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Abstract Background Lung cancer is one of the most frequent cancers and the leading cause of cancer-related deaths worldwide with poor prognosis. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is crucial in the regulation of the extracellular matrix (ECM), impacting its formation, homeostasis and remodeling, and has been linked to cancer progression. However, the specific involvement of ADAMTS4 in the development of lung cancer remains unclear. Methods ADAMTS4 expression was identified in human lung cancer samples by immunohistochemical (IHC) staining and the correlation of ADAMTS4 with clinical outcome was determined. The functional impact of ADAMTS4 on malignant phenotypes of lung cancer cells was explored both in vitro and in vivo. The mechanisms underlying ADAMTS4-mediated lung cancer progression were explored by ubiquitination-related assays. Results Our study revealed a significant upregulation of ADAMTS4 at the protein level in lung cancer tissues compared to para-carcinoma normal tissues. High ADAMTS4 expression inversely correlated with the prognosis of lung cancer patients. Knockdown of ADAMTS4 inhibited the proliferation and migration of lung cancer cells, as well as the tubule formation of HUVECs, while ADAMTS4 overexpression exerted opposite effects. Mechanistically, we found that ADAMTS4 stabilized c-Myc by inhibiting its ubiquitination, thereby promoting the in vitro and in vivo growth of lung cancer cells and inducing HUVECs tubule formation in lung cancer. In addition, our results suggested that ADAMTS4 overexpression activated MAPK signaling pathway. Conclusions We highlighted the promoting role of ADAMTS4 in lung cancer progression and proposed ADAMTS4 as a promising therapeutic target for lung cancer patients.

This study investigates the interactions between virtual cities in electronic (video) games and real urban environments, highlighting a significant gap in the literature regarding the influence of real cities on virtual counterparts and vice versa. Drawing on classical urban theories, it sets two primary objectives: to systematically review how real cities are represented in games and to explore the impacts of virtual cities on real urban areas. Through typological analysis, it identifies two pathways – form and function – through which real cities manifest in games, using specific cases like Cities: Skylines to illustrate these pathways. The principle for virtual city design is also outlined, with an emphasis on the “selection” and “subtraction” of real urban elements in designing processes. Additionally, it discusses how virtual cities impact urban tourism, fostering phenomena like anime pilgrimages, and urban planning, and enhancing public engagement in planning processes. Finally, this research contributes to some newly emerging theories such as Digital Twins by elucidating the interactive relationship between physical and virtual urban spaces.

Abstract The incidence of non-alcoholic fatty liver disease (NAFLD) tends to be younger. And the role of theobromine in fatty liver disease remains unclear. The purpose of this study was to investigate the relationship between dietary theobromine intake and degree of hepatic steatosis in individuals aged 45 and below, using data from the 2017–2020 National Health and Nutrition Examination Survey (NHANES) and liver ultrasonography transient elastography. A total of 1796 participants aged below 45 years were included from NHANES 2017–2020 data after applying exclusion criteria. Multivariate regression and subgroup analyses were conducted to examine the associations between theobromine intake and controlled attenuation parameter (CAP), adjusting for potential confounders. Generalized additive models and two-piecewise linear regression were used to analyze nonlinear relationships. In the unadjusted Model 1 and preliminarily adjusted Model 2, there was no significant correlation between theobromine intake and CAP values. However, in Models 3 and 4, which accounted for confounding factors, a higher intake of theobromine was significantly associated with lower CAP values. Subgroup analyses in the fully adjusted Model 4 revealed a significant negative correlation among individuals aged 18–45, women, and white populations. Nonlinear analysis revealed a U-shaped relationship in black Americans, with the lowest CAP values at 44.5 mg/day theobromine. This study provides evidence that higher theobromine intake is correlated with lower degree of hepatic steatosis in young people, especially those aged 18–45 years, women, and whites. For black Americans, maintaining theobromine intake around 44.5 mg/day may help minimize liver steatosis. These findings may help personalize clinical nutritional guidance, prevent the degree of hepatic steatosis, and provide pharmacological approaches to reverse fatty liver disease in young people.

In recent years, extensive research on dynamic precipitation has led to a growing interest in exploring how deformation affects microstructure and mechanical properties. In this study, the response of microstructure and performance to cold pre-strain and the early aging stage in the Al–Zn–Mg–Cu alloy was investigated using a combination of modelling and experimental approaches. A Kampmann-Wagner based numerical framework was developed and applied to the Al–Zn–Mg–Cu alloy. The deformation or quenching induced dislocations and vacancies, their dynamics and acceleration on the diffusivities of solute atoms, and the competition between homogeneous and heterogeneous nucleation were considered in the framework. The effect of the different pre-strain levels (0%–10%) on the evolution of vacancies, dislocations, precipitation kinetics and hardening are given in detail. The results suggest that the acceleration of precipitation kinetics and hardening during the aging process following pre-strain is primarily attributed to the overall increase in diffusivity resulting from deformation-induced dislocations, rather than vacancies. The simulation framework developed in the current work effectively captures the evolution of microstructure and mechanical properties, which has significant practical implications for materials manufacturing.

The structural changes of cellulose in non-solvent liquid media can provide insights into the high-value utilization of cellulose. This study includes molecular dynamics simulations of 36-chain cellulose Iβ microfibril model (Iβ-MF) behavior in 16 non-solvent liquids with different polarities at room temperature using two carbohydrate force fields (CHARMM36, GLYCAM06). Iβ-MF in CHARMM36 retains more than 70% of the tg conformation in 16 liquids, and the retention of the tg conformation increased with decreasing liquid polarity. Liquid polarity can affect the hydroxymethyl conformation of cellulose, which is only an appearance, and the real driving force behind is the electrostatic interaction between liquid molecules and cellulose. Furthermore, changing the 1,4 electrostatic scaling factor of GLYCAM06 can effectively affect the structural convergence of Iβ-MF. The Iβ-MF forms an alternating layer structure in the gg/gt conformation in a medium to high polarity non-solvent liquid, while the model undergoes untwisting. Model untwisting is inextricably linked to the degree of alternate layer structure formation. This paper provides a theoretical basis for the molecular study of nanocellulose structures from an energy-structure-property perspective.

