Cross-connection of multiplexed cylindrical vector beams using off-axis spin-decoupled metasurfaces.

Cylindrical vector beam (CVB) multiplexing communication demands effective mode cross-connection techniques to establish communication networks. While methods like polarized grating and coordinate transformation have been developed for (de)multiplexing CVB modes, challenges persist in the cross-connection of these multiplexed mode channels, including multi-mode conversion and inhomogeneous polarization control. Herein, we present an independent off-axis spin-orbit interaction strategy utilizing spin-decoupled metasurfaces. Cross-connection is achieved by encoding conjugated Dammann optical vortex grating phases onto the two orthogonal circularly polarized components of CVBs. Experimental results demonstrate the successful interconversion of four CVB modes (CVB+1 and CVB-2, CVB+2 and CVB-4) using a Si-based metasurface with a polarization conversion efficiency exceeding 85%. This facilitates the cross-connection of 200 Gbit/s quadrature phase-shift keying signals with bit-error-rates below 10-6. Offering advantages such as ultra-compact device size, flexible control of CVB modes, and multi-mode parallel processing, this approach shows promise in advancing the networking capabilities of CVB mode multiplexing communication networks.

Multi-dimensional cylindrical vector beam (de)multiplexing through cascaded wavelength- and polarization-sensitive metasurfaces.

Cylindrical vector beams (CVBs) exhibit great potential for multiplexing communication, owing to their mode orthogonality and compatibility with conventional wavelength multiplexing techniques. However, the practical application of CVB multiplexing communication faces challenges due to the lack of effective spatial polarization manipulation technologies for (de)multiplexing multi-dimensional physical dimensions of CVBs. Herein, we introduce a wavelength- and polarization-sensitive cascaded phase modulation strategy that utilizes multiple coaxial metasurfaces for multi-dimensional modulation of CVBs. By leveraging the spin-dependent phase modulation mechanism, these metasurfaces enable the independent transformation of the two orthogonal polarization components of CVB modes. Combined with the wavelength sensitivity of Fresnel diffraction in progressive phase modulation, this approach establishes a high-dimensional mapping relationship among CVB modes, wavelengths, spatial positions, and Gaussian fundamental modes, thereby facilitating multi-dimensional (de)multiplexing involving CVB modes and wavelengths. As a proof of concept, we theoretically demonstrate a 9-channel multi-dimensional multiplexing system, successfully achieving joint (de)multiplexing of 3 CVB modes (1, 2, and 3) and 3 wavelengths (1550 nm, 1560 nm, and 1570 nm) with a diffraction efficiency exceeding 80%. Additionally, we show the transmission of 16-QAM signals across 9 channels with the bit-error-rates below 10-5. By combining the integrability of metasurfaces with the high-dimensional wavefront manipulation capabilities of multilevel modulation, our strategy can effectively address the diverse demands of different wavelengths and CVB modes in optical communication.

T Cell Receptor-Directed Bispecific T Cell Engager Targeting MHC-Linked NY-ESO-1 for Tumor Immunotherapy.

Antibody-based bispecific T cell engagers (TCEs) that redirect T cells to kill tumor cells have shown a promising therapeutic effect on hematologic malignancies. However, tumor-specific targeting is still a challenge for TCEs, impeding the development of TCEs for solid tumor therapy. The major histocompatibility complex (MHC) presents almost all intracellular peptides (including tumor-specific peptides) on the cell surface to be scanned by the TCR on T cells. With the premise of choosing optimal peptides, the final complex peptide-MHC could be the tumor-specific target for TCEs. Here, a novel TCR-directed format of a TCE targeting peptide-MHC was designed named IgG-T-TCE, which was modified from the IgG backbone and prepared in a mammalian cell expression system. The recombinant IgG-T-TCE-NY targeting NY-ESO-1157-165/HLA-A*02:01 could be generated in HEK293 cells with a glycosylated TCR and showed potency in T cell activation and redirecting T cells to specifically kill target tumor cells. We also found that the in vitro activity of IgG-T-TCE-NY could be leveraged by various anti-CD3 antibodies and Fc silencing. The IgG-T-TCE-NY efficiently inhibited tumor growth in a tumor-PBMC co-engrafted mouse model without any obvious toxicities.

