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The specific crystalline form of a compound remarkably affects its physicochemical properties. Therefore, a detailed analysis of the structural features and intermolecular interactions of a multi-component crystal is feasible to understand the relationships among the structure, physicochemical properties and the formation mechanism. In the present study, three novel cocrystal salt solvates of rhein and berberine were reported for the first time. Various solid characterizations and theoretical computations based on density functional theory (DFT) were carried out to demonstrate the intermolecular interactions. The theoretical computation shows that the strongest interaction existed between berberine cation and rhein anion, and the electrostatic interaction play a dominant role. However, no salt bond was observed between them. Further intrinsic dissolution rate analysis in water shows that the monohydrate exhibits 17 times enhancement in comparison with rhein. The rhein and berberine combined in ionic state in cocrystal salt is the main reason for the solubility improvement. This paper suggests that the interactions between the different components can be visualized and qualitatively and quantitatively analyzed by theoretical computation, which is helpful to understand the relationship between stereochemical structure and physicochemical properties of multi-component complex.

Background: Frankincense is a resin secreted by the Boswellia tree. It is used in perfumery, aromatherapy, skincare, and traditional Chinese medicine. However, all Boswellia species are under threat owing to habitat loss and overexploitation. As a result, the market is getting flooded with counterfeit frankincense products. Objective: This study aims to establish a high-throughput method to screen and identify the authenticity of commercial frankincense products. We report, for the first time, a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based method for rapid and high-throughput screening of frankincense samples. Methods: MALDI-TOF MS, HPLC, thin-layer chromatography (TLC), and in vitro anti-inflammatory activity assay were used to examine the frankincense samples. Results: Well-resolved peaks of frankincense triterpenoids in the spectra were observed in the crude extract of commercial samples, including α-boswellic acids (αBAs), β-boswellic acids (βBAs), 11-keto-β-boswellic acids (KBAs), acetyl-11-keto-β-boswellic acids (AKBAs), and their esters. These compounds can be used as indicators for determining the authenticity of frankincense. Conclusion: Unlike LC–MS, which is a time-consuming and expensive method, and TLC, which requires a reference sample, our inexpensive, rapid high-throughput identification method based on MALDI-TOF MS is ideal for large-scale screening of frankincense samples sold in the market.

Based on the structural modification of regorafenib, 28 pyrazinyl–aryl urea derivatives were synthesized and their in vitro antiproliferative activities were evaluated. Six compounds (5-16, 5-17, 5-18, 5-19, 5-22, and 5-23) exhibited favorable inhibitory activity against the human bladder cancer T24 cell line, and 5-23 demonstrated the strongest inhibitory activity (IC(50) = 4.58 ± 0.24 μM) with high selectivity. Compound 5-23 induced apoptosis in the low concentration range (≤7.5 μM) combined with shorter incubation time (≤10 h) via the activation of caspases, while high concentrations and prolonged incubation times led to necroptotic cell death by activating the RIPK1/RIPK3/MLKL signaling pathway. Induced apoptosis and necroptosis were closely associated with intracellular reactive oxygen species generation and decreased mitochondrial membrane potential. Compared with regorafenib, 5-23 displayed improved pharmacokinetic profiles in an in vivo rat model. Molecular docking and structure–activity relationship analyses were in agreement with the biological data. Compound 5-23 may be a potent anti-bladder cancer agent and this small molecule can be considered as a promising structure for further optimization.

To enhance the overall water splitting efficiency, it is widely attractive yet challenging to develop low price, abundance and efficient bifunctional electrocatalysts towards oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). Herein, Fe,Rh-codoped Ni2P nanosheets arrays were in situ anchored on three-dimension (3D) Ni foam under hydrothermal condition and successive phosphorization, denoted as Fe,Rh-Ni2P/NF for simplicity. The unique nanosheets arrays effectively enriched the active sites with easy accessibility. By virtue of the unique sheet-like arrays and 3D porous conductive substrate, the prepared Fe,Rh-Ni2P/NF showed the low overpotentials of 226 mV at 30 mA cm−2 towards the OER and 73 mV at 10 mA cm−2 for the HER. Moreover, the electrocatalyst effectively worked as anode and cathode for overall water splitting system, showing a small voltage of 1.62 V to drive a current density of 10 mA cm−2. The present work provides alternative option for fabricating advanced catalysts in electrocatalysis and energy devices.

Ta3N5 has suitable band positions for visible light photocatalytic hydrogen production from water splitting. However, fast self-recombination of electrons and holes is a drawback for its low efficiency. A Ta3N5/WO3 Z-scheme was therefore considered to solve this problem. Furthermore, a nanohoneycomb (nHC) structure was designed and fabricated based on solution-based nanosphere lithography to offer higher surface area for reaction. The cell size of the nHC was controlled by using 400-, 200-, and 100-nm polystyrene nanospheres as the mask. Under visible light irradiation, the hydrogen generation rates of Ta3N5@WO3 film and Ta3N5@100-nm WO3 nHC were measured to be 4.6 and 8.1 μmol/g·h, respectively, whereas that of pure Ta3N5 nHC was negligible. With deposition of Pt cocatalyst, the hydrogen generation rates for Ta3N5@WO3 film and Ta3N5@100-nm WO3 nHC were further raised to 9.9 and 16.6 μmol/g·h, confirming the effectiveness of the structure design.

A series of nanocatalysts derived from immobilization of palladium nanoparticles (Pd NPs) into three dimensional (3D) tube-type architecture of nitrogen (N) functionalized and without functionalized mesoporous carbon CMK-9 is developed by dual agents chemical reduction approach. Herein, for the first time N-functionalized CMK-9 is explored as supports to immobilize Pd NPs and use as multifunctional catalysts for Suzuki-Miyaura cross-coupling reaction, reduction of 4-nitrophenol and hydrodechlorination of chlorobenzene. The Pd@N-CMK-9 catalysts show excellent activities with 100% conversion for Suzuki-Miyaura reaction between iodobenzene and phenylboronic acid and turnover frequency up to 1992 h−1. When use as catalyst for reduction of 4-nitrophenol to 4-aminophenol, it delivers an outstanding rate constant of 4.22 × 10-2 s−1 with activity parameter of 51719 s-1g−1 with respect to only Pd content. The nanocatalysts also demonstrate 100% conversion of chlorobenzene to benzene within 1 h. In addition, the catalyst exhibits remarkable catalytic stability for several cycles without any significant loss of products. The excellent catalytic activities can be attributed to synergistic effect of uniformly dispersed Pd NPs, favorable interaction between metal and support, and tubular interconnected mesoporous framework of N-functionalized CMK-9 that accelerate mass transportation. The present work signifies the versatility of Pd@N-CMK-9 nanocatalysts for various catalytic reactions.

