Controlled Growth of Submillimeter-Scale Cr5Te8 Nanosheets and the Domain Wall Nucleation Governed Magnetization Reversal Process.

Two-dimensional (2D) ferromagnets have attracted widespread attention for promising applications in compact spintronic devices. However, the controlled synthesis of high-quality, large-sized, and ultrathin 2D magnets via facile, economical method remains challenging. Herein, we develop a hydrogen-tailored chemical vapor deposition approach to fabricating 2D Cr5Te8 ferromagnetic nanosheets. Interestingly, the time period of introducing hydrogen was found to be crucial for controlling the lateral size, and a Cr5Te8 single-crystalline nanosheet of lateral size up to ∼360 µm with single-unit-cell thickness has been obtained. These samples exhibit a leading role of domain wall nucleation in governing the magnetization reversal process, providing important references for optimizing the performances of associated devices. The nanosheets also show notable magnetotransport response, including nonmonotonous magnetic-field-dependent magnetoresistance and sizable anomalous Hall resistivity, demonstrating Cr5Te8 as a promising material for constructing high-performance magnetoelectronic devices. This study presents a breakthrough of large-sized CVD-grown 2D magnetic materials, which is indispensable for constructing 2D spintronic devices.

Size Dependent Phase Transformation of Liquid Gallium.

As the most popular liquid metal (LM), gallium (Ga) and its alloys are emerging as functional materials due to their unique combination of fluidic and metallic properties near room temperature. As an important branch of utilizing LMs, micro- and submicron-particles of Ga-based LM are widely employed in wearable electronics, catalysis, energy, and biomedicine. Meanwhile, the phase transition is crucial not only for the applications based on this reversible transformation process, but also for the solidification temperature at which fluid properties are lost. While Ga has several solid phases and exhibits unusual size-dependent phase behavior. This complex process makes the phase transition and undercooling of Ga uncontrollable, which considerably affects the application performance. In this work, extensive (nano-)calorimetry experiments are performed to investigate the polymorph selection mechanism during liquid Ga crystallization. It is surprisingly found that the crystallization temperature and crystallization pathway to either α -Ga or ß -Ga can be effectively engineered by thermal treatment and droplet size. The polymorph selection process is suggested to be highly relevant to the capability of forming covalent bonds in the equilibrium supercooled liquid. The observation of two different crystallization pathways depending on the annealing temperature may indicate that there exist two different liquid phases in Ga.

Application of molecular dynamics-based pharmacophore and machine learning approaches to identify novel Mcl1 inhibitors through drug repurposing and mechanics research.

Myeloid cell leukemia 1 (Mcl1), a critical protein that regulates apoptosis, has been considered as a promising target for antitumor drugs. The conventional pharmacophore screening approach has limitations in conformation sampling and data mining. Here, we offered an innovative solution to identify Mcl1 inhibitors with molecular dynamics-refined pharmacophore and machine learning methods. Considering the safety and druggability of FDA-approved drugs, virtual screening of the database was performed to discover Mcl1 inhibitors, and the hit was subsequently validated via TR-FRET, cytotoxicity, and flow cytometry assays. To reveal the binding characteristics shared by the hit and a typical Mcl1 selective inhibitor, we employed quantum mechanics and molecular mechanics (QM/MM) calculations, umbrella sampling, and metadynamics in this work. The combined studies suggested that fluvastatin had promising cell inhibitory potency and was suitable for further investigation. We believe that this research will shed light on the discovery of novel Mcl1 inhibitors that can be used as a supplemental treatment against leukemia and provide a possible method to improve the accuracy of drug repurposing with limited computational resources while balancing the costs of experimentation well.

Uncovering the selectivity mechanism of phosphodiesterase 7A/8A inhibitors through computational studies.

