Dissection of potential anti-osteoporosis mechanism of isopsoralen - a quality control marker in Psoraleae Fructus - by metabolite profiling and network pharmacology.

RATIONALE: Isopsoralen (ISO), a quality control marker (Q-marker) in Psoraleae Fructus, is proven to present an obvious anti-osteoporosis effect. Until now, the metabolism and anti-osteoporosis mechanisms of ISO have not been fully elucidated, greatly restricting its drug development. METHODS: The metabolites of ISO in rats were profiled by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-osteoporosis mechanism of ISO in vivo was predicted by using network pharmacology. RESULTS: A total of 15 metabolites were characterized in rats after ingestion of ISO (20 mg/kg/day, by gavage), including 2 in plasma, 12 in urine, 6 in feces, 1 in heart, 3 in liver, 1 in spleen, 1 in lung, 3 in kidney, and 2 in brain. The pharmacology network results showed that ISO and its metabolites could regulate AKT1, SRC, NFKB1, EGFR, MAPK3, etc., involved in the prolactin signaling pathway, ErbB signaling pathway, thyroid hormone pathway, and PI3K-Akt signaling pathway. CONCLUSIONS: This is the first time for revealing the in vivo metabolism features and potential anti-osteoporosis mechanism of ISO by metabolite profiling and network pharmacology, providing data for further verification of pharmacological mechanism.

Recent Advances in Regulating Ceramic Monolithic Catalyst Structure for Preferential Oxidation of CO in H2.

Preferential oxidation of CO (CO-PROX) has tremendous significance in purifying hydrogen for fuel cells to avoid catalyst poisoning by CO molecules. Traditional powder catalysts face numerous challenges, including high pressure drop, aggregation tendency, hotspot formation, poor mass and heat transfer efficiency, and inadequate thermal stability. Accordingly, ceramic monolithic catalysts, known as their excellent thermal stability, high surface area, and superior mass and heat transfer characteristics, are gaining increasing research attention. This review examines recent studies on ceramic monolithic catalysts in CO-PROX, placing emphasis on the regulation of active sites (e.g., precious metals like Pt and Au, and non-precious metals like CuO and CeO2), monolith structures, and coating strategies. In addition, the structure-catalytic performance relationships, as well as the potential and limitations of different ceramic monolithic catalysts in practical application, are discussed. Finally, the challenges of monolithic catalysts and future research prospects in CO-PROX reactions are highlighted.

Overcoming challenges of protonation effects induced by high isoelectric point amino acids through a synergistic strategy towards highly stable and reversible zinc electrode-electrolyte interface.

Amino acids are among the most commercially promising additive solutions for achieving stable zinc anodes. However, greater attention should be given to the limitation arising from the protonation effects induced by high isoelectric point amino acids in the weakly acidic electrolytes of aqueous zinc-ion batteries (AZIBs). In this study, we introduce histidine (HIS) and ethylenediaminetetraacetic acid (EDTA) as hybrid additives into the aqueous electrolyte. Protonated HIS is adsorbed onto the anode interface, inducing uniform deposition and excluding H2O from the inner Helmholtz plane (IHP). Furthermore, the addition of EDTA compensates for the limitation of protonated HIS in excluding solvated H2O. EDTA reconstructs the solvation structure of Zn2+, resulting in a denser zinc deposition morphology. The results demonstrate that the Zn||Zn battery achieved a cycling lifespan exceeding 1480 h at 5 mA cm-2 and 5 mAh cm-2. It also reached over 900 h of cycling at a zinc utilization rate of 70 %. This study provides an innovative perspective for advancing the further development of AZIBs.

Structures and Electron Transport Paths in the Four Families of Flavin-Based Electron Bifurcation Enzymes.