Recombinant adeno-associated virus (rAAV) has emerged as an important gene therapy vector with many clinical trials currently in progress. Analytical characterization and quantitation of particle content remain challenges in both the development and production of rAAV vectors. In this study, charge detection mass spectrometry (CDMS) and gel electrophoresis are used to characterize the DNA content of recombinant AAV8 (rAAV8) vectors with a wide range of target genome sizes. We show that the differences between the masses of empty particles and particles with the genome of interest (GOI) are correlated with the expected genome mass. A small systematic deviation (around 2%) is attributed to the packaging of counterions along with the DNA. In addition to the GOI, a broad distribution of heterogeneous DNA is packaged. The distribution peaks are close to the packaging capacity of the rAAV8 vectors. There is also evidence for the co-packaging of small DNA fragments along with the GOI. Finally, we present evidence that incubation at an elevated temperature can reduce the heterogeneity of the packaged DNA. Taken together, these results show that CDMS is a viable tool for characterization of the packaged genome., Graphical abstract, Charge detection mass spectrometry and gel electrophoresis are used to characterize the DNA content of rAAV8 vectors. In addition to the genome of interest, there is a broad distribution of heterogeneous DNA that peaks near the packaging capacity and evidence for the co-packaging of small DNA fragments.

The objective of this study was to explore the effects and underlying intervention mechanisms of Angelica water extract (AWE) on abnormal uterine bleeding (AUB) based on serum metabolomics. Firstly, the concentration of main active substances in AWE was determined and the chemical components were identified by UPLC‐Q‐Exactive Orbitrap‐MS/MS. A drug‐induced abortion model was established by mifepristone and misoprostol. After administration AWE (2.16 g/kg) for 7 days, the coagulation function, serum hormone levels, H&E staining, and immunohistochemistry observation of uterus were detected. In addition, serum metabolites profiles were performed on ultra‐performance liquid chromatography–quadrupole–time‐of‐flight mass spectrometry (UPLC‐Q‐TOF‐MS). The contents of ferulic acid, senkyunolide A, and ligustilide in AWE were 0.7276, 0.0868, and 1.9908 mg/g, respectively. Twenty‐six compounds were identified in AWE. It was found that AWE was effective in regulation of coagulation function and promoting endometrial recovery. Meanwhile, the levels of E2, Pg, and HCG and the expression of ERα, Erβ, and PR were down‐regulated in AUB model and up‐regulated by the treatment of AWE. Twenty‐one potential biomarkers were eventually identified by multivariate statistical analysis. Study indicated that glycerophospholipid, sphingolipid, amino acids, retinol metabolism and primary bile acid biosynthesis were the main related metabolic pathways involved for the treatment of AUB by AWE. The results showed that AWE has potential therapeutic effect on AUB by altering the metabolic aberrations., Angelica water extract could reduce alleviate pathological injury and regulate the coagulation function to promote recovery of the endometrium. Angelica water extract could increase the levels of E2, Pg, and HCG and the expression of ERα, Erβ, and PR. Angelica water extract could regulate the metabolic pathways which include the glycerophospholipid metabolism, sphingolipid metabolism, glycine, serine and threonine metabolism, and retinol metabolism.

Currently, less than 20% of electronic waste (E-waste) produced in the U.S. is recycled. To improve the recycling rate of E-waste, the study aimed to: (1) identify the major plastics found within electronic shredder residue (ESR), (2) design solvents and processing conditions capable of separating out 90% of the plastic in ESR, and (3) estimate the energy efficiency of the solvent-based process developed. Preliminary screening showed 25 wt.% of the ESR was composed of plastics, with two polymers dominating the sorted plastic fraction—polystyrene (PS, 40 wt.%) and acrylonitrile butadiene styrene (ABS, 25 wt.%). Subsequently, solvents and anti-solvents were screened using Hansen Solubility Parameter Theory for PS, ABS, and ESR dissolution. The pre-screening results showed dichloromethane (DCM) and tetrahydrofuran (THF) as the most effective solvents for PS and ABS, with methanol (MeOH) and ethylene glycol (EG) as the most effective anti-solvents. By optimizing the dissolution time and the solvents used, the highest polymer dissolution yield (99 wt.%) was achieved using DCM for 48 h. Both MeOH and EG precipitated 71 wt.% of the polymer fraction of ESR. EG removed more phosphorus containing flame retardants (94 wt.%) than MeOH (69 wt.%). Energy analysis indicated that the solvent-based processes could save 25–60% of the embodied energy for PS and ABS. Characterization showed that the solvent-based processing could preserve the high molecular weight fraction of the polymers while removing flame retardants at the same time. The results from this study prove the potential of solvent-based processing to produce secondary plastic materials from E-waste for cross-industry reuse.

The MnFe2O4/g-C3N4/diatomite composites (Mn/G/D) were prepared via a facile precipitation-calcination method in this study. The Mn/G/D possessed higher specific surface area, lower electron-hole pairs’ recombination rate, as well as wider and stronger visible light absorption capacity. Since the synergistic effect between g-C3N4 and MnFe2O4, the photogenerated electron could transfer from g-C3N4 to MnFe2O4, which could promote the migration of electrons as well as enhance the photocatalytic activity and peroxymonosulfate (PMS) activation efficiency. Mn/G/D-5% composite displayed the excellent degradation performance of bisphenol A (BPA) with the removal efficiency of 99.9% under PMS/Vis system, which was approximately 2.47 and 63.8 times as high as that of the Mn/G/D-5%/PMS and Mn/G/D-5%/Vis system, respectively. Moreover, negative electricity derived from diatomite surface also promoted the photogenerated carriers’ migration, and the degradation rate constant was around 2.4 times higher than that of MnFe2O4/g-C3N4 (Mn/G). In addition, quenching experiments showed that both radical pathway (h+, ·OH, ·O2− and SO4·−) and non-radical pathway (1O2) were responsible for the degradation of BPA.

