Atomic-Level Regulation of Cu-Based Electrocatalyst for Enhancing Oxygen Reduction Reaction: From Single Atoms to Polymetallic Active Sites.

The slow kinetics of cathodic oxygen reduction reactions (ORR) in fuel cells and the high cost of commercial Pt-based catalysts limit their large-scale application. Cu-based single-atom catalysts (SACs) have received increasing attention as a promising ORR catalyst due to their high atom utilization, high thermodynamic activity, adjustable electronic structure, and low cost. Herein, the recent research progress of Cu-based catalysts is reviewed from single atom to polymetallic active sites for ORR. First, the design and synthesis method of Cu-based SACs are summarized. Then the atomic-level structure regulation strategy of Cu-based catalyst is proposed to improve the ORR performance. The different ORR catalytic mechanism based on the different Cu active sites is further revealed. Finally, the design principle of high-performance Cu-based SACs is proposed for ORR and the opportunities and challenges are further prospected.

Exosomes: compositions, biogenesis, and mechanisms in diabetic wound healing.

Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

Structural analysis of chloroplast tail-anchored membrane protein recognition by ArsA1.

In mammals and yeast, tail-anchored (TA) membrane proteins destined for the post-translational pathway are safely delivered to the endoplasmic reticulum (ER) membrane by a well-known targeting factor, TRC40/Get3. In contrast, the underlying mechanism for translocation of TA proteins in plants remains obscure. How this unique eukaryotic membrane-trafficking system correctly distinguishes different subsets of TA proteins destined for various organelles, including mitochondria, chloroplasts and the ER, is a key question of long standing. Here, we present crystal structures of algal ArsA1 (the Get3 homolog) in a distinct nucleotide-free open state and bound to adenylyl-imidodiphosphate. This approximately 80-kDa protein possesses a monomeric architecture, with two ATPase domains in a single polypeptide chain. It is capable of binding chloroplast (TOC34 and TOC159) and mitochondrial (TOM7) TA proteins based on features of its transmembrane domain as well as the regions immediately before and after the transmembrane domain. Several helices located above the TA-binding groove comprise the interlocking hook-like motif implicated by mutational analyses in TA substrate recognition. Our data provide insights into the molecular basis of the highly specific selectivity of interactions of algal ArsA1 with the correct sets of TA substrates before membrane targeting in plant cells.

Secretory Production of Functional Grouper Type I Interferon from Epinephelus septemfasciatus in Escherichia coli and Bacillus subtilis.

Nervous necrosis virus (NNV) results in high mortality rates of infected marine fish worldwide. Interferons (IFNs) are cytokines in vertebrates that suppress viral replication and regulate immune responses. Heterologous overexpression of fish IFN in bacteria could be problematic because of protein solubility and loss of function due to protein misfolding. In this study, a protein model of the IFN-α of Epinephelus septemfasciatus was built based on comparative modeling. In addition, PelB and SacB signal peptides were fused to the N-terminus of E. septemfasciatus IFN-α for overexpression of soluble, secreted IFN in Escherichia coli (E-IFN) and Bacillus subtilis (B-IFN). Cytotoxicity tests indicated that neither recombinant grouper IFN-α were cytotoxic to a grouper head kidney cell line (GK). The GK cells stimulated with E-IFN and B-IFN exhibited elevated expression of antiviral Mx genes when compared with the control group. The NNV challenge experiments demonstrated that GK cells pretreated or co-treated with E-IFN and B-IFN individually had three times the cell survival rates of untreated cells, indicating the cytoprotective ability of our recombinant IFNs. These data provide a protocol for the production of soluble, secreted, and functional grouper IFN of high purity, which may be applied to aquaculture fisheries for antiviral infection.

Key Node Ranking in Complex Networks: A Novel Entropy and Mutual Information-Based Approach.

