Identification of ASF1A and HJURP by global H3-H4 histone chaperone analysis as a prognostic two-gene model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis. Abnormal expression of H3-H4 histone chaperones has been identified in many cancers and holds promise as a biomarker for diagnosis and prognosis. However, systemic analysis of H3-H4 histone chaperones in HCC is still lacking. Here, we investigated the expression of 19 known H3-H4 histone chaperones in HCC. Integrated analysis of multiple public databases indicated that these chaperones are highly expressed in HCC tumor tissues, which was further verified by immunohistochemistry (IHC) staining in offline samples. Additionally, survival analysis suggested that HCC patients with upregulated H3-H4 histone chaperones have poor prognosis. Using LASSO and Cox regression, we constructed a two-gene model (ASF1A, HJURP) that accurately predicts prognosis in ICGC-LIRI and GEO HCC data, which was further validated in HCC tissue microarrays with follow-up information. GSEA revealed that HCCs in the high-risk group were associated with enhanced cell cycle progression and DNA replication. Intriguingly, HCCs in the high-risk group exhibited increased immune infiltration and sensitivity to immune checkpoint therapy (ICT). In summary, H3-H4 histone chaperones play a critical role in HCC progression, and the two-gene (ASF1A, HJURP) risk model is effective for predicting survival outcomes and sensitivity to immunotherapy for HCC patients.

A Multifunctional Additive Based on the Cation-Anion Synergistic Effect for Highly Stable Zinc Metal Anodes.

The Zn dendrite and hydrogen evolution reaction have been a "stubborn illness" for the life span of zinc anodes, which significantly hinders the development of aqueous zinc batteries (AZBs). Herein, considering the ingenious molecular structure, a multifunctional additive based on the synergistic regulation of cations and anions at the interface is designed to promote a dendrite-free and stable Zn anode. Theoretical calculations and characterization results verified that the electrostatic shield effect of the cation, the solvation sheath structure, and the bilayer structural solid electrolyte film (SEI) jointly account for the uniform Zn deposition and side reaction suppression. Ultimately, a remarkably high average Coulombic efficiency (CE) of 99.4% is achieved in the Zn||Cu cell for 300 cycles, and a steady charge/discharge cycling over 3000 and 300 h at 1.0 mA cm-2/1.0 mAh cm-2 and 10 mA cm-2/10 mAh cm-2 is obtained in the Zn||Zn cell. Furthermore, the assembled full battery demonstrates a prolonged cycle life of 2000 cycles.

Engineering the Activity of a Newly Identified Arylalkylamine N-Acetyltransferase in the Acetylation of 5-Hydroxytryptamine.

Arylalkylamine N-acetyltransferase (AANAT) serves as a key enzyme in the biosynthesis of melatonin by transforming 5-hydroxytryptamine (5-HT) to N-acetyl-5-hydroxytryptamine (NAS), while its low activity may hinder melatonin yield. In this study, a novel AANAT derived from Sus scrofa (SsAANAT) was identified through data mining using 5-HT as a model substrate, and a rational design of SsAANAT was conducted in the quest to improving its activity. After four rounds of mutagenesis procedures, a triple combinatorial dominant mutant M3 was successfully obtained. Compared to the parent enzyme, the conversion of the whole-cell reaction bearing the best variant M3 exhibted an increase from 50 % to 99 % in the transformation of 5-HT into NAS. Additionally, its catalytic efficiency (kcat/Km) was enhanced by 2-fold while retaining the thermostability (Tm>45 °C). In the up-scaled reaction with a substrate loading of 50 mM, the whole-cell system incorporating variant M3 achieved a 99 % conversion of 5-HT in 30 h with an 80 % yield. Molecular dynamics simulations were ultilized to shed light on the origin of improved activity. This study broadens the repertoire of AANAT for the efficient biosynthesis of melatonin.

Engineering the activity and thermostability of a carboxylic acid reductase in the conversion of vanillic acid to vanillin.