Graphical abstract, CRISPR-Cas systems are prokaryotic adaptive immunity against invading phages and plasmids. Phages have evolved diverse protein inhibitors of CRISPR-Cas systems, called anti-CRISPR (Acr) proteins, to neutralize this CRISPR machinery. In response, bacteria have co-evolved Cas variants to escape phage’s anti-CRISPR strategies, called anti-anti-CRISPR systems. Here we explore the anti-CRISPR allosteric inhibition and anti-anti-CRISPR rescue mechanisms between Streptococcus thermophilus Cas9 (St1Cas9) and the anti-CRISPR protein AcrIIA6 at the atomic level, by generating mutants of key residues in St1Cas9. Extensive unbiased molecular dynamics simulations show that the functional motions of St1Cas9 in the presence of AcrIIA6 differ substantially from those of St1Cas9 alone. AcrIIA6 binding triggers a shift of St1Cas9 conformational ensemble towards a less catalytically competent state; this state significantly compromises protospacer adjacent motif (PAM) recognition and nuclease activity by altering interdependently conformational dynamics and allosteric signals among nuclease domains, PAM-interacting (PI) regions, and AcrIIA6 binding motifs. Via in vitro DNA cleavage assays, we further elucidate the rescue mechanism of efficiently escaping AcrIIA6 inhibition harboring St1Cas9 triple mutations (G993K/K1008M/K1010E) in the PI domain and identify the evolutionary landscape of such mutational escape within species. Our results provide mechanistic insights into Acr proteins as natural brakes for the CRISPR-Cas systems and a promising potential for the design of allosteric Acr peptidomimetics.

A rapid on-bead convergent method for preparing branched peptides was reported. Linear peptides were prepared on Dbz resin and ligated various branched cores, including lysine dendrons and other dendritic compounds. Alongside microwave irradiation

Chemotherapy side effects are minimized, and therapeutic results are enhanced by combination therapy, which is extensively utilized in cancer therapy. MTT experiment showed that compared to the free drugs calreticulin (CRT) and gemcitabine (GEM), GEM-CRT@NPs significantly increased the cytotoxicity of endometrial cancer (Ishikawa cells and KLE cells). These drugs were conjugated to a tri-block copolymeric framework. GEM-CRT@NPs were studied using HR-TEM and DLS analysis to determine particle size and zeta potential. Biochemical staining analyses were also used to investigate the morphological characteristics of endometrial cancer cell lines. After KLE and Ishikawa cancer cells were treated with GEM-CRT@NPs, endometrial cell shape was altered, as evidenced by nuclear fragmentation and nuclear condensation (apoptosis hallmarks). Additionally, the most significant apoptosis ratio to mitochondrial membrane potential indicates that the mitochondrial membrane potential is responsible for the cell's death. Upon treatment with GEM-CRT@NPs, systemic toxicity analysis revealed minimal histological abnormalities and significant blood chemistry alterations, and a near-normal look of the organs. Endometrial cancer treatment may be enhanced with the use of the targeted combination therapeutic system.

Ammonia (NH3 ), an air pollutant in the living environment, has many toxic effects on various tissues and organs. However, the underlying mechanisms of NH3 -induced tracheal cell autophagy remains poorly understood. In present study, chickens and LMH cells were used as NH3 exposure models to investigate toxic effects. The change of tracheal tissues ultrastructure showed that NH3 exposure induced autolysosomes. The differential expression of 12 circularRNAs (circRNAs) was induced by NH3 exposure using circRNAs transcriptome analysis in broiler tracheas. We further found that circ-IFNLR1 was down-regulated, and miR-2188-5p was up-regulated in tracheal tissues under NH3 exposure. Bioinformatics analysis and dual luciferase reporter system showed that circ-IFNLR1 bound directly to miR-2188-5p and regulated each other, and miR-2188-5p regulated RNF182. Overexpression of miR-2188-5p caused autophagy and its inhibition partially reversed autophagy in LMH cells which were caused by ammonia stimulation or knockdown of circ-IFNLR1. The expressions of three autophagy-related genes (LC3, Beclin 1, and BNIP3) were observably up-regulated. Our results indicated that NH3 exposure caused autophagy through circ-IFNLR1/miR-2188-5p/RNF182. These results provided new insights for the study of ammonia on environmental toxicology on ceRNA and circRNAs in vivo and vitro.

Cadmium (Cd), as a common environmental pollutant, has been reported to cause T lymphocyte dysfunction and cell apoptosis in multiple organs. However, whether subacute Cd exposure can induce apoptosis of hepatocytes and the relationship with Th1/Th2 imbalance were still unclear. In this study, ten 6-week-old piglets were selected and randomly assigned into two groups, the control group and the Cd group. The control group was fed with the standard diet, and for the Cd group, the standard diet was supplemented with 20 mg/kg CdCl2; liver tissue was collected on the 40th day of the experiment. Immunofluorescence, qRT-PCR, and western blot were performed to detect the expression of miR-369, Th1/Th2 biomarkers, endoplasmic reticulum (ER) stress-related genes, and apoptotic genes. TUNEL assay was applied to stain apoptotic hepatocytes. In the Cd group, the apoptosis of hepatocytes was significantly increased, and associated with the declined expression of miR-369, Th1 polarization, the elevated expression of ER stress pathway genes and their downstream pro-apoptosis genes, and downregulated expression of anti-apoptotic genes. These results manifest that subacute Cd exposure mediates Th1 polarization to promote ER stress-induced porcine hepatocyte apoptosis via regulating miR-369-TNFα. These results not only provide a basis for the enrichment of Cd toxicology but also support a theoretical foundation for the prevention and therapy of Cd poisoning. Schematic diagram illustrating the proposed mechanism of subacute cadmium exposure modulates Th1 polarization to trigger ER stress-induced porcine hepatocyte apoptosis via regulation of miR-369-TNFα axis.