Abstract Background About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to explore the efficacy and safety of dacomitinib, a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKIs), in treating uncommon EGFR-mutated advanced NSCLC. Methods Treatment-naïve advanced NSCLC patients treated with dacomitinib at Hunan Cancer Hospital with uncommon EGFR mutations were evaluated. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Result Between December 2019 and December 2021, a total of 16 patients was included. Median PFS was 14.0 (95% CI 4.32–23.7) months, and median OS was not reached. ORR was 68.8% (95% CI 41.3 to 89.0%) and DCR was 93.8% (95%CI 69.8 to 99.8%), including three achieving complete remission (CR) and eight achieving partial remission (PR). Median PFS for patients with brain metastasis was 9.0 (95%CI 6.9 to 11.1) months. Intracranial ORR was 100%, including 2 CR and 4 PR. Major treatment-related adverse events (TRAEs) included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were ≥ grade 3 TRAEs. Conclusions Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations.

Fungal diseases not only reduce the yield of edible mushrooms but also pose potential threats to the preservation and quality of harvested mushrooms. Cobweb disease, caused primarily by fungal pathogens from the Hypocreaceae family, is one of the most significant diseases affecting edible mushrooms. Deciphering the genomes of these pathogens will help unravel the molecular basis of their evolution and identify genes responsible for pathogenicity. Here, we present high-quality genome sequences of three cobweb disease fungi: Hypomyces aurantius Cb-Fv, Cladobotryum mycophilum CB-Ab, and Cladobotryum protrusum CB-Mi, isolated from Flammulina velutipes, Agaricus bisporus, and Morchella importuna, respectively. The assembled genomes of H. aurantius, C. mycophilum, and C. protrusum are 33.19 Mb, 39.83 Mb, and 38.10 Mb, respectively. This is the first report of the genome of H. aurantius. Phylogenetic analysis revealed that cobweb disease pathogens are closely related and diverged approximately 17.51 million years ago. CAZymes (mainly chitinases, glucan endo-1,3-beta-glucosidases, and secondary metabolite synthases), proteases, KP3 killer proteins, lipases, and hydrophobins were found to be conserved and strongly associated with pathogenicity, virulence, and adaptation in the three cobweb pathogens. This study provides insights into the genome structure, genome organization, and pathogenicity of these three cobweb disease fungi, which will be a valuable resource for comparative genomics studies of cobweb pathogens and will help control this disease, thereby enhancing mushroom quality.

Abstract Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co‐culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF‐β. Additionally, a suspended co‐culture multicellular spheroid model revealed molecular‐level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro‐angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF‐β, IL‐17, Wnt, Notch, PI3K‐Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts‐endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.

Abstract Pure organic materials with persistent and efficient room‐temperature phosphorescence have recently aroused great research interest due to their vast potential in applications. One crucial design principle for such materials is to suppress as much as possible the non‐radiative decay of the triplet exciton while maintaining a moderate phosphorescent radiative rate. However, molecular engineering often exhibits similar regulation trends for the two processes. Here, we propose that the quantum interference caused by aggregation can be utilized to control the phosphorescent and non‐radiative decay channels. We systematically analyze various constructive and destructive transition pathways in aggregates with different molecular packing types and establish clear relationships between the luminescence characters and the signs of the singlet and triplet excitonic couplings. It is shown that the decay channels can be flexibly switched on or off by regulating the packing type and excitonic couplings. Most importantly, an enhanced phosphorescent decay and a completely suppressed non‐radiative decay can be simultaneously realized in the aggregate packed with inversion symmetry. This work lays the theoretical foundation for future experimental realization of quantum interference effects in phosphorescence.

Summary: Background: Platinum-doublet chemotherapy plus immunotherapy has been the standard of care for the first-line treatment of advanced non-small cell lung cancer lacking actional driver mutations. However, optimization of drug combinations is still needed to find a better balance between therapeutic efficacy and safety in the immunotherapy era. We aimed to investigate the efficacy and safety of platinum-free albumin bound paclitaxel (nab-paclitaxel) combined with camrelizumab and apatinib as first-line treatment for patients with advanced lung adenocarcinoma. Methods: In this multicenter open-label, single-arm phase II trial, patients with systemic treatment-naïve advanced lung adenocarcinoma without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations received a rational-based combination of camrelizumab (200 mg intravenously, day one), apatinib (250 mg, q.d., five continuous days per week), and nab-paclitaxel (135 mg/m2 intravenously, days one and eight) every three weeks for four to six cycles in China. Patients with controlled disease were maintained with camrelizumab and apatinib. The primary end point was progression-free survival (PFS). This trial is registered with ClinicalTrials.gov (No. NCT04459078). Findings: Between August 26, 2020 and May 20, 2022, 64 patients were enrolled. The median PFS was 14.3 (95% CI: 9.9, not reached) months. The confirmed objective response rate was 64.1% (95% CI: 51.1, 75.7). The grade 3–4 hematologic treatment-related adverse events (TRAEs) were decreased neutrophil count (14.1%), decreased white blood cell count (7.8%), and anemia (3.1%). The most common non-hematologic TRAEs of grade 3–4 were increased alanine transaminase (18.8%) and aspartate transaminase (15.6%). No treatment-related death occurred. The quality of life was on average not clinically meaningful worse through treatment cycle 14. Interpretation: Nab-paclitaxel plus camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a potential treatment option in patients with advanced lung adenocarcinoma lacking EGFR/ALK mutations. Funding: Heath Research Foundation of Chinese Society of Clinical Oncology, Hunan Provincial Natural Science Foundation of China, Hunan Cancer Hospital Climb Plan, Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, The Science and Technology Innovation Program of Hunan Province, and Suzhou Sheng Diya Biomedical Co., Ltd, a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Shanghai, China).