Vanillin is a valuable natural product that can be used as a fragrance and additive. Recent research in the biosynthesis of vanillin has brought attention to a key enzyme, carboxylic acid reductase (CAR), which catalyzes the reduction of vanillic acid to vanillin. Nevertheless, the biosynthesis of vanillin is hampered by the low activity and stability of CAR. As such, a rational design campaign was conducted on a well-documented carboxylic acid reductase from Segniliparus rugosus (SrCAR), using vanillic acid as the model substrate. After combined active site saturation and iterative site-specific mutagenesis, the best quadruple mutant N292H/K524S/A627L/E1121W (M3) was successfully obtained. In comparison to the wildtype SrCAR, M3 demonstrated a 4.2-fold increase in catalytic efficiency (kcat/Km), and its half-life (t1/2) was enhanced by 3.8 times up to 385.08 minutes at 40 °C. In silico docking and molecular dynamics simulation provided insights into the improved activity and stability. In the subsequent preparative-scale reaction with 100 mM (16.8 g L-1) vanillic acid, the whole cell catalysis utilizing M3 produced 10.15 g·L-1 of vanillin and 1.11 g·L-1 of vanillyl alcohol, respectively. This work demonstrates a dual improvement in the activity and thermal stability of SrCAR, thereby potentially facilitating the application of carboxylic acid reductase in the biosynthesis of vanillin.

Atroposelective Synthesis of Aldehydes via Alcohol Dehydrogenase-Catalyzed Stereodivergent Desymmetrization.

Axially chiral aldehydes have emerged recently as a unique class of motifs for drug design. However, few biocatalytic strategies have been reported to construct structurally diverse atropisomeric aldehydes. Herein, we describe the characterization of alcohol dehydrogenases to catalyze atroposelective desymmetrization of the biaryl dialdehydes. Investigations into the interactions between the substrate and key residues of the enzymes revealed the distinct origin of atroposelectivity. A panel of 13 atropisomeric monoaldehydes was synthesized with moderate to high enantioselectivity (up to >99% ee) and yields (up to 99%). Further derivatization allows enhancement of the diversity and application potential of the atropisomeric compounds. This study effectively expands the scope of enzymatic synthesis of atropisomeric aldehydes and provides insights into the binding modes and recognition mechanisms of such molecules.

Non-contact assessment of cardiac physiology using FO-MVSS-based ballistocardiography: a promising approach for heart failure evaluation.

Continuous monitoring of cardiac motions has been expected to provide essential cardiac physiology information on cardiovascular functioning. A fiber-optic micro-vibration sensing system (FO-MVSS) makes it promising. This study aimed to explore the correlation between Ballistocardiography (BCG) waveforms, measured using an FO-MVSS, and myocardial valve activity during the systolic and diastolic phases of the cardiac cycle in participants with normal cardiac function and patients with congestive heart failure (CHF). A high-sensitivity FO-MVSS acquired continuous BCG recordings. The simultaneous recordings of BCG and electrocardiogram (ECG) signals were obtained from 101 participants to examine their correlation. BCG, ECG, and intracavitary pressure signals were collected from 6 patients undergoing cardiac catheter intervention to investigate BCG waveforms and cardiac cycle phases. Tissue Doppler imaging (TDI) measured cardiac time intervals in 51 participants correlated with BCG intervals. The BCG recordings were further validated in 61 CHF patients to assess cardiac parameters by BCG. For heart failure evaluation machine learning was used to analyze BCG-derived cardiac parameters. Significant correlations were observed between cardiac physiology parameters and BCG's parameters. Furthermore, a linear relationship was found betwen IJ amplitude and cardiac output (r = 0.923, R2 = 0.926, p < 0.001). Machine learning techniques, including K-Nearest Neighbors (KNN), Decision Tree Classifier (DTC), Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), and XGBoost, respectively, demonstrated remarkable performance. They all achieved average accuracy and AUC values exceeding 95% in a five-fold cross-validation approach. We establish an electromagnetic-interference-free and non-contact method for continuous monitoring of the cardiac cycle and myocardial contractility and measure the different phases of the cardiac cycle. It presents a sensitive method for evaluating changes in both cardiac contraction and relaxation in the context of heart failure assessment.

