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The hypoxic and immunosuppressive tumor microenvironment (TME) remains a major obstacle to impede cancer immunotherapy. Here, we found that sononeoperfusion-a new effect of tumor perfusion enhancement induced by low mechanical index ultrasound stimulated microbubble cavitation (USMC)-ameliorated tumor tissue oxygenation and induced tumor vascular normalization (TVN). This TVN might be associated with the down-regulation of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) within tumors. Moreover, the sononeoperfusion effect reduced the accumulation of immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2-like tumor-associated macrophages (M2-TAMs), and decreased the production of immune inhibitory factors like transforming growth factor-β1 (TGF-β1), interleukin 10 (IL-10), chemoattractant chemokines CC-chemokine ligand 22 (CCL22), CCL28, adenosine and lactate within tumors. Notably, flow cytometry analysis revealed that sononeoperfusion not only increased the percentage of tumor infiltrating-CD8 + T cells, but also promoted the generation of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) by these cells. Furthermore, the improved immune TME by sononeoperfusion effect sensitized anti-PD-L1 treatment both in MC38 colon cancer and Lewis lung carcinoma mice, resulting in tumor regression and prolonged survival. Mechanically, the enhanced efficacy of combination therapy was mainly based on promoting the infiltration and function of CD8 + T cells within tumors. Together, sononeoperfusion could ameliorate hypoxia and immunosuppression in the TME, thereby potentiating anti-PD-L1 therapy for solid tumors. This novel method of USMC generating sononeoperfusion effect may provide a new therapeutic modality for facilitating cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Approximately 22 % of human colorectal cancers (CRC) are characterized by IGF2 overexpression, and the tumor-promoting role of IGF2 has been widely reported. Despite promising preclinical results, IGF2 signaling inhibition therapy has exhibited limited efficacy in treating unselected patients with CRC. Recent evidence suggests that IGF2-high CRC are more sensitive to IGF2 signaling blockade therapy in immune-deficient mice, suggesting that IGF2-high CRC can benefit from IGF2 signaling blockade therapy. However, T cells are absent in immunodeficient mice, and the effect of blocking IGF2 signaling on T cell-mediated antitumor immunity remains unknown. Herein, using an implanted mouse tumor model in immunocompetent hosts, we report that PQ401, an IGF2-IGF1R inhibitor, significantly inhibited the growth of IGF2-high CRC cells. PQ401 treatment increased the infiltration and function of tumor-infiltrating CD4 + and CD8 + T cells in a T cell-extrinsic manner. Our findings suggest that myeloid-derived suppressor cells (MDSCs) highly express the IGF2 receptor IGF1R. Moreover, PQ401 treatment inhibits the suppressive function and recruitment of MDSCs, thereby promoting the anti-tumor activity of T cells. These results provide a potential therapeutic regimen for patients with IGF2-high CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Present regulations regarding the management and recycling of spent Lithium-ion batteries (LIBs) are inadequate, which may lead to the pollution of lithium (Li) and heavy metals in water and soil during the informal disposal of such batteries. To comprehend the distribution of toxic metals within spent LIBs and contaminated environmental media, precise analytical methods for toxic metals in these materials are crucial. However, due to the chemical complexity of LIBs materials (e.g., lithium iron phosphate, graphite, separators, and electrolytes), there is still a lack of research on developing and validating analytical techniques for toxic metals in LIB materials across various environmental media., Results: This study establishes a comprehensive and highly precise analytical method for assessing toxic metal constituents in LIBs across various complex media, including sewage, soil, and biological matrices. We assessed the selection of digestion solutions for different LIB materials and identified the most suitable internal standard elements in the mass spectrometric analysis workflow. The devised digestion schemes for all components of LIBs are as follows: aqua regia for all cathode materials (excluding LiMn 0.6 Fe 0.4 PO 4 (LMFP)), nitric acid for diaphragm materials, aqua regia with hydrofluoric acid for the anode material Li 4 Ti 5 O 12 (LTO), and NaOH fusion for graphite and LMFP. LiPF 6 electrolyte can be directly dissolved in ultrapure water. By employing this method, the analysis of cathode materials of LIBs within diverse environmental matrices (sewage, soil, plants, animals) yields recovery rates ranging from 83.6 % to 115.5 %. Furthermore, this research reveals the remarkable accumulation of Li and heavy metals in anode (graphite) of spent LIBs., Significance: This is the first to develop and validate analytical techniques for toxic metals in LIB materials across various environmental media, incorporating both acid digestion and alkaline fusion techniques. This methodology offers comprehensive support for conducting environmental risk assessments of spent LIBs. Using this method, the research elucidates the occurrence characteristics of toxic metals within different parts of commercial spent LIBs, providing valuable insights to enhance recycling efforts and facilitate risk management of spent LIBs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The intestinal microbiome constitutes a sophisticated and massive ecosystem pivotal for maintaining gastrointestinal equilibrium and mucosal immunity via diverse pathways. The gut microbiota is continuously reshaped by multiple environmental factors, thereby influencing overall wellbeing or predisposing individuals to disease state. Many observations reveal an altered microbiome composition in individuals with autoimmune conditions, coupled with shifts in metabolic profiles, which has spurred ongoing development of therapeutic interventions targeting the microbiome. This review delineates the microbial consortia of the intestine, their role in sustaining gastrointestinal stability, the association between the microbiome and immune-mediated pathologies, and therapeutic modalities focused on microbiome modulation. We emphasize the entire role of the intestinal microbiome in human health and recommend microbiome modulation as a viable strategy for disease prophylaxis and management. However, the application of gut microbiota modification for the treatment of immune-related diseases, such as fecal microbiota transplantation and probiotics, remain quite challenging. Therefore, more research is needed into the role and mechanisms of these therapeutics., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lithium (Li) is an important resource that drives sustainable mobility and renewable energy. Its demand is projected to continue to increase in the coming decades. However, the risk of Li pollution has also emerged as a global concern. Here, we investigated the pollution characteristics, sources, exposure levels, and associated health risks of Li in the Jinjiang River basin, the largest area for Li 2 CO 3 production in China. Our results revealed the dominant role of Li extraction activities in the pollution of the river, with over 95% of dissolved Li in downstream river water being emitted from this source. Moreover, the Li concentration in aquatic plants (i.e., water hyacinth) and animals (i.e., fish) significantly increased from upstream to downstream areas, indicating a significant risk to local aquatic ecosystems. More importantly, our study found that local residents were suffering potential chronic noncarcinogenic health risks primarily from consuming contaminated water and vegetables. We also investigated the pollution characteristics of associated elements present in Li ores (e.g., Rb, Cs, Ni, and F - ). By uncovering the remarkable impact of Li extraction activities on the Li content in ecosystems for the first time, our study emphasizes the importance of evaluating Li pollution from Li-related industrial activities, including mining, extraction, and recovery.

