Nanoscale Visualization of Symmetry-Breaking Electronic Orders and Magnetic Anisotropy in a Kagome Magnet YMn6Sn6.

A kagome lattice hosts a plethora of quantum states arising from the interplay between nontrivial topology and electron correlations. The recently discovered kagome magnet RMn6Sn6 (R represents a rare-earth element) is believed to showcase a kagome band closely resembling textbook characteristics. Here, we report the characterization of local electronic states and their magnetization response in YMn6Sn6 via scanning tunneling microscopy measurements under vector magnetic fields. Our spectroscopic maps reveal a spontaneously trimerized kagome electronic order in YMn6Sn6, where the 6-fold rotational symmetry is disrupted while translational symmetry is maintained. Further application of an external magnetic field demonstrates a strong coupling of the YMn6Sn6 kagome band to the field, which exhibits an energy shift discrepancy under different field directions, implying the existence of magnetization-response anisotropy and anomalous g factors. Our findings establish YMn6Sn6 as an ideal platform for investigating kagome-derived orbital magnetic moment and correlated magnetic topological states.

Three-dimensional analysis of mandibular characteristics in patients with skeletal Class II malocclusion and chin deviation.

INTRODUCTION: This study aimed to analyze adults with mandibular characteristics of skeletal Class II malocclusion with chin deviation. METHODS: Seventy-five adult patients aged from 18 to 35 years were included and divided into 3 groups on the basis of sagittal skeletal pattern and chin deviation: skeletal Class I symmetry group, skeletal Class II symmetry group, and skeletal Class II asymmetry group (25 patients per group). Mandibular measurements on cone-beam computed tomography images were performed, and the differences between 2 sides in each group and the differences among the 3 groups were investigated. RESULTS: Compared with the contralateral side, the deviated side of patients in the Class II asymmetry group showed significantly smaller condyle angle to midsagittal plane, condylar height, ramal length, and length of the mandibular body, whereas it showed a significantly larger distance from condylion to the midsagittal plane, ramus angle to the horizontal plane, and distance from gonion to the midsagittal plane. Most linear measurements in the Class II symmetry group were significantly smaller than those in the Class I symmetry group. These linear measurements on the contralateral side of the Class II asymmetry group showed no significant difference with the Class I symmetry group, and these measurements on the deviated side of the Class II asymmetry group showed no significant difference with the Class II symmetry group. CONCLUSIONS: Length of the mandible, rotation of condyle, the inclination of the ramus, and position of gonion should be considered in subjects with skeletal Class II asymmetry when making diagnosis and treatment planning.

Quaternary Ammonium Salt-Functionalized Tetraphenylethene Derivative Boosts Electrochemiluminescence for Highly Sensitive Aqueous-Phase Biosensing.

Aggregation induced emission active compounds (AIEgens) have appeared as a new kind of electrochemiluminescence (ECL) emitters due to their bright emission in the aggregated state but lack functional groups. Herein, we report a quaternary ammonium salt groups-functionalized AIEgen (QAU-1) and discover that coating QAU-1 on the indium tin oxide (ITO) surface (QAU/ITO) enabled QAU-1 to display significant cathodic ECL emission compared with that of QAU-1 in the dissolved state. Inspired by this, we applied QAU-1 as emitters to develop a novel ECL biosensor (Fc-DNA/QAU/ITO) through electrostatic attraction between QAU/ITO and a ferrocene-labeled ssDNA (Fc-DNA), and the developed biosensor was employed to detect bleomycin (BLM) with high sensitivity based on the target-initiated specific cleavage and subsequent removal of Fc molecules from the electrode. We envision this work will open up a new avenue to development of high-performance ECL biosensors, which will display a significant potential application in the field of analysis.

One-Step Synthesis of Methylene Blue-Encapsulated Zeolitic Imidazolate Framework for Dual-Signal Fluorescent and Homogeneous Electrochemical Biosensing.

