Multifunctional DNA Tetrahedron for Alzheimer’s Disease Mitochondria-Targeted Therapy by MicroRNA Regulation

The principal hallmark of Alzheimer’s disease (AD) is neuron mitochondrial dysfunction, whereas mitochondrial miRNAs potentially play important roles. Nevertheless, efficacious mitochondria organelle therapeutic agents for treatment and management of AD are highly advisable. Herein, we report a multifunctional DNA tetrahedron-based mitochondria-targeted therapeutic platform, termed tetrahedral DNA framework-based nanoparticles (TDFNs), which was modified with triphenylphosphine (TPP) for mitochondria-targeting, cholesterol (Chol) for crossing the central nervous system, and functional antisense oligonucleotide (ASO) for both AD diagnosis and gene silencing therapy. After injecting intravenously through the tail vein of 3 × Tg-AD model mice, TDFNs can both easily cross the blood brain barrier and accurately arrive at the mitochondria. The functional ASO could not only be detected via the fluorescence signal for diagnosis but also mediate the apoptosis pathway through knocking miRNA-34a down, leading to recovery of the neuron cells. The superior performance of TDFNs suggests the great potential in mitochondria organelle therapeutics

Engineering Metal–Organic Framework Hybrid AIEgens with Tumor-Activated Accumulation and Emission for the Image-Guided GSH Depletion ROS Therapy

Aggregation-induced emission (AIE)-active luminogens (AIEgens) have demonstrated exciting potential for the application in cancer phototheranostics. However, simultaneously achieving tumor-activated bright emission, enhanced reactive oxygen species (ROS) generation, high tumor accumulation, and minimized ROS depletion remains challenging. Here, a metal–organic framework (MOF) hybrid AIEgen theranostic platform is designed, termed A-NUiO@DCDA@ZIF-Cu, composed of an AIEgen-loaded hydrophobic UiO-66 (A-NUiO@DCDA) core and a Cu-doped hydrophilic ZIF-8 (ZIF-Cu) shell. The fluorescence emission and therapeutic ROS activity of AIEgens are restrained during delivery. After uptake by tumor tissues, ZIF-Cu decomposition occurs in response to an acidic tumor microenvironment (TME), and the hydrophobic A-NUiO@DCDA cores self-assemble into large particles, extremely increasing the tumor accumulation of AIEgens. This results in enhanced fluorescence imaging (FLI) and highly improved 1O2 generation ability during photodynamic therapy (PDT). Meanwhile, the released Cu2+ reacts to glutathione (GSH) to generate Cu+, which provides an extra chemodynamic therapy (CDT) function through Fenton-like reactions with overexpressed H2O2, resulting in the GSH depletion-enhanced ROS therapy. As a result of these characteristics, the MOF hybrid AIEgens can selectively kill tumors with excellent efficacy

Table_1_Exploring Soil Factors Determining Composition and Structure of the Bacterial Communities in Saline-Alkali Soils of Songnen Plain.DOCX

Songnen Plain is originally one of the three major glasslands in China and has now become one of the three most concentrated distribution areas of sodic-saline soil worldwide. The soil is continuously degraded by natural and anthropogenic processes, which has a negative impact on agricultural production. The investigation of microbial diversity in this degraded ecosystem is fundamental for comprehending biological and ecological processes and harnessing the potential of microbial resources. The Illumina MiSeq sequencing method was practiced to investigate the bacterial diversity and composition in saline-alkali soil. The results from this study show that the change in pH under alkaline conditions was not the major contributor in shaping bacterial community in Songnen Plain. The electrical conductivity (EC) content of soil was the most important driving force for bacterial composition (20.83%), and the second most influencing factor was Na+ content (14.17%). Bacterial communities were clearly separated in accordance with the EC. The dominant bacterial groups were Planctomycetes, Proteobacteria, and Bacteroidetes among the different salinity soil. As the salt concentration increased, the indicators changed from Planctomycetes and Bacteroidetes to Proteobacteria and Firmicutes. Our results suggest that Proteobacteria and Firmicutes were the main indicator species reflecting changes of the main microbial groups and the EC as a key factor drives the composition of the bacterial community under alkaline conditions in saline-alkali soil of Songnen Plain.</p