Arterial stiffness (AS) serves as a crucial indicator of arterial elasticity and function, typically requiring expensive equipment for detection. Given the strong correlation between AS and various photoplethysmography (PPG) features, PPG emerges as a convenient method for assessing AS. However, the limitations of independent PPG features hinder detection accuracy. This study introduces a feature selection method leveraging the interactive relationships between features to enhance the accuracy of predicting AS from a single-channel PPG signal. Initially, an adaptive signal interception method was employed to capture high-quality signal fragments from PPG sequences. 58 PPG features, deemed to have potential contributions to AS estimation, were extracted and analyzed. Subsequently, the interaction factor (IF) was introduced to redefine the interaction and redundancy between features. A feature selection algorithm (IFFS) based on the IF was then proposed, resulting in a combination of interactive features. Finally, the Xgboost model is utilized to estimate AS from the selected features set. The proposed approach is evaluated on datasets of 268 male and 124 female subjects, respectively. The results of AS estimation indicate that IFFS yields interacting features from numerous sources, rejects redundant ones, and enhances the association. The interaction features combined with the Xgboost model resulted in an MAE of 122.42 and 142.12 cm/sec, an SDE of 88.16 and 102.56 cm/sec, and a PCC of 0.88 and 0.85 for the male and female groups, respectively. The findings of this study suggest that the stated method improves the accuracy of predicting AS from single-channel PPG, which can be used as a non-invasive and cost-effective screening tool for atherosclerosis.