The expression of phosphodiesterase 7A (PDE7A) and phosphodiesterase 8A (PDE8) genes is integral to human signaling pathways, and the inhibition of PDE7A has been associated with the onset of various diseases, including effects on the immune system and nervous system. The development of PDE7 selective inhibitors can promote research on immune and nervous system diseases, such as multiple sclerosis, chronic inflammation, and autoimmune responses. PDE8A is expressed alongside PDE8B, and its inhibitory mechanism is still unclear. Studying the mechanisms of selective inhibitors against different PDE subtypes is crucial to prevent potential side effects, such as nausea and cardiac toxicity, and the sequence similarity of the two protein subtypes was 55.9%. Therefore, it is necessary to investigate the differences of both subtypes' ligand binding sites. Selective inhibitors of two proteins were chosen to summarize the reason for their selectivity through molecular docking, molecular dynamics simulation, alanine scanning mutagenesis, and MM-GBSA calculation. We found that Phe384PDE7A, Leu401PDE7A, Gln413PDE7A, Tyr419PDE7A, and Phe416PDE7A in the active site positively contribute to the selectivity towards PDE7A. Additionally, Asn729PDE8A, Phe767PDE8A, Gln778PDE8A, and Phe781PDE8A positively contribute to the selectivity towards PDE8A.

Bioisosteric replacement strategy leads to novel DNA gyrase B inhibitors with improved potencies and properties.

The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.

Discovery of novel CDK9 inhibitor with tridentate ligand: Design, synthesis and biological evaluation.

Cyclin-dependent kinase 9 (CDK9) plays a role in transcriptional regulation, which had become an attractive target for discovery of antitumor agent. In this work, beyond traditional CDK9 inhibitor with bidentate ligands in ATP binding domain, a series of novel CDK9 inhibitor with tridentate ligand were designed and synthesized. Surprisingly, this unique tridentate ligand structure endows better CDK9 inhibition selectivity compared to other CDK subtypes, and the lead candidate compound Z4-7a showed effective proliferation inhibition in HCT116 cells with acceptable pharmacokinetic properties. Research on the mechanism indicated that Z4-7a could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression. In brief, introduction of tridentate ligand might work as a promising strategy for the development of novel selective CDK9 inhibitor.

Potential oral VEGFR2 inhibitors: Treatment of wet age-related macular degeneration.

Wet age-related macular degeneration (w-AMD) is one of the leading causes of vision loss in industrialized countries. A large body of evidence suggests that inhibitors targeting VEGFR2 may be effective in the treatment of w-AMD. The identification of an oral VEGFR2 inhibitor for the treatment of w-AMD provides an opportunity for a route of administration other than intravitreal injection. While screening potent VEGFR2 inhibitors at the enzyme and cellular levels, ensuring the safety of the compounds was our primary strategy for screening optimal compounds. Finally, compound 16 was identified, exhibiting enhanced inhibition of VEGFR2 enzyme and proliferation of BaF3-TEL-VEGFR2 cells compared to Vorolanib. Compound 16 had a weak inhibitory effect on human Ether-a-go-go-related gene (hERG) channel currents, showing a cardiac safety profile similar to Vorolanib. Compound 16 showed no significant toxicity to human liver cell LX-2, indicating a liver safety profile similar to Vorolanib. The water solubility of compound 16 was found to be higher than that of Vorolanib when tested at pH = 7.4. In addition, compound 16 was found to inhibit VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner by WB assay. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 16 showed remarkable plasma stability and moderate liver microsomal stability. Based on in vivo pharmacokinetic studies in ICR mice, compound 16 exhibited acceptable oral bioavailability (F = 20.2 %). Overall, these findings provide evidence that compound 16 is a leading potential oral drug candidate for w-AMD.

Design and synthesis of hemicyanine-based NIRF probe for detecting Aß aggregates in Alzheimer's disease.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, has garnered increased attention due to its substantial economic burden and the escalating global aging phenomenon. Amyloid-ß deposition is a key pathogenic marker observed in the brains of Alzheimer's sufferers. Based on real-time, safe, low-cost, and commonly used, near-infrared fluorescence (NIRF) imaging technology have become an essential technique for the detection of AD in recent years. In this work, NIRF probes with hemicyanine structure were designed, synthesized and evaluated for imaging Aß aggregates in the brain. We use the hemicyanine structure as the parent nucleus to enhance the probe's optical properties. The introduction of PEG chain is to improve the probe's brain dynamice properties, and the alkyl chain on the N atom is to enhance the fluorescence intensity of the probe after binding to the Aß aggregates as much as possible. Among these probes, Z2, Z3, Z6, X3, X6 and T1 showed excellent optical properties and high affinity to Aß aggregates (Kd = 24.31 âˆ¼ 59.60 nM). In vitro brain section staining and in vivo NIRF imaging demonstrated that X6 exhibited superior discrimination between Tg mice and WT mice, and X6 has the best brain clearance rate. As a result, X6 was identified as the optimal probe. Furthermore, the docking theory calculation results aided in describing X6's binding behavior with Aß aggregates. As a high-affinity, high-selectivity, safe and effective probe of targeting Aß aggregates, X6 is a promising NIRF probe for in vivo detection of Aß aggregates in the AD brain.