Electrolyte Reactivity at the Charged Ni-Rich Cathode Interface and Degradation in Li-Ion Batteries

The chemical and electrochemical reactions at the positive electrode–electrolyte interface in Li-ion batteries are hugely influential on cycle life and safety. Ni-rich layered transition metal oxides exhibit higher interfacial reactivity than their lower Ni-content analogues, reacting via mechanisms that are poorly understood. Here, we study the pivotal role of the electrolyte solvent, specifically cyclic ethylene carbonate (EC) and linear ethyl methyl carbonate (EMC), in determining the interfacial reactivity at charged LiNi0.33Mn0.33Co0.33O2 (NMC111) and LiNi0.8Mn0.1Co0.1O2 (NMC811) cathodes by using both single-solvent model electrolytes and the mixed solvents used in commercial cells. While NMC111 exhibits similar parasitic currents with EC-containing and EC-free electrolytes during high voltage holds in NMC/Li4Ti5O12 (LTO) cells, this is not the case for NMC811. Online gas analysis reveals that the solvent-dependent reactivity for Ni-rich cathodes is related to the extent of lattice oxygen release and accompanying electrolyte decomposition, which is higher for EC-containing than EC-free electrolytes. Combined findings from electrochemical impedance spectroscopy (EIS), TEM, solution NMR, ICP, and XPS reveal that the electrolyte solvent has a profound impact on the degradation of the Ni-rich cathode and the electrolyte. Higher lattice oxygen release with EC-containing electrolytes is coupled with higher cathode interfacial impedance, a thicker oxygen-deficient rock-salt surface reconstruction layer, more electrolyte solvent and salt breakdown, and higher amounts of transition metal dissolution. These processes are suppressed in the EC-free electrolyte, highlighting the incompatibility between Ni-rich cathodes and conventional electrolyte solvents. Finally, new mechanistic insights into the chemical oxidation pathways of electrolyte solvents and, critically, the knock-on chemical and electrochemical reactions that further degrade the electrolyte and electrodes curtailing battery lifetime are provided

Telaglenastat plus everolimus decreases ECAR and OCR in RCC cell lines.

Cells were treated with 1 μM telaglenastat and 100 nM everolimus for 24 hours prior to measurement. Determination of extracellular acidification rate and oxygen consumption rate using the Seahorse Metabolic Analyzer. Statistical significance was determined using RM 1-way ANOVA with Dunnett’s test for multiple comparisons: *P P P P (PDF)</p

Synergistic anti-proliferative activity of telaglenastat and everolimus in TUHR10TKB cells.

Viability of TUHR10TKB cells treated with telaglenastat, everolimus, or a combination of both inhibitors for 72 hours. All experiments performed in triplicate or quadruplicate. Error bars represent standard deviations. (PDF)</p

Telaglenastat inhibits the mTORC1 pathway in RCC cells.

(A) Western blot of phospho-S6, total S6, phospho-4E-BP1 and total 4E-BP1 in RCC cell lines after 24 hours of telaglenastat treatment (1 μM) or DMSO control. (B) Relative phospho-S6 and phospho-4E-BP1 levels normalized to total S6 and 4E-BP1, respectively, quantified by densitometry. Representative blots of at least two independent experiments are shown.</p

S1 Raw images -

(PDF)</p

Expression of GLS in tumor vs. normal kidney.

mRNA levels were obtained from Compendia Bioscience™ Translational Bioinformatics Services (Life Technologies, Ann Arbor, MI). mRNA expression levels are plotted as the log2 RNA normalized values. Whiskers span the 5th to 95th percentile with data outside this range shown as individual data points. Statistics were performed using Mann-Whitney t test to generate P values: *P ≤ 0.05, **** P ≤ 0.0001, ns (not significant). (PDF)</p

Dose response curves to telaglenastat treatment in pRCC, rhabdoid, and transitional kidney cancer cell lines.

The dashed line indicates the relative CellTiter-Glo signal at the time of telaglenastat addition. EC50 values and histology for each line are noted. (PDF)</p