To improve the cracking behavior of hydrocarbon, Ni–Mo/SiO2 bimetallic catalysts were synthesized by different preparation methods (sol-gel, co-impregnation and single-impregnation) and added the additives (citric acid, polyethylene glycol and cetyltrimethylammonium bromide) based on the most suitable method above. The cracking reaction of methylcyclohexane under supercritical conditions was performed as the probe reaction to estimate the catalytic performance, and the properties of Ni–Mo/SiO2 catalyst were characterized by N2 absorption-desorption, XRD, XPS, H2-TPR, NH3-TPD, in-situ IR of NH3 desorption, HRTEM and STEM-mapping so as to study the structure-activity relationship. The catalyst synthesized via sol-gel method showed the best conversion and heat sink, being 81.8% and 3.81 MJ/kg, which was closely related to strong mutual effect between active components and SiO2 as well as strong acid sites. Besides, the introduction of additives by sol-gel method has an affirmative influence on properties of Ni–Mo/SiO2 catalysts, being that the acidity (more L and B acid sites) was modulated and organic groups interact with metal to suppress the aggregation of metal species (Ni and Mo), thereby enhancing the catalytic activity. At 750 °C, the conversion (89.3%) as well as heat sink (3.99 MJ/kg) of MCH cracking obtained an optimum over Ni–Mo/SiO2 catalyst with addition of citric acid.

Specific antibody interactions with short peptides have made epitope tagging systems a vital tool employed in virtually all fields of biological research. Here, we present a novel epitope tagging system comprised of a monoclonal antibody named GD-26, which recognises the TD peptide (GTGATPADD) derived from Haloarcula marismortui bacteriorhodopsin I (HmBRI) D94N mutant. The crystal structure of the antigen-binding fragment (Fab) of GD-26 complexed with the TD peptide was determined to a resolution of 1.45 A. The TD peptide was found to adopt a 310 helix conformation within the binding cleft, providing a characteristic peptide structure for recognition by GD-26 Fab. Based on the structure information, polar and non-polar forces collectively contribute to the strong binding. Attempts to engineer the TD peptide show that the proline residue is crucial for the formation of the 310 helix in order to fit into the binding cleft. Isothermal calorimetry (ITC) reported a dissociation constant KD of 12 ± 2.8 nM, indicating a strong interaction between the TD peptide and GD-26 Fab. High specificity of GD-26 IgG to the TD peptide was demonstrated by Western blotting, enzyme-linked immunosorbent assays (ELISA) and immunofluorescence as only TD-tagged proteins were detected, suggesting the effectiveness of the GD-26/TD peptide tagging system. In addition to already-existing epitope tags such as the FLAG tag and the ALFA tag adopting either extended or α-helix conformations, the unique 310 helix conformation of the TD peptide together with the corresponding monoclonal antibody GD-26 offers a novel tagging option for research.

The effects of 13 plant growth–promoting rhizobacteria (PGPR) from the maize rhizosphere and a model PGPR strain Azospirillum brasilense Az39 on maize growth were monitored in a 3-year field inoculation experiment (from 2018 to 2020) with low-nitrogen (N) (N input reduced by 50%) and low-phosphorus (P) (no P supply) soils in Northeast China. The effects of four efficient PGPR that stably promoted maize plant growth and affected on the composition and function of the rhizobacterial community were further investigated in 2019 and 2020. On average, Sinorhizobium sp. A15, Bacillus sp. A28, Sphingomonas sp. A55, and Enterobacter sp. P24 stably increased grain yield by 8.1–17.8% and 11.0–20.1% in low-N and low-P soil, respectively. Inoculation of these four strains increased the abundance and species richness of rhizobacteria, enriched special beneficial bacteria such as Chloroflexia_KD4-96 and Bacilli, and decreased bacterial functions related to soil-N loss. We conclude that some PGPR can N- and P-use efficiency and maize yield through reshaping the rhizobacterial community.

The asymmetric assembly and spontaneous resolution of chiral heterometal-organic frameworks from achiral precursors remain a great challenge. Herein, we report the formation and spontaneous resolution of three-dimensional (3D) chiral 3d–4f heterometal-organic frameworks from achiral ligands in the presence of lactic acid enantiomers as chiral inducers. In the absence of a chiral inducer, the reactants randomly generated both enantiopure crystals in equal measure. However, enantiopure lactic acid induced asymmetric resolution to achieve single chiral crystallization. DFT theoretical calculations showed that the absolute chiral resolution of the enantiomers is due to the difference in the interactions between the two enantiomeric Λ/Δ-[FeL3]3− units and the chiral inducer.

Three mutant rice (Oryza sativa L.) lines (AG1, AG2 and AG3) were selected as heat tolerant mutants from a gamma-ray-irradiated population of a heat-susceptible line (AG), based on their floret fertility grown under high temperatures. They were subjected to heat stress treatment (45°C, 22 hrs) at the 5-leaf stage, together with a heat-tolerant cultivar N22 and AG. Analysis of seedling root growth by WinRHIZO scanning revealed that N22 and AG3 were more heat-tolerant than the other lines (AG being the most heat susceptible). Following heat stress, a significantly higher level of oxidative damage, as indicated by TBARS, was observed in AG than in N22 and AG3. The proline accumulation was significantly higher in N22 and AG3（12- to 13.5- fold）than AG (2.5- fold). Similarly, significantly greater increases of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activity were observed in N22 and AG3 than in AG. The expression of four heat shock proteins was also investigated using qPCR: OsHSP16.9, OsHSP80.3 and OsHSP100.9were induced by heat stress to various levels while OsHSP72.6was down-regulated in all tested lines. The heat-induced expression of OsHSP16.9 and OsHSP100.9 in N22 and AG3 was about twice that of AG. Higher proline accumulation and expression of the three HSP genes, as well as elevation ofT-AOC and SOD activity were observed in the heat-tolerant N22 and the mutant line AG3 under heat stress

Ten types of Tf2O/TTBP-mediated amide transformation reactions were investigated. The results showed that compared with pyridine derivatives 2,6-di-tert-butyl-4-methylpyridine (DTBMP) and 2-fluoropyridine (2-F-Pyr.), TTBP can serve as an alternative amide activation system for the direct transformation of both secondary and tertiary amides. For most surveyed examples, higher or comparable yields were generally obtained. In addition, Tf2O/TTBP combination was used to promote the condensation reactions of 2-(tert-butyldimethylsilyloxy)furan (TBSOF) with both tertiary and secondary amides, the one-pot reductive Bischler-Napieralski-type reaction of tertiary lactams, and Movassaghi and Hill's modern version of the Bischler-Napieralski reaction. The value of the Tf2O/TTBP-based methodology was further demonstrated by the concise and high-yielding syntheses of several natural products.