An efflux pump in genomic island GI-M202a mediates the transfer of polymyxin B resistance in Pandoraea pnomenusa M202 / Una bomba de eflujo en la isla genómica GI-M202a media la transferencia de resistencia a la polimixina B en Pandoraea pnomenusa M202

Background: Polymyxin B is considered a last-line therapeutic option against multidrug-resistant gram-negative bacteria, especially in COVID-19 coinfections or other serious infections. However, the risk of antimicrobial resistance and its spread to the environment should be brought to the forefront. Methods: Pandoraea pnomenusa M202 was isolated under selection with 8 mg/L polymyxin B from hospital sewage and then was sequenced by the PacBio RS II and Illumina HiSeq 4000 platforms. Mating experiments were performed to evaluate the transfer of the major facilitator superfamily (MFS) transporter in genomic islands (GIs) to Escherichia coli 25DN. The recombinant E. coli strain Mrc-3 harboring MFS transporter encoding gene FKQ53_RS21695 was also constructed. The influence of efflux pump inhibitors (EPIs) on MICs was determined. The mechanism of polymyxin B excretion mediated by FKQ53_RS21695 was investigated by Discovery Studio 2.0 based on homology modeling. Results: The MIC of polymyxin B for the multidrug-resistant bacterial strain P. pnomenusa M202, isolated from hospital sewage, was 96 mg/L. GI-M202a, harboring an MFS transporter-encoding gene and conjugative transfer protein-encoding genes of the type IV secretion system, was identified in P. pnomenusa M202. The mating experiment between M202 and E. coli 25DN reflected the transferability of polymyxin B resistance via GI-M202a. EPI and heterogeneous expression assays also suggested that the MFS transporter gene FKQ53_RS21695 in GI-M202a was responsible for polymyxin B resistance. Molecular docking revealed that the polymyxin B fatty acyl group inserts into the hydrophobic region of the transmembrane core with Pi-alkyl and unfavorable bump interactions, and then polymyxin B rotates around Tyr43 to externally display the peptide group during the efflux process, accompanied by an inward-to-outward conformational change in the MFS transporter...(AU)

Effect of Starch Plasticization on Morphological, Mechanical, Crystalline, Thermal, and Optical Behavior of Poly(butylene adipate-co-terephthalate)/Thermoplastic Starch Composite Films.

Starches plasticized with glycerol/citric acid/stearic acid and tributyl 2-acetylcitrate (ATBC), respectively, were processed with poly (butylene adipate-Co-terephthalate (PBAT) via extrusion and a film-blown process. All the composite films were determined for morphology, mechanical, thermal stability, crystalline, and optical properties. Results show that the most improved morphology was in the 30% glycerol plasticized PBAT/thermoplastic starch (TPS) composite films, characterized by the smallest and narrowest distribution of TPS particle sizes and a more uniform dispersion of TPS particles. However, the water absorption of PBAT/TPS composite films plasticized with glycerol surpassed that observed with ATBC as a plasticizer. Mechanical properties indicated insufficient plasticization of the starch crystal structure when using 10% ATBC, 20% ATBC, and 20% glycerol as plasticizers, leading to poor compatibility between PBAT and TPS. This resulted in stress concentration points under external forces, adversely affecting the mechanical properties of the composites. All PBAT/TPS composite films exhibited a negative impact on the initial thermal decomposition temperature compared to PBAT. Additionally, the haze value of PBAT/TPS composite films exceeded 96%, while pure PBAT had a haze value of 47.42%. Films plasticized with 10% ATBC, 20% ATBC, and 20% glycerol displayed lower transmittance values in the visible light region. The increased transmittance of films plasticized with 30% glycerol further demonstrated their superior plasticizing effect compared to other PBAT/TPS composite films. This study provides a simple and feasible method for preparing low-cost PBAT composites, and their extensions are expected to further replace general-purpose plastics in daily applications.

Construction of Smart DNA-Based Drug Delivery Systems for Cancer Therapy.

Due to the disadvantages of poor targeting, slow action, and low effectiveness of current commonly used cancer treatments, including surgery, chemotherapy, and radiotherapy, researchers have turned to DNA as a biomaterial for constructing drug delivery nanocarriers. DNA is favored for its biocompatibility and programmability. In order to overcome the limitations associated with traditional drug delivery systems (DDSs), researchers have developed smart-responsive DNA DDSs that can control drug release in response to specific physical or chemical stimuli at targeted sites. In this review, a summary of multiple targeted ligand structures is provided, various shapes of stable DNA nanomaterials, and different stimuli-responsive drug release strategies in DNA DDSs. Specifically, targeted cell recognition, in vivo stable transport, and controlled drug release of smart DDSs are focused. Finally, the further development prospects and challenges of clinical application of DNA nanomaterials in the field of smart drug delivery are discussed. The objective of this review is to enhance researchers' comprehension regarding the potential application of DNA nanomaterials in precision drug delivery, with the aim of expediting the clinical implementation of intelligent DDSs.