In vitro diagnosis requires target biomarkers to be reliably detected at an ultralow level. A dual-signal strategy permits self-calibration to overcome the interferences of experimental and environmental factors, and thus is regarded as a promising approach. However, currently reported works mainly concentrated on the same forms of energy of output signals. Herein, we propose a one-step strategy for synthesis of methylene blue-encapsulated zeolitic imidazolate framework-90 (MB@ZIF-90) with high loading, unique dual-signal property, exceptional recognition capability, and good stability, and we further pioneer MB@ZIF-90 as a dual-signal biosensor for label-free, enzyme-free, and ultrasensitive detection of adenosine triphosphate (ATP) by integration of fluorescence and homogeneous electrochemical techniques. The recognition of MB@ZIF-90 by target ATP spurs the decomposition of ZIF-90, subsequently permitting MB to be released into a supernatant. As compared to the case where ATP does not exist, obviously increased intensities in fluorescence and differential pulse voltammetry current are observed and both signals are directly proportional to ATP concentrations. Thus, the MB@ZIF-90-based biosensor achieved dual-signal detection of ATP in an ultrasensitive manner and displayed a more reliable diagnosis result than previously reported ATP biosensors. This dual-signal strategy provides a new opportunity to develop high-performance biosensors for in vitro diagnosis and demonstrates great potential for future applications in bioinformatics and clinical medicine.

Electropolymerization-Induced Positively Charged Phenothiazine Polymer Photoelectrode for Highly Sensitive Photoelectrochemical Biosensing.

Exploring the fabrication of an electrode with high photoelectric conversion efficiency and abundant functional groups for ideal photoelectrochemical (PEC) sensor development is highly urgent but faces a significant challenge. Herein we report an electropolymerization strategy for the preparation of phenothiazine polymeric film on an indium tin oxide (ITO) surface (PPT/ITO), within only a few seconds, and monomers. The fabricated PPT/ITO electrode possessed excellent stability and abundant quaternary ammonium salt groups for developing a highly sensitive PEC sensor through electrostatic binding with negatively charged materials. In this context, a CdS QDs-functionalized PPT/ITO electrode (CdS/PPT/ITO) was proposed and applied to the analysis of chlorpyrifos, used as a model target organophosphorous pesticide (OP). The thiocholine generated from acetylcholinesterase (AChE)-induced catalyzed hydrolysis of acetylthiocholine (ATCh) efficiently directed CdS QDs away from PPT/ITO via electrostatic repulsion, subsequently decreasing PEC current, whereas chlorpyrifos prohibited the generation of thiocholine through inhibiting AChE activity. As compared to the case where chlorpyrifos is absent, significantly enhanced PEC current is determined and is proportional to chlorpyrifos amounts. Thus, the developed CdS/PPT/ITO-based PEC sensor achieved excellent chlorpyrifos biosensing with improved sensitivity down to approximately ng/mL level with good specificity. We envision the proposed strategy will provide a new path to conveniently fabricate photoelectrodes possessing high performance, which will have more useful applications in PEC sensing.

Regio- and Diastereoselective Synthesis of Cyclohexadienylborons via an Intermolecular Diels-Alder Reaction of Alkenyl MIDA Boronates with 2-Pyrones.

An efficient synthesis of highly functionalized cyclohexadienylborons via an inverse electron-demand Diels-Alder reaction/CO2 extrusion of alkenyl MIDA boronates with 2-pyrones is outlined. By controlling the reaction temperature, the corresponding C(sp3 )-rich bicyclolactones could also be readily formed. The exo-selective reactions feature good functional-group tolerance, broad substrate scope, and excellent regio- and diastereoselectivity. Oxidation of the cyclohexadienylborons in a one-pot procedure led to the construction of aromatic boronates bearing valuable functional groups. Synthetic transformations of the C-B bond were demonstrated.

Diversity-Oriented Synthesis of α-Functionalized Acylborons and Borylated Heteroarenes by Nucleophilic Ring Opening of α-Chloroepoxyboronates.

The ring-opening reactions of N-methyliminodiacetyl (MIDA) α-chloroepoxyboronates with different nucleophiles allow the modular synthesis of a diverse array of organoboronates. These include seven types of α-functionalized acylboronates and seven types of borylated heteroarenes, some of which are difficult-to-access products using alternative methods. The common synthons, α-chloroepoxyboronates, could be viably synthesized by a two-step procedure from the corresponding alkenyl MIDA boronates. Mild reaction conditions, good functional-group tolerance, and generally good efficiency were observed. The utility of the products was also demonstrated.

gem-Difluorination of Alkenyl N-methyliminodiacetyl Boronates: Synthesis of α- and ß-Difluorinated Alkylborons.