Abstract Background Clinical evidence of immune checkpoint inhibitors combined with antiangiogenic drugs in patients with advanced non‐small cell lung cancer (NSCLC) was limited. Recombinant human endostatin (rh‐endostatin), an antiangiogenic drug, and camrelizumab, an anti‐PD‐1 antibody, have been approved for the treatment of advanced NSCLC in China. This study aimed to investigate the efficacy and safety of rh‐endostatin plus camrelizumab and chemotherapy in the treatment of advanced NSCLC. Methods Eligible patients were enrolled and received camrelizumab (200 mg, day 1) every 3 weeks and continuous intravenous infusion of rh‐endostatin (70 mg/day, days 1–3) and cisplatin combined with pemetrexed (for adenocarcinoma) or paclitaxel (for NSCLC other than adenocarcinoma) every 3 weeks. Primary endpoint was progression‐free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. Results Overall, 27 patients were included, and 25 patients were eligible for efficacy evaluation. For these 25 patients, ORR was 48.15% (13/27) and DCR was 85.19% (23/27). With a median follow‐up of 10.37 months, the median PFS was 8.9 (95% CI: 4.23–13.57) months. Median OS was not reached. Overall, 96.3% of patients experienced at least one treatment‐related adverse event, and grade 3 TRAEs occurred in 9 (33.3%) patients. No unexpected AEs were observed. Conclusion Rh‐endostatin plus camrelizumab and chemotherapy showed favorable efficacy and safety profile in patients with advanced NSCLC, representing a promising treatment regimen for these patients.

Labeled hyperspectral image (HSI) information is commonly difficult to acquire, so the lack of valid labeled data becomes a major puzzle for HSI classification. Semi-supervised methods can efficiently exploit unlabeled and labeled data for classification, which is highly valuable. Graph-based semi-supervised methods only focus on HSI local or global data and cannot fully utilize spatial–spectral information; this significantly limits the performance of classification models. To solve this problem, we propose an adaptive global–local feature fusion (AGLFF) method. First, the global high-order and local graphs are adaptively fused, and their weight parameters are automatically learned in an adaptive manner to extract the consistency features. The class probability structure is then used to express the relationship between the fused feature and the categories and to calculate their corresponding pseudo-labels. Finally, the fused features are imported into the broad learning system as weights, and the broad expansion of the fused features is performed with the weighted broad network to calculate the model output weights. Experimental results from three datasets demonstrate that AGLFF outperforms other methods.

ABSTRACTBackground: N6-methyladenosine (m6A) is the most abundant modification in eukaryotic mRNA. However, its role in non-small cell lung cancer (NSCLC) has not been completely elucidated.Objective: To explore whether methyltransferase like 3 (METTL3) in cancer associated fibroblasts (CAFs) affects the secretion of IL-18, which drives NSCLC cells to regulate PD-L1-mediated immunosuppression via the nuclear factor kappa B (NF-κB) pathway.Methods: Histopathological features of NSCLC tissues were identified by H&E and IHC staining. The levels of m6A writers (METTL3), IL-18 and NF-κB pathway related genes were assessed. The quantity of CD8+ T cells was evaluated by flow cytometry (FCM). The direct binding relationship between METTL3 and IL-18 mRNA was detected by RIP assay and RNA pulldown and confirmed by dual – luciferase reporter assay. The level of RNA m6A was detected by RNA m6A dot blot and meRIP assays. A heterotopic implantation model of NSCLC was established in NOD-SCID mice for further explore the effect of CAF derived METTL3 on immunosuppression of NSCLC in vivo.Results: Our results illustrated that METTL3 was down-regulated in CAFs, and CAF derived METTL3 alleviated PD-L1-mediated immunosuppression of NSCLC through IL-18. Subsequently, we found that IL-18 was main effector of CAF-derived METTL3 against immunosuppression of NSCLC, and IL-18 accelerated immunosuppression of NSCLC by driving NF-κB pathway. In vivo, METTL3 knockdown-derived CAFs accelerated immunosuppression of NSCLC.Conclusion: IL-18 served as a main effector of CAF-derived METTL3 against immunosuppression of NSCLC via driving NF-κB pathway.

The incorporation of vasculature is known to be effective in tissue or organ functional regeneration. However, a vague understanding of the interaction between epidermal appendages and their vascular niches is a foremost obstacle to obtaining sweat gland (SG)-specific vasculature units. Here, we map their precise anatomical connections and report that the interplay between SG cells (SGCs) and the surrounding vascular niche is key for glandular development and homeostasis maintenance. To replicate this interplay in vitro, we used three-dimensional (3D) bioprinting to generate reproducible SGC spheroids from differentiated adipose-derived mesenchymal stem cells (ADSCs). With dermal microvascular endothelial cells (DMECs), sacrificial templates made from poly (ε-caprolactone) (PCL) were fabricated to pattern the vascular niche. This interplay model promoted physiologically relevant vascularized glandular morphogenesis in vitro and in vivo. We identified a reciprocal regulatory mechanism for promoting SGs regeneration via contact-independent cell communication and direct cell-cell interactions between SGs and the vasculature. We envision the successful use of our approach for vascularized organ regeneration in the near future.

Discoid lupus erythematosus (DLE) and systemic LE (SLE) can present as cutaneous lesions. Here the authors characterise an scRNA dataset of cutaneous lesions from these patients and compare these to healthy controls showing differential immune cell recruitment, cell type and gene expression.

