Illustration of the Intrinsic Mechanism of Reconstructed Cu Clusters for Enhanced CO2 Electroreduction to Ethanol Production with Industrial Current Density.

Copper-based catalysts have been attracting increasing attention for CO2 electroreduction into value-added multicarbon chemicals. However, most Cu-based catalysts are designed for ethylene production, while ethanol production with high Faradaic efficiency at high current density still remains a great challenge. Herein, Cu clusters supported on single-atom Cu dispersed nitrogen-doped carbon (Cux/Cu-N/C) show ethanol Faradaic efficiency of ∼40% and partial current density of ∼350 mA cm-2. Quasi in situ X-ray photoelectron spectroscopy and operando X-ray absorption spectroscopy results suggest the generation of surface asymmetrical sites of Cu+ and Cu0 as well as Cu clusters by electrochemical reduction and reconstruction during the CO2 electroreduction process. Density functional theory calculations indicate that the interaction between Cu clusters and the Cu-N/C support enhances *CO adsorption, facilitates the C-C coupling step, and favors the hydrogenation rather than dehydroxylation of the critical intermediate *CHCOH toward ethanol in the bifurcation.

CO electrolysis to multicarbon products over grain boundary-rich Cu nanoparticles in membrane electrode assembly electrolyzers.

Producing valuable chemicals like ethylene via catalytic carbon monoxide conversion is an important nonpetroleum route. Here we demonstrate an electrochemical route for highly efficient synthesis of multicarbon (C2+) chemicals from CO. We achieve a C2+ partial current density as high as 4.35 ± 0.07 A cm-2 at a low cell voltage of 2.78 ± 0.01 V over a grain boundary-rich Cu nanoparticle catalyst in an alkaline membrane electrode assembly (MEA) electrolyzer, with a C2+ Faradaic efficiency of 87 ± 1% and a CO conversion of 85 ± 3%. Operando Raman spectroscopy and density functional theory calculations reveal that the grain boundaries of Cu nanoparticles facilitate CO adsorption and C - C coupling, thus rationalizing a qualitative trend between C2+ production and grain boundary density. A scale-up demonstration using an electrolyzer stack with five 100 cm2 MEAs achieves high C2+ and ethylene formation rates of 118.9 mmol min-1 and 1.2 L min-1, respectively, at a total current of 400 A (4 A cm-2) with a C2+ Faradaic efficiency of 64%.

KIr4O8 Nanowires with Rich Hydroxyl Promote Oxygen Evolution Reaction in Proton Exchange Membrane Water Electrolyzer.

The sluggish kinetics for anodic oxygen evolution reaction (OER) and insufficient catalytic performance over the corresponding Ir-based catalysts are still enormous challenges in proton exchange membrane water electrolyzer (PEMWE). Herein, it is reported that KIr4O8 nanowires anode catalyst with more exposed active sites and rich hydroxyl achieves a current density of 1.0 A cm-2 at 1.68 V and possesses excellent catalytic stability with 1230 h in PEMWE. Combining in situ Raman spectroscopy and differential electrochemical mass spectroscopy results, the modified adsorbate evolution mechanism is proposed, wherein the rich hydroxyl in the inherent structure of KIr4O8 nanowires directly participates in the catalytic process for favoring the OER. Density functional theory calculation results further suggest that the enhanced proximity between Ir (d) and O (p) band center in KIr4O8 can strengthen the covalence of Ir-O, facilitate the electron transfer between adsorbents and active sites, and decrease the energy barrier of rate-determining step from OH* to O* during the OER.

High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling

The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling. (AU)

High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling

The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling. (AU)

Functionalized 3D Hydroxyapatite Scaffold by Fusion Peptides-Mediated Small Extracellular Vesicles of Stem Cells for Bone Tissue Regeneration.

3D printing technology offers extensive applications in tissue engineering and regenerative medicine (TERM) because it can create a three-dimensional porous structure with acceptable porosity and fine mechanical qualities that can mimic natural bone. Hydroxyapatite (HA) is commonly used as a bone repair material due to its excellent biocompatibility and osteoconductivity. Small extracellular vesicles (sEVs) derived from bone marrow mesenchymal stem cells (BMSCs) can regulate bone metabolism and stimulate the osteogenic differentiation of stem cells. This study has designed a functionalized bone regeneration scaffold (3D H-P-sEVs) by combining the biological activity of BMSCs-sEVs and the 3D-HA scaffold to improve bone regeneration. The scaffold utilizes the targeting of fusion peptides to increase the loading efficiency of sEVs. The composition, structure, mechanical properties, and in vitro degradation performance of the 3D H-P-sEVs scaffolds were examined. The composite scaffold demonstrated good biocompatibility, substantially increased the expression of osteogenic-related genes and proteins, and had a satisfactory bone integration effect in the critical skull defect model of rats. In conclusion, the combination of EVs and 3D-HA scaffold via fusion peptide provides an innovative composite scaffold for bone regeneration and repair, improving osteogenic performance.