Numerous problems in many fields can be solved effectively through the approach of modeling by complex network analysis. Finding key nodes is one of the most important and challenging problems in network analysis. In previous studies, methods have been proposed to identify key nodes. However, they rely mainly on a limited field of local information, lack large-scale access to global information, and are also usually NP-hard. In this paper, a novel entropy and mutual information-based centrality approach (EMI) is proposed, which attempts to capture a far wider range and a greater abundance of information for assessing how vital a node is. We have developed countermeasures to assess the influence of nodes: EMI is no longer confined to neighbor nodes, and both topological and digital network characteristics are taken into account. We employ mutual information to fix a flaw that exists in many methods. Experiments on real-world connected networks demonstrate the outstanding performance of the proposed approach in both correctness and efficiency as compared with previous approaches.

Experimental characterization of the radio over fiber aided twin-antenna spatial modulation downlink.

In this paper, we present the design and the experimental demonstration of a radio over fiber (RoF) network relying on state-of-the-art spatial modulation (SM), that activates one out of multiple antennas. We propose a novel RoF-aided SM encoding scheme, where the optical single side-band signal generated by a Mach-Zehnder modulator (MZM) is used for both the antenna selection and for the classic modulated symbol selection. The SM encoding is optically processed in a centralized fashion, aiming for the reduction of power consumption and for enabling cost-effective maintenance and management, which can be employed in the context of a cloud radio access network (C-RAN) and a small-cell front-haul. Furthermore, an experimental demonstration of the proposed system is discussed and analyzed, where a 20 km standard single mode fiber (SSMF) is used for transmission. In this experiment, a 2 Gbps transmission relying on two transmit and two receive antennas is achieved with less than 1 dB SNR degradation compared to those operating without RoF.

NrF2/ARE and NF-κB pathway regulation may be the mechanism for lutein inhibition of human breast cancer cell.

AIM: Though lutein can inhibit cancer cell proliferation via alleviating oxidative injury, the molecular mechanisms of lutein involvement in the NrF2/antioxidant response element (ARE) and NF-κB pathways remain poorly understood. MATERIALS & METHODS: MTT, flow cytometry, quantitative real-time PCR (qRT-PCR) and western blot assays were performed. RESULTS: After treatment with lutein, breast cancer cell proliferation was significantly decreased in a dose-dependent manner. Lutein induced nuclear translocation and protein expression of NrF2, improved the expression of cellular antioxidant enzymes and attenuated reactive oxygen species levels. Moreover, lutein treatment decreased NF-κB signaling pathway related NF-κB p65 protein expression. CONCLUSION: The effect of lutein antiproliferation was mediated by activation of the NrF2/ARE pathway, and blocking of the NF-κB signaling pathway.

Structural dynamics of the two-component response regulator RstA in recognition of promoter DNA element.

The RstA/RstB system is a bacterial two-component regulatory system consisting of the membrane sensor, RstB and its cognate response regulator (RR) RstA. The RstA of Klebsiella pneumoniae (kpRstA) consists of an N-terminal receiver domain (RD, residues 1-119) and a C-terminal DNA-binding domain (DBD, residues 130-236). Phosphorylation of kpRstA induces dimerization, which allows two kpRstA DBDs to bind to a tandem repeat, called the RstA box, and regulate the expression of downstream genes. Here we report the solution and crystal structures of the free kpRstA RD, DBD and DBD/RstA box DNA complex. The structure of the kpRstA DBD/RstA box complex suggests that the two protomers interact with the RstA box in an asymmetric fashion. Equilibrium binding studies further reveal that the two protomers within the kpRstA dimer bind to the RstA box in a sequential manner. Taken together, our results suggest a binding model where dimerization of the kpRstA RDs provides the platform to allow the first kpRstA DBD protomer to anchor protein-DNA interaction, whereas the second protomer plays a key role in ensuring correct recognition of the RstA box.

[Effect of Tetramethyl pyrazine on serum levels of IL-1beta, IL-6, and IL-2, and NO and PGE2 in the synovial fluid of CIA rats: an experimental research].

