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Abstract Numerous myofibroblasts are arisen from endothelial cells (ECs) through endothelial to mesenchymal transition (EndMT) triggered by TGF-β. However, the mechanism of ECs transforms to a different subtype, or whether there exists an intermediate state of ECs remains unclear. In present study, we demonstrate Midkine (MDK) mainly expressed by CD31 + ACTA2+ECs going through partial EndMT contribute greatly to myofibroblasts by spatial and single-cell transcriptomics. MDK is induced in TGF-β treated ECs, which upregulates C/EBPβ and increases EndMT genes, and these effects could be reversed by siMDK. Mechanistically, MDK promotes the binding ability of C/EBPβ with ACTA2 promoter by stabilizing the C/EBPβ protein. In vivo, knockout of Mdk or conditional knockout of Mdk in ECs reduces EndMT markers and significantly reverses fibrogenesis. In conclusion, our study provides a mechanistic link between the induction of EndMT by TGF-β and MDK, which suggests that blocking MDK provides potential therapeutic strategies for renal fibrosis.

Abstract Maxillofacial bone defects exhibit intricate anatomy and irregular morphology, presenting challenges for effective treatment. This study aimed to address these challenges by developing an injectable bioactive composite microsphere, termed D‐P‐Ak (polydopamine‐PLGA‐akermanite), designed to fit within the defect site while minimizing injury. The D‐P‐Ak microspheres biodegraded gradually, releasing calcium, magnesium, and silicon ions, which, notably, not only directly stimulated the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) but also activated sensory nerve cells to secrete calcitonin gene‐related peptide (CGRP), a key factor in bone repair. Moreover, the released CGRP enhanced the osteogenic differentiation of BMSCs through epigenetic methylation modification. Specifically, inhibition of EZH2 and enhancement of KDM6A reduced the trimethylation level of histone 3 at lysine 27 (H3K27), thereby activating the transcription of osteogenic genes such as Runx2 and Osx. The efficacy of the bioactive microspheres in bone repair is validated in a rat mandibular defect model, demonstrating that peripheral nerve response facilitates bone regeneration through epigenetic modification. These findings illuminated a novel strategy for constructing neuroactive osteo‐inductive biomaterials with potential for further clinical applications.

Abstract Background Previous studies have observed a link between immunophenotypes and lung cancer, both of which are closely associated with genetic factors. However, the causal relationship between them remains unclear. Methods Bidirectional Mendelian randomization (MR) was performed on publicly available genome-wide association study (GWAS) summary statistics to analyze the causal relationships between 731 immunophenotypes and lung cancer. Sensitivity analyses were conducted to verify the robustness, heterogeneity, and potential horizontal pleiotropy of our findings. Results Following Bonferroni adjustment, CD14− CD16+ monocyte (OR = 0.930, 95%CI 0.900–0.960, P = 8.648 × 10− 6, P Bonferroni = 0.006) and CD27 on CD24+ CD27+ B cells (OR = 1.036, 95%CI 1.020–1.053, P = 1.595 × 10 − 5, P Bonferroni = 0.012) were identified as having a causal role in lung cancer via the inverse variance weighted (IVW) method. At a more relaxed threshold, CD27 on IgD+ CD24+ B cell (OR = 1.035, 95%CI 1.017–1.053, P = 8.666 × 10− 5, P Bonferroni = 0.063) and CD27 on switched memory B cell (OR = 1.037, 95%CI 1.018–1.056, P = 1.154 × 10− 4, P Bonferroni = 0.084) were further identified. No statistically significant effects of lung cancer on immunophenotypes were found. Conclusions The elevated level of CD14− CD16+ monocytes was a protective factor against lung cancer. Conversely, CD27 on CD24+ CD27+ B cell was a risk factor. CD27 on class-switched memory B cells and IgD+ CD24+ B cells were potential risk factors for lung cancer. This research enhanced our comprehension of the interplay between immune responses and lung cancer risk. Additionally, these findings offer valuable perspectives for the development of immunologically oriented therapeutic strategies.

