A Model for Chemomechanical Coupling of Kinesin-3 Motor.

Introduction: Kinesin-3 motor, which is in the monomeric and inactive form in solution, after cargo-induced dimerization can step on microtubules towards the plus end with a high velocity and a supperprocessivity, which is responsible for transporting the cargo in axons and dendrites. The kinesin-3 motor has a large initial landing rate to microtubules and spends the majority of its stepping cycle in a one-head-bound state. Under the load the kinesin-3 motor can dissociate more readily than the kinesin-1 motor. Methods: To understand the physical origin of the peculiar features for the kinesin-3 motor, a model is presented here for its chemomechanical coupling. Based on the model the dynamics of the motor under no load, under the ramping load and under the constant load is studied analytically. Results: The theoretical results explain well the available experimental data under no load and under the ramping load. For comparison, the corresponding available experimental data for the kinesin-1 motor under the ramping load are also explained. The predicted results of the velocity, dissociation rate and run length versus the constant load for the kinesin-3 motor are provided. Conclusions: The study has strong implications for the chemomechanical coupling mechanism of the kinesin-3 dimer. The origin of the kinesin-3 dimer in the predominant one-head-bound state is due to the fact that the rate of ATP transition to ADP in the trailing head is much larger than that of ADP release from the MT-bound head. The study shows that the kinesin-3 ADP-head has an evidently longer interaction distance with microtubule than the kinesin-1 ADP-head, explaining why in the initial ADP state the kinesin-3 motor has the much larger landing rate than the kinesin-1 motor and why under the load the kinesin-3 motor can dissociate more readily than the kinesin-1 motor. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00795-1.

Interval training suppresses nod-like receptor protein 3 inflammasome activation to improve cardiac function in myocardial infarction rats by hindering the activation of the transforming growth factor-ß1 pathway.

OBJECTIVE: Myocardial infarction (MI) -induced cardiac dysfunction can be attenuated by aerobic exercises. This study explored the mechanism of interval training (IT) regulating cardiac function in MI rats, providing some theoretical basis for clarifying MI pathogenesis and new ideas for clinically treating MI. METHODS: Rats were subjected to MI modeling, IT intervention, and treatments of the Transforming growth factor-ß1 (TGF-ß1) pathway or the nod-like receptor protein 3 (NLRP3) activators. Cardiac function and hemodynamic indicator alterations were observed. Myocardial pathological damage and fibrosis, reactive oxygen species (ROS) level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, MDA content, inflammasome-associated protein levels, and inflammatory factor levels were assessed. The binding between TGF-ß1 and receptor was detected. RESULTS: MI rats exhibited decreased left ventricle ejection fraction (LVEF), left ventricle fractional shortening  (LVFS), left ventricular systolic pressure  (LVSP), positive and negative derivates max/min (dP/dt max/min) and increased left ventricular end-systolic pressure (LVEDP), a large number of scar areas in myocardium, disordered cell arrangement and extensive fibrotic lesions, increased TGF-ß1 and receptor binding, elevated ROS level and MDA content and weakened SOD, CAT and GSH-Px activities, and up-regulated NLRP3, apoptosis-associated speck-like protein containing a CARD  (ASC) and cleaved-caspase-1 levels, while IT intervention caused ameliorated cardiac function. IT inactivated the TGF-ß1 pathway to decrease oxidative stress in myocardial tissues of MI rats and inhibit NLRP3 inflammasome activation. Activating NLRP3 partially reversed IT-mediated improvement on cardiac function in MI rats. CONCLUSION: IT diminished oxidative stress in myocardial tissues and suppressed NLRP3 inflammasome activation via inactivating the TGF-ß1 pathway, thus improving the cardiac function of MI rats.

Ziyin Bushen Fang improves Diabetic Osteoporosis by Inhibiting Autophagy and Oxidative Stress In vitro and In vivo.