In this work, we demonstrated a novel approach of corrosion protection based on the fabrication of polyelectrolyte/SiO2 nanoparticles multilayers on magnesium alloys. The original multilayers based merely on electrostatic attraction showed porous morphology and weak anti-corrosion protection for the Mg substrate. However, the heat-treatment process would change the microstructures of the multilayers through the cross-linking between the polyelectrolytes and the capping agents of the nanoparticles, and the barrier effects of the coating could be confirmed by polarization and electrochemical impedance spectroscopy. Thus the heat treatment would be an applicable option for preparing the layer-by-layer assembled anti-corrosive multilayers on biomedical Mg alloys.

Although arsenic trioxide (ATO) is used in the treatment of advanced hepatocellular carcinoma (HCC) in clinical trials, it is not satisfactory in terms of improving HCC patients’ overall survival. Intratumoral hypoxia and overexpression of hypoxia-inducible factor-1α (HIF-1α) may result in ATO resistance and tumor progression. We investigated the mechanisms involving HIF-1α expression and acquired ATO chemoresistance in HCC cells and mice. The therapeutic effects of ATO in normoxic and hypoxic HCC cells were assessed using cell viability and apoptosis assays in vitro and a xenograft model in vivo. mRNA and protein expression of HIF-1α, P-glycoprotein, and VEGF were measured by qRT-PCR and western blotting. HIF-1α inhibition was performed to investigate the mechanism of ATO resistance. VEGF secretion was tested using ELISA and tube formation assays. Compared to normoxic cells, hypoxic HCC cells were more resistant to ATO, with higher IC50 values and less apoptosis, and upregulated HIF-1α protein expression, accompanied with the enhancement of P-glycoprotein and VEGF synthesis after ATO treatment. VEGF secretion was elevated in the supernatant of ATO-treated HCC cells, and this change can potentiate angiogenesis in vitro. HIF-1α inhibition attenuated ATO resistance and angiogenesis and promoted the anticancer effects of ATO both in vitro and in vivo by downregulating therapy-induced P-glycoprotein and VEGF overexpression. Hypoxic HCC cells acquire ATO resistance by upregulating HIF-1α levels; thus, combining ATO with a HIF-1α-targeting agent may lead to enhanced antitumor effects in HCC.

SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with overactivation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion, and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non–small cell lung cancer (NSCLC). However, treatment also increased intratumor granulocytic myeloid-derived suppressor cells (gMDSC) via tumor-intrinsic, NFκB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C inhibitor trials. Combined SHP2 (SHP099)/CXCR1/2 (SX682) inhibition depleted a specific cluster of S100a8/9hi gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in patients with NSCLC. Significance: Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NFκB-dependent upregulation of CXCR2 ligands and recruitment of S100A8hi gMDSCs, which suppress T cells. Combining SHP2/CXCR2 inhibitors blocks gMDSC immigration, resulting in enhanced Th1 polarization, induced CD8+KLRG1+ effector T cells with high cytotoxic activity, and improved survival in multiple NSCLC models. This article is highlighted in the In This Issue feature, p. 1

The construction of an anode material with a conversion-alloying dual mechanism will facilitate the development of potassium-ion batteries (PIBs) with high-energy density. Here a Bi2Se3 nanosheets coated with nitrogen-doped carbon and wrapped with reduced graphene oxide (Bi2Se3@NC@rGO) is fabricated to boost K-ion storage. The Bi2Se3@NC@rGO composite with strong C–O–Bi bonding can provide superior electrode integrity and electrochemical kinetics by combining the synergistic effect of carbon encapsulation and graphene confinement. In situ X-ray diffraction and ex situ transmission electron microscopy analyses demonstrate that K-ion intercalation/deintercalation proceeds via both conversion and alloying/dealloying reactions based on 12-electron transfer per formula unit; the conversion product of K2Se can efficiently suppress the volume expansion during alloying/dealloying process to improve its stability. Hence, a high reversible capacity of 612.0 mAh·g−1 at 100 mA·g−1; a great rate capability with the capacity of 101.6 mAh·g−1 at 5 A·g−1, and an ultra-long cycling life of over 1000 cycles at 500 mA·g−1 is achieved for the Bi2Se3@NC@rGO. The K-ion full cell is also assembled using K2Ni[Fe(CN)6] as the cathode, thereby contributing a high-energy density of 162.9 Wh·kg−1 at 10 mA·g−1 and a great cyclability.

Background The purification of keratinase is essential to enhance the catalytic efficiency of keratinase enzyme for industrial applications. Biphasic system incorporated with electric fields is an effective purification tool for the recovery of biomolecules. Ionic liquids (IL) with good conductivity are ideal phase-forming components for biphasic system which promotes the separation of charged biomolecules via electromigration. Methods This study aimed to evaluate the effect of electric fields on enhanced recovery of Kytococcus sedentarius TWHKC01 keratinase using IL-based biphasic system. Findings Keratinase was recovered with biphasic system incorporated with anode in salt-rich bottom phase and cathode in IL-rich top phase operated at 5 V for 5 min. A total of 95.82% ± 0.17 of keratinase was attained with the biphasic system at pH 9 comprising of 20% (w/w) 1‑butyl‑3-methylimidazolium tetrafluoroborate ((Bmim)BF4) and 25% (w/w) ammonium sulphate loaded with 15% (w/w) K. sedentarius TWHKC01 crude feedstock. The selectivity (S) and purification fold (PFT) of keratinase were increased from 7.25 ± 1.50 to 10.87 ± 0.61 and 5.94 ± 0.22 to 8.22 ± 0.44, respectively with the incorporation of electrodes, demonstrating the efficiency of electric fields in enhancing the purity of recovered keratinase.