Abstract Uncontrolled productive infection of BK polyomaviruses (BKV) in immunocompromised patients was reported to result in serious diseases, especially renourinary malignancies. However, the mechanism of BKV as a role of human carcinogen is still unknown. In this study, we showed that there is a significant association between BKV infection and metastasis of urothelial carcinoma (UCA). BKV-infected tumor tissues exhibit invasive histologic phenomena with vascular invasion and myometrial invasion. Then we identified that BKV promotes UCA invasion in a mode of dual regulation of tumor cells (TCs) invasion and endothelial cells (ECs) adhesion by encoding miRNAs. In cancer cells, BKV-B1-miR-5p promotes cell motility and invasiveness by directly targeting CLDN1. Moreover, exosomal-BKV-B1-miR-3p derived from BK-infected BC cells would be transferred to ECs and increase its adhesion to tumor cells by switching on the CLDN1 enhancer, which subsequently destroyed endothelial monolayers and increased permeability. In a human urothelial cancer metastasis mouse model, BK-inoculated cells exhibited higher incidence of vascular leakage and liver colonization. However, the vascular leakage and liver metastasis could be reduced when knocking down miRNAs in BK-inoculated cells. Our research delineates the bifunctional impact of BKV-encoded microRNAs on the expression of CLDN1 within both TCs and ECs, which orchestrates the establishment of a pre-metastatic niche in UCA.

Abstract The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve–bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.

BackgroundThe aim of this study was to identify inflammatory biomarkers in traumatic proliferative vitreoretinopathy (TPVR) patients and further validate the expression curve of particular biomarkers in the rabbit TPVR model.MethodsThe Olink Inflammation Panel was used to compare the differentially expressed proteins (DEPs) in the vitreous of TPVR patients 7–14 days after open globe injury (OGI) (N = 19) and macular hole patients (N = 22), followed by correlation analysis between DEPs and clinical signs, protein–protein interaction (PPI) analysis, area under the receiver operating characteristic curve (AUC) analysis, and function enrichment analysis. A TPVR rabbit model was established and expression levels of candidate interleukin family members (IL-6, IL-7, and IL-33) were measured by enzyme-linked immunosorbent assay (ELISA) at 0, 1, 3, 7, 10, 14, and 28 days after OGI.ResultsForty-eight DEPs were detected between the two groups. Correlation analysis showed that CXCL5, EN-RAGE, IL-7, ADA, CD5, CCL25, CASP8, TWEAK, and IL-33 were significantly correlated with clinical signs including ocular wound characteristics, PVR scoring, PVR recurrence, and final visual acuity (R = 0.467–0.699, p < 0.05), and all with optimal AUC values (0.7344–1). Correlations between DEP analysis and PPI analysis further verified that IL-6, IL-7, IL-8, IL-33, HGF, and CXCL5 were highly interactive (combined score: 0.669–0.983). These DEPs were enriched in novel pathways such as cancer signaling pathway (N = 14, p < 0.000). Vitreous levels of IL-6, IL-7, and IL-33 in the rabbit TPVR model displayed consistency with the trend in Olink data, all exhibiting marked differential expression 1 day following the OGI.ConclusionIL-7, IL-33, EN-RAGE, TWEAK, CXCL5, and CD5 may be potential biomarkers for TPVR pathogenesis and prognosis, and early post-injury may be an ideal time for TPVR intervention targeting interleukin family biomarkers.

ABSTRACTNumerous studies have described the notable impact of gut microbiota on the brain in Alzheimer’s disease (AD) via the gut – brain axis. However, the molecular mechanisms underlying the involvement of gut microbiota in the development of AD are limited. This study aimed to explore the potential mechanisms of gut microbiota in AD by integrating multi-omics data. In this study, APP/PS1 and WT mice at nine months of age were used as study mouse model. Cognitive function was assessed using the Morris water maze test. The levels of Aβ plaque and neuroinflammation in the brain were detected using immunofluorescence and PET/CT. In addition, we not only used 16S rRNA gene sequencing and metabolomics to explore the variation characteristics of gut microbiota and serum metabolism abundance, but also combined spatial metabolomics and transcriptomics to explore the change in the brain and identify their potential correlation. APP/PS1 mice showed significant cognitive impairment and amyloid-β deposits in the brain. The abundance of gut microbiota was significantly changed in APP/PS1 mice, including decreased Desulfoviobrio, Enterococcus, Turicibacter, and Ruminococcus and increased Pseudomonas. The integration of serum untargeted metabolomics and brain spatial metabolomics showed that glycerophospholipid metabolism was a common alteration pathway in APP/PS1 mice. Significant proliferation and activation of astrocyte and microglia were observed in APP/PS1 mice, accompanied by alterations in immune pathways. Integration analysis and fecal microbiota transplantation (FMT) intervention revealed potential association of gut microbiota, host glycerophospholipid metabolism, and neuroinflammation levels in APP/PS1 mice.

m6A modification has been reported to play roles in many developmental and pathological processes, but its role in AKI remains poorly understood. Here, the authors show the role and the mechanism of the m6A demethylase, ALKBH5 on IRI induced AKI.