Flexible Sensors Based on Conductive Polymer Composites.

Elastic polymer-based conductive composites (EPCCs) are of great potential in the field of flexible sensors due to the advantages of designable functionality and thermal and chemical stability. As one of the popular choices for sensor electrodes and sensitive materials, considerable progress in EPCCs used in sensors has been made in recent years. In this review, we introduce the types and the conductive mechanisms of EPCCs. Furthermore, the recent advances in the application of EPCCs to sensors are also summarized. This review will provide guidance for the design and optimization of EPCCs and offer more possibilities for the development and application of flexible sensors.

Controlled Growth and Size-Dependent Magnetic Domain States of 2D γ-Fe2O3.

Nonlayered two-dimensional (2D) magnets have attracted special attention, as many of them possess magnetic order above room temperature and enhanced chemical stability compared to most existing vdW magnets, which offers remarkable opportunities for developing compact spintronic devices. However, the growth of these materials is quite challenging due to the inherent three-dimensionally bonded nature, which hampers the study of their magnetism. Here, we demonstrate the controllable growth of air-stable pure γ-Fe2O3 nanoflakes by a confined-vdW epitaxial approach. The lateral size of the nanoflakes could be adjusted from hundreds of nanometers to tens of micrometers by precisely controlling the annealing time. Interestingly, a lateral-size-dependent magnetic domain configuration was observed. As the sizes continuously increase, the magnetic domain evolves from single domain to vortex and finally to multidomain. This work provides guidance for the controllable synthesis of 2D inverse spinel-type crystals and expands the range of magnetic vortex materials into magnetic semiconductors.

Enhanced Stress Stability in Flexible Co/Pt Multilayers with Strong Perpendicular Magnetic Anisotropy.

Due to the magnetoelastic coupling, the magnetic properties of many flexible magnetic films (such as Fe, Co, and Ni) are sensitive to mechanical stress, which deteriorates the performance of flexible magnetoelectronic devices. We show that by stacking Co and Pt alternatively to form multilayers with strong perpendicular magnetic anisotropy (PMA), both magnetic hysteresis and magnetic domain measurements reveal robust PMA against external stress. As the PMA weakens at increased Co thickness, the magnetic anisotropy is vulnerable to external stress. These results were understood based on a micromagnetic model, which suggests that the strength of magnetoelastic anisotropy with respect to initial effective magnetic anisotropy affects the stress-stability of the film. Although the stress coefficient of magnetoelastic anisotropy is enhanced at reduced Co thickness, the concomitant increase of initial effective magnetic anisotropy guarantees a robust PMA against external stress. Our results provide a route to constructing flexible magnetoelectronic devices with enhanced stress stability.

Synthesis and Antitumor Activity Evaluation of Novel Echinatin Derivatives with a 1,3,4-Oxadiazole Moiety.

A series of novel echinatin derivatives with 1,3,4-oxadiazole moieties were designed and synthesized. Most of the newly synthesized compounds exhibited moderate antiproliferative activity against the four cancer cell lines. Notably, Compound T4 demonstrated the most potent activity, with IC50 values ranging from 1.71 µM to 8.60 µM against the four cancer cell lines. Cell colony formation and wound healing assays demonstrated that T4 significantly inhibited cell proliferation and inhibited migration. We discovered that T4 exhibited moderate binding affinity with the c-KIT protein through reverse docking. The results were effectively validated through subsequent molecular docking and c-KIT enzyme activity assays. In addition, Western blot analysis revealed that T4 inhibits the phosphorylation of downstream proteins of c-KIT. The results provide valuable inspiration for exploring novel insights into the design of echinatin-related hybrids as well as their potential application as c-KIT inhibitors to enhance the efficacy of candidates.