Background: Acute lung injury (ALI) is a clinical syndrome characterized by pulmonary inflammation. Ultrashort wave diathermy (USWD) has been shown to be effective at in inhibiting ALI inflammation, although the underlying mechanism remains unclear. Previous studies have demonstrated that USWD generates a therapeutic thermal environment that aligns with the temperature required for heat shock protein 70 (HSP70), an endogenous protective substance. In this study, we examined the correlation between HSP70 and USWD in alleviating lung inflammation in ALI., Methods: Forty-eight male C57BL/6 mice were randomly divided into control, model, USWD intervention (LU) 1, 2, and 3, and USWD preintervention (UL) 1, 2, and 3 groups (n = 6 in each group). The mice were pretreated with LPS to induce ALI. The UL1, 2, and 3 groups received USWD treatment before LPS infusion, while the LU1, 2, and 3 groups received USWD treatment after LPS infusion. Lung function and structure, inflammatory factor levels and HSP70 protein expression levels were detected., Results: USWD effectively improved lung structure and function, and significantly reduced IL-1β, IL-10, TGF-β1, and TNF-α levels in both the USWD preintervention and intervention groups. However, HSP70 expression did not significantly differ across the experimental groups although the expression of TLR4 was significantly decreased, suggesting that USWD may have anti-inflammatory effects through multiple signaling pathways or that the experimental conditions should be restricted., Conclusions: Both USWD intervention and preintervention effectively reduced the inflammatory response, alleviated lung injury symptoms, and played a protective role in LPS-pretreated ALI mice. HSP70 was potentially regulated by USWD in this process, but further studies are urgently needed to elucidate the correlation and mechanism., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Magnetic particles (MPs), with magnetite (Fe 3 O 4 ) and maghemite (γ-Fe 2 O 3 ) as the most abundant species, are ubiquitously present in the natural environment. MPs are among the most applied engineered particles and can be produced incidentally by various human activities. Identification of the sources of MPs is crucial for their risk assessment and regulation, which, however, is still an unsolved problem. Here, we report a novel approach, hierarchical classification-aided stable isotopic fingerprinting, to address this problem. We found that naturally occurring, incidental, and engineered MPs have distinct Fe and O isotopic fingerprints due to significant Fe/O isotope fractionation during their generation processes, which enables the establishment of an Fe-O isotopic library covering complex sources. Furthermore, we developed a three-level machine learning model that not only can distinguish the sources of MPs with a high precision (94.3%) but also can identify the multiple species (Fe 3 O 4 or γ-Fe 2 O 3 ) and synthetic routes of engineered MPs with a precision of 81.6%. This work represents the first reliable strategy for the precise source tracing of particles with multiple species and complex sources.

Background: Cancer is the leading cause of death among older adults. Although the integration of immunotherapy has revolutionized the therapeutic landscape of cancer, the complex interactions between age and immunotherapy efficacy remain incompletely defined. Here, we aimed to elucidate the relationship between aging and immunotherapy resistance., Methods: Flow cytometry was performed to evaluate the infiltration of immune cells in the tumor microenvironment (TME). In vivo T cell proliferation, cytotoxicity and migration assays were performed to evaluate the antitumor capacity of tumor antigen-specific CD8 + T cells in mice. Real-time quantitative PCR (qPCR) was used to investigate the expression of IFN-γ-associated gene and natural killer (NK)-associated chemokine. Adoptive NK cell transfer was adopted to evaluate the effects of NK cells from young mice in overcoming the immunotherapy resistance of aged mice., Results: We found that elderly patients with advanced non-small cell lung cancer (aNSCLC) aged ≥ 75 years exhibited poorer progression-free survival (PFS), overall survival (OS) and a lower clinical response rate after immunotherapy. Mechanistically, we showed that the infiltration of NK cells was significantly reduced in aged mice compared to younger mice. Furthermore, the aged NK cells could also suppress the activation of tumor antigen-specific CD8 + T cells by inhibiting the recruitment and activation of CD103 + dendritic cells (DCs). Adoptive transfer of NK cells from young mice to aged mice promoted TME remodeling, and reversed immunotherapy resistance., Conclusion: Our findings revealed the decreased sensitivity of elderly patients to immunotherapy, as well as in aged mice. This may be attributed to the reduction of NK cells in aged mice, which inhibits CD103 + DCs recruitment and its CD86 expression and ultimately leads to immunotherapy resistance., (© 2024. The Author(s).)

Video-based Photoplethysmography (VPPG) offers the capability to measure heart rate (HR) from facial videos. However, the reliability of the HR values extracted through this method remains uncertain, especially when videos are affected by various disturbances. Confronted by this challenge, we introduce an innovative framework for VPPG-based HR measurements, with a focus on capturing diverse sources of uncertainty in the predicted HR values. In this context, a neural network named HRUNet is structured for HR extraction from input facial videos. Departing from the conventional training approach of learning specific weight (and bias) values, we leverage the Bayesian posterior estimation to derive weight distributions within HRUNet. These distributions allow for sampling to encode uncertainty stemming from HRUNet's limited performance. On this basis, we redefine HRUNet's output as a distribution of potential HR values, as opposed to the traditional emphasis on the single most probable HR value. The underlying goal is to discover the uncertainty arising from inherent noise in the input video. HRUNet is evaluated across 1,098 videos from seven datasets, spanning three scenarios: undisturbed, motion-disturbed, and light-disturbed. The ensuing test outcomes demonstrate that uncertainty in the HR measurements increases significantly in the scenarios marked by disturbances, compared to that in the undisturbed scenario. Moreover, HRUNet outperforms state-of-the-art methods in HR accuracy when excluding HR values with 0.4 uncertainty. This underscores that uncertainty emerges as an informative indicator of potentially erroneous HR measurements. With enhanced reliability affirmed, the VPPG technique holds the promise for applications in safety-critical domains.