Clusters of regularly interspaced short palindromic repeats (CRISPR)/Cas systems have a powerful ability to edit DNA and RNA targets. However, the need for a specific recognition site, protospacer adjacent motif (PAM), of the CRISPR/Cas system limits its application in gene editing. Some Argonaute (Ago) proteins have endonuclease functions under the guidance of 5′ phosphorylated or hydroxylated guide DNA (gDNA). The NgAgo protein might perform RNA gene editing at 37 °C, suggesting its application in mammalian cells; however, its mechanisms are unclear. In the present study, the target of NgAgo in RNA was confirmed in vitro and in vivo. Then, an in vitro RNA cleavage system was designed and the cleavage site was verified by sequencing. Furthermore, NgAgo and gDNA were transfected into cells to cleave an intracellular target sequence. We demonstrated targeted degradation of GFP, HCV, and AKR1B10 RNAs in a gDNA-dependent manner by NgAgo both in vitro and in vivo, but no effect on DNA was observed. Sequencing demonstrated that the cleavage sites are located at the 3′ of the target RNA which is recognized by 5′ sequence of the gDNA. These results confirmed that NgAgo–gDNA cleaves RNA not DNA. We observed that the cleavage site is located at the 3′ of the target RNA, which is a new finding that has not been reported in the past.

Background. Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4 ′ -amino-5 ′ ,8 ′ -difluoro-1 ′ H-spiro[piperidine-4,2 ′ -quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation. Methods. An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [18F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution ( V t ), and area under the curve (AUC) based on the [18F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues. Results. At the end of synthesis, the yield of [18F]FBAT was 2.2–3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125–137 GBq/μmol. In vitro, [18F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [18F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [18F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [18F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16 ± 0.18 , 1.53 ± 0.25 , 1.41 ± 0.21 , and 1.90 ± 0.12 , respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution ( V t , mL/cm3), and K i (influx rate) of [18F]FBAT were 1.9 ± 0.21 - and 1.4 ± 0.22 -fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain K i of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and V t values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS. Conclusion. An automated robotic method was established for radiosynthesis of [18F]FBAT, and the preliminary in vitro and in vivo results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI.

Pot experiments with alfalfa, milkvetch root and swamp morning glory were conducted to elucidate the effect of soil vanadium (V) on plant growth and to evaluate their phytoremediation potential under V(V) exposure. Based on biomass analysis, swamp morning glory showed higher tolerance than alfalfa and milkvetch root in response to different soil V(V) levels. The accumulation of V in plants increased with the increasing soil V and the V concentration in roots was 1.95-4.31 times that in shoots. After planting, soil total V, V(V), bioavailable V and water-soluble V all reduced, and the decreases in bioavailable V and V(V) showed significant. The decreased percentage of V(V) in total V in soils demonstrated that the planting process may stimulate the mechanism of V(V) reduction to V(IV). Therefore, the three tested plants, particularly swamp morning glory can be promising phytostabilizers applied to V phytoremediation practices.

Age-related cognitive impairment is associated with diminished autophagy and progressively increased neuroinflammation. Histone acetylation has been shown to be a key process in sevoflurane-induced neurobehavioral abnormalities. Here, we investigated whether histone acetylation regulates the interaction between autophagy and the NLRP3 inflammasome in models of sevoflurane-induced cognitive impairment and explored the underlying molecular mechanisms. Aged C57BL/6 J mice and cultured primary hippocampal neurons were exposed to 3% sevoflurane for 2 h. Hippocampal tissue samples and hippocampal neurons were harvested. The processes of histone acetylation and autophagy and the activation of the NLRP3 inflammasome were observed using western blotting, immunofluorescence staining, and transmission electron microscopy. Suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylases, increased histone H3 and H4 acetylation in both the mouse hippocampus and primary neurons. Concomitantly, sevoflurane upregulated components of the NLRP3 inflammasome (NLRP3, cleaved caspase-1, and IL-1β) by promoting autophagic degradation in the aging brain. Cognitive deficits and inadequate autophagy induced by sevoflurane were reversed and NLRP3 inflammasome activation was inhibited by SAHA. Treatment with 3-MA, an autophagy inhibitor, eliminated the neuroprotective effects of SAHA on improving cognition in mice, activating autophagy and downregulating the NLRP3 inflammasome. Based on these results, histone acetylation activates autophagy plays an important role in inhibiting the activation of the NLRP3 inflammasome to protect the host from excessive neuroinflammation and sevoflurane-induced cognitive dysfunction in the aging brain.

The 5-nm-thick Mg0.05Sn0.95O x thin film deposited using mist chemical vapor deposition is used as a channel layer of the thin-film transistor (TFT). Mg0.05Sn0.95O x improves the crystallinity, reduces the number of oxygen deficiencies, and enlarges the energy bandgap compared with SnO2. Mg0.05Sn0.95O x -based TFT shows higher field-effect mobility (144.9 cm2V−1s−1), steeper subthreshold slope (134 mV/decade), and significant ON/OFF current ratio (>109) than the SnO2-based TFT. Owing to fewer oxygen-related defects, wide energy bandgaps, and stable Mg-O chemical bonding, the Mg0.05Sn0.95O x -based TFT exhibits more stable electrical performance than the SnO2 TFT after negative bias illumination stress testing. These results suggest that Mg0.05Sn0.95O x is a promising material for high electron mobility TFT applications.

Background and aims The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. Methods Low-density lipoprotein (LDL) receptor null (LDLr−/−) mice were fed Western diet with or without D-4F. We then measured atherosclerotic lesion formation, endothelial nitric oxide synthase (eNOS) phosphorylation and its association with heat shock protein 90 (HSP90), nitric oxide (NO) and superoxide anion (O2•-) production, and tetrahydrobiopterin (BH4) and GTP-cyclohydrolase 1 (GCH-1) concentration in the aorta. Human umbilical vein endothelial cells (HUVECs) and aortas were treated with oxidized LDL (oxLDL) with or without D-4F; subsequently, BH4 and GCH-1 concentration, NO and O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. Results Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- production were increased, whereas BH4 and GCH-1 concentration and NO production were reduced in atherosclerosis. D-4F significantly inhibited atherosclerosis, eNOS phosphorylation, eNOS-HSP90 association, and O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. Conclusions Hypercholesterolemia enhanced uncoupled eNOS activity by decreasing GCH-1 concentration, thereby reducing BH4 levels. D-4F reduced uncoupled eNOS activity by increasing BH4 levels through GCH-1 expression and decreasing eNOS phosphorylation and eNOS-HSP90 association. Our findings elucidate a novel mechanism by which hypercholesterolemia induces atherosclerosis and D-4F inhibits it, providing a potential therapeutic approach.