Much attention has been paid to the solubilization and conversion processes of cellulose, hemicellulose, and lignin to produce high value-added chemicals and fuels. Computer simulation shows great potential in understanding the conversion process of plant biomass. This paper reviewed the solubilization processes, catalytic conversion, and pyrolysis of cellulose, hemicellulose, and lignin by density functional theory and molecular dynamics. The authors also provide prospects for the challenges and future developments in this area.

Abstract Aiming at solving the performance degradation of federated learning (FL) under heterogeneous data distribution, personalized FL (PFL) was proposed. It is designed to produce a dedicated model for each client. However, the existing PFL solution only focuses on the performance of personalized model, ignoring the performance of global model, which will affect the willingness of new clients to participate. In order to solve this problem, this paper proposes a new PFL solution, a two‐stage PFL based on sparse pretraining, which can not only train a sparse personalized model for each client, but also obtain a sparse global model. The whole training process is divided into sparse pretraining and sparse personalized training, which focus on the performance of global model and personalized model respectively. Also, we propose a mask sparse aggregation technique to maintain the sparsity of the global model in the sparse personalized training stage. Experimental results show that compared with existing algorithms, our proposed algorithm can improve the accuracy of the global model while maintaining advanced personalized model accuracy, and has higher communication efficiency.

Abstract The perivascular epithelioid cell tumor (PEComa) is a rare tumor of interstitial origin characterized by several immunological and muscle cell markers. The clear cell sugar tumor (CCST) of the lung is a type of PEComa defined by thin cell walls and high levels of glycogen in the cytoplasm. We herein reported the case of a 48‐year‐old male with a recurrence of lung CCST. The preoperative diagnosis of the lung mass was performed by percutaneous needle biopsy. During the thoracoscopic resection, multiple adhesions in the thoracic cavity were described. The tumor invaded the chest wall, and the boundaries between the tumor and surrounding normal tissues were unclear. The mediastinal lymph nodes were significantly enlarged. No relevant gene mutations were detected. After concomitant chemoradiotherapy, the patient's condition was stable. We also conducted a literature review and discussed the overall findings.

Increasing evidence indicated that liquid crystal monomers (LCMs) in liquid crystal displays can be released into the environment, and ubiquitously detected in environmental matrices and even human bodies. Yet databases regarding its uptake and distribution in mammals are lacking. In this study, four LCMs (namely 3dFB, 2OdF3B, 2teFT, and 6OCB) with various physiochemical properties and structures were selected as the target compounds. The LCMs were in vivo and in vitro exposed to mice and rat liver microsomes (RLM). LCMs were found in all mouse tissues, including brain. Pharmacokinetics parameters, Cmax-tissue/Cmax-blood, ranged from 27.5 to 214, indicating the preferential deposition of LCMs to tissues rather than blood. The LCMs distributed preferentially to lipophilic tissues, and relative mass contribution of LCMs from liver and adipose was 43–98 %. The physicochemical properties (i.e., Kow, molecular weight, and functional groups) had pronounced effect on distribution and accumulation of LCMs. The 2teFT with the highest Kow and molecular weight showed the relatively higher accumulation potential and half elimination time in all the tissues. The 6OCB containing cyano-group was more accumulative than the fluorinated 3dFB with the comparable Kow. In RLM assays, 2teFT and 6OCB were resistant to metabolic degradation. While 3dFB and 2OdF3B underwent rapid degradation with 93.7 % and 72.4 % being metabolized at 360 min. Findings in this study bear significant implications for the biomonitoring and overall risk evaluation of LCMs.

IntroductionPsoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels.MethodsThe therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action.ResultsNcs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions.DiscussionTaken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug.

Supersaturated (Ti,Al)N materials with face centered cubic (fcc) structure offer unique combinations of thermal stability and mechanical properties. However, their thermally-induced decomposition processes are crucial for extracting their full potential. Detailed experimental studies by X-ray diffraction and transmission electron microscopy reveal that the formation of the thermodynamically stable wurtzite-type w-AlN starts with 1000 °C at 100 °C lower annealing temperatures (Ta) when applying a multilayer-concept with TiN to form (Ti,Al)N/TiN multilayers. Nevertheless, the hardness of (Ti,Al)N/TiN multilayers peaks with 32.3 ± 1.0 GPa at a 100 °C higher Ta (900 °C) than the (Ti,Al)N coating, and the hardness declining trend with increasing Ta is milder. This is because the (Ti,Al)N decomposes towards a layered structure of Al-rich and Ti-rich regions, when coherently grown with fcc-TiN. Ab initio calculations highlight that Al within the (Ti,Al)N layers preferentially diffuses away from the coherent interface with the TiN layers. Thus, out of one (Ti,Al)N layer more layers form, and even upon the phase-transformation of the Al-rich layers to w-AlN, their layered structure remains. Together, the computational and experimental results suggest that the layered arrangement provides a higher resistance against dislocation glide and is beneficial for the coating integrity.

With the rapid development of the Internet and the normalization of COVID-19 epidemic prevention and control, Online health communities (OHCs) have gradually become one of the important ways for people to obtain health information, and users have to go through a series of information processing when facing the massive amount of data. Understanding the factors influencing user information processing is necessary to promote users’ health literacy, health knowledge popularization and health behavior shaping. Based on the Heuristic-Systematic Model (HSM), Information Ecology Theory, Privacy Trade-Off and Self-Efficacy Theory, we constructed a model of factors influencing user information processing in online health communities. We found that information quality and emotional support had indirect effects on heuristic and systematic information processing, and these effects were mediated by privacy concerns and self-efficacy. In our research model, systematic information processing was most positively influenced directly by self-efficacy. Privacy concerns had a direct negative correlation with both dual information processing pathways. Therefore, OHCs managers should develop relevant regulations to ensure the information quality in OHCs and improve privacy protection services to promote user information processing by improving users’ self-efficacy and reducing their privacy concerns. Providing a user-friendly and interactive environment for users is also recommended to create more emotional support, thus facilitating more systematic information processing.