Deciphering Structure-Activity Relationship Towards CO2 Electroreduction over SnO2 by A Standard Research Paradigm.

Authentic surface structures under reaction conditions determine the activity and selectivity of electrocatalysts, therefore, the knowledge of the structure-activity relationship can facilitate the design of efficient catalyst structures for specific reactivity requirements. However, understanding the relationship between a more realistic active surface and its performance is challenging due to the complicated interface microenvironment in electrocatalysis. Herein, we proposed a standard research paradigm to effectively decipher the structure-activity relationship in electrocatalysis, which is exemplified in the CO2 electroreduction over SnO2 . The proposed practice has aided in discovering authentic/resting surface states (Sn layer) of SnO2 accountable for the electrochemical CO2 reduction reaction (CO2 RR) performance under electrocatalytic conditions, which then is corroborated in the subsequent CO2 RR experiments over SnO2 with different morphologies (nanorods, nanoparticles, and nanosheets) in combination with in situ characterizations. This proposed methodology is further extended to the SnO electrocatalysts, providing helpful insights into catalytic structures. It is believed that our proposed standard research paradigm is also applicable to other electrocatalytic systems, in the meantime, decreases the discrepancy between theory and experiments, and accelerates the design of catalyst structures that achieve sustainable performance for energy conversion.

Steering CO2 Electroreduction to C2+ Products via Enhancing Localized *CO Coverage and Local Pressure in Conical Cavity.

The electrochemical carbon dioxide (CO2 ) reduction reaction (CO2 RR) involves a multistep proton-coupled electron transfer (PCET) process that generates a variety of intermediates, making it challenging to transform them into target products with high activity and selectivity. Here, a catalyst featuring a nanosheet-stacked sphere structure with numerous open and deep conical cavities (OD-CCs) is reported. Under the guidance of the finite-element method (FEM) simulations and theoretical analysis, it is shown that exerting control over the confinement space results in diffusion limitation of the carbon intermediates, thereby increasing local pressure and subsequently enhancing localized *CO coverage for dimerization. The nanocavities exhibit a structure-driven shift in selectivity of multicarbon (C2+ ) product from 41.8% to 81.7% during the CO2 RR process.

An efflux pump in genomic island GI-M202a mediates the transfer of polymyxin B resistance in Pandoraea pnomenusa M202.

BACKGROUND: Polymyxin B is considered a last-line therapeutic option against multidrug-resistant gram-negative bacteria, especially in COVID-19 coinfections or other serious infections. However, the risk of antimicrobial resistance and its spread to the environment should be brought to the forefront. METHODS: Pandoraea pnomenusa M202 was isolated under selection with 8 mg/L polymyxin B from hospital sewage and then was sequenced by the PacBio RS II and Illumina HiSeq 4000 platforms. Mating experiments were performed to evaluate the transfer of the major facilitator superfamily (MFS) transporter in genomic islands (GIs) to Escherichia coli 25DN. The recombinant E. coli strain Mrc-3 harboring MFS transporter encoding gene FKQ53_RS21695 was also constructed. The influence of efflux pump inhibitors (EPIs) on MICs was determined. The mechanism of polymyxin B excretion mediated by FKQ53_RS21695 was investigated by Discovery Studio 2.0 based on homology modeling. RESULTS: The MIC of polymyxin B for the multidrug-resistant bacterial strain P. pnomenusa M202, isolated from hospital sewage, was 96 mg/L. GI-M202a, harboring an MFS transporter-encoding gene and conjugative transfer protein-encoding genes of the type IV secretion system, was identified in P. pnomenusa M202. The mating experiment between M202 and E. coli 25DN reflected the transferability of polymyxin B resistance via GI-M202a. EPI and heterogeneous expression assays also suggested that the MFS transporter gene FKQ53_RS21695 in GI-M202a was responsible for polymyxin B resistance. Molecular docking revealed that the polymyxin B fatty acyl group inserts into the hydrophobic region of the transmembrane core with Pi-alkyl and unfavorable bump interactions, and then polymyxin B rotates around Tyr43 to externally display the peptide group during the efflux process, accompanied by an inward-to-outward conformational change in the MFS transporter. Additionally, verapamil and CCCP exhibited significant inhibition via competition for binding sites. CONCLUSIONS: These findings demonstrated that GI-M202a along with the MFS transporter FKQ53_RS21695 in P. pnomenusa M202 could mediate the transmission of polymyxin B resistance.