Asymmetric adhesive SIS-based wound dressings for therapeutically targeting wound repair.

Severe tissue injuries pose a significant risk to human health. Conventional wound dressings fall short in achieving effective tissue regeneration, resulting in suboptimal postoperative healing outcomes. In this study, an asymmetric adhesive wound dressing (marked as SIS/PAA/LAP) was developed, originating from acrylate acid (AA) solution with laponite (LAP) nanoparticles polymerization and photo-crosslinked on the decellularized extracellular matrix small intestinal submucosa (SIS) patch. Extensive studies demonstrated that the SIS/PAA/LAP exhibited higher tissue adhesion strength (~ 33 kPa) and burst strength (~ 22 kPa) compared to conventional wound dressings like Tegaderm and tissue adhesive products. Importantly, it maintained favorable cell viability and demonstrated robust angiogenic capacity. In animal models of full-thickness skin injuries in rats and skin injuries in Bama miniature pigs, the SIS/PAA/LAP could be precisely applied to wound sites. By accelerating the formation of tissue vascularization, it displayed superior tissue repair outcomes. This asymmetrically adhesive SIS-based patch would hold promising applications in the field of wound dressings.

High fat diet-induced downregulation of TRPV2 mediates hepatic steatosis via p21 signalling.

The global prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) are exhibiting an increasing trend. NAFLD is characterized by a significant accumulation of lipids, though its underlying mechanism is still unknown. Here we report that high-fat diet (HFD) feeding induced hepatic steatosis in mice, which was accompanied by a reduction in the expression and function of hepatic TRPV2. Moreover, conditional knockout of TRPV2 in hepatocytes exacerbated HFD-induced hepatic steatosis. In an in vitro model of NAFLD, TRPV2 regulated lipid accumulation in HepG2 cells, and TRPV2 activation inhibited the expression of the cellular senescence markers p21 and p16, all of which were mediated by AMPK phosphorylation. Finally, we found that administration of probenecid, a TRPV2 agonist, impaired HFD-induced hepatic steatosis and suppressed HFD-induced elevation in p21 and p16. Collectively, our findings imply that hepatic TRPV2 protects against the accumulation of lipids by modulating p21 signalling.

Glucagon Enhances Chemotherapy Efficacy By Inhibition of Tumor Vessels in Colorectal Cancer.

Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti-cancer therapy. In a series of in vitro experiments, glucagon inhibited cell migration and tube formation in both endothelial and tumor cells. In vivo studies demonstrated decreased tumor blood vessels and fewer pseudo-vessels in mice treated with glucagon. The combination of glucagon and chemotherapy exhibited enhanced tumor inhibition. Mechanistic studies demonstrated that glucagon increased the permeability of blood vessels, leading to a pronounced disruption of vessel morphology. Signaling pathway analysis identified a VEGF/VEGFR-dependent mechanism whereby glucagon attenuated angiogenesis through its receptor. Clinical data analysis revealed a positive correlation between elevated glucagon expression and chemotherapy response. This is the first study to reveal a role for glucagon in inhibiting angiogenesis and vascular mimicry. Additionally, the delivery of glucagon-encapsulated PEGylated liposomes to tumor-bearing mice amplified the inhibition of angiogenesis and vascular mimicry, consequently reinforcing chemotherapy efficacy. Collectively, the findings demonstrate the role of glucagon in inhibiting tumor vessel network and suggest the potential utility of glucagon as a promising predictive marker for patients with CRC receiving chemotherapy.

Tumor Microenvironment-Activated Nanostructure to Enhance MRI Capability and Nanozyme Activity for Highly Tumor-Specific Multimodal Theranostics.

Copper-based nanozymes exhibit excellent antitumor activity but are easily inactivated due to the disturbance of proteins or other macromolecules with sulfhydryl. A tumor microenvironment-responsive CuMnO@Fe3O4 (CMF) core-shell nanozyme for highly efficient tumor theranostics is developed. A platelet-derived growth factor receptor-ß-recognizing cyclic peptide (PDGFB) target is conjugated to the surface of CMF to fabricate a tumor-specific nanozyme (PCMF). The core-shell nanostructure significantly avoids the oxidation and inactivation of copper-based nanozyme, promoting the antitumor activity of PCMF. The weak acid- and GSH-activated T1 and T2 relaxation rate of PCMF contributes to T1 and T2 dual contrast imaging at the tumor site. In addition, the PCMF disintegrates and produces some metal ions that possess Fenton catalytic activity (i.e., Cu+, Mn2+, and Fe2+) under TME. This process significantly depletes GSH, accelerates Fenton and Fenton-like reactions, enhances cellular reactive oxygen species (ROS) levels, and induces cancer cell apoptosis and ferroptosis. PCMF also exhibits photothermal functions, so it can be used in combined photothermal therapy, ferroptosis therapy, and chemodynamic therapy, improving anticancer activity. This work provides insights into the design of an exquisite nanostructure for high-sensitive and tumor-specific theranostics.