Since non-covalent bound character and widespread application in numerous products, people are exposed to di-n-butyl phthalate (DBP) at low levels through various ways. Epidemiological studies suggested an association between DBP exposure and atherosclerosis (AS). Still, molecular mechanisms remain unclear. This study aimed to explore the effects of DBP on monocyte recruitment, a key and initial step of AS. EA.hy926 cells were treated with DBP (10−9–10−5 M) or DMSO as control. Chemotaxis assay was applied to investigate THP-1 recruitment. Expression of mRNA /miRNAs and proteins were measured by qRT-PCR and Western blotting, respectively. Levels of monocyte chemotactic protein 1 (MCP-1) in supernatant were detected by ELISA assay. Receptor internalization assay was performed to confirm C-C chemokine receptor type 2 (CCR2) subcellular localization in THP-1 cells and the binding between CCR2 and MCP-1. Dual-luciferase reporter assay was used to analyze the combination between miR-137-3p and specificity protein 1 (SP1), as well as SP1 and MCP-1. Results showed that number of recruited THP-1 cells after EA.hy926 cells treated by DBP was significantly higher than that in the control group due to promoted MCP-1 expression. In addition, expression of MCP-1 was regulated through miR-137-3p-SP1 cascade. Besides, overexpression of miR-137-3p reversed the increased number of recruited THP-1 cells. Our results implied that DBP might promote THP-1 recruitment by targeting miR-137-3p-SP1-MCP-1 in EA.hy926 cells.

Abstract Ammonia is an indispensable chemical, of which the industrial production is still dominated by Haber‐Bosch process operated at harsh conditions. The ecofriendly electrocatalytic N2 reduction reaction (NRR) emerges as an alternative, however, such technique currently suffers from tough dynamics on account of difficulties in the adsorption or protonation of N2 on catalysts. To eliminate the obstacle, a simple and valid strategy of ferrous iron replacing copper is proposed to regulate the electronic structure of layered double hydroxide (LDH) for boosting the NRR activity. Thanks to the ferrous iron, the Fe(II)Cu(II)Fe(III)‐LDH catalyst attains a NH3 yield rate of 33.1 ± 2.5 µg h−1 mgcat.−1 and a desirable Faradaic efficiency (FE) of 21.7 ± 1.8% in a neutral electrolyte of 0.1 m Na2SO4, outclassing the Cu(II)Fe(III)‐LDH catalyst without Fe(II). The introduction of ferrous iron can adjust the d‐band center position to improve the N2 adsorption and can reduce the energy barrier of the potential determining step (PDS) to facilitate the NRR process. This work provides a new insight on engineering efficient electrocatalysts for nitrogen fixation under ambient conditions.

Background: Cannabinoid receptor 2 (CB2R) is a potential target for anti-inflammatory and pain therapeutics given its significant immunomodulatory and analgesic effects. However, the role of CB2R in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) and itch is poorly understood.Objective: To investigate the function and mechanism of CB2R in PsD and itch in mice.Methods: Following daily treatment with topical IMQ cream for 5-7 consecutive days in C56BL/6 wild-type (WT) and CB2R gene knockout (KO) mice, we assessed the Psoriasis Area and Severity Index (PASI) scores and the scratch bouts every day, and hematoxylin and eosin (H&E) staining, toluidine blue staining were used to observe the histological changes. mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were detected by western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF) and cytometric bead array (CBA). Flow cytometry (FCM) was used to examine the proportion of Th17/Treg cells.Results: We found that CB2R expression levels were increased in mice with psoriasis. Compared with WT mice, CB2R deficiency exacerbated IMQ-induced PsD and scratching bouts and upregulated the expression of proinflammatory cytokines by increasing the infiltration of CD4+ T cells and the Th17/Treg ratio. Obvious proliferation and prolongation of nerve fibers and high expression of nerve growth factor (NGF) were observed in PsD and CB2R KO mice. Pretreatment with the CB2R agonist, JWH-133 significantly reversed inflammation and scratching bouts. CB2R didn't participate in the induction of itch in psoriasis by regulating the expression of IL-31, thymic stromal lymphopoietin (TSLP) and mast cells in mouse skins.Conclusion: Our results demonstrate that CB2R plays a pivotal role in the pathophysiology of psoriasis, providing a new potential target for anti-inflammatory and antipruritic drugs.

Abstract Psoriasis is a chronic, systemic, hyper-proliferative immune-mediated inflammatory skin disease. The results of epidemiological investigations have shown that psoriasis affects around 2% of the general population worldwide, and the total number of psoriasis patients is more than 6 million in China. Apart from the skin manifestations, psoriasis has been verified to associate with several metabolic comorbidities, such as insulin resistance, diabetes and obesity. However, the underlying mechanism is still not elucidated. Adipocytes, considered as the active endocrine cells, are dysfunctional in obesity which displays increased synthesis and secretion of adipokines with other modified metabolic properties. Currently, growing evidence has pointed to the central role of adipokines in adipose tissue and the immune system, providing new insights into the effect of adipokines in linking the pathophysiology of obesity and psoriasis. In this review, we summarize the current understanding of the pathological role of adipokines and the potential mechanisms whereby different adipokines link obesity and psoriasis. Furthermore, we also provide evidence which identifies a potential therapeutic target aiming at adipokines for the management of these two diseases.

Abstract Low-density lipoprotein cholesterol (LDL-C) has been recommended as the primary treatment target on lipid management in coronary heart disease (CHD) patients for past several decades. However, even by aggressive LDL-C lowering treatment, patients still present a significant residual risk of major adverse cardiovascular events (MACE). Non-high-density lipoprotein cholesterol (non-HDL-C) contained all the atherogenic lipoproteins, such as chylomicron, very-low density lipoprotein (VLDL), LDL, intermediate density lipoprotein (IDL). Many prospective observation studies have found that non-HDL-C was better than LDL-C in predicting risks of MACE. Since non-HDL-C appears to be superior for risk prediction beyond LDL-C, current guidelines have emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies and have flagged non-HDL-C as a co-primary therapeutic target. The goals of non-HDL-C were recommended as 30 mg/dl higher than the corresponding LDL-C goals, but the value seemed inappropriate. This review provide evidence for changing lipid management strategy to focus on non-HDL-C and appropriate values for adding to LDL-C goals would be proposed.

