Erratum: ATF6 aggravates angiogenesis-osteogenesis coupling during ankylosing spondylitis by mediating FGF2 expression in chondrocytes.

[This corrects the article DOI: 10.1016/j.isci.2021.102791.].

Enhancer-mediated FOXO3 expression promotes MSC adipogenic differentiation by activating autophagy.

BACKGROUND: Mesenchymal stem cells (MSCs) are pluripotent stem cells capable of differentiating into osteocytes, adipocytes and chondrocytes. However, in osteoporosis, the balance of differentiation is tipped toward adipogenesis and the key mechanism is controversial. Researches have shown that, as upstream regulatory elements of gene expression, enhancers ar involved in the expression of identity genes. In this study, we identified enhancers-mediated gene FOXO3 promoting MSC adipogenic differentiation by activating autophagy. METHODS: We integrated data of RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and ATAC-sequencing (ATAC-seq) to find the identity gene FOXO3. The expression of FOXO3 protein, adipogenic transcription factors and the substrate of autophagy were measured by western blotting. The Oil Red O (ORO) staining was used to visualize the adipogenesis of MSCs. Immunohistochemistry was used to visualize the FOXO3 expression in adipocytes in bone marrow. Immunofluorescence was used to detect the expression of PPARγ and LC3B. RESULTS: During adipogenesis, enhancers redistribute to genes associated with adipogenic differentiation, among which we identified the pivotal identity gene FOXO3. FOXO3 could promote the expression of the adipogenic transcription factors PPARγ, CEBPα, and CEBPß during adipogenic differentiation, while PPARγ, CEBPα, and CEBPß could in turn bind to FOXO3 and continue to promote FOXO3 expression to form a positive feedback loop. Consistently elevated FOXO3 expression promotes autophagy by activating the PI3K-AKT pathway which mediates adipogenic differentiation. CONCLUSIONS: Pivotal identity gene FOXO3 promotes autophagy by activating PI3K-AKT pathway, which provokes adipogenic differentiation of MSCs. Enhancer-regulated adipogenic identity gene FOXO3 could be an attractive treatment for osteoporosis.

Low expression of ZFP36L1 in osteosarcoma promotes lung metastasis by inhibiting the SDC4-TGF-ß signaling feedback loop.

ZFP36L1, which is a negative regulator of gene transcripts, has been proven to regulate the progression of several carcinomas. However, its role in sarcoma remains unknown. Here, by using data analyses and in vivo experiments, we found that ZFP36L1 inhibited the lung metastasis of osteosarcoma (OS). Knockdown of ZFP36L1 promoted OS cell migration by activating TGF-ß signaling and increasing SDC4 expression. Intriguingly, we observed a positive feedback loop between SDC4 and TGF-ß signaling. SDC4 protected TGFBR3 from matrix metalloproteinase (MMP)-mediated cleavage and therefore relieved the inhibition of TGF-ß signaling by soluble TGFBR3, while TGF-ß signaling positively regulated SDC4 transcription. We also proved that ZFP36L1 regulated SDC4 mRNA decay through adenylate-uridylate (AU)-rich elements (AREs) in its 3'UTR. Furthermore, treatment with SB431542 (a TGF-ß receptor kinase inhibitor) and MK2 inhibitor III (a MAPKAPK2 inhibitor that increases the ability of ZFP36L1 to degrade mRNA) dramatically inhibited OS lung metastasis, suggesting a promising therapeutic approach for the treatment of OS lung metastasis.

Research on programmatic multi-attribute decision-making problem: An example of bridge pile foundation project in karst area.

The selection of construction plans for adverse geological conditions frequently encountered during the construction of bridge pile foundations will have a significant impact on the project's progress, quality, and cost. There is a need for the optimization of multi-attribute decision-making methods, considering the subjectivity in in weight allocation and the practical implementation obstacles. In this study, an evaluation framework for pile foundation construction schemes in karst areas was established. The directed graph and Bellman-Ford algorithm are employed to improve the Analytic Network Process (ANP) in the systematic structure, thereby calculating the subjective weights of various indicators. Simultaneously, based on the concept of dynamic weighting, a multiple linear regression is introduced for analyzing the weights of similar projects, resulting in the derivation of universal weights for the primary indicators within the evaluation system. The combination weights are subsequently determined through the weighted average of the two types of weights. Finally, the comprehensive scores of alternative schemes are computed using the grey-fuzzy evaluation method to enable decision-making in scheme selection. Cloud model, ELECTRE-II, and VIKOR methodologies were utilized for the comparison of results. Combining with a case study of a bridge project in karst development area in southern China, the findings indicate that the improved ANP method possesses practical applicability and yields effective computational results. The introduction of universal weights serves to ameliorate the inherent subjectivity in weight allocation. The pile foundation quality achieved using the optimal construction plan is classified as Class I, which prove the feasibility of the model.