Selective Dual-Ion Modulation in Solid-State Magnetoelectric Heterojunctions for In-Memory Encryption.

Nanoionic technologies are identified as a promising approach to modulating the physical properties of solid-state dielectrics, which have resulted in various emergent nanodevices, such as nanoionic resistive switching devices and magnetoionic devices for memory and computing applications. Previous studies are limited to single-type ion manipulation, and the investigation of multiple-type ion modulation on the coupled magnetoelectric effects, for developing information devices with multiple integrated functionalities, remains elusive. Here, a dual-ion solid-state magnetoelectric heterojunction based on Pt/HfO2- x /NiOy /Ni with reconfigurable magnetoresistance (MR) characteristics is reported for in-memory encryption. It is shown that the oxygen anions and nickel cations can be selectively driven by voltages with controlled polarity and intensity, which concurrently change the overall electrical resistance and the interfacial magnetic coupling, thus significantly modulate the MR symmetry. Based on this device, a magnetoelectric memory prototype array with in-memory encryption functionality is designed for the secure storage of image and digit information. Along with the advantages including simple structure, multistate encryption, good reversibility, and nonvolatile modulation capability, this proof-of-concept device opens new avenues toward next-generation compact electronics with integrated information functionalities.

Design, synthesis, and evaluation of N-methyl-propargylamine derivates as isoform-selective monoamine oxidases inhibitors for the treatment of nervous system diseases.

A novel series of N-methyl-propargylamine derivates were designed, synthesized, and evaluated as isoform-selective monoamine oxidases (MAO) inhibitors for the treatment of nervous system diseases. The in vitro studies showed some of the compounds exhibited considerable MAO-A selective inhibitory activity (IC50 of 14.86-17.16 nM), while some of the others exhibited great MAO-B selective inhibitory activity (IC50 of 4.37-17.00 nM). Further studies revealed that compounds A2 （IC50 against MAO-A: 17.16 ± 1.17 nM） and A5 (IC50 against MAO-B: 17.00 ± 1.10 nM) had significant abilities to protect PC12 cells from H2O2-induced apoptosis and reactive oxygen species (ROS) production. The parallel artificial membrane permeability assay showed A2 and A5 would be potent to cross the blood-brain barrier. The results indicated that A2 showed potential use in the therapy of MAO-A related diseases, such as depression and anxiety; while A5 exhibited promising ability in the treatment of MAO-B related diseases, such as Alzheimer's disease and Parkinson's disease.

Design, synthesis and evaluation of OA-tacrine hybrids as cholinesterase inhibitors with low neurotoxicity and hepatotoxicity against Alzheimer's disease.

A series of OA-tacrine hybrids with the alkylamine linker was designed, synthesized, and evaluated as effective cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some hybrids possessed significant inhibitory activities against acetylcholinesterase (AChE). Among them, compounds B4 (hAChE, IC50 = 14.37 ± 1.89 nM; SI > 695.89) and D4 (hAChE, IC50 = 0.18 ± 0.01 nM; SI = 3374.44) showed excellent inhibitory activities and selectivity for AChE as well as low nerve cell toxicity. Furthermore, compounds B4 and D4 exhibited lower hepatotoxicity than tacrine in cell viability, apoptosis, and intracellular ROS production for HepG2 cells. These properties of compounds B4 and D4 suggest that they deserve further investigation as promising agents for the prospective treatment of AD.

Flexible Magnetic Sensors.

With the merits of high sensitivity, high stability, high flexibility, low cost, and simple manufacturing, flexible magnetic field sensors have potential applications in various fields such as geomagnetosensitive E-Skins, magnetoelectric compass, and non-contact interactive platforms. Based on the principles of various magnetic field sensors, this paper introduces the research progress of flexible magnetic field sensors, including the preparation, performance, related applications, etc. In addition, the prospects of flexible magnetic field sensors and their challenges are presented.

Discovery of Robust Ferroelectricity in 2D Defective Semiconductor α-Ga2 Se3.