Influence of silver doping on pro-inflammatory and pro-fibrogenic effects of nano-titanium dioxide in murine lung.

Silver is usually loaded on nano-titanium dioxide (TiO2 ) through photodeposition method to enhance visible-light catalytic functions for environment purification. However, little is known about how the toxicity changes after silver doping and how the physicochemical properties of loaded components affect nanocomposite toxicity. In this study, Ag-TiO2 with different sizes and contents of silver particles were obtained by controlling photodeposition time (PDT) and silver addition amount. Pro-inflammatory and pro-fibrogenic responses of these photocatalysts were evaluated in male C57BL/6J murine lung. As a result, silver was well assembled on TiO2 , promoting visible-light catalytic activity. Notably, the size of silver particles increased with PDT. Meanwhile, toxicity results showed that pure TiO2 (P25) mainly caused neutrophil infiltration, while 2 wt/wt% silver-loaded TiO2 recruited more types of inflammatory cells in the lung. Both of them caused the increase of proinflammatory cytokines while decreasing the anti-inflammatory cytokine in bronchoalveolar lavage fluid. However, 2 wt/wt% silver doping also accelerated the lung pro-fibrogenic response of photocatalysts in the subacute phase from evidence of collagen deposition and hydroxyproline concentrations. Mechanistically, the overactivation of TGFBR2 receptors in TGF-ß/smads pathways by silver-loaded TiO2 rather than pure TiO2 may be the reason why silver-loaded TiO2 can promote pro-fibrogenic effect response. Intriguingly, the increased toxicity caused by silver doping can be rescued by increasing the size of the loaded silver or decreasing the silver amount. These results may be important for the new understanding of the toxicity of TiO2 -based photocatalysts.

The toxicological effects of nano titanium dioxide on target organs and mechanisms of toxicity.

Nano-titanium dioxide (TiO2 NPs) is widely used for its extremely high stability, corrosion resistance, and photocatalytic properties and has penetrated into various fields of production and life. Assessing its toxicity to different organs should be a key part of preclinical toxicity assessment of TiO2 NPs, which is relatively incomprehensive yet. Therefore, this review focuses on the toxic effects of TiO2 NPs on various organs in mammals and biological mechanisms from different organs. The commonality of toxic effects on various target organs reflected in tissue structure damage and dysfunction, such as liver damage and dysfunction; pulmonary fibrosis; and renal impairment (including hematuria and nephritis); damage of brain tissue and neurons; alteration of intestinal villi; and weight loss. And effects on the reproductive system are affected by different sexes, including ovarian dysfunction, testicular development damage, and sperm viability reduction. We believe that the toxic mechanisms of TiO2 NPs in target organs have commonalities, such as oxidative stress, inflammatory responses, and organelle damage. However, different target organ toxicities also have their specificities. TiO2 NPs disturb the intestinal flora and cause undesirable changes in feces products. And in spleen are infiltration of neutrophils and lymphadenopathy and eventually immune deficiency. Although the toxic pathways are different, but there may be a close link between the different toxic pathways. In this article, the main manifestations of the toxic effects of titanium dioxide nanoparticles on major mammalian organs are reviewed, in order to provide basic data for their better application from a medical perspective.