Histatin 1-modified SIS hydrogels enhance the sealing of peri-implant mucosa to prevent peri-implantitis.

Dental implants make it possible to replace teeth in more sophisticated ways. Nevertheless, peri-implantitis is one of the leading causes of implant failure, which can be avoided with proper soft tissue sealing. The aim of this study was to achieve the promotion of the synthesis of peri-implant epithelial hemidesmosome through Histatin 1 and porcine small intestinal submucosa (SIS) hydrogel to form a good peri-implant seal. The results show that hydrogel can improve the biological barrier function around implants by combining antibacterial, promoting soft tissue healing and promoting epithelial bonding. This means that the morphology and anti-infection ability of soft tissue are enhanced, which ensures the long-term stability of the implant.SIS-Hst1 hydrogel has certain clinical application in the prevention and early treatment of peri-implantitis. In conclusion, Hst1-SIS hydrogel, as a local administration system, provides experimental evidence for the prevention of peri-implant disease.

Altered pupil responses to social and non-social stimuli in Shank3 mutant dogs.

Pupillary response, an important process in visual perception and social and emotional cognition, has been widely studied for understanding the neural mechanisms of neuropsychiatric disorders. However, there have been few studies on pupil response to social and non-social stimuli in animal models of neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we developed a pupilometer using a robust eye feature-detection algorithm for real-time pupillometry in dogs. In a pilot study, we found that a brief light flash induced a less-pronounced and slower pupil dilation response in gene-edited dogs carrying mutations in Shank3; mutations of its ortholog in humans were repeatedly identified in ASD patients. We further found that obnoxious, loud firecracker sound of 120 dB induced a stronger and longer pupil dilation response in Shank3 mutant dogs, whereas a high reward food induced a weaker pupillary response in Shank3 mutants than in wild-type control dogs. In addition, we found that Shank3 mutants showed compromised pupillary synchrony during dog-human interaction. These findings of altered pupil response in Shank3 mutant dogs recapitulate the altered sensory responses in ASD patients. Thus, this study demonstrates the validity and value of the pupilometer for dogs, and provides an effective paradigm for studying the underlying neural mechanisms of ASD and potentially other psychiatric disorders.

Directing the Selectivity of CO Electrolysis to Acetate by Constructing Metal-Organic Interfaces.

Electrochemically converting CO2 to valuable chemicals holds great promise for closing the anthropogenic carbon cycle. Owing to complex reaction pathways and shared rate-determining steps, directing the selectivity of CO2 /CO electrolysis to a specific multicarbon product is very challenging. We report here a strategy for highly selective production of acetate from CO electrolysis by constructing metal-organic interfaces. We demonstrate that the Cu-organic interfaces constructed by in situ reconstruction of Cu complexes show very impressive acetate selectivity, with a high Faradaic efficiency of 84.2 % and a carbon selectivity of 92.1 % for acetate production, in an alkaline membrane electrode assembly electrolyzer. The maximum acetate partial current density and acetate yield reach as high as 605 mA cm-2 and 63.4 %, respectively. Thorough structural characterizations, control experiments, operando Raman spectroscopy measurements, and density functional theory calculation results indicate that the Cu-organic interface creates a favorable reaction microenvironment that enhances *CO adsorption, lowers the energy barrier for C-C coupling, and facilitates the formation of CH3 COOH over other multicarbon products, thus rationalizing the selective acetate production.

Defensive responses: behaviour, the brain and the body.

Most animals live under constant threat from predators, and predation has been a major selective force in shaping animal behaviour. Nevertheless, defence responses against predatory threats need to be balanced against other adaptive behaviours such as foraging, mating and recovering from infection. This behavioural balance in ethologically relevant contexts requires adequate integration of internal and external signals in a complex interplay between the brain and the body. Despite this complexity, research has often considered defensive behaviour as entirely mediated by the brain processing threat-related information obtained via perception of the external environment. However, accumulating evidence suggests that the endocrine, immune, gastrointestinal and reproductive systems have important roles in modulating behavioural responses to threat. In this Review, we focus on how predatory threat defence responses are shaped by threat imminence and review the circuitry between subcortical brain regions involved in mediating defensive behaviours. Then, we discuss the intersection of peripheral systems involved in internal states related to infection, hunger and mating with the neurocircuits that underlie defence responses against predatory threat. Through this process, we aim to elucidate the interconnections between the brain and body as an integrated network that facilitates appropriate defensive responses to threat and to discuss the implications for future behavioural research.