Organofluorine compounds are widely used in pharmaceutical, agrochemical, and materials sciences. The syntheses and applications of fluorinated organoborons facilitate the rapid and modular assemblies of fluorine-containing molecules because of the versatility of C-B bonds in diverse chemical transformations. Reported herein is a migratory geminal difluorination of aryl-substituted alkenyl N-methyliminodiacetyl (MIDA) boronates using commercially available Py⋅HF as the fluorine source and hyperiodine as the oxidant. The protocol offers facile access to α- and ß-difluorinated alkylboron compounds, both of which have previously been challenging to prepare. Mild reaction conditions, broad substrate scope, good functional-group tolerance, and moderate to good yields were observed. The utility of these products is demonstrated by further transformations of the C-B bond into other valuable functional groups.

PARP-1 serves as a novel molecular marker for hepatocellular carcinoma in a Southern Chinese Zhuang population.

PARP-1 (poly(ADP-ribose) polymerase-1) plays an important role in tumorigenesis. Since its effects on different populations are varied, this study investigated the impact of PARP-1 on primary hepatocellular carcinoma in a Southern Chinese Zhuang population. We assessed the global PARP-1 messenger RNA expression in patients with hepatocellular carcinoma using The Cancer Genome Atlas dataset. Increased PARP-1 expression, related to alpha-fetoprotein level, was observed. The area under the receiver operating characteristic curve value was 0.833. Kaplan-Meier survival curves indicated that higher PARP-1 expression was not correlated with poorer overall survival and recurrence-free survival. In a Zhuang population, PARP-1 messenger RNA and protein levels were increased in the hepatocellular carcinoma tissue and its adjacent liver tissues as assessed by quantitative polymerase chain reaction, immunohistochemistry, and western blotting. Higher PARP-1 level was associated with a higher tumor stage (p < 0.05), without correlation with age, gender, smoking, drinking, tumor size, serum alpha-fetoprotein level, hepatitis B virus infection, metastasis, and invasion (p > 0.05). Further analysis suggested that H2AX, a PARP-1 protein interaction partner, was coordinated with PARP-1 in hepatocellular carcinoma tumorigenesis. Overall, some new characteristics of PARP-1 expression were noted in the Zhuang population. PARP-1 is a novel promising diagnostic marker for hepatocellular carcinoma in the Southern Chinese Zhuang population.

Stereoselective Direct Chlorination of Alkenyl MIDA Boronates: Divergent Synthesis of E and Z α-Chloroalkenyl Boronates.

The individual molecules of α-chloroalkenyl boronates include both an electrophilic C-Cl bond and a nucleophilic C-B bond, which makes them intriguing organic synthons. Reported herein is a stereodivergent synthesis of both E and Z α-chloroalkenyl N-methyliminodiacetyl (MIDA) boronates through the direct chlorination of alkenyl MIDA boronates using tBuOCl and PhSeCl reagents, respectively. Both reaction processes are stereospecific and the use of sp3 -B MIDA boronate is the key contributor to the reactivity. The synthetic value of the boronate products was also demonstrated.

Oxidative Difunctionalization of Alkenyl MIDA Boronates: A Versatile Platform for Halogenated and Trifluoromethylated α-Boryl Ketones.

The synthesis of halogenated and trifluoromethylated α-boryl ketones via a one-pot oxidative difunctionalization of alkenyl MIDA boronates is reported. These novel densely functionalized organoborons bearing synthetically and functionally valuable carbonyl, halogen/CF3 and boronate moieties within the same molecule are synthetically challenging for the chemist, but have great synthetic potential, as demonstrated by their applications in a straightforward synthesis of borylated furans. The generality of this reaction was extensively investigated. This reaction is attractive since the starting materials, alkenyl MIDA boronates, are easily accessible.

Serum quantitative proteomic analysis reveals potential zinc-associated biomarkers for nonbacterial prostatitis.