Histone deacetylase 6 (HDAC6), as the key regulatory enzyme, plays an important role in the development of the nervous system. More and more studies indicate that HDAC6 has become a promising therapeutic target for CNS diseases. Herein we designed and synthesized a series of novel HDAC6 inhibitors with benzothiadiazinyl systems as cap groups and evaluated their activity in vitro and in vivo. Among them, compound 3 exhibited superior selective inhibitory activity against HDAC6 (IC 50  = 5.1 nM, about 30-fold selectivity over HDAC1). The results of docking showed that compound 3 can interact well with the key amino acid residues of HDAC6. Compound 3 showed lower cytotoxicity (20 μM to SH-SY5Y cells, inhibition rate = 25.75%) and better neuroprotective activity against L-glutamate-induced SH-SY5Y cell injury model in vitro. Meanwhile, compound 3 exhibited weak cardiotoxicity (10 μM hERG inhibition rate = 17.35%) and possess good druggability properties. Especially, compound 3 could significantly reduce cerebral infarction from 49.87% to 32.18%, and similar with butylphthalide in MCAO model, indicating potential clinical application prospects for alleviating ischemic stroke-induced brain infarction., (© 2024 John Wiley & Sons Ltd.)

Anti-PD-(L)1 therapy has shown great efficacy in some patients with cancer. However, a significant proportion of patients with cancer do not respond to it. Another unmet clinical need for anti-PD-(L)1 therapy is the dynamic monitoring of treatment effects. Therefore, identifying biomarkers that can stratify potential responders before PD-(L)1 treatment and timely monitoring of the efficacy of PD-(L)1 treatment are crucial in the clinical setting. The identification of biomarkers by liquid biopsy has attracted considerable attention. Among the identified biomarkers, circulating T cells are one of the most promising because of their indispensable contribution to anti-PD-(L)1 therapy. The present review aimed to thoroughly explore the potential of circulating T cells as biomarkers of anti-PD-(L)1 therapy and its advantages and limitations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2024 Hou, Yang, Xie, Zhu and Zha.)

In recent years, imaging photoplethysmograph (iPPG) pulse signals have been widely used in the research of non-contact blood pressure (BP) estimation, in which BP estimation based on pulse features is the main research direction. Pulse features are directly related to the shape of pulse signals while iPPG pulse signals are easily disturbed during the extraction process. To mitigate the impact of pulse feature distortion on BP estimation, it is necessary to eliminate interference while retaining valuable shape details in the iPPG pulse signal. Contact photoplethysmograph (cPPG) pulse signals measured at rest can be considered as the undisturbed reference signal. Transforming the iPPG pulse signal to the corresponding cPPG pulse signal is a method to ensure the effectiveness of shape details. However, achieving the required shape accuracy through direct transformation from iPPG to the corresponding cPPG pulse signals is challenging. We propose a method to mitigate this challenge by replacing the reference signal with an average cardiac cycle (ACC) signal, which can approximately represent the shape information of all cardiac cycles in a short time. A neural network using multi-scale convolution and self-attention mechanisms is developed for this transformation. Our method demonstrates a significant improvement in the maximal information coefficient (MIC) between pulse features and BP values, indicating a stronger correlation. Moreover, pulse signals transformed by our method exhibit enhanced performance in BP estimation using different model types. Experiments are conducted on a real-world database with 491 subjects in the hospital, averaging 60 years of age., Competing Interests: The authors declare that there are no conflicts of interest related to this article., (© 2024 Optica Publishing Group.)

