectivity or the ability to escape from interferon induction. Moreover, these MxB resistant HIV-1 variants do not lose MxB recognition. Surprisingly, MxB resistant CA variants are most commonly found in the Clade C HIV-1 that is the most rapidly expanding Clade throughout the world. Accumulation of MxB resistant mutations is also observed during HIV-1 spreading in human populations. These findings support a potential role for MxB as a selective force during HIV-1 transmission and evolution.

Noise induced hearing loss (NIHL), a multifactorial disease involving both genetic and environmental factors, is one of the most important occupational health hazards. Nonetheless, the influence of FOXO3 variants on NIHL risk have not been illuminated. This research was conducted to explore the effects of FOXO3 polymorphisms on individual susceptibility to NIHL. A total of 2689 industrial workers from one textile factory of east China were recruited to participate in the current research. Venous blood was collected, questionnaire and pure-tone audiometry (PTA) was conducted by specialist physicians. Then, we performed genotyping of three selected SNPs (rs2802292, rs10457180, and rs12206094) in FOXO3 gene in 566 NIHL patients and 566 controls. Subsequently, the main effects of genotype and its interactions were evaluated. Our results revealed that individuals with the G allele of rs2802292, G allele of rs10457180, T allele of rs12206094 (OR = 1.43, 1.43, and 1.31 respectively) and the haplotype GAC and others (TGT/GGT/GGC/GAT) (rs2802292-rs10457180-rs12206094) (OR = 1.49 and 2.09 respectively) are associated with an increased risk of NIHL in a Chinese population. Stratified analysis showed that an increased NIHL risk was found in the subjects who exposed to noise >16 years with rs2802292 GG/GT and rs10457180 AG/GG genotype with an OR of 1.62 and 1.66 respectively. Multifactor dimensionality reduction analysis indicated that rs10457180, rs2802292, and rs12206094 have interactions and are related to increased NIHL risk (OR = 1.53). The genetic polymorphism rs2802292, rs10457180, and rs12206094 within FOXO3 gene are associated with an increased risk of NIHL in a Chinese population and have potential to be biomarkers for noise exposed workers.