Abstract Two new amides (E)-N-cinnamoyl-2-methoxypiperidine (1) and (R)-1-(2-oxopyrrolidin-3-yl)-5,6-dihydropyridin-2(1H)-one (2), four new amide glucosides, retrofractosides A–D (3–6), and two new phenylpropanoid glucosides, retrofractosides E (7) and F (8), together with 24 known compounds (9–32) were isolated from the fruits of Piper retrofractum. The chemical structures of these new compounds were elucidated based on extensive spectroscopic analysis. All of these isolates (1–32) were evaluated for inhibitory activity against mouse platelet aggregation induced by the peptide AYPGKF-NH2. (E)-N-(Tetrahydro-2H-pyran-2-yl)cinnamamide (9) showed a weak inhibitory effect, with an inhibition ratio of 52.0% at a concentration of 150 μM. Graphical Abstract

(1) Objective: To explore Chinese residents’ willingness to receive COVID-19 vaccine booster shots and identify predictors of the level of willingness based on the health belief model (HBM). (2) Methods: The snowball sampling method was used to distribute online questionnaires. A chi-square test was used to analyze the relationship between different variables. The causal relationship between HBM-related factors and booster vaccination intentions was explored by Structural equation modeling (SEM). (3) Results: A total of 898 complete responses were included; 64.3% had already received the booster injection. Most respondents intended to vaccinate themselves, while 16.1% were hesitant. Nearly half of the respondents chose to take the booster injection to support China’s vaccination policy. Using the SEM, perceived susceptibility and perceived barriers were found to have a negative effect on booster vaccination intentions, whereas perceived benefit and cues to action positively affected booster vaccination intentions in the HBM. (4) Conclusions: Factors included in this study have different effects on the willingness to take the COVID-19 booster injections. Sociodemographic characteristics and characteristics of participants’ COVID-19 vaccination have a significant effect on the willingness to receive vaccine booster shots. The HBM constructs can serve as good predictors of the acceptance of vaccine booster shots with the exception of perceived severity, which may benefit health officials in terms of conducting targeted strategies in vaccine programs.

Objective Psoriasis is an immune-mediated chronic inflammatory disease with skin and joint manifestations. Smoking is considered an unfavorable lifestyle factor for psoriasis. We aimed to explore the association between smoking, disease risk, and treatment efficacy in relation to psoriasis. Methods We searched the Cochrane Library, Embase, and PubMed databases for studies examining the relationship between smoking and psoriasis, up to 12 April 2020. We then conducted a meta-analysis using a fixed-effects model to obtain odds ratios (ORs) with 95% confidence intervals (CIs). Results Ever, current, and former smokers all had higher risks of developing psoriasis than non-smokers (pooled ORs (95% CIs): 1.60 (1.51–1.69), 1.63 (1.48–1.80), and 1.36 (1.13–1.64), respectively). Ever smokers were less likely to show disease improvement at 6 months following treatment with biologic agents than non-smokers (pooled OR (95% CI): 0.80 (0.67–0.95)). Conclusions Smoking increases psoriasis risk and negatively impacts the benefits of biologic agents. However, the number of reports is limited and more studies are needed to confirm the effects of smoking and smoking cessation on therapeutic response in patients with psoriasis. Education to encourage a healthy lifestyle remains a valuable approach in clinical practice.

Fossil resources are increasingly exhausted and energy problems are facing severe challenges. The synthesis of ethanol from abundant lignocellulose is conducive to alleviating energy shortage, reducing environmental pollution, and achieving sustainable development. In this paper, compared with the traditional process, the whole process simulation of lignocellulose to biofuel ethanol is established, and a deep-eutectic solvents (DES) pretreatment process for Lignocellulose is proposed. Firstly, to verify the feasibility of the process, the steady-state simulation of the biofuel ethanol production process is carried out using Aspen Plus. Secondly, based on the steady-state simulation, the process is optimised to obtain the optimal operating parameters. Finally, DES is used as an entrainer to increase the concentration of ethanol, and its mechanism is investigated by molecular dynamics simulation (MD). The simulation results show that the DES has good effect in pretreatment and extractive distillation. The final yield of ethanol is 16.8 kg/h and the purity is 99 %. The results of molecular dynamics simulation show that the interaction between DES and water is much larger than that between DES and ethanol. The results are consistent with the process simulation results.

Objective: To investigate the uptake and vaccination willingness of the COVID-19 vaccine among Chinese residents and analyze the difference and factors that impact vaccination. Methods: The snowball sampling method was used to distribute online questionnaires. Relevant sociodemographic data along with the circumstances of COVID-19 vaccination were collected from the respondents. The χ2 test, independent samples t test and binary logistic regression analysis were used to analyze the data. Results: Among 786 respondents, 84.22% had been vaccinated. Over 80% of the vaccinated population have completed all the injections because of supporting the national vaccination policies of China, while the unvaccinated population (23.91%) is mainly due to personal health status. Meanwhile, statistical analysis revealed that the main predictors of not being vaccinated were younger age (3 to 18 years old), personal health status, and lower vaccinated proportion of family members and close friends (p < 0.05). Conclusions: There was a high level of uptake of the COVID-19 vaccine in China, and people who have not been vaccinated generally had a low willingness to vaccinate in the future. Based on our results, it suggested the next work to expand the coverage of the COVID-19 vaccination should be concentrated on targeted publicity and education for people who have not been vaccinated.