OBJECTIVE: Diabetic osteoporosis (DOP) belongs to the group of diabetes-induced secondary osteoporosis and is the main cause of bone fragility and fractures in many patients with diabetes. The aim of this study was to determine whether Ziyin Bushen Fang (ZYBSF) can improve DOP by inhibiting autophagy and oxidative stress. METHODS: Type 1 diabetes mellitus (T1DM) was induced in rats using a high-fat high-sugar diet combined with streptozotocin. Micro-CT scanning was used to quantitatively observe changes in the bone microstructure in each group. Changes in the serum metabolites of DOP rats were analyzed using UHPLC-QTOF-MS. The DOP mouse embryonic osteoblast precursor cell model (MC3T3-E1) was induced using high glucose levels. RESULTS: After ZYBSF treatment, bone microstructure significantly improved. The bone mineral density, trabecular number, and trabecular thickness in the ZYBSF-M and ZYBSF-H groups significantly increased. After ZYBSF treatment, the femur structure of the rats was relatively intact, collagen fibers were significantly increased, and osteoporosis was significantly improved. A total of 1239 metabolites were upregulated and 1527 were downregulated in the serum of T1DM and ZYBSF-treated rats. A total of 20 metabolic pathways were identified. In cellular experiments, ZYBSF reduced ROS levels and inhibited the protein expression of LC3II / I, Beclin-1, and p-ERK. CONCLUSION: ZYBSF may improve DOP by inhibiting the ROS/ERK-induced autophagy signaling pathway.

The origins of odor (ß-cyclocitral) under different water nutrient conditions: Algae or submerged plants?

Among the problems caused by water eutrophication, the issue of odor compounds has attracted notable attention. ß-Cyclocitral, a widely distributed and versatile odor compound, is commonly derived from both algae and aquatic plants. Planting aquatic plants is a common method of water purification. However, there is limited study on their impact on ß-cyclocitral levels in water. Here, we conducted a study on the ß-cyclocitral levels in water and the submerged plant leaves under three nutrient levels and six plant density treatments. Our findings revealed the following: (1) Chlorophyll-a (Chla), ß-cyclocitral in the water (Wcyc), ß-cyclocitral in Potamogeton lucens leaves (Pcyc) and the biomass of the submerged plants increase with rising nutrient concentration, which increased about 83 %, 95 %, 450 %, 320 % from eutrophic treatment to oligotrophic treatment, respectively. (2) In water, ß-cyclocitral is influenced not only by algae but also by submerged plants, with primary influencing factors varying across different nutrient levels and plant densities. The main source of ß-cyclocitral in water becomes from plants to algae as the water eutrophication and plant density decrease. (3) As submerged plants have the capability to emit ß-cyclocitral, the release of ß-cyclocitral increases with the density of submerged plants. Hence, when considering planting submerged plants for water purification purposes, it is crucial to carefully manage submerged plant density to mitigate the risk of odor pollution emanating from aquatic plants. This study offers fresh insights into selecting optimal water density for submerged plants and their role in mitigating the release of ß-cyclocitral.

Embracing the future: Integrating ChatGPT into China's nursing education system.

This article delves into the role of ChatGPT within the rapidly evolving field of artificial intelligence, especially highlighting its significant potential in nursing education. Initially, the paper presents the notable advancements ChatGPT has achieved in facilitating interactive learning and providing real-time feedback, along with the academic community's growing interest in this technology. Subsequently, summarizing the research outcomes of ChatGPT's applications in nursing education, including various clinical disciplines and scenarios, showcases the enormous potential for multidisciplinary education and addressing clinical issues. Comparing the performance of several Large Language Models (LLMs) on China's National Nursing Licensure Examination, we observed that ChatGPT demonstrated a higher accuracy rate than its counterparts, providing a solid theoretical foundation for its application in Chinese nursing education and clinical settings. Educational institutions should establish a targeted and effective regulatory framework to leverage ChatGPT in localized nursing education while assuming corresponding responsibilities. Through standardized training for users and adjustments to existing educational assessment methods aimed at preventing potential misuse and abuse, the full potential of ChatGPT as an innovative auxiliary tool in China's nursing education system can be realized, aligning with the developmental needs of modern teaching methodologies.