BACKGROUND: Prostatitis is one of the most common urological problems afflicting adult men. The etiology and pathogenesis of nonbacterial prostatitis, which accounts for 90-95% of cases, is largely unknown. As serum proteins often indicate the overall pathologic status of patients, we hypothesized that protein biomarkers of prostatitis might be identified by comparing the serum proteomes of patients with and without nonbacterial prostatitis. METHODS: All untreated samples were collected from subjects attending the Fangchenggang Area Male Health and Examination Survey (FAMHES). We profiled pooled serum samples from four carefully selected groups of patients (n = 10/group) representing the various categories of nonbacterial prostatitis (IIIa, IIIb, and IV) and matched healthy controls using a mass spectrometry-based 4-plex iTRAQ proteomic approach. More than 160 samples were validated by ELISA. RESULTS: Overall, 69 proteins were identified. Among them, 42, 52, and 37 proteins were identified with differential expression in Category IIIa, IIIb, and IV prostatitis, respectively. The 19 common proteins were related to immunity and defense, ion binding, transport, and proteolysis. Two zinc-binding proteins, superoxide dismutase 3 (SOD3), and carbonic anhydrase I (CA1), were significantly higher in all types of prostatitis than in the control. A receiver operating characteristic curve estimated sensitivities of 50.4 and 68.1% and specificities of 92.1 and 83.8% for CA1 and SOD3, respectively, in detecting nonbacterial prostatitis. The serum CA1 concentration was inversely correlated to the zinc concentration in expressed-prostatic secretions. CONCLUSIONS: Our findings suggest that SOD3 and CA1 are potential diagnostic markers of nonbacterial prostatitis, although further large-scale studies are required. The molecular profiles of nonbacterial prostatitis pathogenesis may lay a foundation for discovery of new therapies.

Regio- and stereoselective access to highly substituted vinylphosphine oxides via metal-free electrophilic phosphonoiodination of alkynes.

In general, the P-centered ring-opening of quaternary phosphirenium salts (QPrS) predominantly leads to hydrophosphorylated products, while the C-centered ring-opening is primarily confined to intramolecular nucleophilic reactions, resulting in the formation of phosphorus-containing cyclization products instead of difunctionalized products generated through intermolecular nucleophilic processes. Here, through the promotion of ring-opening of three-member rings by iodine anions and the quenching of electronegative carbon atoms by iodine cations, we successfully synthesize ß-functionalized vinylphosphine oxides by the P-addition of QPrS intermediates generated in situ. Multiple ß-iodo-substituted vinylphosphine oxides can be obtained with exceptional regio- and stereo-selectivity by reacting secondary phosphine oxides with unactivated alkynes. In addition, a variety of ß-functionalized vinylphosphine oxides converted from C-I bonds, especially the rapid construction of benzo[b]phospholes oxides, demonstrates the significance of this strategy.

Unfolding Protein-Based Hapten Coupling via Thiol-Maleimide Click Chemistry: Enhanced Immunogenicity in Anti-Nicotine Vaccines Based on a Novel Conjugation Method and MPL/QS-21 Adjuvants.

Vaccines typically work by eliciting an immune response against larger antigens like polysaccharides or proteins. Small molecules like nicotine, on their own, usually cannot elicit a strong immune response. To overcome this, anti-nicotine vaccines often conjugate nicotine molecules to a carrier protein by carbodiimide crosslinking chemistry to make them polymeric and more immunogenic. The reaction is sensitive to conditions such as pH, temperature, and the concentration of reactants. Scaling up the reaction from laboratory to industrial scales while maintaining consistency and yield can be challenging. Despite various approaches, no licensed anti-nicotine vaccine has been approved so far due to the susboptimal antibody titers. Here, we report a novel approach to conjugate maleimide-modified nicotine hapten with a disulfide bond-reduced carrier protein in an organic solvent. It has two advantages compared with other approaches: (1) The protein was unfolded to make the peptide conformation more flexible and expose more conjugation sites; (2) thiol-maleimide "click" chemistry was utilized to conjugate the disulfide bond-reduced protein and maleimide-modified nicotine due to its availability, fast kinetics, and bio-orthogonality. Various nicotine conjugate vaccines were prepared via this strategy, and their immunology effects were investigated by using MPL and QS-21 as adjuvants. The in vivo study in mice showed that the nicotine-BSA conjugate vaccines induced high anti-nicotine IgG antibody titers, compared with vaccines prepared by using traditional condensation methods, indicating the success of the current strategy for further anti-nicotine or other small-molecule vaccine studies. The enhancement was more significant by using MPL and QS-21 than that of traditional aluminum adjuvants.