OBJECTIVE: To observe the effect of Tetramethyl pyrazine (TMP) on the cytokines and inflammatory mediators in the serum and the synovial fluid of collagen-induced arthritis (CIA)rats, and further to investigate its possible mechanisms for treating rheumatoid arthritis (RA). METHODS: Type II CIA rat model was established. Rats in the TMP group were administered with TMP at 50 mg/kg and 100 mg/kg, once daily. Dexamethasone at 2.0 mg/kg was intramuscularly injected to those in the Dexamethasone treated group, once daily. Normal saline at 2 mL/kg was given to those in the normal control group and the model group, once daily. All medication was started from the 7th day, lasting to the 35th day. CIA rats' foot swelling degree was observed. Contents of serum IL-1, IL-6, IL-2, NO and PGE2in the synovial fluid were detected by radioimmunoassay and nitrate reduction method. RESULTS: Compared with the normal group, the foot swelling obviously increased, contents of NO and PGE2 in the synovial fluid were obviously elevated in the model group (P < 0.01). Compared with the model group, the foot swelling could be obviously inhibited by 100 mg/kg TMP and Dexamethasone; serum levels of IL-1 and IL-6 obviously decreased, serum IL-2 level obviously increased, contents of NO and PGE, decreased (P < 0.01). TMP 50 mg/kg could obviously inhibit the foot swelling of CIA rats (P < 0.01). There was no statistical difference in other indices (P > 0.05). CONCLUSIONS: TMP at 100 mg/kg showed obvious inhibition on CIA rats. Its inhibitory effect might be correlated to inhibiting activities of endogenous cytokines and the generation of inflammatory mediators in inflammation local regions, improving contents of anti-inflammation cytokines, and inducing the balance of the inflammatory cytokine network.

Design Principles of Single-Atom Catalysts for Oxygen Evolution Reaction: From Targeted Structures to Active Sites.

Hydrogen production from electrolytic water electrolysis is considered a viable method for hydrogen production with significant social value due to its clean and pollution-free nature, high hydrogen production efficiency, and purity, but the anode oxygen evolution reaction (OER) process is complex and kinetically slow. Single-atom catalysts (SACs) with 100% atom utilization and homogeneous active sites often exhibit high catalytic activity and are expected to be extensively applied. The catalytic performance of OER can be further improved by precise regulation of the structure through electronic effects, coordination environment, heteroatomic doping, and so on. In this review, the mechanisms of OER under different conditions are introduced, the latest research progress of SACs in the field of OER is systematically summarized, and then the effects of various structural regulation strategies on catalytic performance are discussed, and principles and ideas for the design of SACs for OER are proposed. In the end, the outstanding issues and current challenges in this field are summarized.

Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.

Advancements in melanoma immunotherapy: the emergence of Extracellular Vesicle Vaccines.

Malignant melanoma represents a particularly aggressive type of skin cancer, originating from the pathological transformation of melanocytes. While conventional interventions such as surgical resection, chemotherapy, and radiation therapy are available, their non-specificity and collateral damage to normal cells has shifted the focus towards immunotherapy as a notable approach. Extracellular vesicles (EVs) are naturally occurring transporters, and are capable of delivering tumor-specific antigens and directly engaging in the immune response. Multiple types of EVs have emerged as promising platforms for melanoma vaccination. The effectiveness of EV-based melanoma vaccines manifests their ability to potentiate the immune response, particularly by activating dendritic cells (DCs) and CD8+ T lymphocytes, through engineering a synergy of antigen presentation and targeted delivery. Here, this review mainly focuses on the construction strategies for EV vaccines from various sources, their effects, and immunological mechanisms in treating melanoma, as well as the shortcomings and future perspectives in this field. These findings will provide novel insights into the innovative exploitation of EV-based vaccines for melanoma immune therapy.

Exosomes from mesenchymal stem cells: Potential applications in wound healing.

Wound healing is a continuous and complex process regulated by multiple factors, which has become an intractable clinical burden. Mesenchymal stem cell-derived exosomes (MSC-exos) possess low immunogenicity, easy preservation, and potent bioactivity, which is a mirror to their parental cells MSC-exos are important tools for regulating the biological behaviors of wound healing-associated cells, including fibroblasts, keratinocytes, immune cells, and endothelial cells. MSC-exos accelerate the wound healing process at cellular and animal levels by modulating inflammatory responses, promoting collagen deposition and vascularization. MSC-exos accelerate wound healing at the cellular and animal levels by modulating inflammatory responses and promoting collagen deposition and vascularization. This review summarizes the roles and mechanisms of MSC-exos originating from various sources in promoting the healing efficacy of general wounds, diabetic wounds, burn wounds, and healing-related scars. It also discusses the limitations and perspectives of MSC-exos in wound healing, in terms of exosome acquisition, mechanistic complexity, and exosome potentiation modalities. A deeper understanding of the properties and functions of MSC-exos is beneficial to advance the therapeutic approaches for achieving optimal wound healing.