Oxidoreductases facilitating electron transfer between molecules are pivotal in metabolic pathways. Flavin-based electron bifurcation (FBEB), a recently discovered energy coupling mechanism in oxidoreductases, enables the reversible division of electron pairs into two acceptors, bridging exergonic and otherwise unfeasible endergonic reactions. This chapter explores the four distinct FBEB complex families and highlights a decade of structural insights into FBEB complexes. In this chapter, we discuss the architecture, electron transfer routes, and conformational changes across all FBEB families, revealing the structural foundation that facilitate these remarkable functions.

Embracing Multiheterogeneity and Privacy Security Simultaneously: A Dynamic Privacy-Aware Federated Reinforcement Learning Approach.

With growing demand for privacy-preserving reinforcement learning (RL) applications, federated RL (FRL) has emerged as a potential solution. However, existing FRL methods struggle with multiple sources of heterogeneity, while lacking robust privacy guarantees. In this study, we propose DPA-FedRL, the dynamic privacy-aware FRL framework, to simultaneously mitigate both issues. First, we innovatively put forward the concept of "multiheterogeneity" and embed the environmental heterogeneity into agents' state representations. Next, to ensure privacy during model aggregation, we incorporate a differentially private mechanism in form of Gaussian noise and modify its global sensitivity, tailored to suit FRL's unique characteristics. Encouragingly, our approach dynamically allocates privacy budget based on heterogeneity levels, which strikes a balance between privacy and utility. From the theoretical perspective, we give rigorous convergence, privacy, and sensitivity guarantees for our proposed method. Through extensive experiments on diverse datasets, we demonstrate that DPA-FedRL surpasses state-of-the-art approaches (PPO-DP-SGD, PAvg, and QAvg) in some highly heterogeneous environments. Notably, our novel privacy attack simulations enable quantitative privacy assessment, validating that DPA-FedRL offers over 1.359 × stronger protection than baselines.

Characterization of metabolic features and potential anti-osteoporosis mechanism of pinoresinol diglucoside using metabolite profiling and network pharmacology.

RATIONALE: Eucommia cortex is the core herb in traditional Chinese medicine preparations for the treatment of osteoporosis. Pinoresinol diglucoside (PDG), the quality control marker and the key pharmacodynamic component in Eucommia cortex, has attracted global attention because of its definite effects on osteoporosis. However, the in vivo metabolic characteristics of PDG and its anti-osteoporotic mechanism are still unclear, restricting its development and application. METHODS: Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to analyze the metabolic characteristics of PDG in rats, and its anti-osteoporosis targets and mechanism were predicted using network pharmacology. RESULTS: A total of 51 metabolites were identified or tentatively characterized in rats after oral administration of PDG (10 mg/kg/day), including 9 in plasma, 28 in urine, 13 in feces, 10 in liver, 4 in heart, 3 in spleen, 11 in kidneys, and 5 in lungs. Furan-ring opening, dimethoxylation, glucuronidation, and sulfation were the main metabolic characteristics of PDG in vivo. The potential mechanism of PDG against osteoporosis was predicted using network pharmacology. PDG and its metabolites could regulate BCL2, MARK3, ALB, and IL6, involving PI3K-Akt signaling pathway, estrogen signaling pathway, and so on. CONCLUSIONS: This study was the first to demonstrate the metabolic characteristics of PDG in vivo and its potential anti-osteoporosis mechanism, providing the data for further pharmacological validation of PDG in the treatment of osteoporosis.

Conversion of Carbon Dioxide into a Series of CBxOy- Compounds Mediated by LaB3,4O2- Anions: Synergy of the Electron Transfer and Lewis Pair Mechanisms to Construct B-C Bonds.