Use of a pH-responsive imatinib mesylate sustained-release hydrogel for the treatment of tendon adhesion by inhibiting PDGFRß/CLDN1 pathway.

Adhesion after tendon injury, which can result in limb movement disorders, is a common clinical complication; however, effective treatment methods are lacking. Hyaluronic acid hydrogels are a new biomedical material used to prevent tendon adhesion owing to their good biocompatibility. In addition, potential drugs that inhibit adhesion formation have gradually been discovered. The anti-adhesion effects of a combination of loaded drugs into hydrogels have become an emerging trend. However, current drug delivery systems usually lack specific regulation of drug release, and the effectiveness of drugs for treating tendon adhesions is mostly flawed. In this study, we identified a new drug, imatinib mesylate (IM), that prevents tendon adhesion and explored its related molecular pathways. In addition, we designed a pH-responsive sustained-release hydrogel for delivery. Using the metal-organic framework ZIF-8 as a drug carrier, we achieved controlled drug release to increase the effective drug dose at the peak of adhesion formation to achieve better therapeutic effects. The results showed that IM blocked the formation of peritendon adhesions by inhibiting the PDGFRß/ERK/STAT3/CLDN1 pathway. Furthermore, the hydrogel with ZIF-8 exhibited better physical properties and drug release curves than the hydrogel loaded only with drugs, showing better prevention and treatment effects on tendon adhesion.

Electron-Assisted Generation and Straight Movement of Skyrmion Bubble in Kagome TbMn6Sn6.

Topological magnetic textures are promising candidates as binary data units for the next-generation memory device. The precise generation and convenient control of nontrivial spin topology at zero field near room temperature endows the critical advantages in skyrmionic devices but is not simultaneously integrated into one material. Here, in the Kagome plane of quantum TbMn6Sn6, the expedient generation of the skyrmion bubbles in versatile forms of lattice, chain, and isolated one by converging the electron beam, where the electron intensity gradient contributes to the dynamic generation from local anisotropy variation near spin reorientation transition (SRT) is reported. Encouragingly, by utilizing the dynamic shift of the SRT domain interface, the straight movement is actualized with the skyrmion bubble slave to the SRT domain interface forming an elastic composite object, avoiding the usual deflection from the skyrmion Hall effect. The critical contribution of the SRT domain interface via conveniently electron-assisted heating is further theoretically validated in micromagnetic simulation, highlighting the compatible application possibility in advanced devices.

BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression.

Interest in the use of proteolysis-targeting chimeras (PROTACs) in cancer therapy has increased in recent years. Targeting bromodomain and extra terminal domain (BET) proteins, especially bromodomain-containing protein 4 (BRD4), has shown inhibitory effects on basal-like breast cancer (BLBC). However, the bioavailability of BRD4 PROTACs is restricted by their non-selective biodegradability and low tumor-targeting ability. We demonstrated that 6b (BRD4 PROTAC) suppresses BLBC cell growth by targeting BRD4, but not BRD2 and BRD3, for cereblon (CRBN)-mediated ubiquitination and proteasomal degradation. Compound 6b also inhibited expression of Krüppel-like factor 5 (KLF5) transcription factor, a key oncoprotein in BLBC, controlled by BRD4-mediated super-enhancers. Moreover, 6b inhibited HCC1806 tumor growth in a xenograft mouse model. The combination of 6b and KLF5 inhibitors showed additive effects on BLBC. These results suggest that BRD4-specific PROTAC can effectively inhibit BLBC by downregulating KLF5, and that 6b has potential as a novel therapeutic drug for BLBC.

Iron ions-sequestrable and antioxidative carbon dot-based nano-formulation with nitric oxide release for Parkinson's disease treatment.

