The Lithium Storage Mechanism of Zero-Strain Anode Materials with Ultralong Cycle Lives.

At present, graphite is a widely used anode material in commercial lithium-ion batteries for its low cost, but the large volume expansion (about 10%) after fully lithiated makes the material prone to cracking and even surface stripping in the cycle. Therefore, the development of zero-strain anode materials (volume change <1%) is of great significance. LiAl5O8 is a zero-strain insertion anode material with a high theoretical specific capacity. However, the Li+ storage mechanism remains unclear, and the cycle life as well as fast-charging capability need to be greatly improved to meet the practical requirements. In this study, LiAl5O8 nanorods are prepared by utilizing aluminum ethoxide nanowires as a soft template and doped with the Zr element to further improve the Li+ diffusion coefficient and electronic conductivity, which in turn improves cycle and rate performances. The Zr-doped LiAl5O8 presents a high reversible capacity of 227.2 mAh g-1 after 20,000 cycles under 5 A g-1, which significantly outperforms the state-of-the-art anode materials. In addition, the Li+ storage mechanisms of LiAl5O8 and Zr-doped LiAl5O8 are clearly clarified with a variety of characterization techniques including nuclear magnetic resonance. This work greatly promotes the practical process of zero-strain insertion anode materials.

The Interaction in Electrolyte Additives Accelerates Ion Transport to Achieve High-Energy Non-Aqueous Lithium Metal Batteries.

Electrolyte engineering is a feasible strategy to realize high energy density lithium metal batteries. However, stabilizing both lithium metal anodes and nickel-rich layered cathodes is extremely challenging. To break through this bottleneck, a dual-additives electrolyte containing fluoroethylene carbonate (10 vol.%) and 1-methoxy-2-propylamine (1 vol.%) in conventional LiPF6 -containing carbonate-based electrolyte is reported. The two additives can polymerize and thus generate dense and uniform LiF and Li3 N-containing interphases on both electrodes' surfaces. Such robust ionic conductive interphases not only prevent lithium dendrite formation in lithium metal anode but also suppress stress-corrosion cracking and phase transformation in nickel-rich layered cathode. The advanced electrolyte enables Li||LiNi0.8 Co0.1 Mn0.1 O2 stably cycle for 80 cycles at 60 mA g-1 with a specific discharge capacity retention of 91.2% under harsh conditions.

Zero-Strain Insertion Anode Material of Lithium-Ion Batteries.

The insertion type materials are the most important anode materials for lithium-ion batteries, but their insufficient capacity is the bottleneck of practical application. Here, LiAl5 O8 nanowires with high theoretical capacity and Li-ions diffusion coefficient are prepared and studied as an insertion anode material, which exhibits zero-strain properties upon electrochemical cycling. However, the poor electronic conductivity of LiAl5 O8 definitely sacrifices the capacity and limits the rate performance. Therefore, compact LiAl5 O8 and carbon composite are further synthesized, in which nanosized LiAl5 O8 particles are uniformly embedded in an amorphous carbon matrix. It displays a reversible capacity of 490.9 mAh g-1 at 1 A g-1 , and the capacity rises continuously to 996.8 mAh g-1 after 1000 cycles due to the interfacial storage mechanism, that the excess Li+ ions can be accommodated in the grain boundaries and C/LiAl5 O8 interfaces.

Novel 11ß-substituted estradiol conjugates: Transition from ERα agonizts to effective PROTAC degraders.

Endocrine therapy is widely used in clinic for breast cancer treatment, but long-term treatment inevitably causes drug resistance. Most of endocrine therapy-resistant breast cancers continue to depend on ERα signaling for growth and survival. In this regard, small molecule-induced ERα degradation, i.e. proteolysis targeting chimeras (PROTACs), represents an effective strategy to overcome endocrine resistance. Herein, we describe the design, synthesis, and biological evaluation of novel ERα-targeting PROTACs, wherein a E3 ligase ligand was attached to the 11ß-position of estradiol via various linkers. Our efforts have identified a potent ERα PROTAC 15b that achieved excellent ERα degradation activity (DC50 = 67 nM) and induced comparable inhibition of cell growth to that of fulvestrant in MCF-7 cells. Besides, 15b displayed antagonistic effects in uterine cells and favorable physicochemical properties, making it as a good lead compound for further development as anti-breast agents.

Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo.

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (21c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC50 = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c. Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.

Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator.

Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity.

Discovery of potent and highly selective covalent inhibitors of Bruton's tyrosine kinase bearing triazine scaffold.