CovEpiAb: a comprehensive database and analysis resource for immune epitopes and antibodies of human coronaviruses.

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/.

Structure-Guided and Phage-Assisted Evolution of Therapeutic Antibodies to Reverse On-Target Point Mutation-Mediated Resistance.

Resistance to therapeutic antibodies caused by on-target point mutations is a major obstacle in anticancer therapy, creating an "unmet clinical need." To tackle this problem, researchers are developing new generations of antibody drugs that can overcome the resistance mechanisms of existing agents. We have previously reported a structure-guided and phage-assisted evolution (SGAPAE) approach to evolve cetuximab, a therapeutic antibody, to effectively reverse the resistance driven by EGFRS492R or EGFRG465R mutations, without changing the binding epitope or compromising the antibody efficacy. In this protocol, we provide detailed instructions on how to use the SGAPAE approach to evolve cetuximab, which can also be applied to other therapeutic antibodies for reversing on-target point mutation-mediated resistance. The protocol consists of four steps: structure preparation, computational prediction, phage display library construction, and antibody candidate selection.

STING licensing of type I dendritic cells potentiates antitumor immunity.

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations, including cancer cells, with distinct cellular functions, such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here, using a polymeric STING-activating nanoparticle (PolySTING) with a shock-and-lock dual activation mechanism, we show that conventional type 1 dendritic cells (cDC1s) are essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells (Tmem173-/-) is important for antitumor efficacy. Specific depletion of cDC1 (Batf3-/-) or STING deficiency in cDC1 (XCR1creSTINGfl/fl) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wild-type cDC1 in Batf3-/- mice restored antitumor efficacy, whereas transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wild-type but not Batf3-/- mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival. Furthermore, STING-cDC1 signature was increased after neoadjuvant pembrolizumab therapy in patients with non-small cell lung cancer. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis.

STING Licensing of Type I Dendritic Cells Potentiates Antitumor Immunity.

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a "shock-and-lock" dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells ( Tmem173 -/- ) is important for antitumor efficacy. Specific depletion of cDC1 ( Batf3 -/- ) or STING deficiency in cDC1 ( XCR1 cre STING fl/fl ) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wildtype cDC1 in Batf3 -/- mice restored antitumor efficacy while transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wildtype but not Batf3 -/- mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival while also showing increased expressions after neoadjuvant pembrolizumab therapy in non-small cell lung cancer patients. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis. One Sentence Summary: A "shock-and-lock" nanoparticle agonist induces direct STING signaling in type 1 conventional dendritic cells to drive antitumor immunity with defined biomarkers.

Comprehensive modular analyses of scar subtypes illuminate underlying molecular mechanisms and potential therapeutic targets.

Pathological scarring resulting from traumas and wounds, such as hypertrophic scars and keloids, pose significant aesthetic, functional and psychological challenges. This study provides a comprehensive transcriptomic analysis of these conditions, aiming to illuminate underlying molecular mechanisms and potential therapeutic targets. We employed a co-expression and module analysis tool to identify significant gene clusters associated with distinct pathophysiological processes and mechanisms, notably lipid metabolism, sebum production, cellular energy metabolism and skin barrier function. This examination yielded critical insights into several skin conditions including folliculitis, skin fibrosis, fibrosarcoma and congenital ichthyosis. Particular attention was paid to Module Cluster (MCluster) 3, encompassing genes like BLK, TRPV1 and GABRD, all displaying high expression and potential implications in immune modulation. Preliminary immunohistochemistry validation supported these findings, showing elevated expression of these genes in non-fibrotic samples rich in immune activity. The complex interplay of different cell types in scar formation, such as fibroblasts, myofibroblasts, keratinocytes and mast cells, was also explored, revealing promising therapeutic strategies. This study underscores the promise of targeted gene therapy for pathological scars, paving the way for more personalised therapeutic approaches. The results necessitate further research to fully ascertain the roles of these identified genes and pathways in skin disease pathogenesis and potential therapeutics. Nonetheless, our work forms a strong foundation for a new era of personalised medicine for patients suffering from pathological scarring.

Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

Full-duplex cylindrical vector beam multiplexing communication using spin-dependent phase modulation metasurfaces.

Cylindrical vector beam (CVB) has recently gained attention as a promising carrier for signal multiplexing owing to its mode orthogonality. However, the full-duplex multiplexing communication has not been previously explored for the lack of effective technologies to parallelly couple and separate CVB modes. Herein, we present a full-duplex solution for CVB multiplexing communication that utilizes spin-dependent phase modulation metasurfaces. By independently phase-modulating the two spin eigenstates of CVBs with the metasurface via spin-dependent orbital interactions, and loading two binary Dammann vortex gratings, we enabled an independent and reciprocal wave vector manipulation of CVBs for full-duplex (de)multiplexing operation. To demonstrate this concept, we constructed a 16-channel (including 4 CVB modes and 4 wavelengths) full-duplex CVB multiplexing communication system and achieved the bidirectional transmission of 800 Gbit/s quadrature-phase shift-keying (QPSK) signals over a 5 km few-mode fiber. Our results demonstrate the successful multiplexing and demultiplexing of 2 radial CVB modes and 2 azimuthal CVB modes in full-duplex communication with the bit-error-rates approaching 1.87 × 10-5.

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma.

At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D × anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3ε. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.

Highly efficient synergistic activity of an α-L-arabinofuranosidase for degradation of arabinoxylan in barley/wheat.

Here, an α-L-arabinofuranosidase (termed TtAbf62) from Thermothelomyces thermophilus is described, which efficiently removes arabinofuranosyl side chains and facilitates arabinoxylan digestion. The specific activity of TtAbf62 (179.07 U/mg) toward wheat arabinoxylan was the highest among all characterized glycoside hydrolase family 62 enzymes. TtAbf62 in combination with endoxylanase and ß-xylosidase strongly promoted hydrolysis of barley and wheat. The release of reducing sugars was significantly higher for the three-enzyme combination relative to the sum of single-enzyme treatments: 85.71% for barley hydrolysis and 33.33% for wheat hydrolysis. HPLC analysis showed that TtAbf62 acted selectively on monosubstituted (C-2 or C-3) xylopyranosyl residues rather than double-substituted residues. Site-directed mutagenesis and interactional analyses of enzyme-substrate binding structures revealed the catalytic sites of TtAbf62 formed different polysaccharide-catalytic binding modes with arabinoxylo-oligosaccharides. Our findings demonstrate a "multienzyme cocktail" formed by TtAbf62 with other hydrolases strongly improves the efficiency of hemicellulose conversion and increases biomass hydrolysis through synergistic interaction.

DeepTAP: An RNN-based method of TAP-binding peptide prediction in the selection of tumor neoantigens.

The transport of peptides from the cytoplasm to the endoplasmic reticulum (ER) by transporters associated with antigen processing (TAP) is a critical step in the intracellular presentation of cytotoxic T lymphocyte (CTL) epitopes. The development and application of computational methods, especially deep learning methods and new neural network strategies that can automatically learn feature representations with limited knowledge, provide an opportunity to develop fast and efficient methods to identify TAP-binding peptides. Herein, this study presents a comprehensive analysis of TAP-binding peptide sequences to derive TAP-binding motifs and preferences for N-terminal and C-terminal amino acids. A novel recurrent neural network (RNN)-based method called DeepTAP, using bidirectional gated recurrent unit (BiGRU), was developed for the accurate prediction of TAP-binding peptides. Our results demonstrated that DeepTAP achieves an optimal balance between prediction precision and false positives, outperforming other baseline models. Furthermore, DeepTAP significantly improves the prediction accuracy of high-confidence neoantigens, especially the top-ranked ones, making it a valuable tool for researchers studying antigen presentation processes and T-cell epitope screening. DeepTAP is freely available at https://github.com/zjupgx/deeptap and https://pgx.zju.edu.cn/deeptap.