Converting CO2 into value-added products containing B-C bonds is a great challenge, especially for multiple B-C bonds, which are versatile building blocks for organoborane chemistry. In the condensed phase, the B-C bond is typically formed through transition metal-catalyzed direct borylation of hydrocarbons via C-H bond activation or transition metal-catalyzed insertion of carbenes into B-H bonds. However, excessive amounts of powerful boryl reagents are required, and products containing B-C bonds are complex. Herein, a novel method to construct multiple B-C bonds at room temperature is proposed by the gas-phase reactions of CO2 with LaBmOn- (m = 1-4, n = 1 or 2). Mass spectrometry and density functional theory calculations are applied to investigate these reactions, and a series of new compounds, CB2O2-, CB3O3-, and CB3O2-, which possess B-C bonds, are generated in the reactions of LaB3,4O2- with CO2. When the number of B atoms in the clusters is reduced to 2 or 1, there is only CO-releasing channel, and no CBxOy- compounds are released. Two major factors are responsible for this quite intriguing reactivity: (1) Synergy of electron transfer and boron-boron Lewis acid-base pair mechanisms facilitates the rupture of C═O double bond in CO2. (2) The boron sites in the clusters can efficiently capture the newly formed CO units in the course of reactions, favoring the formation of B-C bonds. This finding may provide fundamental insights into the CO2 transformation driven by clusters containing lanthanide atoms and how to efficiently build B-C bonds under room temperature.

Rapid identification of early infections in febrile patients after CD19 target CAR-T cell therapy for B-cell malignancies.

BACKGROUND: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies. METHODS: In this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson's Chi-square test, t-test, Mann-Whitney U-test, Kaplan-Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression. RESULTS: In this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262-15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577-5.345], P < 0.001) and severe infection (9.040 [2.256-36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy. CONCLUSIONS: CRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.

Revealing the Limitation Induced by Hydroxyl in Regulating Solvation Structure of Zn2+ and Overcoming Challenges with Hybrid Additives towards Highly Stable Zinc Anodes.

In the field of electrolyte design for aqueous zinc-ion batteries (AZIBs), additives containing hydroxyl have been demonstrated to effectively modulate the solvation structure of Zn2+. However, reported studies typically focus solely on the effectiveness of hydroxyl while neglecting the issues that emerge during solvation structure regulation. The strong electron-attracting capability of Zn2+ attracts electrons from the oxygen in hydroxyl, thereby weakening the strength of hydroxyl, the hydrogen evolution reaction (HER) is also pronounced. This work innovatively reveals the limitation of hydroxyl-containing additives and proposes a synergistic regulation strategy based on hybrid additives. Arginine with a high isoelectric point is introduced into the electrolyte system containing hydroxyl additives. The protonation effect and electrostatic attraction of arginine enable it to absorb protons at the anode released by the weakened hydroxyl, thereby compensating for the limitation of hydroxyl additives. Under the synergistic action of hybrid additives, the Zn|Zn battery achieved stable deposition/stripping for over 1200 hours under 10 mA cm-2 and 10 mAh cm-2. Moreover, the Zn|Cu battery cycled for over 570 hours with a high Coulombic efficiency of 99.82%. This study presents a pioneering perspective for the further application of AZIBs.

Molecular Orientation Regulation of Hole Transport Semicrystalline-Polymer Enables High-Performance Carbon-Electrode Perovskite Solar Cells.

Carbon-based perovskite solar cells (PSCs) coupled with solution-processed hole transport layers (HTLs) have shown potential owing to their combination of low cost and high performance. However, the commonly used poly(3-hexylthiophene) (P3HT) semicrystalline-polymer HTL dominantly shows edge-on molecular orientation, in which the alkyl side chains directly contact the perovskite layer, resulting in an electronically poor contact at the perovskite/P3HT interface. The study adopts a synergetic strategy comprising of additive and solvent engineering to transfer the edge-on molecular orientation of P3HT HTL into 3D molecular orientation. The target P3HT HTL possesses improved charge transport as well as enhanced moisture-repelling capability. Moreover, energy level alignment between target P3HT HTL and perovskite layer is realized. As a result, the champion devices with small (0.04 cm2) and larger areas (1 cm2) deliver notable efficiencies of 20.55% and 18.32%, respectively, which are among the highest efficiency of carbon-electrode PSCs.

Corrigendum: Pre-operative evaluation and mid-term outcomes of anomalous origin of the left coronary artery from the pulmonary artery based on left ventricular ejection fraction.