Meniscus regeneration could be enhanced by targeting meniscus cells and mesenchymal stromal cells (MSCs) with the right growth factors. Combining these growth factors with the Collagen Meniscus Implant (CMI®) could accelerate cell ingrowth and tissue formation in the implant and thereby improve clinical outcomes. Using a transwell migration assay and a micro‐wound assay, the effect of insulin‐like growth factor‐1, platelet‐derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF‐β1), fibroblast growth factor, and platelet lysate (PL) on migration and proliferation of meniscus cells and MSCs was assessed. The formation of extracellular matrix under influence of the above‐mentioned growth factors was assessed after 28 days of culture of both MSCs and meniscus cells. As a proof of concept, the CMI® was functionalized with a VEGF binding peptide and coated with platelet‐rich plasma (PRP) for clinical application. Our results demonstrate that PDGF, TGF‐β1, and PL stimulate migration, proliferation, and/or extracellular matrix production of meniscus cells and MSCs. Additionally, the CMI® was successfully functionalized with a VEGF binding peptide and PRP which increased migration of meniscus cell and MSC into the implant. This study demonstrates proof of concept of functionalizing the CMI® with growth factor binding peptides. A CMI® functionalized with the right growth factors holds great potential for meniscus replacement after partial meniscectomy.

Calcium aluminate cement (CAC) has excellent resistance to seawater erosion, but the mechanism remains to be explored. Effects of NaCl and CaCl2 on the hydration of CAC at 5, 20 and 40°C were investigated in this paper by X-ray diffraction(XRD), thermal analyzer(TG-DSC), scanning electron microscopy(SEM), acoustic and electroacoustic spectrometer. Results show that the varieties of chlorides have great impacts on the chloride binding ability, mechanical properties and microstructure of cement pastes at different temperatures. At 5°C and 20°C, the formation of C2AH8 is suppressed by chloride attack. Though the addition of NaCl promotes the formation of CAH10, CaCl2 leads to a denser microstructure and the improvement in compressive strength. At 40°C, C2AH8 disappears by chloride attack, while C3AH6 and Friedel’s salt increase. Comparing with the attack of CaCl2, NaCl contributes to the formation of C3AH6. Therefore, it results in a the retraction in compressive strength, ascribing to a coarser structure. In addition, although NaCl is superior in chemical binding ability, CaCl2 has better physical adsorption ability which dominants the binding process, and thus leading to greater amount of bonded chloride than that with NaCl. This research provides the oretical basis for the application of CAC in marine environment.

Inhibition of α-glucosidase can slow carbohydrate metabolism, which is known as an effective strategy for diabetes treatment. The aim of this study is to evaluate the effect of thermal treatment (50, 60, and 70℃) for 15 days on the α-glucosidase inhibitory activity of bitter melon. The results show that the bitter melon heated at 70℃ for 12 days had the best α-glucosidase inhibitory effect. However, the amount of free polyphenols, 5-hydroxymethyl-2-furfural (5-HMF), and the browning degree of bitter melon generally increased with the time (15 days) and temperature of the thermal treatment, which is positively related to their antioxidant and α-glucosidase inhibitory activities. In conclusion, aged bitter melon shows great α-glucosidase inhibitory activity, which may be related to the increased free form of the involved phenolic compounds and Maillard reaction products. This suggests that thermal processing may be a good way to enhance the application of bitter melon for diabetes treatment. PRACTICAL APPLICATION: The thermal processing of bitter melon provides an application for diabetes treatment. This study demonstrated that heat-treated bitter melon can lower the blood glucose level; therefore, it can be used as a potential anti-hyperglycemic and functional food.

The purpose of this research is to develop a new type of environmentally friendly container which has thermostatic effect and is biodegradable. This study is based on polylactic acid (PLA) and maleic anhydride grafted polybutylene succinate (MAPBS). Subsequently, the diatomite which adsorbed polyethylene glycol (PEG) was added to prepare a thermostatic biodegradable composite. The addition of MAPBS is to improve the compatibility between PLA and diatomite. In addition, the thermostatic effect, tensile strength, thermal deformation temperature and impact strength of the composite were investigated.

Programmed –1 ribosomal frameshifting is an essential regulation mechanism of translation in viruses and bacteria. It is stimulated by mRNA structures inside the coding region. As the structure is unfolded repeatedly by consecutive translating ribosomes, whether it can refold properly each time is important in performing its function. By using single-molecule approaches and molecular dynamics simulations, we found that a frameshift-stimulating RNA pseudoknot folds sequentially through its upstream stem S1 and downstream stem S2. In this pathway, S2 folds from the downstream side and tends to be trapped in intermediates. By masking the last few nucleotides to mimic their gradual emergence from translating ribosomes, S2 can be directed to fold from the upstream region. The results show that the intermediates are greatly suppressed, suggesting that mRNA refolding may be modulated by ribosomes. Moreover, masking the first few nucleotides of S1 favors the folding from S2 and yields native pseudoknots, which are stable enough to retrieve the masked nucleotides. We hypothesize that translating ribosomes can remodel an intermediate mRNA structure into a stable conformation, which may in turn stimulate backward slippage of the ribosome. This supports an interactive model of ribosomal frameshifting and gives an insightful account addressing previous experimental observations.

This study investigated the combustion behaviors of pure iron and mixed particles, particularly iron–aluminum and iron–coal mixtures, doped into methane (CH4)–air premixed flames. The mechanically mixed particles were prepared with a weight ratio of 1:1. Thermogravimetric analysis revealed that the Fe particles and the Fe–coal mixture underwent oxidation in similar regions of relatively low temperatures; the Fe‒Al mixture underwent a multistage oxidation process. A conical CH4–air premixed flame—with the CH4–air equivalence ratio maintained at the stoichiometric value—was doped with micron-sized solid fuels at various feed rates. Increasing the particle feed rate appeared to alter the flame front characteristics. The interdependency between solid fuels and the CH4–air premixed flame was investigated with respect to flame temperatures, gas emissions, and metal oxide products. Particle microexplosions occurred in the Fe–coal combustion. Regarding the mechanism underlying the microexplosions, we hypothesized that the bubbles inside the Fe particles may have contained dissolved O2, N2, and CO; the dissolved CO may have generated iron carbonyl (Fe(CO)5). Coalescence, repeated bubbling, and bubble expansion processes led to the expansion of iron oxides with hollow shells. The rapid increase in inner pressure and explosive internal combustion caused by the ripening and flammability of the (Fe(CO)5)/O2 bubbles engendered the microexplosions. CO was added to the Fe flame to validate this hypothesis.

