Biodegradable Polymeric Nanoparticles Containing an Immune Checkpoint Inhibitor (aPDL1) to Locally Induce Immune Responses in the Central Nervous System

Immunotherapy is an efficient approach to clinical oncology. However, the immune privilege of the central nervous system (CNS) limits the application of immunotherapeutic strategies for brain cancers, especially glioblastoma (GBM). Tumor resistance to immune checkpoint inhibitors is a further challenge in immunotherapies. To overcome the immunological tolerance of brain tumors, a novel multifunctional nanoparticle (NP) for highly efficient synergetic immunotherapy is reported. The NP contains an anti-PDL1 antibody (aPDL1), upconverting NPs, and the photosensitizer 5-ALA; the surface of the NP is conjugated with the B1R kinin ligand to facilitate transport across the blood-tumor-barrier. Upon irradiation with a 980 nm laser, 5-ALA is transformed into protoporphyrin IX, generating reactive oxygen species. Photodynamic therapy (PDT) further promotes intratumoral infiltration of cytotoxic T lymphocytes and sensitizes tumors to PDL1 blockade therapy. It is demonstrated that combining PDT and aPDL1 can effectively suppress GBM growth in mouse models. The proposed NPs provide a novel and effective strategy for boosting anti-GBM photoimmunotherapy.     

Achieving fabrication of highly transparent Y2O3 ceramics via air pre-sintering by deionization treatment of suspension

An easy albeit quite effective deionization suspension treatment was adopted to alleviate the detrimental effects related to the hydrolysis of Y₂O₃ in an aqueous medium. Fabrication of highly transparent Y₂O₃ ceramics with a fine grain size via air pre-sintering and post–hot isostatic pressing (HIP) treatment without using any sintering additive was achieved using the treated suspensions. The hydrolysis issue of Y₂O₃ powder in an aqueous medium was effectively alleviated by using deionization treatment, and a well-dispersed suspension with a low concentration of dissolved Y³⁺ species was obtained. The dispersed suspensions were consolidated by the centrifugal casting method, and the green bodies derived from the suspension of 35.0 vol% solid loading showed an improved homogeneity with a relative density of 52.1%. Fully dense Y₂O₃ transparent ceramic with high transparency was obtained by pre-sintering consolidated green compacts at a low temperature of 1400°C for 16 h in air followed by a post-HIP treatment at 1550°C for 2 h under 200 MPa pressure. The sample had a fine average grain size of 690 nm. The in-line transmittance of the sample reached 83.3% and 81.8% at 1100 nm and 800 nm, respectively, very close to the theoretical values of Y₂O₃.     

Microstructure and electromagnetic properties of LiFe5O8 ferrite ceramics prepared from wet- and dry-milled powders

The effect of dry and wet ball milling of LiFe₅O₈ ferrite powder on the microstructure and electromagnetic properties of ferrite ceramics was studied using XRD analysis, scanning electron microscopy, dilatometry, thermogravimetry, calorimetry, and measurement of specific magnetization and electrical resistance. The sintering temperature was 1050 °C; the sintering time was 2 h. It was found that ferrite fabricated from dry-milled powder exhibits an ordered α-LiFe₅O₈ phase with bulk density of 91%. Its saturation magnetization and Curie temperature are 55 emu/g and 628°С, respectively. Specific electrical resistance is 4?10⁶ Ω cm. Wet milling in isopropyl alcohol causes formation of a disordered β-LiFe₅O₈ phase. Ceramics produced by this method shows higher bulk density (97%) and low porosity, and an order of magnitude lower resistivity. Its saturation magnetization and Curie temperature are 51 emu/g and 607°С, respectively.     

High dielectric constant of NiFe2O4–LaFeO3 nanocomposite: Interfacial conduction and dielectric loss

Materials exhibiting colossal dielectric constant are the most sought-after materials due to their variety of applications in various electronics industries. NiFe₂O₄ and LaFeO₃ belonging to the spinel and perovskite structures, respectively, were coupled into a nanocomposite by adapting a one-pot sol-gel synthesis. The ratio of NiFe₂O₄:LaFeO₃ was varied and the synthesized materials were studied for their dielectric behaviors. Interestingly, among the samples studied, the nanocomposite with the ratio of 1:2 of NiFe₂O₄–LaFeO₃ exhibited a high dielectric constant value of 10390 at a frequency of 1 kHz with a several-fold increase in conductivity. The high conductivity resulted in a high dielectric loss. The origin of such a high dielectric constant and loss have been attributed to the Maxwell-Wagner type space charge polarization arising from the microstructure that consists of large and continuous grain boundaries, and the conducting phase at the interface, respectively.     