Soluble interleukin-2 receptor combined with interleukin-8 is a powerful predictor of future adverse cardiovascular events in patients with acute myocardial infarction.

Background: Little is known about the role of interleukin (IL) in patients with acute myocardial infarction (MI), especially soluble IL-2 receptor (sIL-2R) and IL-8. We aim to evaluate, in MI patients, the predictive value of serum sIL-2R and IL-8 for future major adverse cardiovascular events (MACEs), and compare them with current biomarkers reflecting myocardial inflammation and injury. Methods: This was a prospective, single-center cohort study. We measured serum concentrations of IL-1ß, sIL-2R, IL-6, IL-8 and IL-10. Levels of current biomarkers for predicting MACEs were measured, including high-sensitivity C reactive protein, cardiac troponin T and N-terminal pro-brain natriuretic peptide. Clinical events were collected during 1-year and a median of 2.2 years (long-term) follow-up. Results: Twenty-four patients (13.8%, 24/173) experienced MACEs during 1-year follow-up and 40 patients (23.1%, 40/173) during long-term follow-up. Of the five interleukins studied, only sIL-2R and IL-8 were independently associated with endpoints during 1-year or long-term follow-up. Patients with high sIL-2R or IL-8 levels (higher than the cutoff value) had a significantly higher risk of MACEs during 1-year (sIL-2R: HR 7.7, 3.3-18.0, p < 0.001; IL-8: HR 4.8, 2.1-10.7, p < 0.001) and long-term (sIL-2R: HR 7.7, 3.3-18.0, p < 0.001; IL-8: HR 4.8, 2.1-10.7, p < 0.001) follow-up. Receiver operator characteristic curve analysis regarding predictive accuracy for MACEs during 1-year follow-up showed that the area under the curve for sIL-2R, IL-8, sIL-2R combined with IL-8 was 0.66 (0.54-0.79, p = 0.011), 0.69 (0.56-0.82, p < 0.001) and 0.720 (0.59-0.85, p < 0.001), whose predictive value were superior to that of current biomarkers. The addition of sIL-2R combined with IL-8 to the existing prediction model resulted in a significant improvement in predictive power (p = 0.029), prompting a 20.8% increase in the proportion of correct classifications. Conclusions: High serum sIL-2R combined with IL-8 levels was significantly associated with MACEs during follow-up in patients with MI, suggesting that sIL-2R combined with IL-8 may be a helpful biomarker for identifying the increased risk of new cardiovascular events. IL-2 and IL-8 would be promising therapeutic targets for anti-inflammatory therapy.

T52 attenuates oncogenic STAT3 signaling and suppresses osteosarcoma.

BACKGROUND: T52 is a steroidal saponin extracted from the traditional Chinese herb Rohdea fargesii (Baill.), and it is reported to possess strong anti-proliferative capabilities in human pharyngeal carcinoma cell lines. However, whether T52 has anti-osteosarcoma properties, and its potential mechanism is remains unknown. PURPOSE: To examine the outcome and underlying mechanism of T52 in osteosarcomas (OS). METHODS/STUDY DESIGNS: The physiological roles of T52 in OS cells were examined using CCK-8, colony formation (CF), EdU staining, cell cycle/apoptosis and cell migration/invasion assays. The relevant T52 targets against OS were assessed via bioinformatics prediction, and the binding sites were analyzed by molecular docking. Western blot analysis was carried out to examine the levels of factors associated with apoptosis, cell cycle, and STAT3 signaling pathway activation. RESULTS: T52 markedly diminished the proliferation, migration, and invasion of OS cells, and promoted G2/M arrest and apoptosis in a dose-dependent fashion (DDF) in vitro. Mechanistically, molecular docking predicted that T52 stably associated with STAT3 Src homology 2 (SH2) domain residues. Western blot revealed that T52 suppressed the STAT3 signaling pathway, as well as the expression of the downstream targets, such as, Bcl-2, Cyclin D1, and c-Myc. In addition, the anti-OS property of T52 were partially reversed by STAT3 reactivation, which confirmed that STAT3 signaling is critical for regulating the anti-OS property of T52. CONCLUSION: We firstly demonstrated that T52 possessed strong anti-osteosarcoma property in vitro, which was brought on by the inhibition of the STAT3 signaling pathway. Our findings provided pharmacological support for treating OS with T52.