Influence of environmental filtering and spatial processes on macroinvertebrate community in urban lakes in the Taihu Lake Basin, China.

Studies identifying the relative importance of multiple ecological processes in macroinvertebrate communities in urban lakes at a basin scale are rare. In this study, 14 urban lakes in the Taihu Lake Basin were selected to explore the relative importance of environmental filtering and spatial processes in the assembly of macroinvertebrate communities. Our findings revealed significant spatiotemporal variations in macroinvertebrate communities, both between lakes and across seasons. We found that environmental filtering exerted a greater influence on taxonomic total beta diversity and its individual components (species turnover and nestedness) compared to spatial processes. Key environmental variables such as water depth, water temperature, total dissolved solids, chlorophyll a, and lake surface area were found to be crucial in shaping macroinvertebrate communities within these urban lakes. The observed high spatial heterogeneity in environmental conditions, along with intermediate basin areas, good connectivity and short distances between lakes, and the high dispersal ability of dominant taxa, likely contributed to the dominance of environmental filtering in macroinvertebrate community assembly. Our study contributes to a better understanding of the underlying mechanisms governing macroinvertebrate community assembly in urban lakes, thereby providing valuable insights for studies on community ecology and water environmental protection in urban lakes.

ATP Concentration-Dependent Fractions of One-Head-Bound and Two-Head-Bound States of the Kinesin Motor during Its Chemomechanical Coupling Cycle.

Kinesin is a typical motor protein that can use the chemical energy of ATP hydrolysis to step processively on microtubules, alternating between one-head-bound and two-head-bound states. Some published experimental results showed that the duration of the one-head-bound state increases greatly with a decrease in ATP concentration, whereas the duration of the two-head-bound state is independent of ATP concentration, indicating that ATP binding occurs in the one-head-bound state. On the contrary, other experimental results showed that the duration of the two-head-bound state increases greatly with a decrease in ATP concentration, whereas the duration of the one-head-bound state increases slightly with a decrease in ATP concentration, indicating that ATP binding occurs mainly in the two-head-bound state. Here, we explain consistently and quantitatively these contradictory experimental results, resolving the controversy that is critical to the chemomechanical coupling mechanism of the kinesin motor.

Modeling Studies of the Mechanism of Context-Dependent Bidirectional Movements of Kinesin-14 Motors.

Kinesin-14s, a subfamily of the large superfamily of kinesin motor proteins, function mainly in spindle assembly and maintenance during mitosis and meiosis. KlpA from Aspergillus nidulans and GiKIN14a from Giardia intestinalis are two types of kinesin-14s. Available experimental results puzzlingly showed that while KlpA moves preferentially toward the minus end in microtubule-gliding setups and inside parallel microtubule overlaps, it moves preferentially toward the plus end on single microtubules. More puzzlingly, the insertion of an extra polypeptide linker in the central region of the neck stalk switches the motility direction of KlpA on single microtubules to the minus end. Prior experimental results showed that GiKIN14a moves preferentially toward the minus end on single microtubules in either tailless or full-length forms. The tail not only greatly enhances the processivity but also accelerates the ATPase rate and velocity of GiKIN14a. The insertion of an extra polypeptide linker in the central region of the neck stalk reduces the ATPase rate of GiKIN14a. However, the underlying mechanism of these puzzling dynamical features for KlpA and GiKIN14a is unclear. Here, to understand this mechanism, the dynamics of KlpA and GiKIN14a were studied theoretically on the basis of the proposed model, incorporating potential changes between the kinesin head and microtubule, as well as the potential between the tail and microtubule. The theoretical results quantitatively explain the available experimental results and provide predicted results. It was found that the elasticity of the neck stalk determines the directionality of KlpA on single microtubules and affects the ATPase rate and velocity of GiKIN14a on single microtubules.

Selective microRNA expression of exosomes from retinal pigment epithelial cells by oxidative stress.