Efficient cross-protection against serotype 4/8a fowl adenoviruses (FAdVs): recombinant FAdV-4 with FAdV-8a Fiber.

IMPORTANCE: Epidemiological data reveal that FAdV-4 and FAdV-8a are the dominant serotypes of FAdVs in the poultry industry in China. Although three commercial inactivated vaccines against FAdV-4 have been licensed in China, the bivalent vaccine against both FAdV-4 and FAdV-8a is not available. Here, we used CRISPR-Cas9 and Cre-LoxP system to generate a recombinant virus FAdV4-F/8a-rF2 expressing the Fiber of FAdV-8a. Notably, FAdV4-F/8a-rF2 was highly attenuated and could provide efficient protection against both FAdV-4 and FAdV-8a in the chicken infection model, highlighting the applaudable application of FAdV4-F/8a-rF2 as a novel live-attenuated bivalent vaccine against the diseases caused by the infection of FAdV-4 and FAdV-8a.

SIRPA enhances osteosarcoma metastasis by stabilizing SP1 and promoting SLC7A3-mediated arginine uptake.

The function of signal regulatory protein alpha (SIRPA) has been well studied in macrophages and dendritic cells, but relatively less in tumors. Notably, SIRPA is upregulated in osteosarcoma tissues, particularly in metastatic tissues, and is associated with unfavorable clinical outcomes. Knockdown of SIRPA impaired OS cell migration by decreasing specificity protein 1 (SP1) stability and arginine uptake. Importantly, SIRPA phosphorylated SP1 at threonine 278 (Thr278) through extracellular signal-regulated kinase (ERK) activation to protect SP1 from proteasomal degradation. In addition, SP1 increased solute carrier family 7 member 3 (SLC7A3) expression by binding to the SLC7A3 promoter and increased the capability of arginine uptake, thereby facilitating OS cell migration. More interestingly, arginine promoted the stability of SP1 in an ERK-independent manner and thus formed the "SP1 stabilization circle". Combined treatment with the anti-SIRPA antibody and arginase, which blocked the circle, impaired tumor metastasis in mice bearing xenografts formed from SIRPA-overexpressing cells. In summary, our study demonstrates that the upregulation of SIRPA promotes OS metastasis via the "SP1 stabilization circle" and SLC7A3-mediated arginine uptake, which might serve as a target for OS treatment.

Immunomodulatory zinc-based materials for tissue regeneration.

Zinc(Zn)-based materials have contributed greatly to the rapid advancements in tissue engineering. The qualities they possess that make them so beneficial include their excellent biodegradability, biocompatibility, anti-bacterial activity, among and several others. Biomedical materials that act as a foreign body, will inevitably cause host immune response when introduced to the human body. As the osteoimmunology develops, the immunomodulatory characteristics of biomaterials have become an appealing concept to improve implant-tissue interaction and tissue restoration. Recently, Zn-based materials have also displayed immunomodulatory functions, especially macrophage polarization states. It can promote the transformation of M1 macrophages into M2 macrophages to enhance the tissue regeneration and reconstruction. This review covers mainly Zn-based materials and their characteristics, including metallic Zn alloys and Zn ceramics. We highlight the current advancements in the type of immune responses, as well as the mechanisms, that are induced by Zn-based biomaterials, most importantly the regulation of innate immunity and the mechanism of promoting tissue regeneration. To this end, we discuss their applications in biomedicine, and conclude with an outlook on future research challenges.

Administration methods of lipid-based nanoparticle delivery systems for cancer treatment.