Abstract Apolipoprotein A5 (apoA5) has been identified to play an important role in lipid metabolism, specifically in triglyceride (TG) and TG-rich lipoproteins (TRLs) metabolism. Numerous evidence has demonstrated for an association between apoA5 and the increased risk of obesity and metabolic syndrome, but the mechanism remains to be fully elucidated. Recently, several studies verified that apoA5 could significantly reduce plasma TG level by stimulating lipoprotein lipase (LPL) activity, and the intracellular role of apoA5 has also been proved since apoA5 is associated with cytoplasmic lipid droplets (LDs) and affects intrahepatic TG accumulation. Furthermore, since adipocytes provide the largest storage depot for TG and play a crucial role in the development of obesity, we could infer that apoA5 also acts as a novel regulator to modulate TG storage in adipocytes. In this review, we focus on the association of gene and protein of apoA5 with obesity and metabolic syndrome, and provide new insights into the physiological role of apoA5 in humans, giving a potential therapeutic target for obesity and associated disorders.

Objective:To observe whether baicalein have therapeutic value on diabetes mellitus (DM) with cerebral small vessel disease (CSVD) so as to explore the pathogenesis and therapy of the cognitive ability and behavioral function disorder caused by chronic cerebral ischemia and hypoxia.Methods:A total of thirty male SD rats were randomly divided into normal control group, model group and treatment group, 10 rats in each group. After the stable models of DM with CSVD were established, cognitive function scores of all rats were evaluated by Morris water maze test, and the levels of acetylcholine (Ach) and acetylcholinesterase (AchE) in brain were assessed to evaluate the protective effects of baicalein.Results:Morris water maze test showed that learning and memory function had been significantly impaired in rats of DM with CSVD since the 7th day of modeling. Spatial probe test founded that the times of crossing platform in the model group were significantly lower than those in the normal control group (PPPP

Kunitz-type proteins or peptides have been found in many blood-sucking animals, but the identity of them in leeches remained elusive. In the present study, five Kunitz-type peptides named WPK1-WPK5 were identified from the leech Whitmania pigra. Recombinant WPK1-WPK5 were expressed in Pichia pastoris GS115, and their inhibitory activity against Factor XIa (FXIa) was tested. WPK5 showed inhibitory activity against FXIa with an IC50 value of 978.20 nM. To improve its potency, the loop replacement strategy was used. The loop 1 (TGPCRSNLER) and loop 2 (QYGGC) in WPK5 were replaced by loop 1 (TGPCRAMISR) and loop 2 (FYGGC) in PN2KPI, respectively, and the resulting peptide named WPK5-Mut showed an IC50 value of 8.34 nM to FXIa, which is about 100-fold the potency of FXIa compared to that of WPK5. WPK5-Mut was further evaluated for its extensive bioactivity in vitro and in vivo. It dose-dependently prolonged APTT on both murine plasma and human plasma, and potently inhibited FeCl3-induced carotid artery thrombosis in mice at a dose of 1.5 mg/kg. Additionally, WPK5-Mut did not show significant bleeding risk at a dose of 6 mg/kg. Together, these results showed that WPK5-Mut is a promising candidate for the development of an antithrombotic drug.

Scaffold-based peptides (SBPs) are fragments of large proteins that are characterized by potent bioactivity, high thermostability, and low immunogenicity. Some SBPs have been approved by the FDA for human use. In the present study, we developed SBPs from the venom gland of Deinagkistrodon acutus (D. acutus) by combining transcriptome sequencing and Pfam annotation. To that end, 10 Kunitz peptides were discovered from the venom gland of D. acutus, and most of which peptides exhibited Factor XIa (FXIa) inhibitory activity. One of those, DAKS1, exhibiting strongest inhibitory activity against FXIa, was further evaluated for its anticoagulant and antithrombotic activity. DAKS1 prolonged twofold APTT at a concentration of 15 μM in vitro. DAKS1 potently inhibited thrombosis in a ferric chloride-induced carotid-artery injury model in mice at a dose of 1.3 mg/kg. Furthermore, DAKS1 prevented stroke in a transient middle cerebral-artery occlusion (tMCAO) model in mice at a dose of 2.6 mg/kg. Additionally, DAKS1 did not show significant bleeding risk at a dose of 6.5 mg/kg. Together, our results indicated that DAKS1 is a promising candidate for drug development for the treatment of thrombosis and stroke disorders.

By combining the broad learning and a convolutional neural network (CNN), a block-diagonal constrained multi-stage convolutional broad learning (MSCBL-BD) method is proposed for hyperspectral image (HSI) classification. Firstly, as the linear sparse feature extracted by the conventional broad learning method cannot fully characterize the complex spatial-spectral features of HSIs, we replace the linear sparse features in the mapped feature (MF) with the features extracted by the CNN to achieve more complex nonlinear mapping. Then, in the multi-layer mapping process of the CNN, information loss occurs to a certain degree. To this end, the multi-stage convolutional features (MSCFs) extracted by the CNN are expanded to obtain the multi-stage broad features (MSBFs). MSCFs and MSBFs are further spliced to obtain multi-stage convolutional broad features (MSCBFs). Additionally, in order to enhance the mutual independence between MSCBFs, a block diagonal constraint is introduced, and MSCBFs are mapped by a block diagonal matrix, so that each feature is represented linearly only by features of the same stage. Finally, the output layer weights of MSCBL-BD and the desired block-diagonal matrix are solved by the alternating direction method of multipliers. Experimental results on three popular HSI datasets demonstrate the superiority of MSCBL-BD.