2D ferroelectrics with robust polar order in the atomic-scale thickness at room temperature are needed to miniaturize ferroelectric devices and tackle challenges imposed by traditional ferroelectrics. These materials usually have polar point group structure regarding as a prerequisite of ferroelectricity. Yet, to introduce polar structure into otherwise nonpolar 2D materials for producing ferroelectricity remains a challenge. Here, by combining first-principles calculations and experimental studies, it is reported that the native Ga vacancy-defects located in the asymmetrical sites in cubic defective semiconductor α-Ga2 Se3 can induce polar structure. Meanwhile, the induced polarization can be switched in a moderate energy barrier. The switched polarization is observed in 2D α-Ga2 Se3 nanoflakes of ≈4 nm with a high switching temperature up to 450 K. Such polarization switching could arise from the displacement of Ga vacancy between neighboring asymmetrical sites by applying an electric field. This work removes the point group limit for ferroelectricity, expanding the range of 2D ferroelectrics into the native defective semiconductors.

Design, synthesis and antitumor activity evaluation of novel indole acrylamide derivatives as IMPDH inhibitors.

Inosine 5'-monophosphate dehydrogenase (IMPDH; EC1.1.1.205) is the rate-limiting enzyme of GMP biosynthesis. The inhibition of IMPDH limits the growth and survival of tumors. Based on the systematic summary of clinical IMPDH inhibitors, 38 acrylamide derivatives with differently substituted indoles at the 3-position as the core scaffold were designed and synthesized. In addition, the actions of these compounds at the enzyme and cellular levels were evaluated. An MTT assay with different kinds of cells was used to assess the cytotoxic activities of compounds 14e and 14n, which displayed potent hIMPDH2 inhibitory activities (IC50 = 4.207 and 2.948 µM, respectively). Biological evaluation indicated that target compounds 14e and 14n displayed the most significant effects on SW480 human colon cancer cells (IC50 = 15.34 ± 0.06 and 15.31 ± 0.09 µM, respectively), and it was determined that these compounds are effective and valuable IMPDH inhibitors for cancer intervention.

Identification of Novel Artemisinin Hybrids Induce Apoptosis and Ferroptosis in MCF-7 Cells.

A series of novel 1,3,4-oxadiazole-artemisinin hybrids have been designed and synthesized. An MTT assay revealed that most of tested hybrids showed more enhanced anti-proliferative activities than artemisinin, among which A8 had the superior potency with IC50 values ranging from 4.07 µM to 9.71 µM against five tested cancer cell lines. Cell colony formation assays showed that A8 could inhibit significantly more cell proliferation than artemisinin and 5-fluorouracil. Further mechanism studies reveal that A8 induces apoptosis and ferroptosis in MCF-7 cells in a dose-dependent manner, and CYPs inhibition assays reveal that A8 has a moderate inhibitory effect on CYP1A2 and CYP3A4 in the human body at 10 µM. The present work indicates that hybrid A8 may merit further investigation as a potential therapeutic agent.

Synthesis, Molecular Docking Analysis, and Biological Evaluations of Saccharide-Modified Sulfonamides as Carbonic Anhydrase IX Inhibitors.

Based on the strategy of the "tail approach", 15 novel saccharide-modified sulfonamides were designed and synthesised. The novel compounds were evaluated as inhibitors of three human carbonic anhydrase (CA) isoforms, namely cytoplasmic CA II, transmembrane CA IX, and XII. Most of these compounds showed good activity against CAs and high topological polar surface area (TPSA) values, which had a positive effect on the selective inhibition of transmembrane isoforms CA IX and XII. In the in vitro activity studies, compounds 16a, 16b, and 16e reduced the viability of HT-29 and MDA-MB-231 cells with a high expression of CA IX under hypoxia. The inhibitory activity of compound 16e on the human osteosarcoma cell line MG-63 with a high expression of CA IX and XII was better than that of AZM. Moreover, high concentrations of compounds 16a and 16b reversed the acidification of the tumour microenvironment. In addition, compound 16a had a certain inhibitory effect on the migration of MDA-MB-231 cells. All the above results indicate that the saccharide-modified sulfonamide has further research value for the development of CA IX inhibitors.