Skin pigmentation depends not only on melanosomes produced by melanocytes but also on the migration of melanosomes to adjacent keratinocytes and their distribution on the skin surface. The inhibitory effects of cardanol diene (CADI), a major phenolic compound extracted from cashew nut shell liquid (CNSL), on melanin transfer in B16F10-HaCAT co-culture cells and a crude extracted compound of cashew nut shell oil (CNCE) on melanin production in zebrafish were investigated. β-arbutin was used as a positive control. CADI inhibited the expression levels of the melanin phagocytosis-associated protein PAR-2 and filopodia-associated protein NMDAR1, and the effect was better than that of β-arbutin at the same concentration. To further study the inhibitory mechanism of CADI in melanin transfer, fluorescence microspheres were used to simulate melanin and co-culture with keratinocytes. The results indicated that CADI inhibited melanin transfer through suppressing keratinocyte phagocytosis, dendrite formation and filopodia three channels. We also found that CNCE inhibited melanin production in zebrafish and showed significant inhibitory effects on TYR, DCT and α-MSH. Thus, the natural components extracted from CNSL effectively inhibited skin pigmentation, providing insight into the application of new anti-melanin drugs in cosmetics and medicine.

This study investigates how ambient/carrier gases affect the material characteristics of amorphous indium–gallium–zinc oxide (a-InGaZnO) thin films deposited using the ultrasonic spray pyrolysis deposition (USPD) method. Nitrogen and air are used as the ambient/carrier gases in this study. The crystallinity, oxygen deficiency, energy bandgap, and trap level in the a-InGaZnO thin films are analyzed. The performance of the thin-film transistors (TFTs) based on a-InGaZnO with different ambient/carrier gases is investigated as well. It is found that oxygen deficiency is suppressed when air is used as the ambient/carrier gas. When nitrogen is used as the ambient/carrier gas to deposit a-InGaZnO thin film, the TFT shows higher field-effect mobility and saturation mobility. However, when the a-InGaZnO thin film is deposited with air as the ambient/carrier gas, the subthreshold swing, ON-/ OFF-current ratio, interface trap density, and stability of the TFT are improved. This study demonstrates how ambient/carrier gases in the USPD system affect the performance of a-InGaZnO TFT.

Background Subarachnoid hemorrhage (SAH) is a life-threatening disease worldwide, and effective pharmaceutical treatment is still lacking. Celastrol is a plant-derived triterpene which showed neuroprotective potential in several types of brain insults. This study aimed to investigate the effects of celastrol on early brain injury (EBI) after SAH. Methods A total of sixty-one male Sprague-Dawley rats were used in this study. Rat SAH endovascular perforation model was established to mimic the pathological changes of EBI after SAH. Multiple methods such as 3.0T MRI scanning, immunohistochemistry, western blotting and propidium iodide (PI) labeling were used to explore the therapeutic effects of celastrol on SAH. Results Celastrol treatment attenuated SAH-caused brain swelling, reduced T2 lesion volume and ventricular volume in MRI scanning, and improved overall neurological score. Albumin leakage and the degradation of tight junction proteins were also ameliorated after celastrol administration. Celastrol protected blood-brain bairrer integrity through inhibiting MMP-9 expression and anti-neuroinflammatory effects. Additionally, necroptosis-related proteins RIP3 and MLKL were down-regulated and PI-positive cells in the basal cortex were less in the celastrol-treated SAH group than that in untreated SAH group. Conclusions Celastrol exhibits neuroprotective effects on EBI after SAH and deserves to be further investigated as an add-on pharmaceutical therapy.

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.

CD28 is required for T cell activation as well as the generation of CD4+Foxp3+ Treg. It is unclear, however, how CD28 costimulation affects the development of CD8+ T cell suppressive function. Here, by use of Hepa1.6.gp33 in vitro killing assay and B16.gp33 tumor mouse model we demonstrate that CD28 engagement during TCR ligation prevents CD8+ T cells from becoming suppressive. Interestingly, our results showed that ectonucleotidase CD73 expression on CD8+ T cells is upregulated in the absence of CD28 costimulation. In both murine and human tumor-bearing hosts, CD73 is upregulated on CD28−CD8+ T cells that infiltrate the solid tumor. UPLC-MS/MS analysis revealed that CD8+ T cells activation without CD28 costimulation produces elevated levels of adenosine and that CD73 mediates its production. Adenosine receptor antagonists block CD73-mediated suppression. Our data support the notion that CD28 costimulation inhibits CD73 upregulation and thereby prevents CD8+ T cells from becoming suppressive. This study uncovers a previously unidentified role for CD28 costimulation in CD8+ T cell activation and suggests that the CD28 costimulatory pathway can be a potential target for cancer immunotherapy. Lai et al. report that the immunosuppressive molecule CD73 is negatively regulated by CD28 costimulation during CD8+ T cell activation. Their study implicates a lack of CD28 costimulation renders CD8+ T cells immunosuppressive and less able to eliminate solid tumors.

Four pairs of chiral 3D coordination polymers (CPs), [Zn2(BDC)(lac)(DMF)]·guest (2) (H2BDC = benzene dicarboxylic acid; H2lac = lactic acid; guest = 1.5DMF + i-PrOH), [Co2(BDC)(lac)(DMF)]·guest (3) (guest = DMF + 2H2O), [Fe4(BDC)3(lac)2(DMF)2](CO3)·guest (4) (guest = DMF + 2H2O), and {Zn11(BPDC)6(lac)6[NH2(CH3)2]2}·guest (H2BPDC = 3,3'-biphenyldicarboxylic acid; guest = 6DMF + 18H2O) (5), are prepared through the reactions of racemic lactic acid (rac-H2lac) with different metal ions and auxiliary ligands. Structural analyses and DFT calculations reveal that forming more and stronger coordination bonds between the auxiliary ligand and metal ions is more conducive to the spontaneous resolution of enantiomers in 3D CPs than simply increasing the entropy of the auxiliary ligand itself.