Transcranial Direct Current Stimulation for Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The effects of transcranial direct current stimulation (tDCS) in the treatment of knee osteoarthritis (KOA) is still unclear. The objective is to evaluate the efficacy and safety of tDCS in improving symptoms in patients with KOA. METHODS: The following electronic databases were searched for eligible randomized controlled trials (RCTs): PubMed, Embase, Web of Science, and the Cochrane Library. The search was performed from the inception dates to April 30, 2023. Data extraction and quality assessment were performed by two independent reviewers. Standard mean differences (SMDs) with 95% confidence intervals (95% CIs) for pooled data were calculated. A random-effects model was used for the data analyses. The primary outcomes were pain and physical function. Secondary outcomes included stiffness, mobility performance, quality of life, pressure pain tolerance, and plasma levels of brain-derived neurotrophic factor (BDNF). RESULTS: This meta-analysis included 13 RCTs. tDCS was significantly associated with pain decrease compared with sham tDCS (SMD = -0.62, 95% CI -0.87 to -0.37, P < 0.00001). When comparing tDCS plus other non-tDCS with sham tDCS plus other non-tDCS, there was no longer a significant association with pain decrease (SMD = -0.45, 95% CI -1.08 to 0.17, P = 0.16). The changes in physical function were not significantly different between the tDCS and sham tDCS groups (SMD = -0.09, 95% CI -0.56 to 0.38, P = 0.71). When comparing tDCS plus other non-tDCS with sham tDCS plus other non-tDCS, there was still no significant association with improvement in physical function (SMD = -0.66, 95% CI -1.63 to 0.30, P = 0.18). There was no significant difference with improvement in stiffness (SMD = -0.21, 95% CI -0.77 to 0.34, P = 0.45), mobility performance (SMD = 4.58, 95% CI -9.21 to 18.37, P = 0.51), quality of life (SMD = -7.01, 95% CI -22.61 to 8.59, P = 0.38), and pressure pain tolerance (SMD = 0.30, 95% CI -0.09 to 0.69, P = 0.13). There was a statistically significant reduction in plasma levels of BDNF (SMD = -13.57, 95% CI -24.23 to -2.92, P = 0.01). CONCLUSION: In conclusion, tDCS could significantly alleviate pain, but it might have no efficacy in physical function, stiffness, mobility performance, quality of life, and pressure pain tolerance among patients with KOA.

Assessing the ecological impacts of polycyclic aromatic hydrocarbons petroleum pollutants using a network toxicity model.

Polycyclic aromatic hydrocarbons (PAHs) are significant petroleum pollutants that have long-term impacts on human health and ecosystems. However, assessing their toxicity presents challenges due to factors such as cost, time, and the need for comprehensive multi-component analysis methods. In this study, we utilized network toxicity models, enrichment analysis, and molecular docking to analyze the toxicity mechanisms of PAHs at different levels: compounds, target genes, pathways, and species. Additionally, we used the maximum acceptable concentration (MAC) value and risk quotient (RQ) as an indicator for the potential ecological risk assessment of PAHs. The results showed that higher molecular weight PAHs had increased lipophilicity and higher toxicity. Benzo[a]pyrene and Fluoranthene were identified as core compounds, which increased the risk of cancer by affecting core target genes such as CCND1 in the human body, thereby influencing signal transduction and the immune system. In terms of biological species, PAHs had a greater toxic impact on aquatic organisms compared to terrestrial organisms. High molecular weight PAHs had lower effective concentrations on biological species, and the ecological risk was higher in the Yellow River Delta region. This research highlights the potential application of network toxicity models in understanding the toxicity mechanisms and species toxicity of PAHs and provides valuable insights for monitoring, prevention, and ecological risk assessment of these pollutants.

LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8+ T cells for improving anti-PD-1 antibody therapy.

Anti-PD-1 antibody therapy has achieved success in tumor treatment; however, the duration of its clinical benefits are typically short. The functional state of intratumoral CD8+ T cells substantially affects the efficacy of anti-PD-1 antibody therapy. Understanding how intratumoral CD8+ T cells change will contribute to the improvement in anti-PD-1 antibody therapy. In this study, we found that tumor growth was not arrested after the late administration of anti-PD-1 antibody and that the antitumor function of CD8+ T cells decreased with tumor progression. The results of the RNA sequencing of CD8+ T cells infiltrating the tumor site on days 7 and 14 showed that the cell adhesion molecule Lymphocyte Function-associated Antigen-1 (LFA-1) participates in regulating the antitumor function of CD8+ T cells and that decreased LFA-1 expression in intratumoral CD8+ T cells is associated with tumor progression. By analyzing the Gene Expression Omnibus (GEO) database and our results, we found that the antitumor function of intratumoral CD8+ T cells with high LFA-1 expression was stronger. The formation of immune synapses is impaired in Itgal-si CD8+ T cells, resulting in decreased anti-tumor function. LFA-1 expression in intratumoral CD8+ T cells is regulated by the IL-2/STAT5 pathway. The combination of IL-2 and anti-PD-1 antibody effectively enhanced LFA-1 expression and the antitumor function of intratumoral CD8+ T cells. The adoptive transfer of OT-1 T cells overexpressing LFA-1, STAT5A, or STAT5B resulted in higher antitumor function, deferred tumor growth, and prolonged survival. These findings indicate that LFA-1-mediated immune synapse acts as a regulator of the antitumor function of intratumoral CD8+ T cells, which can be applied to improve anti-PD-1 antibody therapy.