Nondestructive penetration of the blood-brain barrier (BBB) to specifically prevent iron deposition and the generation of reactive oxygen species (ROS) shows great potential for treating Parkinson's disease (PD). However, effective agents with distinct mechanisms of action remain scarce. Herein, a N-doping carbon dot (CD) emitting red light was prepared, which can sacrifice ROS and produce nitric oxide (NO) owing to its surface N-involved groups conjugated to the sp2-hybrided π-system. Meanwhile, CD can chelate iron ions, thus depressing the catalytic Fe cycle and *OH detaching to inhibit the Fenton reaction. By modifying lactoferrin (Lf) via polyethylene glycol (PEG), the resulting CD-PEG-Lf (CPL) can nondestructively cross the BBB, targeting the dopaminergic neurons via both NO-mediated reversible BBB opening and Lf receptor-mediated transportation. Accordingly, it can serve as an antioxidant, reducing oxidative stress via its unique iron chelation, free radical sacrificing, and synergy with iron reflux prevention originating from Lf. Thus, it can significantly reduce brain inflammation and improve the behavioral performance of PD mice. Additionally, CPL can image the PD via its red fluorescence. Finally, this platform can be metabolized out of the brain through cerebrospinal fluid circulation without causing obvious side effects, promising a robust treatment for PD.

In Situ Attached Photothermal Immunomodulation-Enhanced Nanozyme for the Inhibition of Postoperative Malignant Glioma Recurrence.

Glioblastoma (GBM) is one of the most challenging malignant brain tumors to treat. Herein, we describe a nanoenzyme hemostatic matrix strategy with the tumor cavity in situ application that simultaneously serves as photothermal agent and induces immunogenic cell death after GBM surgical resection to enhance the antitumor immunity and delay tumor recurrence. The hemostatic matrix system (Surgiflo@PCN) contains Surgiflo, a multispace structure that can be used to penetrate different shapes of tumor cavities to prevent postoperative tumor cavity hemorrhage. As well, porous palladium-copper nanoclusters (PCNs) have adjustable enzyme-like activities (oxidase, peroxidase, and catalase) responsible for formation of reactive oxygen species (ROS) under near-infrared (808 nm) laser irradiation. When the Surgiflo@PCN entered the resected tumor cavity, the first action was the direct killing of glioma cells via ROS and photothermal therapy (PTT). The second action was the induction of immunogenic cell death by PCN-enhanced oxidative stress and PTT, which reversed the immunosuppressive tumor microenvironment and enhanced the antitumor immune response. This eradicated residual glioma cells and prevented recurrence. The collective findings demonstrate that Surgiflo@PCN kills glioma cells directly through ROS and PTT and enhances antiglioma immunity and kills glioma cells indirectly. The "one-stone, two-birds" strategy could become an effective photothermal immunotherapy in GBM patients.

Diabetes immunity-modulated multifunctional hydrogel with cascade enzyme catalytic activity for bacterial wound treatment.

Diabetes immunity-modulated wound treatment in response to the varied microenvironments at different stages remains an urgent challenge. Herein, glucose oxidase (GOx) and quasi-amorphous Fe2O3 are co-incorporated into Zn-MOF nanoparticle (F-GZ) for cascade enzyme catalytic activities, where not only the high blood glucose in the wound is consumed via the GOx catalysis, but also the effective anti-bacteria is achieved via the degradedly released Zn2+ synergistically with the catalytically produced ·OH during the bacterial infection period with the low pH microenvironment. Simultaneously, the reactive oxygen species scavenging and hypoxia relief is realized via catalyzing H2O2 to produce O2 at the relatively elevated pH environment during the wound recovery period. Subsequently, a multifunctional hydrogel with injectable, self-healing and hemostasis abilities, as well as uniformed F-GZ loading is prepared via the copolymerization reaction. This hydrogel behaves as F-GZ but reduces the toxic effects, which thus accelerates the diabetic wound healing. More importantly, this hydrogel is found to modulate the diabetes immunity possibly mediated via the released Zn2+, which thus contributes to the recovered pancreatic islet functions with improved glucose tolerance and increased insulin secretion for enhanced diabetic wound treatments. This work initiates a new strategy for simultaneous diabetic wound management and also suggests a potential way for diabetic immunity modulation.