Killing two birds with one stone: A therapeutic copper-loaded bio-patch promoted abdominal wall repair via VEGF pathway.

Hernia and life-threatening intestinal obstruction often result from abdominal wall injuries, and the regeneration of abdominal wall defects is limited due to the lack of biocompatible, antibacterial and angiogenic scaffolding materials for treating injured tissues. Taking inspiration from the facile preparation of dopamine polymerization and its surface modification technology, in this study, multi-therapeutic copper element was introduced into porcine small intestinal submucosa (SIS) bio-patches through polydopamine (PDA) deposition, in order to regenerate abdominal wall injury. In both in vitro antibacterial assays, cytocompatibility assays and in vivo abdominal wall repair experiments, the SIS/PDA/Cu bio-patches exhibited robust antibacterial efficiency (＞99%), excellent biocompatibility to cells (＞90%), and enhanced neovascularization and improved collagen maturity compared to other commercially available patches (3.0-fold higher than the PP mesh), due to their activation of VEGF pathway. These findings indicated the bio-patch was a promising application for preventing visceral adhesion, bacterial infection, and promoting soft tissue regeneration.

Multi-objective optimization via evolutionary algorithm (MOVEA) for high-definition transcranial electrical stimulation of the human brain.

Designing a transcranial electrical stimulation (tES) strategy requires considering multiple objectives, such as intensity in the target area, focality, stimulation depth, and avoidance zone. These objectives are often mutually exclusive. In this paper, we propose a general framework, called multi-objective optimization via evolutionary algorithm (MOVEA), which solves the non-convex optimization problem in designing tES strategies without a predefined direction. MOVEA enables simultaneous optimization of multiple targets through Pareto optimization, generating a Pareto front after a single run without manual weight adjustment and allowing easy expansion to more targets. This Pareto front consists of optimal solutions that meet various requirements while respecting trade-off relationships between conflicting objectives such as intensity and focality. MOVEA is versatile and suitable for both transcranial alternating current stimulation (tACS) and transcranial temporal interference stimulation (tTIS) based on high definition (HD) and two-pair systems. We comprehensively compared tACS and tTIS in terms of intensity, focality, and steerability for targets at different depths. Our findings reveal that tTIS enhances focality by reducing activated volume outside the target by 60%. HD-tTIS and HD-tDCS can achieve equivalent maximum intensities, surpassing those of two-pair tTIS, such as 0.51 V/m under HD-tACS/HD-tTIS and 0.42 V/m under two-pair tTIS for the motor area as a target. Analysis of variance in eight subjects highlights individual differences in both optimal stimulation policies and outcomes for tACS and tTIS, emphasizing the need for personalized stimulation protocols. These findings provide guidance for designing appropriate stimulation strategies for tACS and tTIS. MOVEA facilitates the optimization of tES based on specific objectives and constraints, advancing tTIS and tACS-based neuromodulation in understanding the causal relationship between brain regions and cognitive functions and treating diseases. The code for MOVEA is available at https://github.com/ncclabsustech/MOVEA.

A Bone Targeting Nanoparticle Loaded OGP to Restore Bone Homeostasis for Osteoporosis Therapy.

Restoring bone homeostasis is the key to the treatment of osteoporosis. How to increase osteogenic ability or inhibit osteoclast activity has always been a topic of great concern. In recent years, short peptides with biological activity have received great attention in bone repair. However, the application of short peptides is still limited due to the lack of a stable and targeted delivery system. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles modified by alendronate (AL) to transport osteogenic peptides (OGP) (AL-PLGA@P NPs) are designed. Benefiting from the high affinity of AL for hydroxyapatite, AL-PLGA@P NPs have the ability to target bone. In this delivery system, OGP that promotes osteogenesis synergizes with AL, which inhibits osteoclasts, to regulate bone homeostasis, which gives them more advantages in the treatment of osteoporosis. The data shows that nanoparticles can selectively deliver peptides to the bone surface without systemic toxicity. Moreover, nanoparticles can upregulate osteogenesis-related factors (ALP, Runx-2, and BMP2) and downregulate osteoclast-related factors (TRAP and CTSK) in vitro. With AL-PLGA@P NPs, bone microarchitecture and bone mass are improved in ovariectomized osteoporosis rats. Therefore, this study proposes a novel osteoporosis-based drug system that effectively improves bone density.