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Immune response is an important factor in determining the fate of bone replacement materials, in which macrophages play an important role. It is a new idea to design biomaterials with immunomodulatory function to reduce inflammation and promote bone integration by regulating macrophages polarization. In this work, the immunomodulatory properties of CaP Zn-Mn-Li alloys and the specific mechanism of action were investigated. We found that the CaP Zn0.8Mn0.1Li alloy promoted the polarization of macrophages towards M2 and reduced inflammation, which could effectively up-regulate osteogenesis-related factors and promote new bone formation, indicating the important role of macrophages polarization in biomaterial induction of osteogenesis. In vivo studies further demonstrated that CaP Zn0.8Mn0.1Li alloy could stimulate osteogenesis better than other Zn-Mn-Li alloys implanttions by regulating macrophages polarization and reducing inflammation. In addition, transcriptome results showed that CaP Zn0.8Mn0.1Li played an important regulatory role in the life process of macrophages, activating Toll-like receptor signaling pathway, which participated in the activation and attenuation of inflammation, and accelerated bone integration. Thus, by preparing CaP coatings on the surface of Zn-Mn-Li alloys and combining the bioactive ingredient with controlled release, the biomaterial will be imbibed with beneficial immunomodulatory properties that promote bone integration.

Mineralized collagen (MC) is a biomaterial that is commonly used in the treatment of bone defects. However, the inflammatory response after biomaterial implantation is a recurrent problem that requires urgent attention. Our previous studies on MC-macrophage interactions were descriptive but we did not perform an in-depth analysis on a genetic level to investigate the underlying mechanisms. In this study, we cultured RAW264.7 cells on MC or collagen and examined the proliferation of the macrophages by Cell Counting Kit-8 assay. We sequenced the RNA of the cultured cells to discover differential gene expression patterns and found that a total of 1183 genes were differentially expressed between the MC- and collagen-cultured groups, of which 396 genes were upregulated and 787 were downregulated. Gene ontology analysis revealed that biological processes in MC-cultured cells, such as inflammation and innate immunity, were downregulated; whereas nucleosome assembly, megakaryocyte differentiation, and chromatin assembly were upregulated. We identified several pathways associated with immunity that were significantly enriched using the Kyoto Encyclopedia of Genes and Genomes. Furthermore, we validated the differentially expressed genes from RNA sequencing by quantitative real-time polymerase chain reaction. This study provides insight into the macrophage phenotype based on the microenvironment, which is the foundation for the clinical application of MC-based interventions.

Repairing damage in the craniofacial skeleton is challenging. Craniofacial bones require intramembranous ossification to generate tissue-engineered bone grafts via angiogenesis and osteogenesis. Here, we designed a mineralized collagen delivery system for BMP-2 and vascular endothelial growth factor (VEGF) for implantation into animal models of mandibular defects. BMP-2/VEGF were mixed with mineralized collagen which was implanted into the rabbit mandibular. Animals were divided into (i) controls with no growth factors; (ii) BMP-2 alone; or (iii) BMP-2 and VEGF combined. CT and hisomputed tomography and histological staining were performed to assess bone repair. New bone formation was higher in BMP-2 and BMP-2-VEGF groups in which angiogenesis and osteogenesis were enhanced. This highlights the use of mineralized collagen with BMP-2/VEGF as an effective alternative for bone regeneration.

Delta-like ligands (DLLs) control Notch signaling. DLL1, DLL3 and DLL4 are frequently deregulated in cancer and influence tumor growth, the tumor vasculature and tumor immunity, which play different roles in cancer progression. DLLs have attracted intense research interest as anti-cancer therapeutics. In this review, we discuss the role of DLLs in cancer and summarize the emerging DLL-relevant targeting methods to aid future studies.

Five new zinc coordination polymers based on flexible carboxylate ligands, namely, [Zn2(chtc)(H2O)]·3H2O (1), [Zn2(chtc)(4,4′-bpy)0.5] (2), [Zn(H2chtc)(bpe)] (3), [Zn(cis-chdc)(bpe)]·3H2O (4), and [Zn(trans-chdc)(bpe)(NO3)(H2O)]·H2O (5) (chtc/H2chtc = deprotonated/half-protonated cyclohexane-1e,2a,4a,5e-tetracarboxylic acid, cis/trans-chdc = cyclohexane-1e,2a/1e,2e-dicarboxylic acid, 4,4′-bpy = 4,4′-bipyridine, bpe = trans-1,2-(bis(4-pyridyl)ethene)) have been constructed and characterized. Owing to the tunability of linking ligands, these complexes show different interesting topological networks, namely uninodal umc three-dimensional network for 1, mtc three-dimensional non-manifold topology for 2, (4,4) net for the two-dimensional structure of 3, dmp-c interpenetrated network for 4, and one-dimensional ladder chain for 5. Notably, all complexes exhibit selectivity and sensitivity for Fe3+ ions with detection limit of less than 3.5 μM, which was correlated to the dimensionalities of the structures, implying their potential application in sewage detection.