Abstract Background The study aimed to compare the dentoskeletal effects of Vanbeek Activator, Herbst, Twin-Block and Mandibular Advancement with clear aligners in children with skeletal Class II malocclusions. Methods A sample with sixty-three patients (37 males, 26 females) was included and divided into untreated control group (C, n = 12), Vanbeek Activator group (V, n = 14), Herbst group (H, n = 11), Twin-Block group (TB, n = 12) and MA group (MA, n = 14). Cephalometric analysis and Johnston Pitchfork analysis were performed to quantify the skeletal and dentoalveolar components in molar relationship and overjet correction. Compare the differences of cephalometric data and Johnston-analysis data. Results The treatment changes showed significant differences in SNB, FH-NP, NA-PA, Co-Go, Co-Pog, ANB, lower facial height ratio, U1-PP, U6-PP, L1-MP and U1-L1. All the appliances improved overjet relationships significantly (Vanbeek, Herbst, Twin-Block and MA were 2.77 mm, 5.53 mm, 4.73 mm and 3.66 mm respectively) with significant retraction of maxillary incisors. The lower incisor displacement of group V and MA was negative, while that of group H and TB was positive and there were significant differences. Molar relationships were also improved by 3.45 mm, 6.85 mm, 3.48 mm and 0.92 mm for Vanbeek, Herbst, Twin-Block and MA. Mandible displacement showed a trend of group H > TB > V > MA. The displacement of maxillary molars in group H was greater than that in group C, TB and MA, and that of mandibular ones was greater than that in group C, V and MA, significantly. Herbst, Twin-Block and MA have more significant dentoalveolar effect than Vanbeek, while Vanbeek has more skeletal effect than the others especially in restraining maxillary growth. Conclusions Four appliances are all effective in mandibular advancement, modification of class II molar relationship and deep overjet, with unavoidable increase in lower facial ratio. Vanbeek Activator has the most skeletal effects. Vanbeek and MA have a good control of mandibular incisors while more compensatory lower incisors proclination in Herbst and Twin-Block. Herbst has greater maxillary molar distalization. MA allows aligning and leveling meanwhile leading the mandible forward.

Diabetic wounds always have puzzled patients and caused serious social problems. Due to the lack of local blood vessels, severe hypoxia is generated in the defect area, which is an essential reason for the difficulty of wound healing. We have constructed a photocatalytic oxygen evolution and antibacterial biomimetic repair membrane to solve the problems of wound repair. A scanning electron microscope and transmission electron microscope characterized the biomimetic repair membrane. The oxygen evolution of the biomimetic membrane was tested by an oxygen meter. The excellent antibacterial performance of the biomimetic repair membrane was also verified by co-culture with Staphylococcus aureus and Escherichia coli. It was confirmed that the expression of collagen and HIF1-α in fibroblasts was significantly increased in vitro. And the mitochondrial activity of the vascular and nerve was increased considerably. In vivo, the healing time of diabetes wounds treated with the biomimetic repair membrane was significantly reduced, the collagen and the number of pores were increased considerably, and vascular regeneration was enhanced. The biomimetic repair membrane has an excellent performance in photocatalytic oxygen evolution and antibacterial and can significantly promote the repair of diabetes wounds. This will provide a promising treatment for diabetes wound repair.

Regional integration, as an essential measurement for solving unbalanced and uncoordinated regional development, plays an important role in achieving regional sustainable development. In this study, we aimed to construct a systematic research framework to facilitate the development of regional integration. Using 31 prefecture-level cities in the urban agglomeration in the Middle Reaches of the Yangtze River (MYR-UA) as case sites, this study applied box plots, kernel density estimation, GIS visualization tools, Markov chains, and geographic detectors to reveal the dynamic spatiotemporal evolution and factors influencing regional integration from 2009 to 2018. The results indicate that the level of regional integration and its subsystem development is suboptimal in MYR-UA; the temporal characteristic shows an upward fluctuating trend, and the spatial distribution shows remarkable spatial correlation and clustering characteristics. Additionally, we found that the level of regional integration development in MYR-UA has both “path dependence” and “self-locking” effects, and the spatial lag type has a crucial impact on the degree of regional transfer stability. The dominant factors affecting regional integration development include the GDP per capita, economic openness, industrial structure, proportion of education expenditure in fiscal expenditure, urbanization rate, proportion of environmental investment in fiscal expenditure, population density, capital flow, information flow, and technology flow. Finally, based on the findings of this study, policy recommendations for promoting regional integration are proposed.