As nano medications have developed in the recent four decades, nano-delivery systems have been applied in treating various diseases and are especially common in cancer treatment. Nano-delivery systems could target cancer-associated cells, enhance the accuracy and efficacy of treatment, and reduce systemic side effects. Among the many drugs on nano-carriers, the load system of lipid-based nanoparticles has the brightest prospect due to the high level of biocompatibility, biodegradability, loading capability, and immunogenicity. Previous reviews have comprehensively introduced their effects and progress. However, most of them did not provide great attention to practical applications. This article will focus on different intake methods, which decide the biological process of drugs. This suggests that we can modify lipid-based nano-delivery systems according to how they are capable of prolonging the half-life span and magnifying therapy effects in treating cancer. Besides, we put forth the problems that should be further studied in the future and their probable solutions.

Prognosis-related molecular subtyping in head and neck squamous cell carcinoma patients based on glycolytic/cholesterogenic gene data.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) remains an unmet medical challenge. Metabolic reprogramming is a hallmark of diverse cancers, including HNSCC. METHODS: We investigated the metabolic profile in HNSCC by using The Cancer Genome Atlas (TCGA) (n = 481) and Gene Expression Omnibus (GEO) (n = 97) databases. The metabolic stratification of HNSCC samples was identified by using unsupervised k-means clustering. We analyzed the correlations of the metabolic subtypes in HNSCC with featured genomic alterations and known HNSCC subtypes. We further validated the metabolism-related subtypes based on features of ENO1, PFKFB3, NSDHL and SQLE expression in HNSCC by Immunohistochemistry. In addition, genomic characteristics of tumor metabolism that varied among different cancer types were confirmed. RESULTS: Based on the median expression of coexpressed cholesterogenic and glycolytic genes, HNSCC subtypes were identified, including glycolytic, cholesterogenic, quiescent and mixed subtypes. The quiescent subtype was associated with the longest survival and was distributed in stage I and G1 HNSCC. Mutation analysis of HNSCC genes indicated that TP53 has the highest mutation frequency. The CDKN2A mutation frequency has the most significant differences amongst these four subtypes. There is good overlap between our metabolic subtypes and the HNSCC subtype. CONCLUSION: The four metabolic subtypes were successfully determined in HNSCC. Compared to the quiescent subtype, glycolytic, cholesterogenic and mixed subtypes had significantly worse outcome, which might offer guidelines for developing a novel treatment strategy for HNSCC.

The interaction between obesity and visceral hypersensitivity.

Obesity has been a worldwide problem associated with numerous chronic diseases such as cardiovascular disease, type 2 diabetes, and metabolic disorders. It may also play a role in visceral hypersensitivity, contributing to irritable bowel syndrome. (i) Adipose tissue secretes various inflammatory mediators, causing intestinal hyperpermeability and nerve endings activation. (ii) Obesity and gastrointestinal microbiota could affect each other, and microbial metabolites can increase sensitivity of the colon. (iii) Vitamin D deficiency contributes to both fat accumulation and disruption of the intestinal mucosal barrier. (iv) Brain-gut axis may be another bridge from obesity to visceral hypersensitivity.

CLP36 promotes p53 deficient sarcoma progression through suppression of atrophin-1 interacting protein-4 (AIP-4)-dependent degradation of YAP1.

Background: p53 deficiency is a key causal factor for tumor development and progression. p53 acts in this process through, at least in part, cooperation with YAP1 but the underlying molecular mechanism is incompletely understood. In this paper, we show that CLP36, an actinin-binding cytoskeletal protein, links p53 deficiency to up-regulation of YAP1 expression and sarcoma progression. Methods: Immunohistochemical staining and Western blotting were used to investigate the effect of p53 deficiency on CLP36 expression in sarcoma tissues and cells. Furthermore, molecular, cellular, and genetic knockout and knockdown approaches were employed to investigate the functions of CLP36 in regulation of sarcoma cell behavior in culture and tumor growth in mice. Finally, biochemical approaches were used to investigate the molecular mechanism by which CLP36 regulates the malignant behavior of p53 deficient sarcoma cells. Results: We have found that the expression of CLP36 is up-regulated in response to loss of p53 in sarcoma tissues and cells. Depletion of CLP36 inhibited malignant behavior of p53 deficient sarcoma cells. Furthermore, knockout of CLP36 in mice markedly inhibited p53 deficiency-induced tumorigenesis and improved the survival of the p53 deficient mice. Mechanistically, CLP36 promoted p53 deficiency-induced tumorigenesis through inhibition of E3 ligase atrophin-1 interacting protein-4 (AIP-4)-dependent proteasomal degradation of YAP1 and consequently increase of YAP1 expression. Conclusions: Our results reveal a crucial role of CLP36 in linking p53 deficiency to up-regulation of YAP1 expression and sarcoma progression. Our findings suggest that therapeutic targeting the CLP36/YAP1 signaling axis may provide an effective strategy for alleviation of p53 deficient sarcoma progression.