More than one hundred studies have used the mainland Chinese version of the MATRICS Consensus Cognitive Battery (MCCB) to assess cognition in schizophrenia, but the results of these studies, the quality of the reports, and the strength of the evidence provided in the reports have not been systematically assessed. We identified 114 studies from English-language and Chinese-language databases that used the Chinese MCCB to assess cognition in combined samples of 7394 healthy controls (HC), 392 individuals with clinical high risk for psychosis (CHR-P), 4922 with first-episode schizophrenia (FES), 1549 with chronic schizophrenia (CS), and 2925 with schizophrenia of unspecified duration. The mean difference (MD) of the composite MCCB T-score (-13.72) and T-scores of each of the seven cognitive domains assessed by MCCB (-14.27 to -7.92) were significantly lower in individuals with schizophrenia than in controls. Meta-analysis identified significantly greater cognitive impairment in FES and CS than in CHR-P in six of the seven domains and significantly greater impairment in CS than FES in the reasoning and problem-solving domain (i.e., executive functioning). The only significant covariate of overall cognitive functioning in individuals with schizophrenia was a negative association with the severity of psychotic symptoms. These results confirm the construct validity of the mainland Chinese version of MCCB. However, there were significant limitations in the strength of the evidence provided about CHR-P (small pooled sample sizes) and the social cognition domain (inconsistency of results across studies), and the quality of many reports (particularly those published in Chinese) was rated 'poor' due to failure to report sample size calculations, matching procedures or methods of handling missing data. Moreover, almost all studies were cross-sectional studies limited to persons under 60 with at least nine years of education, so longitudinal studies of under-educated, older individuals with schizophrenia are needed., Competing Interests: All authors declare no conflict of interest., (© 2024 The Author(s).)

The widespread application of metal-organic frameworks (MOFs) is seriously hindered by their structural instability and it is still very challenging to probe the stability of MOFs during application by current techniques. Here, we report a novel structure-responsive mass spectrometry (SRMS) imaging technique to probe the stability of MOFs. We discovered that intact CuBTC (as a model of MOFs) could generate the characteristic peaks of organic ligands and carbon cluster anions in laser desorption/ionization mass spectrometry, but these peaks were significantly changed when the structure of CuBTC was dissociated, thus enabling a label-free probing of the stability. Furthermore, SRMS can be performed in imaging mode to visualize the degradation kinetics and reveal the spatial heterogeneity of the stability of CuBTC. This technique was successfully applied in different application scenarios (in water, moist air, and CO 2 ) and also validated with different MOFs. It thus provides a versatile new tool for better design and application of environment-sensitive materials., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Persistent inflammation in damaged joints results in metabolic dysregulation of the synovial microenvironment, causing pathogenic alteration of cell activity in rheumatoid arthritis (RA). Recently, the role of metabolite and metabolite-sensing G protein-coupled receptors (GPCRs) in the RA-related inflammatory immune response (IIR) has become a focus of research attention. These GPCRs participate in the progression of RA by modulating immune cell activation, migration, and inflammatory responses. Here, we discuss recent evidence implicating metabolic dysregulation in RA pathogenesis, focusing on the connection between RA-related IIR and GPCR signals originating from the synovial joint and gut. Furthermore, we discuss future directions for targeting metabolite-sensing GPCRs for therapeutic benefit, emphasizing the importance of identifying endogenous ligands and investigating the various transduction mechanisms involved., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Geological hazards, especially landslides and mudslides, are frequent in Caoke County, Sichuan Province, China. In September 2022, the mechanical parameters of the soil were obtained through a basic investigation of the landslide characteristics of Ni changgou. Upon that, the finite element-discrete element method was used to reconstruct the three-dimensional numerical model of the landslide on the right bank of Ni changgou, and the initiation mechanism of rainfall on landslide and the formation of debris flow impact dam process were simulated. Furthermore, the pore pressure, stability coefficient as well as displacement of the landslide body were analyzed. It turned out that with the increase of rainfall intensity, the pore water pressure value also increases, where pore water pressure rises rapidly. the slope is close to the unstable edge, Eventually, it tends to one under rainfall conditions, and due to gravity, the slide of the landslide is induced. The duration of landslide movement is about 200 s, the maximum average velocity of the landslide reaches 4.85 m/s, and the average movement distance is close to 500 m. In addition, this method is applied to the Chutougou debris flow, and the corresponding hazard analysis is added which could better show the treatment and application of debris flow in actual engineering., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs' proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. We have reported the deletion of G-protein-coupled receptor kinase 2 (GRK2) reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling. However, as more GRK2-interacting proteins were discovered, the GRK2 interactome mechanisms in RA have been understudied. Thus, in the collagen-induced arthritis mouse model, we performed genetic GRK2 deletion using GRK2 f/f Lyz2 -Cre +/- mice. Synovial inflammation and M1 polarization were improved in GRK2 f/f Lyz2 -Cre +/- mice. Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptor γ (PPAR γ ) as a new GRK2-interacting protein. We further confirmed that fms-related tyrosine kinase 1 (Flt-1), which promoted macrophage migration to induce angiogenesis, was inhibited by GRK2-PPAR γ signaling. Mechanistically, excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPAR γ ligand-binding domain and enhanced Flt-1 transcription. Furthermore, the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology, Flt-1 + macrophages induced-synovial inflammation, and angiogenesis. Altogether, we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling. Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration, affording a distinct way to control joint inflammation and angiogenesis of RA., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Authors.)