Improving the tumor selectivity of T cell engagers by logic-gated dual tumor-targeting.

Targeting single tumor antigens makes it difficult to provide sufficient tumor selectivity for T cell engagers (TCEs), leading to undesirable toxicity and even treatment failure, which is particularly serious in solid tumors. Here, we designed novel trispecific TCEs (TriTCEs) to improve the tumor selectivity of TCEs by logic-gated dual tumor-targeting. TriTCE can effectively redirect and activate T cells to kill tumor cells (∼18 pM EC50) by inducing the aggregation of dual tumor antigens, which was ∼70- or 750- fold more effective than the single tumor-targeted isotype controls, respectively. Further in vivo experiments indicated that TriTCE has the ability to accumulate in tumor tissue and can induce circulating T cells to infiltrate into tumor sites. Hence, TriTCE showed a stronger tumor growth inhibition ability and significantly prolonged the survival time of the mice. Finally, we revealed that this concept of logic-gated dual tumor-targeted TriTCE can be applied to target different tumor antigens. Cumulatively, we reported novel dual tumor-targeted TriTCEs that can mediate a robust T cell response by simultaneous recognition of dual tumor antigens at the same cell surface. TriTCEs allow better selective T cell activity on tumor cells, resulting in safer TCE treatment.

Optical Logic Gates Excited by a Gauss Vortex Interference Beam Based on Spatial Self-Phase Modulation in 2D MoS2.

Vortex beams with optical orbital angular momentum have broad prospects in future high-speed and large-capacity optical communication. In this investigation of materials science, we found that low-dimensional materials have feasibility and reliability in the development of optical logic gates in all-optical signal processing and computing technology. We found that spatial self-phase modulation patterns through the MoS2 dispersions can be modulated by the initial intensity, phase, and topological charge of a Gauss vortex superposition interference beam. We utilized these three degrees of freedom as the input signals of the optical logic gate, and the intensity of a selected checkpoint on spatial self-phase modulation patterns as the output signal. By setting appropriate thresholds as logic codes 0 and 1, two sets of novel optical logic gates, including AND, OR, and NOT gates, were implemented. These optical logic gates are expected to have great potential in optical logic operations, all-optical networks, and all-optical signal processing.

Analysis of The Curative Effect of Tubularized Incised Plate Urethroplasty for Distal Hypospadias With The Dysplastic Corpus Spongiosum Covering Technique.

PURPOSE: To investigate the use of tubularized incised plate (TIP) urethroplasty for distal second- and third-degree hypospadias to free the dysplastic forked corpus spongiosum and Buck's fascia, which are used as a covering material for the new urethra, thereby reducing the incidence of urinary fistula and other complications in the coronal sulcus. MATERIALS AND METHODS: Clinical data of 113 patients with distal hypospadias treated with TIP urethroplasty from January 2017 to December 2020 were retrospectively analyzed. The study group comprised 58 patients (use of dysplastic corpus spongiosum and Buck's fascia to cover the new urethra), and the control group comprised 55 patients (use of dorsal Dartos fascia to cover the new urethra). RESULTS: All children were followed up for more than 12 months. In the study group, 4 patients developed urinary fistulas, 4 developed a urethral stricture, and no case developed glans fissure. In the control group, 11 patients developed urinary fistulas, 2 developed a urethral stricture, 3 developed a glans cracking. CONCLUSION: Using the dysplastic corpus spongiosum to cover the new urethra increases the amount of tissue in the coronal sulcus and reduces the incidence of urethral fistula, but it may increase the incidence of urethral stricture.