Environmental Factors Affecting Diversity, Structure, and Temporal Variation of Airborne Fungal Communities in a Research and Teaching Building of Tianjin University, China.

Airborne fungi are widely distributed in the environment and may have adverse effects on human health. A 12-month survey on the diversity and concentration of culturable airborne fungi was carried out in a research and teaching building of Tianjin University. Indoor and outdoor environments were analyzed using an HAS-100B air sampler. A total of 667 fungal strains, belonging to 160 species and 73 genera were isolated and identified based on morphological and molecular analysis. The most abundant fungal genera were Alternaria (38.57%), Cladosporium (21.49%), and Aspergillus (5.34%), while the most frequently appearing species was A. alternata (21%), followed by A. tenuissima (12.4%), and C. cladosporioides (9.3%). The concentration of fungi in different environments ranged from 0 to 150 CFU/m3 and was significantly higher outdoor than indoor. Temperature and sampling month were significant factors influencing the whole building fungal community, while relative humidity and wind speed were highly correlated with fungal composition outdoor. Variations in the relative abundance of major airborne fungal taxa at different heights above-ground could lead to different community structures at different floors. Our results may provide valuable information for air quality monitoring and microbial pollution control in university building environments.

A dual-mode immunosensing strategy for prostate specific antigen detection: Integration of resonance Raman scattering and photoluminescence properties of ZnS:Mn2+ nanoprobes.

Luminescence-based methods are widely used for the detection of prostate specific antigen (PSA), for example during the diagnosis of prostate cancer. However, the accuracy of these methods is sub-optimal. The aim of this study was to develop an accurate and sensitive dual-mode immunosensing technique using a combination of resonance Raman scattering (RRS) and photoluminescence (PL) signals for the detection of PSA. A ZnS:Mn2+ nanoprobe was used as the signal reporter, which exhibits both multi-phonon RRS and PL properties. The RRS signal intensity at 348 cm-1 and the PL signal intensity at 590 nm were used for the quantitative assay of PSA. The reproducibility, selectivity and specificity of this dual-mode immunosensing strategy demonstrated an improvement compared with commercial PSA ELISA kits in the analysis of serum samples. Therefore, the RRS-PL immunosensing technique developed in this study shows potential as a reliable technique to be used in the clinical diagnosis of prostate cancer.

ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway.

BACKGROUND: The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear. METHODS: We collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells. RESULTS: The expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666-15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis. CONCLUSIONS: We demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment.

ATF6 aggravates angiogenesis-osteogenesis coupling during ankylosing spondylitis by mediating FGF2 expression in chondrocytes.

Although angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription factor 6 (ATF6) as an important regulator of angiogenesis in the pathogenesis of AS. First, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and in cartilage of pateints with AS1. The proangiogenic activity of human chondrocytes was enhanced by the activation of the ATF6-FGF2 axis following 7 days of stimulation with inflammatory factors, e.g., tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ) or interleukin-17 (IL-17). Mechanistically, ATF6 interacted with the FGF2 promotor and promoted its transcription. Treatment with the ATF6 inhibitor Ceapin-A7 inhibited angiogenesis in vitro and angiogenesis-osteogenesis coupling in vivo. ATF6 may aggravate angiogenesis-osteogenesis coupling during AS by mediating FGF2 transcription in chondrocytes, implying that ATF6 represents a promising therapeutic target for AS.

Kindlin-2 links mechano-environment to proline synthesis and tumor growth.