Introduction: The adverse effects of high glucose on embryos can be traced to the preimplantation stage. This study aimed to observe the effect of high glucose on early-stage embryos., Methods and Results: Seven-week-old ICR female mice were superovulated and mated, and the zygotes were collected. The zygotes were randomly cultured in 5 different glucose concentrations (control, 20mM, 40mM, 60mM and 80mM glucose). The cleavage rate, blastocyst rate and total cell number of blastocyst were used to assess the embryo quality. 40 mM glucose was selected to model high glucose levels in this study. 40mM glucose arrested early embryonic development, and the blastocyst rate and total cell number of the blastocyst decreased significantly as glucose concentration was increased. The reduction in the total cell number of blastocysts in the high glucose group was attributed to decreased proliferation and increased cell apoptosis, which is associated with the diminished expression of GLUTs (GLUT1, GLUT2, GLUT3). Furthermore, the metabolic characterization of blastocyst culture was observed in the high-glucose environment., Discussion: The balance of glycolysis and oxidative phosphorylation at the blastocyst stage was disrupted. And embryo development arrest due to high glucose is associated with changes in glycolysis and oxidative phosphorylation, as well as abnormalities in the TCA cycle and amino acid metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hong, Tong, Wang, Lv, He, Yang, Wang, Xu, Liang, Feng, Niu, Niu and Lu.)

Many populations worldwide are suffering from central nervous system (CNS) diseases such as brain tumors, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and Huntington's disease) and stroke. There is a shortage of effective drugs for most CNS diseases. As one of the regulatory mechanisms of epigenetics, the particular role and therapeutic benefits of histone deacetylases (HDACs) in the CNS have been extensively studied. In recent years, HDACs have attracted increasing attention as potential drug targets for CNS diseases. In this review, we summarize the recent applications of representative histone deacetylases inhibitors (HDACis) in CNS diseases and discuss the challenges in developing HDACis with different structures and better blood-brain barrier (BBB) permeability, hoping to promote the development of more effective bioactive HDACis for the treatment of CNS diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Extracellular matrix (ECM) is a three-dimensional network entity composed of extracellular macromolecules. ECM in synovium not only supports the structural integrity of synovium, but also plays a crucial role in regulating homeostasis and damage repair response in synovium. Obvious disorders in the composition, behavior and function of synovial ECM will lead to the occurrence and development of arthritis diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and psoriatic arthritis (PsA). Based on the importance of synovial ECM, targeted regulation of the composition and structure of ECM is considered to be an effective measure for the treatment of arthritis disease. This paper reviews the current research status of synovial ECM biology, discusses the role and mechanism of synovial ECM in physiological status and arthritis disease, and summarizes the current strategies for targeting synovial ECM to provide information for the pathogenesis, diagnosis and treatment of arthritis disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Recent studies have found that blood volume pulse (BVP) in facial videos contains features highly correlated to blood pressure (BP). However, the mapping from BVP features to BP varies from person to person. To address this issue, VidBP has been proposed as a BP detector that can be calibrated based on an individual's data. VidBP is pre-trained on a large dataset to extract BP-related features from BVP. Then, BVP samples and BP labels of an individual are fed into the pre-trained VidBP to create a personal dictionary of BP-related features. When estimating the individual's BP, the current BP-related feature is compared to the features saved in the dictionary, and the BP labels of the similar features are considered as the BP estimate. The performance of VidBP was evaluated on 640 samples of 16 subjects, and it demonstrated significantly lower errors in BP estimation compared to state-of-the-art methods. The personalized calibration of VidBP is a significant advantage, enabling it to better capture the unique mapping from BVP features to BP for each individual.Clinical relevance This study reports a feasible method to estimate BP from facial videos, providing a convenient and cost-effective way for home BP monitoring.