[This corrects the article DOI: 10.3389/fcvm.2022.961491.].

Associations of collagen type 1 α1 gene polymorphisms and musculoskeletal soft tissue injuries: a meta-analysis with trial sequential analysis.

Numerous studies have investigated the role of collagen type 1 α1 (COL1A1) polymorphisms in musculoskeletal soft tissue injuries (MSTIs), yielding conflicting results. This study was designed to synthesize existing evidence and clarify the relationship between COL1A1 polymorphisms and MSTI susceptibility. We conducted a comprehensive literature search using PubMed, Cochrane Library, Web of Science, EMBASE, and Wanfang databases. Associations were assessed using odds ratios (ORs) with 95% confidence intervals (95% CIs) across five genetic models. Subgroup analyses were performed based on ethnicity and injury type. Additionally, trial sequential analysis (TSA) was utilized to assess information size and statistical power. We analyzed a total of 16 articles from 358 retrieved studies, encompassing 2094 MSTI cases and 4105 controls. Our pooled data revealed that individuals with the TT genotype of the rs1800012 polymorphism had a significantly reduced risk of MSTIs (TT vs. GG, OR = 0.53, 95% CI 0.35-0.82, P = 0.004; TT vs. TG + GG, OR = 0.54, 95% CI 0.36-0.80, P = 0.002). Ethnicity-based stratification showed a significant association in Caucasians but not Asians. However, no significant association was observed between the rs1107946 polymorphism and MSTIs, regardless of ethnicity or injury type. TSA indicated that the sample sizes may have been insufficient to yield conclusive results. In conclusion, our study supports the protective effect of the TT genotype of the rs1800012 polymorphism against MSTIs, particularly among Caucasians. However, the rs1107946 polymorphism does not appear to influence MSTI susceptibility.

Flexible transparent and hydrophobic SiNCs/PDMS coatings for anti-counterfeiting applications.

Silicon nanocrystals (SiNCs) have attracted considerable attention in many advanced applications due to silicon's high natural abundance, low toxicity, and impressive optical properties. However, little attention has been paid to fluorescence anti-counterfeiting applications based on lipophilic silicon nanocrystals. Moreover, it is also a challenge to fabricate aging-resistant anti-counterfeiting coatings based on silicon nanocrystals. Herein, this paper presents a demonstration of aging-resistant fluorescent anti-counterfeiting coatings based on red fluorescent silicon nanocrystals. In this work, lipophilic silicon nanocrystals (De-SiNCs) with red fluorescence were prepared first by thermal hydrosilylation between hydrogen-terminated silicon nanocrystals (H-SiNCs) and 1-decene. Subsequently, a new SiNCs/PDMS coating (De-SiNCs/DV) was fabricated by dispersing De-SiNCs into reinforcing PDMS composites with vinyl-capped silicone resin. Interestingly, the De-SiNCs/DV composites exhibit superior transparency (up to 85%) in the visible light range, outstanding fluorescence stabilities with an average lifetime of 20.59 µs under various conditions including acidic/alkaline environments, different organic solvents, high-humidity environments and UV irradiation. Meanwhile, the encapsulation of De-SiNCs is beneficial to enhancing the mechanical properties and thermal stability of De-SiNCs/DV composites. Additionally, the De-SiNCs/DV coating exhibits an excellent anti-counterfeiting effect on cotton fabrics when used as an ink in screen-printing. These findings pave the way for developing innovative flexible multifunctional anti-counterfeiting coatings in the future.

Water-Soluble, Self-Healing, and Debonding Primer for the Interface between Silicone Leather and Polydimethylsiloxane Composites.