The function of exosomal miRNAs (miRs) in retinal degeneration is largely unclear. We were aimed to investigate the functions of exosomes as well as their miRs derived from retinal pigment epithelial (RPE) cells following exposure to oxidative stress (OS). After the OS by lipopolysaccharide and rotenone on RPE cells, interleukin-1 beta (IL-1ß), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α) were upregulated, along with the decreased mitochondrial membrane potential and upregulated oxidative damage marker 8-OH-dG in RPE cells. RPE-derived exosomes were then isolated, identified, injected into the subretinal space in mice. After subretinal injection, RPE-exosomes after OS not only induced higher ROS level and apoptotic retinal cells, but also elevated IL-1ß, IL-6 alongside TNF-α expressions among retina/RPE/choroidal complex. Next, miRs inside the exosomes were sequenced by the next generation sequencing (NGS) technology. NGS revealed that certain miRs were abundant in exosomes, while others were selectively kept by RPE cells. Further, downregulated miRs, like miR-125b-5p, miR-125a-5p, alongside miR-128-3p, and upregulated miR, such as miR-7-5p were validated byRT-qPCR. Finally, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to find the possible target genes of those selective exosomal miRs. Our results proved that the RPE-derived exosomes after OS selectively express certain miRs, providing novel insights into the pathogenesis of age-related macular degeneration (AMD) in future.

Intravascular ultrasound-guided versus angiography-guided percutaneous coronary intervention in acute coronary syndromes (IVUS-ACS): a two-stage, multicentre, randomised trial.

BACKGROUND: Intravascular ultrasound-guided percutaneous coronary intervention has been shown to result in superior clinical outcomes compared with angiography-guided percutaneous coronary intervention. However, insufficient data are available concerning the advantages of intravascular ultrasound guidance for patients with an acute coronary syndrome. This trial aimed to investigate whether the use of intravascular ultrasound guidance, as compared with angiography guidance, improves the outcomes of percutaneous coronary intervention with contemporary drug-eluting stents in patients presenting with an acute coronary syndrome. METHODS: In this two-stage, multicentre, randomised trial, patients aged 18 years or older and presenting with an acute coronary syndrome at 58 centres in China, Italy, Pakistan, and the UK were randomly assigned to intravascular ultrasound-guided percutaneous coronary intervention or angiography-guided percutaneous coronary intervention. Patients, follow-up health-care providers, and assessors were masked to random assignment; however, staff in the catheterisation laboratory were not. The primary endpoint was target vessel failure, a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularisation at 1 year after randomisation. This trial is registered at ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Aug 20, 2019 and Oct 27, 2022, 3505 patients with an acute coronary syndrome were randomly assigned to intravascular ultrasound-guided percutaneous coronary intervention (n=1753) or angiography-guided percutaneous coronary intervention (n=1752). 1-year follow-up was completed in 3504 (>99·9%) patients. The primary endpoint occurred in 70 patients in the intravascular ultrasound group and 128 patients in the angiography group (Kaplan-Meier rate 4·0% vs 7·3%; hazard ratio 0·55 [95% CI 0·41-0·74]; p=0·0001), driven by reductions in target vessel myocardial infarction or target vessel revascularisation. There were no significant differences in all-cause death or stent thrombosis between groups. Safety endpoints were also similar in the two groups. INTERPRETATION: In patients with an acute coronary syndrome, intravascular ultrasound-guided implantation of contemporary drug-eluting stents resulted in a lower 1-year rate of the composite outcome of cardiac death, target vessel myocardial infarction, or clinically driven revascularisation compared with angiography guidance alone. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Exosomal lncRNA-MIAT promotes neovascularization via the miR-133a-3p/MMP-X1 axis in diabetic retinopathy.