Video-based Photoplethysmography (VPPG) can identify arrhythmic pulses during atrial fibrillation (AF) from facial videos, providing a convenient and cost-effective way to screen for occult AF. However, facial motions in videos always distort VPPG pulse signals and thus lead to the false detection of AF. Photoplethysmography (PPG) pulse signals offer a possible solution to this problem due to the high quality and resemblance to VPPG pulse signals. Given this, a pulse feature disentanglement network (PFDNet) is proposed to discover the common features of VPPG and PPG pulse signals for AF detection. Taking a VPPG pulse signal and a synchronous PPG pulse signal as inputs, PFDNet is pre-trained to extract the motion-robust features that the two signals share. The pre-trained feature extractor of the VPPG pulse signal is then connected to an AF classifier, forming a VPPG-driven AF detector after joint fine-tuning. PFDNet has been tested on 1440 facial videos of 240 subjects (50% AF absence and 50% AF presence). It achieves a Cohen's Kappa value of 0.875 (95% confidence interval: 0.840-0.910, P<0.001) on the video samples with typical facial motions, which is 6.8% higher than that of the state-of-the-art method. PFDNet shows significant robustness to motion interference in the video-based AF detection task, promoting the development of opportunistic screening for AF in the community.

It has been proven that intra-articular injection of mesenchymal stromal cells (MSCs) can alleviate cartilage damage in osteoarthritis (OA) by differentiating into chondrocytes and protecting inherent cartilage. However, the mechanism by which the OA articular microenvironment affects MSCs' therapeutic efficiency is yet to be fully elucidated. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in various cellular processes, such as osteogenesis and immune regulation. Tryptophan (Trp) metabolites, most of which are endogenous ligand for AHR, are abnormally increased in synovial fluid (SF) of OA and rheumatoid arthritis (RA) patients. In this study, the effects of kynurenine (KYN), one of the most important metabolites of Trp, were evaluated on the chondrogenic and chondroprotective effects of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs). hUC-MSCs were cultured in conditioned medium containing different proportions of OA/RA SF, or stimulated with KYN directly, and then, AHR activation, proliferation, and chondrogenesis of hUC-MSCs were measured. Moreover, the chondroprotective efficiency of short hairpin-AHR-UC-MSC (shAHR-UC-MSC) was determined in a rat surgical OA model (right hind joint). OA SF could activate AHR signaling in hUC-MSCs in a concentration-dependent manner and inhibit the chondrogenic differentiation and proliferation ability of hUC-MSCs. Similar results were observed in hUC-MSCs stimulated with KYN in vitro. Notably, shAHR-UC-MSC exhibited superior therapeutic efficiency in OA rat upon intra-articular injection. Taken together, this study indicates that OA articular microenvironment is not conducive to the therapeutic effect of hUC-MSCs, which is related to the activation of the AHR pathway by tryptophan metabolites, and thus impairs the chondrogenic and chondroprotective effects of hUC-MSCs. AHR might be a promising modification target for further improving the therapeutic efficacy of hUC-MSCs on treatment of cartilage-related diseases such as OA., (© 2022. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: Pancreatic cancer is among the most common malignant tumours, and effective therapeutic strategies are still lacking. While Corynoxine (Cory) can induce autophagy in neuronal cells, it remains unclear whether Cory has anti-tumour activities against pancreatic cancer., Methods: Two pancreatic cancer cell lines, Patu-8988 and Panc-1, were used. Effects of Cory were evaluated by cell viability analysis, EdU staining, TUNEL assay, colony formation assay, and flow cytometry. Quantitative PCR and Western blot were performed to analyse mRNA and protein levels, respectively. In vivo anti-tumour efficacy of Cory was determined by a xenograft model., Results: Cory treatment inhibited cell proliferation, induced endoplasmic reticulum (ER) stress, and triggered apoptosis in the pancreatic cancer cell lines. CHOP knockdown-mediated inhibition of ER stress alleviated the Cory-induced apoptosis but showed a limited effect on cell viability. Cory induced cell death partially via promoting reactive oxygen species (ROS) production and activating p38 signalling. Pretreatment with ROS scavenger N-acetylcysteine and p38 inhibitor SB203580 relieved the Cory-induced inhibition on cell growth. Cory remarkably blocked pancreatic tumour growth in vivo., Conclusions: Cory exerts an anti-tumour effect on pancreatic cancer primarily via ROS-p38-mediated cytostatic effects. Cory may serve as a promising therapeutic agent for pancreatic cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Spontaneous preterm birth (SPB) has drawn public attention due to its increasing incidence and adverse effects on fetal growth. Effect of copper (Cu) imbalance in maternal bodies on the risk of SPB remains a subject of debate, and the related mechanisms are still unraveled. Here we applied natural stable copper isotopes to explore the underlying association and mechanism of copper imbalance with SPB using a nested case-control study. We collected maternal sera at the early pregnancy stage and then measured their copper isotopic ratio ( 65 Cu/ 63 Cu, expressed as δ 65 Cu) as well as physiological and biochemical indexes from women with and without delivering SPB. We found that SPB cases had no significant difference in serum copper level from their controls, but their serum copper was significantly isotopically heavier than the controls (δ 65 Cu value = 0.15 ± 0.34 ‰ versus -0.15 ± 0.17 ‰, P = 0.0149). Compared with the controls with lower δ 65 Cu values, the crude odds ratio (OR) associated with SPB risk increased to 4.00 (95 % confidence interval (CI): 1.37-11.70) and the adjusted OR reached up to 11.35 (95 % CI: 1.35-95.60). Furthermore, via the copper isotopic fractionation, we revealed that dietary intake and blood ceruloplasmin may play more important roles than blood lipids and mother-to-child transmission in the copper imbalance associated with SPB. Further studies will be needed to understand the mechanisms of isotope fractionation related to reproductive health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective . Daily blood pressure (BP) monitoring is essential since BP levels can reflect the functions of heart pumping and vasoconstriction. Although various neural network-based BP estimate approaches have been proposed, they have certain practical shortcomings, such as low estimation accuracy and poor model generalization. Based on the strategy of pre-training and partial fine-tuning, this work proposes a non-invasive method for BP estimation using the photoplethysmography (PPG) signal. Approach . To learn the PPG-BP relationship, the deep convolutional bidirectional recurrent neural network (DC-Bi-RNN) was pre-trained with data from the public medical information mark for intensive care (MIMIC III) database. A tiny quantity of data from the target subject was used to fine-tune the specific layers of the pre-trained model to learn more individual-specific information to achieve highly accurate BP estimation. Main results. The mean absolute error and the Pearson correlation coefficient ( r ) of the proposed algorithm are 3.21 mmHg and 0.919 for systolic BP, and 1.80 mmHg and 0.898 for diastolic BP (DBP). The experimental results show that our method outperforms other methods and meets the requirements of the Association for the Advancement of Medical Instrumentation standard, and received an A grade according to the British Hypertension Society standard. Significance. The proposed method applies the strategy of pre-training and partial fine-tuning to BP estimation and verifies its effectiveness in improving the accuracy of non-invasive BP estimation., (© 2022 Institute of Physics and Engineering in Medicine.)