The efficiency and accuracy of the synthesis of structural lipids are closely related to the regiospecificity of lipases. Understanding the structural mechanism of their regiospecificity contributes to the regiospecific redesign of lipases for meeting the technological innovation needs. Here, we used a thermostable lipase from Streptomyces sp. W007 (MAS1), which has been recently reported to show great potential in industry, to gain an insight into the structural basis of its regiospecificity by molecular modelling and mutagenesis experiments. The results indicated that increasing the steric hindrance of the site for binding a non-reactive carbonyl group of TAGs could transform the non-specific MAS1 to a α-specific lipase, such as the mutants G40E, G40F, G40Q, G40R, G40W, G40Y, N45Y, H108W and T237Y (PSI > 80). In addition, altering the local polarity of the site as well as the conformational stability of its composing residues could also impact the regiospecificity. Our present study could not only aid the rational design of the regiospecificity of lipases, but open avenues of exploration for further industrial applications of lipases.

Pulmonary arterial hypertension (PAH) is a type of high morbidity and mortality disease. Currently, the intrinsic metabolic alteration and potential mechanism of PAH are still not fully uncovered. Previously, we have found that polyphenol resveratrol (Rev) reversed the remodeling of the pulmonary vasculature and decreased the number of mitochondria in pulmonary arterial smooth muscle cells (PASMCs) (Lei Yu et al. (2017)). However, potential effects of Rev on the changed metabolic molecules derived from lung tissue and serum have no fully elucidated. Thus, we conducted a systematic elaboration through the metabonomics method. Various of metabolites in different pathways including amino acid metabolism, tricarboxylic acid cycle (TCA), acetylcholine metabolism, fatty acid metabolism and biosynthesis in male Wistar rats’ sera and lung tissues were explored in three groups (normal group, PAH group, PAH and Rev treatment group). We found that leucine and isoleucine degradation, valine, leucine and isoleucine biosynthesis, tryptophan metabolism and aminoacyl-tRNA biosynthesis were involved in the development of PAH. Hydroxyphenyllactic, isopalmitic acid and cytosine might be significant key metabolites. Further work in this area may inform personalized treatment approaches in clinical practice of PAH through elucidating pathophysiology mechanisms of experimental verification.

In this paper, by using the transfer matrix method and introducing the plasma as the dispersion medium, we propose the tunable one-dimensional magnetized ternary plasma photonic crystal structure (APB)N, and study its omnidirectional absorption properties of TM wave in terahertz band, where A and B are two different dielectric layers, P is plasma layer, and studied the regulation of the frequency and peak of the absorption channel by the number of periods, the relative refractive index of the dielectric layer, length, density, collision frequency and magnetic field intensity of the plasma layer to the absorption channel frequency and peak value. Therefore, this paper provides an idea for the design of terahertz absorbers for omnidirectional plasma photonic crystals.

Tropical overshooting convection has a strong impact on both heat budget and moisture distribution in the upper troposphere and lower stratosphere, and it can pose a great risk to aviation safety. Cloud-top height is one of the essential concerns of overshooting convection for both the climate system and the aviation weather forecast. The main purpose of our work is to verify the application of the machine learning method, taking the random forest (RF) model as an instance, in overshooting cloud-top height retrieval from Himawari-8 data. By using collocated CloudSat observations as a reference, we utilize several infrared indicators of Himawari-8 that are commonly recognized to relate to cloud-top height, along with some temporal and geographical parameters (latitude, month, satellite zenith angle, etc.), as predictors to construct and validate the model. Analysis of variable importance shows that the brightness temperature of 6.2 um acts as the dominant predictor, followed by satellite zenith angle, brightness temperature of 13.3 um, latitude, and month. In the comparison between the RF model and the traditional single-channel interpolation method, retrievals from the RF model agree well with observation with a high correlation coefficient (0.92), small RMSE (222 m), and small MAE (164 m), while these metrics from traditional single-channel interpolation method shows lower skills (0.70, 1305 m, and 1179 m). This work presents a new sight of overshooting cloud-top height retrieval based on the machine learning method.

Location choice for outward foreign direct investment (OFDI) is key to companies' strategic decision-making on internationalization. We provide a comprehensive framework for Chinese companies selecting OFDI locations based on an eclectic (OLI) paradigm and neo-institutional economics. We reveal that investment motivation and host country's quality of institutions and bilateral institutional distance play interactive, complex roles in China's location choice for direct investment in ASEAN. Chinese companies prefer investing in ASEAN countries with better institutional quality, especially higher political stability, absence of violence/terrorism, government regulatory quality, and rule of law. Institutional quality significantly promotes market-seeking, efficiency-seeking, and resource-seeking investments; among institutional quality factors, rule of law and corruption control significantly promote market-seeking, resource-seeking, and efficiency-seeking investments, while regulatory quality and government effectiveness significantly promote market-seeking and efficiency-seeking investment. The better the host country's institutional quality, the more attractive it is for market-seeking and efficiency-seeking investments, but less for resource-seeking investments. [ABSTRACT FROM AUTHOR]