Research and publication trends on knee osteoarthritis and cellular senescence: a bibliometric analysis.

Background: Cellular senescence is associated with age-related pathological changes, senescent cells promote the development of knee osteoarthritis. A better understanding between knee osteoarthritis and cellular senescence may enhance the effectiveness of therapies that aim to slow or stop the progression of this disease. Purpose: This study aimed to systematically analyze and visualize the publication trends, research frontiers and current research hotspots of knee osteoarthritis and cellular senescence by using bibliometrics. Methods: The publication search was performed on the Web of Science Core Collection database for documents published from 1992 to 2023. VOSviewer, Citespace, R package Bibliometrix and Microsoft Office Excel were used to study the characteristics of the publications. The publication number, countries, institutions, authors, journals, citations and co-citations, keywords were analyzed. Results: A total of 1,074 publications were analyzed, with an average annual growth rate of 29.89%. United States accounted for the biggest contributor, ranked first in publications and citations. Publications of this field were published in 420 journals, OSTEOARTHRITIS and CARTILAGE was the most influential. A total of 5,657 authors contributed to this research. The most productive author was Lotz, MK (n = 31, H-index = 22, Total citation = 2,619), followed by Loeser, R.F (n = 16, H-index = 14, Total citation = 2,825). However, the collaboration between authors was relatively weak. Out of the 1,556 institutions involved, 60% were from the United States. Scripps Research ranked first with 25 papers and a total of 2,538 citations. The hotspots of this field had focused on the pathomechanisms (e.g., expression, inflammation, apoptosis, autophagy, oxidative stress) and therapeutics (e.g., stem cell, platelet-rich plasma, transplantation, autologous chondrocytes, repair), and the exploration of Senolytics might be the important direction of future research. Conclusion: Research on the cross field of knee osteoarthritis and cellular senescence is flourishing. Age-related pathomechanism maps of various cells in the joint and the targeted medicines for the senescent cells may be the future trends. This bibliometric study provides a comprehensive analysis of this cross field and new insights into future research.

Application and challenges of a metaverse in medicine.

Metaverse has been confirmed as a relatively amorphous concept of innovation, which refers to technological advancement. Metaverse, i.e., a coalition between reality world and virtual world, has created significant significance and convenience in education, communication, economy, etc. The COVID-19 outbreak has stimulated the growth of metaverse applications in medicine. The above-mentioned technology has broad applications while comprising online remote medical treatment, online conferences, medical education, preparation of surgical plans, etc. Moreover, technical, security, and financial challenges should be tackled down by the future widespread use of metaverse. Metaverse is limitlessly promising, and it will exert a certain effect on future scientific and technological advancements in the medical industry. The review article primarily aims to summarize the application of the metaverse in medicine and their challenge in the future of medicine.

Uncovering the complex regulatory network of spring bud sprouting in tea plants: insights from metabolic, hormonal, and oxidative stress pathways.

The sprouting process of tea buds is an essential determinant of tea quality and taste, thus profoundly impacting the tea industry. Buds spring sprouting is also a crucial biological process adapting to external environment for tea plants and regulated by complex transcriptional and metabolic networks. This study aimed to investigate the molecular basis of bud sprouting in tea plants firstly based on the comparisons of metabolic and transcriptional profiles of buds at different developmental stages. Results notably highlighted several essential processes involved in bud sprouting regulation, including the interaction of plant hormones, glucose metabolism, and reactive oxygen species scavenging. Particularly prior to bud sprouting, the accumulation of soluble sugar reserves and moderate oxidative stress may have served as crucial components facilitating the transition from dormancy to active growth in buds. Following the onset of sprouting, zeatin served as the central component in a multifaceted regulatory mechanism of plant hormones that activates a range of growth-related factors, ultimately leading to the promotion of bud growth. This process was accompanied by significant carbohydrate consumption. Moreover, related key genes and metabolites were further verified during the entire overwintering bud development or sprouting processes. A schematic diagram involving the regulatory mechanism of bud sprouting was ultimately proposed, which provides fundamental insights into the complex interactions involved in tea buds.