Construction of n-type homogeneous to improve interfacial carrier transfer for enhanced photoelectrocatalytic hydrolysis.

Photoelectrocatalyzed hydrogen production plays an important role in the path to carbon neutrality. The construction of heterojunctions provides an ideal example of an oxygen precipitation reaction. In this work, the performance of the n-n type heterojunction CeBTC@FeBTC/NIF in the photoelectronically coupled catalytic oxygen evolution reaction (OER) reaction is presented. The efficient transfer of carriers between components enhances the catalytic activity. Besides, the construction of heterojunctions optimizes the energy level structure and increases the absorption of light, and the microstructure forms holes with a blackbody effect that also enhances light absorption. Consequently, CeBTC@FeBTC/NIF has excellent photoelectric coupling catalytic properties and requires an overpotential of only 300 mV to drive a current density of 100 mA cm-2 under illumination. More importantly, the n-n heterojunction was found to be effective in enhancing charge and photogenerated electron migration by examining the carrier density of each component and carrier diffusion at the interface.

Novel SARS-CoV-2 inhibition properties of the anti-cancer Kang Guan Recipe herbal formula.

The ongoing COVID-19 pandemic is a persistent challenge, with continued breakthrough infections despite vaccination efforts. This has spurred interest in alternative preventive measures, including dietary and herbal interventions. Previous research has demonstrated that herbal medicines can not only inhibit cancer progression but also combat viral infections, including COVID-19 by targeting SARS-CoV-2, indicating a multifaceted potential to address both viruses and cancer. Here, we found that the Kang Guan Recipe (KGR), a novel herbal medicine formula, associates with potent inhibition activity against the SARS-CoV-2 viral infection. We demonstrate that KGR exhibits inhibitory activity against several SARS-CoV-2 variants of concern (VOCs). Mechanistically, we found that KGR can block the interaction of the viral spike and human angiotensin-converting enzyme 2 (ACE2). Furthermore, we assessed the inhibitory effect of KGR on SARS-CoV-2 viral entry in vivo, observing that serum samples from healthy human subjects having taken KGR exhibited suppressive activity against SARS-CoV-2 variants. Our investigation provides valuable insights into the potential of KGR as a novel herbal-based preventive and therapeutic strategy against COVID-19.

Impact of an AI-Based laparoscopic cholecystectomy coaching program on the surgical performance: a randomized controlled trial.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the gold standard for treating symptomatic gallstones but carries inherent risks like bile duct injury (BDI). While critical view of safety (CVS) is advocated to mitigate BDI, its real-world adoption is limited. Additionally, significant variations in surgeon performance impede procedural standardization, highlighting the need for a feasible, innovative, and effective training approach. The aim of this study is to develop an Artificial Intelligence (AI)-assisted coaching program for LC to enhance surgical education and improve surgeon's performance. MATERIALS AND METHODS: We conducted a multi-center, randomized controlled trial from May 2022 to August 2023 to assess the impact of an AI-based coaching program, SmartCoach, on novice performing LC. Surgeons and patients meeting specific inclusion criteria were randomly assigned to either a coaching group with AI-enhanced feedback or a self-learning group. The primary outcome was assessed using the Laparoscopic Cholecystectomy Rating Form (LCRF), with secondary outcomes including surgical safety, efficiency, and adverse events. Statistical analyses were performed using SPSS, with significance set at P-value less than 0.05. RESULTS: Between May 2022 and August 2023, 22 surgeons were initially enrolled from 10 hospitals, with 18 completing the study. No demographic differences were noted between coaching and self-learning groups. In terms of surgical performance (LCRF scores), the coaching group showed significant improvement over time (31 to 40, P=0.008), outperforming the self-learning group by study end (40 vs 38, P=0.032). Significant improvements in CVS achievement were also noted in the coaching group (11% to 78%, P=0.021). Overall, the coaching program was well-received, outpacing traditional educational methods in both understanding and execution of CVS and participants in the intervention group expressed strongly satisfaction with the program. CONCLUSIONS: The AI-assisted surgical coaching program effectively improved surgical performance and safety for novice surgeons in LC procedures. The model holds significant promise for advancing surgical education.

Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy.

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

Interaction surface and topology of Get3-Get4-Get5 protein complex, involved in targeting tail-anchored proteins to endoplasmic reticulum.

Recent work has uncovered the "GET system," which is responsible for endoplasmic reticulum targeting of tail-anchored proteins. Although structural information and the individual roles of most components of this system have been defined, the interactions and interplay between them remain to be elucidated. Here, we investigated the interactions between Get3 and the Get4-Get5 complex from Saccharomyces cerevisiae. We show that Get3 interacts with Get4-Get5 via an interface dominated by electrostatic forces. Using isothermal titration calorimetry and small-angle x-ray scattering, we further demonstrate that the Get3 homodimer interacts with two copies of the Get4-Get5 complex to form an extended conformation in solution.

Structure of the Sgt2 dimerization domain complexed with the Get5 UBL domain involved in the targeting of tail-anchored membrane proteins to the endoplasmic reticulum.

The insertion of tail-anchored membrane (TA) proteins into the appropriate membrane is a post-translational event that requires stabilization of the transmembrane domain and targeting to the proper destination. Sgt2, a small glutamine-rich tetratricopeptide-repeat protein, is a heat-shock protein cognate (HSC) co-chaperone that preferentially binds endoplasmic reticulum-destined TA proteins and directs them to the GET pathway via Get4 and Get5. The N-terminal domain of Sgt2 seems to exert dual functions. It mediates Get5 interaction and allows substrate delivery to Get3. Following the N-terminus of Get5 is a ubiquitin-like (Ubl) domain that interacts with the N-terminus of Sgt2. Here, the crystal structure of the Sgt2 dimerization domain complexed with the Get5 Ubl domain (Sgt2N-Get5Ubl) is reported. This complex reveals an intimate interaction between one Sgt2 dimer and one Get5 monomer. This research further demonstrates that hydrophobic residues from both Sgt2 and Get5 play an important role in cell survival under heat stress. This study provides detailed molecular insights into the specific binding of this GET-pathway complex.

Herbal Compounds Dauricine and Isoliensinine Impede SARS-CoV-2 Viral Entry.

Targeting viral entry has been the focal point for the last 3 years due to the continued threat posed by SARS-CoV-2. SARS-CoV-2's entry is highly dependent on the interaction between the virus's Spike protein and host receptors. The virus's Spike protein is a key modulator of viral entry, allowing sequential cleavage of ACE2 at the S1/S2 and S2 sites, resulting in the amalgamation of membranes and subsequent entry of the virus. A Polybasic insertion (PRRAR) conveniently located at the S1/S2 site can also be cleaved by furin or by serine protease, TMPRSS2, at the cell surface. Since ACE2 and TMPRSS2 are conveniently located on the surface of host cells, targeting one or both receptors may inhibit receptor-ligand interaction. Here, we show that Dauricine and Isoliensinine, two commonly used herbal compounds, were capable of inhibiting SARS-CoV-2 viral entry by reducing Spike-ACE2 interaction but not suppressing TMPRSS2 protease activity. Further, our biological assays using pseudoviruses engineered to express Spike proteins of different variants revealed a reduction in infection rates following treatment with these compounds. The molecular modeling revealed an interconnection between R403 of Spike protein and both two compounds. Spike mutations at residue R403 are critical, and often utilized by ACE2 to gain cell access. Overall, our findings strongly suggest that Dauricine and Isoliensinine are effective in blocking Spike-ACE2 interaction and may serve as effective therapeutic agents for targeting SARS-CoV-2's viral entry.