Diabetic retinopathy (DR), a most common microangiopathy of diabetes, causes vision loss and even blindness. The mechanisms of exosomal lncRNA remain unclear in the development of DR. Here, we first identifed the pro-angiogenic effect of exosomes derived from vitreous humor of proliferative diabetic retinopathy patients, where lncRNA-MIAT was enriched inside. Secondly, lncRNA-MIAT was demonstrated significantly increased in exosomes from high glucose induced human retinal vascular endothelial cell, and can regulate tube formation, migration and proliferation ability to promote angiogenesis in vitro and in vivo. Mechanistically, the pro-angiogenic effect of lncRNA-MIAT was via the lncRNA-MIAT/miR-133a-3p/MMP-X1 axis. The reduced level of lncRNA-MIAT in this axis mitigated the generation of retinal neovascular in mouse model of oxygen-induced retinopathy (OIR), providing crucial evidence for lncRNA-MIAT as a potential clinical target. These findings enhance our understanding of the role of exosomal lncRNA-MIAT in retinal angiogenesis, and propose a promising therapeutic strategy against diabetic retinopathy.

Sleep duration time and human papillomavirus infection risk: The U-shaped relationship revealed by NHANES data.

PURPOSE: This study aims to investigate the relationship between sleep factors (sleep duration time [SDT] and obstructive sleep apnea [OSA]) and human papillomavirus (HPV)/high-risk HPV(HR-HPV) infection, utilizing data from the National Health and Nutrition Examination Survey (NHANES). METHODS: We conducted a cross-sectional analysis using NHANES data, focusing on SDT and OSA's association with HPV/HR-HPV infection. The primary statistical methods included weighted multivariate linear regression and logistic regression to assess the association between SDT, OSA, and HPV/HR-HPV infection. The study employed restricted cubic splines (RCS) for evaluating potential non-linear relationships between SDT and HPV/HR-HPV infection. Subgroup analyses were conducted. Interaction terms were used to examine the heterogeneity in associations across different subgroups. RESULTS: The study identified a U-shaped relationship between SDT and HPV infection. Specifically, 7 hours of sleep was associated with the lowest risk of HPV infection. In comparison, SDT less than 7 hours resulted in a 26.3% higher risk of HPV infection (Odds Ratio [OR] = 1.26, 95% Confidence Interval [CI]: 1.029, 1.549), and more than 9 hours of sleep showed a 57.4% increased risk (OR = 1.574, 95% CI: 1.116, 2.220). The relationship between SDT and HR-HPV infection was significant in the first two models, but not in the fully adjusted model. No significant interaction was found between sleep duration and other covariates. There was no association between OSA and HPV/HR-HPV infection. CONCLUSION: The study underscores the complex relationship between sleep duration and HPV infection risk, suggesting both very short and very long sleep durations may increase HPV infection likelihood. The findings highlight the need for further research to explore the biological mechanisms underpinning this association and to consider broader population groups and more precise sleep assessment methods in future studies.

A water quality assessment model involving novel fluorescence technology.

The reasonable utilization of water resources and real-time monitoring of water pollution are the core tasks of current world hydrological and water conservancy work. Novel technologies and methods for monitoring water pollution are important means to ensure water health. However, the absence of intuitive and simple analysis methods for the assessment of regional pollution in large-scale water bodies has prevented scientists from quickly grasping the overall situation of water pollution. In this study, we propose a strategy based on the unique combination of fluorescence technology and simple kriging (SK) interpolation (FL-SK) for the first time. This strategy could present the relative magnitude and distribution of the physicochemical indicators of a whole natural lake intuitively and accurately. The unique FL-SK model firstly offers a simple and effective water quality method that provides the pollution index of different sampling points in lakes. The macroscopic evaluation of large-scale water bodies by the FL-SK model primarily relies on the fluorescence response of the RDM-TPE to the comprehensive indicators of the water body, as experimental results have revealed a good correlation between fluorescent responses and six normalized physicochemical indicators. Multiple linear regression and fluorescence response experiments on RDM-TPE indicate that to some extent, the fluorescence signals of the FL-SK model may originate from a certain type of sulfide in the water body. Pattern discovery could enable the analysis of pollution levels in other ecosystems and promote early pollution assessment in the future.

Cardiac involvement in muscular dystrophies: Role of myocardial perfusion imaging.