Cell metabolism is strongly influenced by mechano-environment. We show here that a fraction of kindlin-2 localizes to mitochondria and interacts with pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme for proline synthesis. Extracellular matrix (ECM) stiffening promotes kindlin-2 translocation into mitochondria and its interaction with PYCR1, resulting in elevation of PYCR1 level and consequent increase of proline synthesis and cell proliferation. Depletion of kindlin-2 reduces PYCR1 level, increases reactive oxygen species (ROS) production and apoptosis, and abolishes ECM stiffening-induced increase of proline synthesis and cell proliferation. In vivo, both kindlin-2 and PYCR1 levels are markedly increased in lung adenocarcinoma. Ablation of kindlin-2 in lung adenocarcinoma substantially reduces PYCR1 and proline levels, and diminishes fibrosis in vivo, resulting in marked inhibition of tumor growth and reduction of mortality rate. Our findings reveal a mechanoresponsive kindlin-2-PYCR1 complex that links mechano-environment to proline metabolism and signaling, and suggest a strategy to inhibit tumor growth.

Effects of Income and Psychological Identification on the Mental Health of China's Migrated Agricultural Population.

BACKGROUND: The Migrated Agricultural Population (MAP) of China continues to increase with the continuous development of urbanization. As MAP is a socially disadvantaged group, their mental health issues require urgent attention. METHODS: An ordinary least squares regression model was established by using the newest survey data from the 2016 Chinese General Social Survey. Moreover, the effects of income and psychological identification on the mental health status of China's MAP were also examined using the Stata 12.0 software. The differences in the examination results under the influence of gender, educational level, and marital factors were compared. RESULTS: The mental health level of China's MAP is affected by both income and psychological identification. Specifically, income has a more significant influence on men's mental health, whereas psychological identification is more significant for women. The mental health of MAP with spouses or those who received secondary education also reflects the overall characteristics of the sample. By contrast, those without spouses or those who did not receive other forms of education are mainly affected by psychological identification. Additionally, the mental health of the unmarried group is mainly affected by the family's actual income and subjective well-being based on the psychological identification. CONCLUSION: The influence of income and psychological identification on the mental health of China's MAP shows population differences. Therefore, different emphasis should be placed on the interventions of mental health in various groups of MAP. This study can provide decision-making references for the mental health management and psychological pressure counseling of MAP.

Olefin metathesis for effective polymer healing via dynamic exchange of strong carbon-carbon double bonds.

In this article, we demonstrate transition-metal-catalyzed olefin metathesis as a simple, effective method for healing polymers via dynamic exchange of strong carbon-carbon double bonds. Upon introducing a very low level of the Grubbs' second-generation Ru metathesis catalyst into cross-linked polybutadiene (PBD) network, the material self-heals effectively at various conditions under moderate pressures. In sharp contrast, catalyst-free control samples with identical network topology and cross-linking density show minimal healing. The healing efficiency of the materials was carefully investigated under different concentrations of the Ru catalyst, compression pressures, and temperatures. It is demonstrated for the first time that a bulk polymer could effectively heal via dynamic covalent bond formation at sub-ambient temperature. The Ru-loaded PBD samples not only heal well with themselves but also with control samples without any catalyst. Furthermore, a completely Ru-free PBD network can heal effectively upon simply applying a very small amount of Ru catalyst only at the fracture surface. The simplicity and effectiveness of this self-healing approach make it potentially applicable to a wide range of olefin-containing polymers.

Making insoluble polymer networks malleable via olefin metathesis.

Covalently cross-linked polymers have many technological applications for their excellent properties, but they suffer from the lack of processability and adaptive properties. We report a simple, efficient method of generating adaptive cross-linked polymers via olefin metathesis. By introducing a very low level of the Grubbs' second-generation Ru metathesis catalyst, a chemically cross-linked polybutadiene network becomes malleable at room temperature while retaining its insolubility. The stress relaxation capability increases with increasing level of catalyst loading. In sharp contrast, catalyst-free control samples with identical network topology and cross-linking density do not show any adaptive properties. This chemistry should offer a possibility to combine the dimensional stability and solvent resistance of cross-linked polymers and the processability/adaptibility of thermoplastics.

Helical polymers based on intramolecularly hydrogen-bonded aromatic polyamides.

Inspired by arylamide-based oligomeric foldermers that are stabilized by intramolecular hydrogen bonding, a series of polyamides with intramolecular hydrogen-bonding motifs were synthesized via polycondensation reactions. These polymers can fold into helical conformation different from their linear control. The chirality of helical conformation can further be tuned via acid-base complexation using chiral residues.