Bruton's tyrosine kinase (BTK), as a key regulator of the B cell receptor (BCR) signaling pathway, is an attractive therapeutic target for the treatment of various diseases such as leukemia and B-cell malignancies. Herein, a series of compounds bearing 1, 3, 5-triazine core were prepared, and their biological activities on BTK were determined. Then the molecular docking study and ADME property prediction were made and a highly potent selective BTK inhibitor B8 (IC50 = 21.0 nM) was discovered. Compound B8 exhibited excellent activity with 5.14 nM inhibition of Raji cells and 6.14 nM inhibition of Ramos cells respectively. Additionally, B8 potently inhibited BTK kinase Y223 auto-phosphorylation, arrested cell cycle in G2/M phase and induced apoptosis in Ramos cells. The high selectivity for BTK and high potency in TMD8 cells of B8 suggested a low risk of off-target related adverse effects. Further molecular docking and dynamic simulation on B8 furnished insights into its binding profile within BTK. With significant efficacy in cellular assays and good ADME and safety profiles, B8 can be identified as a promising BTK inhibitor worthy of further profiling.

Efficient All-2D Amorphous Cobalt Sulfide Nanosheets/Multilayered Molybdenum Disulfide Hybrid Heterojunction Catalyst for Electrochemical Hydrogen Evolution.

Hydrogen energy is considered to be a critical environmentally friendly and widely sourced renewable energy source that can be used as an alternative to fossil fuels. At present, the preparation of hydrogen (H2) mainly depends on traditional fossil fuels. In order to achieve sustainable development of environmental protection, great attention has been paid to the preparation of H2 by electrocatalysis, photocatalysis, and photoelectrochemistry. Here, it is reported for the first time that a novel active catalyst for the hydrogen evolution reaction, consisting of all-2D amorphous nanosheets/2D crystal layer heterojunction structure and without any noble metal (no precious metals are present in the preparation or measuring), is almost entirely fabricated by laser ablation in liquid (LAL) growth of amorphous cobalt sulfide on the surface of multilayered molybdenum disulfide. In acidic media, the amorphous cobalt sulfide nanosheets/multilayered molybdenum disulfide (a-CoS/MoS2) catalyst exhibits fast hydrogen evolution kinetics with onset potential of -147 mV and a Tafel slope of 126 mV per decade, which is much better than only the amorphous cobalt sulfide and molybdenum disulfide layer. The high hydrogen evolution activity of the amorphous cobalt sulfide nanosheets/multilayered molybdenum disulfide hybrid is likely due to the unique electrocatalytic synergistic effects between hydrogen evolution-active amorphous cobalt sulfide nanosheets and layered crystal molybdenum disulfide materials, as well as the much-increased catalytic sites. This work provides a new general route based on all-2D amorphous nanosheets/2D crystal structure for designing and preparing novel layered materials with effectively manipulated catalytic properties and active functionality surface.

High temperature stable W/O emulsions prepared with in-situ hydrophobically modified rodlike sepiolite.

HYPOTHESIS: Hydrophobic modification can influence interparticle interaction, their interfacial adsorption, and stability of particle-stabilized emulsions. Emulsions stabilized by rodlike particles are more stable than those prepared with spherical particles even at low concentrations. Moreover, interfacial adsorption of particles will be tuned by controlling the modification. Thus, it is possible to prepare stable W/O emulsions with in-situ modified rodlike particles. EXPERIMENTS: Rodlike sepiolite particles were in-situ modified in oil using dimethyldioctadecylammonium chloride (DODMAC). High salinity solution (water) in paraffin oil (W/O) emulsion was prepared with the modified particles. Stability of emulsions at room temperature and after aging at 160°C for 24h was studied. Mechanism of emulsion stability was explored by rheological measurements and confocal fluorescent microscopy. FINDINGS: Remarkable stability against coalescence was found at high temperature. The enhanced stability is due to the high viscosity of continuous phase. Moreover, modification of sepiolite particles at high DOMDAC concentrations enhances particle adsorption at water-oil interfaces and network in continuous phase, which improve the stability against sedimentation and coalescence of the W/O emulsions.

Nicotine enhances contextual fear memory reconsolidation in rats.

There is increasing evidence that nicotine is involved in learning and memory. However, there remains no study that has explored the relationship between nicotine and memory reconsolidation. At present study, we tested the effects of nicotine on the reconsolidation of contextual fear memory in rats. Behavior procedure involved four training phases: habituation (Day 0), fear conditioning (Day 1), reactivation (Day 2) and test (Day 3). Rats were injected saline or nicotine (0.25, 0.5 and 1.0mg/kg) immediately after reactivation. Percent of time spent freezing was used to measure conditioned fear response. Results showed that compared with saline rats, rats with nicotine at 1.0mg/kg presented a significant increase of freezing response on Day 3. Nicotine at 1.0mg/kg was ineffective when injected 6h after reactivation. Further results showed that the enhancement of freezing response induced by nicotine at 1.0mg/kg was dependent on fear memory reconsolidation, and was not attributed to an enhancement of the nonspecific freezing response 24h after nicotine administration. The results suggest that nicotine administration immediately after reactivation enhances contextual fear memory reconsolidation. Our present finding extends previous research on the nicotinic effects on learning and memory.