Technetium-99m-methoxy isobutyl isonitrile (99mTc-MIBI) myocardial perfusion imaging (MPI) is a functional imaging method with relatively poor specificity but high sensitivity. We present 48-year-old man with cardiac involvement due to muscular dystrophies (MD). Myocardial perfusion imaging rest images revealed regional myocardial perfusion decrease in multiple walls, enlarged heart and decreased left ventricular systolic function. The lesion location of MPI was consistent with that seen on CMR. Our case showed MPI was useful for detection and evaluation of the MD patient with cardiac involvement. In addition, imaging findings in combination with clinical history and other data are important. The case highlight is thevalue of MPI in myocardiopathy.

FNIRS based study of brain network characteristics in children with cerebral palsy during bilateral lower limb movement.

BACKGROUND: Motor dysfunctions in children with cerebral palsy (CP) are caused by nonprogressive brain damage. Understanding the functional characteristics of the brain is important for rehabilitation. PURPOSE: This paper aimed to study the brain networks of children with CP during bilateral lower limb movement using functional near-infrared spectroscopy (fNIRS) and to explore effective fNIRS indices for reflecting functional brain activity. METHODS: Using fNIRS, cerebral oxygenation signals in the bilateral prefrontal cortex (LPFC/RPFC) and motor cortex (LMC/RMC) were recorded from fifteen children with spastic CP and seventeen children with typical development (CTDs) in the resting state and during bilateral lower limb movement. Functional connectivity matrices based on phase-locking values (PLVs) were calculated using Hilbert transformation, and binary networks were constructed at different sparsity levels. Network metrics such as the clustering coefficient, global efficiency, local efficiency, and transitivity were calculated. Furthermore, the time-varying curves of network metrics during movement were obtained by dividing the time window and using sparse inverse covariance matrices. Finally, conditional Granger causality (GC) was used to explore the causal relationships between different brain regions. RESULTS: Compared to CTDs, the connectivity between RMC-RPFC (p = 0.017) and RMC-LMC (p = 0.002) in the brain network was decreased in children with CP, and the clustering coefficient (p = 0.003), global efficiency (p = 0.034), local efficiency (p = 0.015), and transitivity (p = 0.009) were significantly lower. The standard deviation of the changes in global efficiency of children with CP during motion was also greater than that of CTDs. Using GC, it was found that there was a significant increase in causal strength from the RMC to the RPFC (p = 0.04) and from the RMC to the LMC (p = 0.042) in children with CP during motion. Additionally, there were significant negative correlations between the PLV of LMC-RMC (p = 0.002) and the Gross Motor Function Classification System (GMFCS) and between the GMFCS and the clustering coefficient (p = 0.01). CONCLUSIONS: During rehabilitation training of the lower limbs, there were significant differences in brain network indices between children with CP and CTDs. The indicators proposed in this paper are effective at evaluating motor function and the real-time impact of rehabilitation training on the brain network and have great potential for application in guiding clinical motor function assessment and planning rehabilitation strategies.

Exploration and Application of a Muscle Fatigue Assessment Model Based on NMF for Multi-Muscle Synergistic Movements.

Muscle fatigue significantly impacts coordination, stability, and speed in daily activities. Accurate assessment of muscle fatigue is vital for effective exercise programs, injury prevention, and sports performance enhancement. Current methods mostly focus on individual muscles and strength evaluation, overlooking overall fatigue in multi-muscle movements. This study introduces a comprehensive muscle fatigue model using non-negative matrix factorization (NMF) weighting. NMF is employed to analyze the duration multi-muscle weight coefficient matrix (DMWCM) during synergistic movements, and four electromyographic (EMG) signal features in time, frequency, and complexity domains are selected. Particle Swarm Optimization (PSO) optimizes feature weights. The DMWCM and weighted features combine to calculate the Comprehensive Muscle Fatigue Index (CMFI) for multi-muscle synergistic movements. Experimental results show that CMFI correlates with perceived exertion (RPE) and Speed Dynamic Score (SDS), confirming its accuracy and real-time tracking in assessing multi-muscle synergistic movements. This model offers a more comprehensive approach to muscle fatigue assessment, with potential benefits for exercise training, injury prevention, and sports medicine.

Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers.