Abstract Background The detection of somatic mutations in primary tumors is critical for the understanding of cancer evolution and targeting therapy. Multiple technologies have been developed to enable the detection of such mutations. Next generation sequencing (NGS) is a new platform that is gradually becoming the technology of choice for genotyping cancer samples, owing to its ability to simultaneously interrogate many genomic loci at massively high efficiency and increasingly lower cost. However, multiple barriers still exist for its broader adoption in clinical research practice, such as fragmented workflow and complex bioinformatics analysis and interpretation. Methods We performed validation of the QIAGEN GeneReader NGS System using the QIAact Actionable Insights Tumor Panel, focusing on clinically meaningful mutations by using DNA extracted from formalin-fixed paraffin-embedded (FFPE) colorectal tissue with known KRAS mutations. The performance of the GeneReader was evaluated and compared to data generated from alternative technologies (PCR and pyrosequencing) as well as an alternative NGS platform. The results were further confirmed with Sanger sequencing. Results The data generated from the GeneReader achieved 100% concordance with reference technologies. Furthermore, the GeneReader workflow provides a truly integrated workflow, eliminating artifacts resulting from routine sample preparation; and providing up-to-date interpretation of test results. Conclusion The GeneReader NGS system offers an effective and efficient method to identify somatic (KRAS) cancer mutations.

At present many researchers pay attention to a combination of spectral features and spatial features to enhance hyperspectral image (HSI) classification accuracy. However, the spatial features in some methods are utilized insufficiently. In order to further improve the performance of HSI classification, the spectral-spatial joint classification of HSI based on the broad learning system (BLS) (SSBLS) method was proposed in this paper; it consists of three parts. Firstly, the Gaussian filter is adopted to smooth each band of the original spectra based on the spatial information to remove the noise. Secondly, the test sample’s labels can be obtained using the optimal BLS classification model trained with the spectral features smoothed by the Gaussian filter. At last, the guided filter is performed to correct the BLS classification results based on the spatial contextual information for improving the classification accuracy. Experiment results on the three real HSI datasets demonstrate that the mean overall accuracies (OAs) of ten experiments are 99.83% on the Indian Pines dataset, 99.96% on the Salinas dataset, and 99.49% on the Pavia University dataset. Compared with other methods, the proposed method in the paper has the best performance.

Bio-oil is often extracted from biomass using liquid solvent or supercritical carbon dioxide. However, extraction using these methods has several disadvantages. In this study, expanded hexane with carbon dioxide is examined as a new extraction solvent. The objective of this study is to develop a new technique for the extraction of bio-oil from biomass using expanded hexane with carbon dioxide; rice bran is used as the raw biomass. The extraction was carried out at 25— 27°C, 5.0—5.3 MPa, and 0.78—0.94 mole fraction of carbon dioxide in expanded hexane. At 26°C, 5.1 MPa, 0.87 of mole fraction of carbon dioxide, the oil yield was 1.6 times greater than that with normal liquid hexane because of the low viscosity and high permeability of expanded hexane. Furthermore, the phosphorus concentration in the extracted oil was 9.5 ppm. This was very low, compared with that in rice bran,in which it is approximately 350 ppm. This was because the solvent power of expanded hexane to extract neutral lipid decreased slightly while that to extract polar components decreased significantly. As a result, expanded hexane with carbon dioxide could extract the phosphorus-free bio-oil in high yield under mild conditions.

Based on the in-depth implementation of the strategy of "network power", the Internet plus thinking has been integrated into every field of social construction, especially in the field of financial management, which has provided great convenience for the depreciation management of fixed assets, and also made depreciation more and more important. Based on the digital background, this paper analyzes the problems existing in the depreciation of fixed assets in China from the aspects of acquisition, maintenance, treatment and management of fixed assets. At the same time, in order to improve the quality of fixed assets depreciation management under the background of digitization, enterprises need to scientifically select depreciation methods for digital application in fixed assets management based on conditional support, optimize fixed assets management methods with digitalization, strengthen the skills training of fixed assets management personnel, encourage enterprises to reasonably avoid taxes, and increase the management of fixed assets depreciation by the society The supervision strength.

Based on the structure of AAP, a novel anti-thrombotic peptide from snake venom which we discovered in our previous study, more than 60 compounds were designed and synthesized. One of these termed as LX0702 exhibited stronger anti-platelet aggregation activity than AAP. This study aims to investigate the effects of LX0702 on anti-thrombotic formation and its underlying mechanism. We found that LX0702 inhibited platelet aggregation induced by ADP, thrombin and collagen in a dose dependent manner, with IC50 values of 49.90 ± 2.03, 50.65 ± 0.34 and 83.90 ± 2.06 μM, respectively. It also inhibited thrombus formation in the rat arterio-venous shunt model. In addition, the effect of LX0702 on hemostasis system was tested. Compared to control saline, bleeding time was not prolonged. Furthermore, the ELISA revealed that LX0702 inhibited fibrinogen binding with GPIIb/IIIa in a dose dependent manner with an IC50 value of 1.26 ± 0.13 μM. These findings clearly demonstrate that LX0702 has anti-platelet/anti-thrombotic effects without increased bleeding risk. Therefore it might be developed into an effective drug for the prevention or treatment of thrombotic diseases.

Animal venoms are considered as one of the most important sources for drug development. Deinagkistrodon acutus is famous for its toxicity to the human hematological system and envenomed patients develop a coagulation disorder with the symptoms of hemorrhage and microthrombi formation. The purpose of this study was to separate antiplatelet peptides from D. acutus venom using a combination of an ultrafiltration technique and reversed-phase high performance liquid chromatography (HPLC), which was guided by monitoring antiplatelet aggregation bioactivity. A novel octa-peptide named DAA-8 was found. This peptide inhibited protease-activated receptor1 (PAR-1) agonist (SFLLRN-NH2) induced platelet aggregation and it also inhibited platelet aggregation induced by thrombin, ADP, and collagen. Furthermore, DAA-8 showed significant antithrombotic activity and resulted in a slightly increased bleeding risk in vivo. This is the first report of a peptide derived from snake venom, which inhibited PAR-1 agonist-induced platelet aggregation. This peptide may provide a template to design a new PAR-1 inhibitor.