Gallic acid-grafted chitosan antibacterial hydrogel incorporated with polydopamine-modified hydroxyapatite for enhancing bone healing

An open critical-size bone defect is a major medical problem because of the difficulty in self-healing, leading to an increased risk of bacterial infection owing to wound exposure, resulting in treatment failure. Herein, a composite hydrogel was synthesized by chitosan, gallic acid, and hyaluronic acid, termed “CGH.” Hydroxyapatite was modified with polydopamine (PDA@HAP) and introduced to CGH to obtain a mussel-inspired mineralized hydrogel (CGH/PDA@HAP). The CGH/PDA@HAP hydrogel exhibited excellent mechanical performances, including self-healing and injectable properties. Owing to its three-dimensional porous structure and polydopamine modifications, the cellular affinity of the hydrogel was enhanced. When adding PDA@HAP into CGH, Ca2+ and PO43- could release and then promoted differentiation of BMSCs into osteoblasts. Without any osteogenic agent or stem cells, the area of new bone at the site of defect was enhanced and the newly formed bone had a dense trabecular structure after implanting of the CGH/PDA@HAP hydrogel for 4 and 8 weeks. Moreover, the growth of Staphylococcus aureus and Escherichia coli was effectively inhibited through the grafting of gallic acid onto chitosan. Above, this study provides a reasonable alternative strategy to manage open bone defects

Overview of the Microscope Objective

Microscopes are widely used in research and industry. The objective lens is the most significant part of the microscope. Some characteristics and different types of microscope objectives are discussed in this thesis. The markings on the objective indicate some main optical characteristics. However, it is not always possible to know the materials, the radius or the thickness of each surface in an objective lens and it is not easy to simulate an objective without this data. In this thesis, we build a first order model which can simulate a refractive microscope objective when the magnification and numerical aperture are known. The model contains a thin lens made by two standard surfaces and also simulates the principal planes. This model provides more accurate ray heights and it is aplanatic. Some design examples of an objective lens are also discussed in order to get a better understanding of design and optimization considerations

The Role of β-Catenin in Th1 Immune Response against Tuberculosis and Profiles of Expression in Patients with Pulmonary Tuberculosis

β-Catenin is a key molecule of canonical Wnt/β-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of β-catenin in CD4+ T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4+ T cell-specific β-catenin conditional knockout mice (β-CAT-cKO mice) were aerosol infected with Mycobacteria tuberculosis (Mtb) H37RV with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-γ, TNF-α, and TCF-7 in the lungs of mice was measured. CD4, CD8, β-catenin, IFN-γ, and TNF-α in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of β-catenin, IFN-γ, TNF-α, and PD-1 in CD4+ and CD8+ T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-γ/TNF-α mRNA expression and secretion by CD4+ T cells in the lungs of infected β-CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. β-catenin expressions in CD4+ and CD8+ T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of β-catenin, resulted in the increase in CD4+ T cell frequency, as well as their secretion of IFN-γ and TNF-α. β-Catenin demonstrated a moderately positive correlation with PD-1 in CD4+ T cells. β-Catenin along with PD-1 and IFN-γ in CD4+ T cells had a high correlation with those in CD8+ T cells. In conclusion, β-catenin may be involved in the regulation of Th1 response and CD4+ T cell frequency in TB

Critical Content of Ultrahigh-Molecular-Weight Polyethylene To Induce the Highest Nucleation Rate for Isotactic Polypropylene in Blends

The influence of the addition of low amounts of ultrahigh-molecular-weight polyethylene (UHMWPE) on the crystallization kinetics of isotactic polypropylene (iPP) in iPP/UHMWPE blends has been investigated by means of differential scanning calorimetry (DSC) and polarized optical microscopy. During the nonisothermal crystallization process, the primarily formed UHMWPE crystals serve as heterogeneous nucleating agents for iPP nucleation, whereas during the isothermal crystallization process, UHMWPE is in the molten state, iPP nucleation preferentially occurs at the UHMWPE and iPP phase interfaces, and the spherulitic growth rates are not obviously affected. It is particularly interesting to find a critical UHMWPE content (2.5 wt %) in the blends to induce the highest iPP nucleation rate; however, above the critical UHMWPE content, the iPP nucleation rate slows because of aggregation of the UHMWPE component. A delicately designed DSC measurement provides insight into the nucleation mechanism of iPP at the interfaces between the UHMWPE and iPP phase domains. It is proposed that the concentration fluctuations generated from the unstable inhomogeneous phase interfaces in the iPP/UHMWPE blends promote the formation of nuclei, which eventually enhances the nucleation and overall crystallization rates of the iPP component

Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy

Abstract Background Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity. Methods Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade. Results We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1. Conclusions This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically “hot” and “cold” cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy

Older but Stronger: Development of Platinum-Based Antitumor Agents and Research Advances in Tumor Immunity

Platinum (Pt) drugs have developed rapidly in clinical applications because of their broad and highly effective antitumor effects. In recent years, with the rapid development of immunotherapy, Pt-based antitumor agents have gained new challenges and opportunities. Since the discovery of their pharmacological effects in immunotherapy and tumor microenvironment regulation, research into Pt drugs has progressed to multi-ligand and multi-functional Pt precursors and their own shortcomings have been further highlighted. With the development of antitumor immunotherapy and the rise of combination therapy, the development of Pt-based drugs has started to move in the direction of multi-targeting, nanocarrier modification, immunotherapy and photodynamic therapy. In this paper, we first overview the recent applications of Pt-based drugs in antitumor inorganic chemistry, with a focus on summarizing the application of Pt-based drugs and their precursors in the anticancer immune response. The paper also provides a reasonable outlook on the future development of Pt-based drugs from the chemical and immunological perspectives, relying on the existing content and problems of Pt-based drug development. On the basis of the gathered information, joint multidisciplinary programs on implementing comprehensive immune analyses for the future development of novel anticancer metal compounds should be initiated

Experience with 2 years’ intervention to progressively reduce salt supply to kitchens in elderly care facilities—challenges and further research: post hoc analysis of the DECIDE-Salt randomized clinical trial

Abstract Background Progressive reduction of sodium intake is an attractive approach for addressing excessive salt intake, but evidence for this strategy in real practice is limited. We aimed to determine the feasibility, effectiveness, and safety of a progressive sodium intake reduction intervention in real-world setting. Methods We randomized 48 residential elderly care facilities in China, with 1612 participants aged 55 years and older, to either progressive reduction (PR, 24 facilities) or no reduction (NR, 24 facilities) of the supply of study salt to the kitchens of these facilities for 2 years. The primary efficacy outcome was systolic blood pressure (SBP) at any scheduled follow-up visit. Secondary efficacy outcomes included diastolic blood pressure (DBP) at any scheduled follow-up visit, and major adverse cardiovascular events (comprising non-fatal stroke, non-fatal myocardial infarction, hospitalized non-fatal heart failure, or vascular death) and total mortality. The perception of food saltiness, the addition of out-of-study salt in meals, and 24-h urinary sodium excretion were used as process indicators. Results Pre-specified analysis per randomization found no effect of the intervention on the 2-year overall mean systolic and diastolic blood pressure (SBP, DBP) and any other outcomes. However, post hoc analysis showed that the intervention effect on blood pressure varied over multiple follow-up visits (p for interaction < 0.046) and presented favorable differences at the 24-month visit (SBP =  − 3.0 mmHg, 95%CI =  − 5.6, − 0.5; p = 0.020; DBP =  − 2.0 mmHg, 95%CI − 3.4, − 0.63; p = 0.004). The effect on 24-h sodium was non-significant (− 8.4 mmol, 95%CI =  − 21.8 to 4.9, p = 0.216), though fewer participants with NR than with PR reported food tasting bland (odds ratio 0.46; 95%CI 0.29 to 0.73; p = 0.001). Reporting of bland food taste and other process measures indicated that intervention delivery and adherence were not fully achieved as designed. Conclusions The experience of this real-world study demonstrated that achieving acceptability and sustainability of the progressive sodium intake reduction strategy among older adults was challenging, but it has shown potential for effectiveness in these and potentially other residential settings if the lessons of DECIDE-Salt are applied in further studies. Trial registration ClinicalTrials.gov (NCT03290716)