Synthesis,Anticancer Activity,Structure-Activity Relationship and Mechanistic Investigations of Falcarindiol Analogues

Forty samples of optically active falcarindiol analogues are synthesized by using the easily available C2 symmetric (R)- and (S)-1,1’-binaphth-2-ol (BINOL) in combination with Ti(OⁱPr)₄, Zn powder and EtI. Their anticancer activities on Hccc-9810, HepG2, MDA-MB-231, Hela, MG-63 and H460 cells are assayed to elucidate their structure-activity relationships. These results showed that the falcarindiol analogue (3R,8S)- 2 i with the terminal double bond has the most potent anti-proliferation effect on Hccc-9810 cells with IC₅₀ value of 0.46 μM. The falcarindiol analogue (3R,8S)- 2 i can induce obvious Hccc-9810 cell apoptosis in a concentration-dependent manner by Hoechst staining and flow cytometry analysis. The proposed mechanism suggests that the falcarindiol analogue (3R,8S)- 2 i increases LDH release and MDA content, and reduces the levels of SOD activity, which lead to the accumulation of oxidative stress and induce apoptosis in Hccc-9810 cells.     

Preliminary Structural Data Revealed That the SARS-CoV-2 B.1.617 Variant's RBD Binds to ACE2 Receptor Stronger Than the Wild Type to Enhance the Infectivity

The evolution of new SARS-CoV-2 variants around the globe has made the COVID-19 pandemic more worrisome, further pressuring the health care system and immunity. Novel variations that are unique to the receptor-binding motif (RBM) of the receptor-binding domain (RBD) spike glycoprotein, i. e. L452R-E484Q, may play a different role in the B.1.617 (also known as G/452R.V3) variant's pathogenicity and better survival compared to the wild type. Therefore, a thorough analysis is needed to understand the impact of these mutations on binding with host receptor (RBD) and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to explore the impact of specific mutations (L452R-E484Q) in the B.1.617 variant on the binding of RBD to the host receptor ACE2. Our analysis revealed that the B.1.617 variant possesses different dynamic behaviours by altering dynamic-stability, residual flexibility and structural compactness. Moreover, the new variant had altered the bonding network and structural-dynamics properties significantly. MM/GBSA technique was used, which further established the binding differences between the wild type and B.1.617 variant. In conclusion, this study provides a strong impetus to develop novel drugs against the new SARS-CoV-2 variants.     

Adaptive response and tolerance to weak acids in Saccharomyces cerevisiae boulardii: a metabolomics approach

Weak acids inhibit the growth of probiotics, such as Saccharomyces boulardii. We explored the tolerance of S. boulardii to different weak acids. S. boulardii had better fermentation ability under lactic acid conditions compared with acetic and butyric acid conditions; however, the budding of S. boulardii was significantly stronger than that of Saccharomyces cerevisiae under acetic acid conditions. Although the surface structure of S. boulardii was destroyed, it produced more daughter cells. S. boulardii metabolites were also significantly different from S. cerevisiae under acidic stress. The growth of S. boulardii under weak acid conditions differed significantly from that of S. cerevisiae. S. boulardii-mediated fingerprints under weak acid conditions were identified as latent biomarkers, related to fructose and mannose metabolism, tricarboxylic acid cycle, and the glycolysis pathway. Identified biomarkers will aid in the genetic engineering of S. boulardii and other Saccharomyces strains for improved acid resistance and biomass yield.     

Double emulsion (W/O/W) gel stabilised by polyglycerol polyricinoleate and calcium caseinate as mangiferin carrier: insights on formulation and stability properties

Mangiferin (MGF) is a phenolic compound isolated from mango, but its poor solubility significantly limits its use. In this study, MGF was embedded into the inner aqueous phase of W₁/O/W₂ emulsions. Firstly, the dissolution method of MGF was determined. MGF remained stable in solution with pH 13 at 30 min, and its solubility reached 10 mg mL⁻¹. When the pH of MGF solutions was adjusted from pH 13 to pH 6, MGF did not immediately crystallise, providing sufficient time to construct the MGF-loaded W₁/O/W₂ emulsions. Subsequently, the MGF-loaded W₁/O/W₂ emulsions were constructed using polyglycerol polyricinoleate (PGPR) and calcium caseinate (CAS). The formation and stability of the W₁/O/W₂ emulsions were investigated. The MGF-loaded W₁/O/W₂ emulsions stabilised with 1% PGPR and 1% – 3% CAS exhibited a low viscosity, limited loading capacity, and poor stability. Conversely, the MGF-loaded W₁/O/W₂ emulsions stabilised by 3%PGPR–3%CAS exhibited optimal loading capacity (encapsulation efficiency = 95.31% and loading efficiency = 0.91%) and stability, which was attributed to the fact that high viscosity and gel state retarded the migration of inner aqueous phase. These results indicated that the W₁/O/W₂ emulsions stabilised by PGPR and CAS may be a potential alternative for encapsulating mangiferin.