The exceptional hydrophobicity and antifouling properties of polydimethylsiloxane (PDMS) composites have attracted extensive interest as a result of low surface energy. However, PDMS composites are hardly bound by common primers, greatly limiting their practical applications. To address this issue, an EPMS/VTMS (EV) primer synthesized by hydrolytic polycondensation of 3-[(2,3)-epoxypropoxypropyl]methyldiethoxysilane (EPMS) and vinyltrimethoxysilane (VTMS) in acidic conditions is proposed. Interestingly, the EV primer exhibits exceptional reactivity, self-healing capabilities, and strong adhesion to various substrates, including metals, plastics, and glass. The bonding aluminum plates are easily debonded by immersion in water without any residue left. Subsequently, the EV primer has been applied to the interface between silicone leather and the PDMS composite. Results show that the bonding strength for the silicone leather coated with the EV/PDMS composite is 16 times higher than that of the silicone leather modified with the PDMS composite. Meanwhile, the modified silicone leather exhibits impressive antifouling performance, including aqueous and oily stains, appreciable breathability, and excellent wear resistance, even if suffering from 20 000 cycles of abrasion. These excellent advantages for the modified silicone leather should be attributable to the synergistic effect of the EV primer and the PDMS composite. These findings pave the way to develop an ecofriendly debonding primer for PDMS composites, greatly facilitating applications of silicone leather.

Chemical profiling of Zhi-Ke-Bao pills and its potential mechanism against cough by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry and network pharmacology.

Zhi-Ke-Bao pills (ZKB), a traditional Chinese medicine preparation composed of 13 herbs, is generally used to treat cough caused by external wind cold, phlegm, etc in clinical applications, and it plays a core role in relieving cough caused by COVID-19 and influenza in China. Till now, the understanding of its chemical constituents was dramatically limited due to its chemical complexity, restricting its clinical application or development. In this work, a developed ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS) method, a targeted and non-targeted strategy and network pharmacology were used to comprehensively characterize the chemical compositions in ZKB and predict its mechanism against cough. A total of 164 compounds (148 targeted compounds and 16 non-targeted ones) were identified or tentatively characterized in ZKB, including 65 flavonoids, 25 alkaloids, 19 organic acids, 41 saponins, 9 coumarins, 2 phenylpropanoids, 2 anthraquinones, and 1 other types. Among them, 37 compounds were unambiguously identified by comparison to reference standards. Meanwhile, the fragmentation behaviors of five main chemical structure types were also summarized. 309 targets and two core signaling pathways of ZKB against cough were predicted by network pharmacology, including MAPK and PI3K-Akt signaling pathways. It was the first time to characterize the chemical compounds of ZKB and reveal its potential mechanism against cough, providing the material basis for further quality control or pharmacodynamic evaluation of ZKB.

Atomic Ruthenium-Promoted Cadmium Sulfide for Photocatalytic Production of Amino Acids from Biomass Derivatives.

Amino acids are the building blocks of proteins and are widely used as important ingredients for other nitrogen-containing molecules. Here, we report the sustainable production of amino acids from biomass-derived hydroxy acids with high activity under visible-light irradiation and mild conditions, using atomic ruthenium-promoted cadmium sulfide (Ru1/CdS). On a metal basis, the optimized Ru1/CdS exhibits a maximal alanine formation rate of 26.0 molAla ⋅ gRu -1 ⋅ h-1, which is 1.7 times and more than two orders of magnitude higher than that of its nanoparticle counterpart and the conventional thermocatalytic process, respectively. Integrated spectroscopic analysis and density functional theory calculations attribute the high performance of Ru1/CdS to the facilitated charge separation and O-H bond dissociation of the α-hydroxy group, here of lactic acid. The operando nuclear magnetic resonance further infers a unique "double activation" mechanism of both the CH-OH and CH3-CH-OH structures in lactic acid, which significantly accelerates its photocatalytic amination toward alanine.

The phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity of Forsythiae Fructus: An updated systematic review.