The effective healing of a bone defect is dependent on the careful coordination of inflammatory and bone-forming cells. In the current work, pro-inflammatory M1 and anti-inflammatory M2 macrophages were co-cultured with primary murine bone mesenchymal stem cells (BMSCs), in vitro, to establish the cross-talk among polarized macrophages and BMSCs, and as well as their effects on osteogenesis. Meanwhile, macrophages influence the osteogenesis of BMSCs through paracrine forms such as exosomes. We focused on whether exosomes of macrophages promote osteogenic differentiation. The results indicated that M1 and M2 polarized macrophage exosomes all can promote osteogenesis of BMSCs. Especially, M1 macrophage-derived exosomes promote osteogenesis of BMSCs through microRNA-21a-5p at the early stage of inflammation. This research helps to develop an understanding of the intricate interactions among BMSCs and macrophages, which can help to improve the process of bone healing as well as additional regenerative processes by local sustained release of exosomes.

Earthworms are useful indicator organisms of soil health and Eisenia fetida have been extensively used as test organisms in ecotoxicological studies. In order to gain insight into the gene expression profiles associated with physiological functions of earthworms, a full‑length enriched cDNA library of the Eisenia fetida genome was successfully constructed using Switching Mechanism at 5'End of RNA Template technology. Construction of a cDNA library and analysis of Expressed Sequence Tags (ESTs) are efficient approaches for collecting genomic information and identifying genes important for a given biological process. Furthermore, analysis of the expression abundance of ESTs was performed with the aim of providing genetic and transcriptomic information on the development and regenerative process of earthworms. Phrep and Crossmatch were used to process EST data and a total of 1,140 high‑quality EST sequences were determined by sequencing random cDNA clones from the library. Clustering analysis of sequences revealed a total of 593 unique sequences including 225 contiguous and 368 singleton sequences. Basic Local Alignment Search Tool analysis against the Kyoto Encyclopedia of Genes and Genomes database resulted in 593 significant hits (P‑value

Additional file 1: Online supplemental figures and tables.docx. Figure S1. Linear plot of concentration-time profile for dalpiciclib by dose. Table S1. Dose modifications after DLT assessment period. Table S2. Treatment emergent AEs occurring in ≥2 patients and AEs of special interest. Table S3. Pharmacokinetics and pharmacological characteristics of CDK4/6 inhibitors.

This study aimed at exploring the effects of combined epidural anesthesia and general anesthesia on the cognitive function and stress responses of elderly patients undergoing liver cancer surgery. One hundred and fifteen elderly patients were enrolled as research subjects. They were admitted to our hospital and underwent liver cancer surgery from August 2017 to May 2019. Fifty five cases were treated with general anesthesia (GA) (GA group), while the other sixty cases were treated with combined epidural anesthesia and general anesthesia (joint group). Scoring standards of Mini-Mental State Examination (MMSE) were used to evaluate the patients before and after operation. Their operating time, total fluid input (TFI), spontaneous breathing recovery time (SBRT), preoperative and postoperative indices of stress responses (epinephrine (EPI), cortisol (Cor), and norepinephrine (NE)), and postoperative adverse reactions were observed. There were statistically significant differences between the two groups with respect to anesthesia time, TFI, postoperative SBRT, and postoperative directional recovery time (DRT) (c P < 0.05 ). There was no difference in operating time, total fluid loss (TFL), and hospitalization time ( P > 0.05 ). After operation, patients in both groups experienced a cognitive decline of different degrees and the MMSE scores decreased. There was no significant difference in the score between the two groups before operation and 3 days and 7 days after operation ( P > 0.05 ). The score was significantly better in the joint group than that in the GA group at 6 hours and 1 day after operation ( P < 0.05 ). There were no significant differences in levels of EPI, Cor, and NE between the two groups before operation ( P > 0.05 ), but there were significant differences after operation. The total incidence of postoperative adverse reactions was 11.67% in the joint group and 25.45% in the GA group. In conclusion, combined epidural anesthesia and general anesthesia can significantly reduce postoperative cognitive dysfunction and inhibit postoperative stress responses in elderly patients undergoing liver cancer surgery. It has good application value in clinical practice.