Despite widespread utilization of immunotherapy, treating immune-cold tumors remains a challenge. Multiomic analyses and experimental validation identified the OTUD4/CD73 proteolytic axis as a promising target in treating immune-suppressive triple negative breast cancer (TNBC). Mechanistically, deubiquitylation of CD73 by OTUD4 counteracted its ubiquitylation by TRIM21, resulting in CD73 stabilization inhibiting tumor immune responses. We further demonstrated the importance of TGF-ß signaling for orchestrating the OTUD4/CD73 proteolytic axis within tumor cells. Spatial transcriptomics profiling discovered spatially resolved features of interacting malignant and immune cells pertaining to expression levels of OTUD4 and CD73. In addition, ST80, a newly developed inhibitor, specifically disrupted proteolytic interaction between CD73 and OTUD4, leading to reinvigoration of cytotoxic CD8+ T cell activities. In preclinical models of TNBC, ST80 treatment sensitized refractory tumors to anti-PD-L1 therapy. Collectively, our findings uncover what we believe to be a novel strategy for targeting the immunosuppressive OTUD4/CD73 proteolytic axis in treating immune-suppressive breast cancers with the inhibitor ST80.

CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy. Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.

Effectiveness and safety of a mumps containing vaccine in preventing laboratory-confirmed mumps cases from 2002 to 2017: A meta-analysis.

Emerging evidence has figured that serum conversion rate of mumps is a crucial link of mumps disease. Nevertheless, a rising number of mumps outbreaks caused our attention and studies examining the serum conversion cases were conducted in small samples previously; this meta-analysis was conducted to assess the immunogenicity and safety of a mumps containing vaccine (MuCV) before 2019. We identified a total of 17 studies from the year of 2002-2017. In the case-control studies, the vaccine effectiveness (VE) of MuCV in preventing laboratory-confirmed mumps was 68% (odds risk: 0.32; 95% confidence interval [CI], 0.14-0.70) while in the cohort studies and randomised control trials, 58% (relative risk [RR]: 0.42; 95% CI, 0.26-0.69). Similar intervals of effectiveness rates were found during non-outbreak periods compared with outbreak periods (VE: 66%; RR: 0.34; 95% CI, 0.18-0.68 versus VE: 49%; RR: 0.51; 95% CI, 0.21-1.27). In addition, the MuCV group with two and three doses did not show enhanced laboratory-confirmed mumps than one dose (VE: 58%; RR: 0.42; 95% CI, 0.20-0.88 versus VE: 65%, RR: 0.35; 95% CI, 0.20-0.61) for the reason of the overlap of 95% CI. MuCV had comparable effectiveness comparing non-outbreak and outbreak period, one dose, and two or three doses. MuCV displayed acceptable adverse event profiles.

Surgical tumor-derived nanoplatform targets tumor-associated macrophage for personalized postsurgical cancer immunotherapy.

Directly activating CD8+ T cells within the tumor through antigen-presenting cells (APCs) hold promise for tumor elimination. However, M2-like tumor-associated macrophages (TAMs), the most abundant APCs in tumors, hinder CD8+ T cell activation due to inefficient antigen cross-presentation. Here, we demonstrated a personalized nanotherapeutic platform using surgical tumor-derived galactose ligand-modified cancer cell membrane (CM)-coated cysteine protease inhibitor (E64)-loaded mesoporous silica nanoparticles for postsurgical cancer immunotherapy. The platform targeted M2-like TAMs and released E64 within lysosomes, which reshaped antigen cross-presentation and directly activated CD8+ T cells, thus suppressing B16-OVA melanoma growth. Furthermore, this platform, in combination with anti-PD-L1 antibodies, enhanced the therapeutic efficacy and substantially inhibited 4T1 tumor growth. CMs obtained from surgically resected tumors were used to construct a personalized nanotherapeutic platform, which, in synergy with immune checkpoint blockade (ICB), effectively inhibited postsurgical tumor recurrence in 4T1 tumor. Our work offered a robust, safe strategy for cancer immunotherapy and prevention of postsurgical tumor recurrence.