Forsythiae Fructus (FF), the dried fruit of F. suspensa, is commonly used to treat fever, inflammation, etc in China or other Asian countries. FF is usually used as the core herb in traditional Chinese medicine preparations for the treatment of influenza, such as Shuang-huang-lian oral liquid and Yin-qiao powder, etc. Since the wide application and core role of FF, its research progress was summarized in terms of traditional uses, phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity. Meanwhile, the anti-influenza substances and mechanism of FF were emphasized. Till now, a total of 290 chemical components are identified in F. suspensa, and among them, 248 components were isolated and identified from FF, including 42 phenylethanoid glycosides, 48 lignans, 59 terpenoids, 14 flavonoids, 3 steroids, 24 cyclohexyl ethanol derivatives, 14 alkaloids, 26 organic acids, and 18 other types. FF and their pure compounds have the pharmacological activities of anti-virus, anti-inflammation, anti-oxidant, anti-bacteria, anti-tumor, neuroprotection, hepatoprotection, etc. Inhibition of TLR7, RIG-I, MAVS, NF-κB, MyD88 signaling pathway were the reported anti-influenza mechanisms of FF and phenylethanoid glycosides and lignans are the main active groups. However, the bioavailability of phenylethanoid glycosides and lignans of FF in vivo was low, which needed to be improved. Simultaneously, the un-elucidated compounds and anti-influenza substances of FF strongly needed to be explored. The current quality control of FF was only about forsythoside A and phillyrin, more active components should be taken into consideration. Moreover, there are no reports of toxicity of FF yet, but the toxicity of FF should be not neglected in clinical applications.

Aucubin Promotes Osteogenic Differentiation and Facilitates Bone Formation through the lncRNA-H19 Driven Wnt/ß-Catenin Signaling Regulatory Axis.

Objectives: Traditional Chinese medicine Cortex Eucommiae has been used to treat bone fracture for hundreds of years, which exerts a significant improvement in fracture healing. Aucubin, a derivative isolated from Cortex Eucommiae, has been demonstrated to possess anti-inflammatory, immunoregulatory, and antioxidative potential. In the present study, our aim was to explore its function in bone regeneration and elucidate the underlying mechanism. Materials and Methods: The effects of Aucubin on osteoblast and osteoclast were examined in mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) and RAW 264.7 cells, respectively. Moreover, the lncRNA H19 and Wnt/ß-catenin signaling were detected by qPCR examination, western blotting, and luciferase activity assays. Using the femur fracture mice model, the in vivo effect of Aucubin on bone formation was monitored by X-ray, micro-CT, histomorphometry, and immunohistochemistry staining. Results: In the present study, Aucubin was found to significantly promote osteogenic differentiation in vitro and stimulated bone formation in vivo. Regarding to the underlying mechanism, H19 was found to be obviously upregulated by Aucubin in MSCs and thus induced the activation of Wnt/ß-catenin signaling. Moreover, H19 knockdown partially reversed the Aucubin-induced osteogenic differentiation and successfully suppressed the activation of Wnt/ß-catenin signaling. We therefore suggested that Aucubin induced the activation of Wnt/ß-catenin signaling through promoting H19 expression. Conclusion: Our results demonstrated that Aucubin promoted osteogenesis in vitro and facilitated fracture healing in vivo through the H19-Wnt/ß-catenin regulatory axis.

Control of defensive behavior by the nucleus of Darkschewitsch GABAergic neurons.

The nucleus of Darkschewitsch (ND), mainly composed of GABAergic neurons, is widely recognized as a component of the eye-movement controlling system. However, the functional contribution of ND GABAergic neurons (NDGABA) in animal behavior is largely unknown. Here, we show that NDGABA neurons were selectively activated by different types of fear stimuli, such as predator odor and foot shock. Optogenetic and chemogenetic manipulations revealed that NDGABA neurons mediate freezing behavior. Moreover, using circuit-based optogenetic and neuroanatomical tracing methods, we identified an excitatory pathway from the lateral periaqueductal gray (lPAG) to the ND that induces freezing by exciting ND inhibitory outputs to the motor-related gigantocellular reticular nucleus, ventral part (GiV). Together, these findings indicate the NDGABA population as a novel hub for controlling defensive response by relaying fearful information from the lPAG to GiV, a mechanism critical for understanding how the freezing behavior is encoded in the mammalian brain.