H3PO4-Induced Nano-Li3PO4 Pre-reduction Layer to Address Instability between the Nb-Doped Li7La3Zr2O12 Electrolyte and Metallic Li Anode.

Solid-state batteries based on a metallic Li anode and nonflammable solid electrolytes (SEs) are anticipated to achieve high energy and power densities with absolute safety. In particular, cubic garnet-type Nb-doped Li7La3Zr2O12 (Nb-LLZO) SEs possess superior ionic conductivity, are feasible to prepare under ambient conditions, have strong thermal stability, and are of low cost. However, the interfacial compatibility with Li metal and Li dendrite hazards still hinder the applications of Nb-LLZO. Herein, a quick and efficient solution was applied to address this issue, generating a nano-Li3PO4 pre-reduction layer from the reaction of H3PO4 with the ion-exchanged passivation layer (Li2CO3/LiOH) on the surface of Nb-LLZO. A lithiophilic, electrically insulating interlayer is in situ created when the Li3PO4 modified layer interacts with molten Li, successfully preventing the reduction of Nb5+. The interlayer, which mostly consists of Li3P and Li3PO4, also has a high shear modulus and relatively high Li+ conductivity, which effectively inhibit the growth of Li dendrites. The Li|Li3PO4|Nb-LLZO|Li3PO4|Li symmetric cells stably cycled for over 5000 h at 0.05 mA cm-2 and over 1000 h at a high rate of 0.15 mA cm-2 without any short circuits. The LiFePO4 and S/C hybrid solid-state batteries using the modified Nb-LLZO electrolyte also demonstrated good electrochemical performances, confirming the practical application of this interfacial engineering in various solid-state battery systems. This work offers an efficient solution to the instability issue between the Nb-LLZO SE and metallic Li anode.

M13, an anthraquinone compound isolated from Morinda officinalis promotes the osteogenic differentiation of MSCs by targeting Wnt/ß-catenin signaling.

BACKGROUND: Morinda officinalis (MO) is a herb used in Traditional Chinese Medicine (TCM) for the treatment of osteoporosis. M13, a MO-based anthraquinone compound is known to suppress osteoclast activity. However, whether M13 promotes MSCs osteogenic differentiation and its potential mechanism remains unknown. PURPOSE: To examine the influence of M13 on MSCs proliferation and osteogenic differentiation and elucidate the underlying mechanism. METHODS/STUDY DESIGNS: The effect of M13 exposure on MSCs proliferation was assessed via CCK8 assay, clone formation assay, immunofluorescence, RT-qPCR, and Western blot. The M13-mediated osteogenesis in vitro and ex vivo were evaluated via ALP and Alizarin red S staining, osteogenesis-associated gene (Runx2, Col1a1 and Opn) expression, and fetal limb explants culture. Molecular docking was employed for target signal pathway screening. The potential signaling mechanisms of M13-promoted MSCs osteogenic differentiation were analyzed by introducing XAV939 (Wnt/ß-catenin signaling inhibitor). RESULTS: M13 induced certain obvious positive effects on MSCs proliferation and osteogenic differentiation. Treatment with M13 enhanced MSCs viability and clone numbers. Meanwhile, M13 promoted osteogenic gene expression, enhanced ALP intensity and Alizarin red S staining in MSCs. In terms of mechanism, M13 strongly interacted with the docking site of the WNT signaling complex, thereby activating the Wnt/ß-catenin pathway. Furthermore, the M13-mediated osteogenic effect was partially inhibited by XAV939 both in vitro and ex vivo, which confirmed that the Wnt/ß-catenin axis is a critical regulator of M13-induced osteogenic differentiation of MSCs. CONCLUSION: Our study elucidated for the first time that M13 significantly promoted osteogenic differentiation of MSCs via stimulation of the Wnt/ß-catenin pathway in vitro and ex vivo.Our findings offered new additional evidence to support the MO or M13-based therapy of osteoporosis.