Soot, mainly derived from incomplete combustion of fossil fuel and biomass, exists ubiquitously in different environmental matrixes. To study the detrimental effects of soot on climate, air quality, and human health, accurate quantification of soot is an important prerequisite. However, until now, quantification of soot in environmental media, especially in carbonaceous media, is still very challenging. Here, we report a matrix-free laser desorption/ionization mass spectrometry (LDI-MS) method for in situ imaging of soot particles in size-segregated aerosol samples collected on filter membranes. A series of round-shaped sample spots in filter membranes were selected and subjected to MS imaging analysis, enabling direct in situ quantification of soot without solvent extraction or separation. Especially, the MS imaging with serial sample spots can overcome the problems of sweet-spot in LDI-MS and inhomogeneous distribution of soot in the filter membrane, thus greatly improving the precision of quantification. The limit of detection of soot was 4 ng/m 2 and the recovery was 84.4-126%. By using this method, we found that a higher soot content was present in larger-sized particulate matter than smaller-sized particles, suggesting that aerosol soot was mainly derived from primary emission sources. Furthermore, this method also shows the potential to analyze nitrate and sulfate species in PM 2.5 . To the best of our knowledge, it is the first method capable of simultaneous analysis of inorganic salts and soot in air samples. It represents a novel strategy for in situ quantification of aerosol soot with the advantages of high specificity, high sensitivity, separation-, solvent- and matrix-free.

Remote photoplethysmography (RPPG) can detect heart rate from facial videos in a non-contact way. However, head movement often affects its performance in the real world. In this paper, a novel anti-motion interference method named T-SNE-based signal separation (TSS) is proposed to solve this problem. TSS first decomposes the observed color traces into pulse-related vectors and noise vectors using the T-SNE algorithm. Then, it selects the vector with the most significant spectral peak as the pulse signal for heart rate measurement. The proposed method is tested on a self-collected dataset (17 males and 8 females) and two public datasets (UBFC-RPPG and VIPL-HR). Experimental results show that the proposed method outperforms state-of-the-art methods, especially on the videos containing head movements, improving the Pearson correlation coefficient by 5% compared with the best contrasting method. To summarize, this work significantly strengthens the motion robustness of RPPG, which makes a substantial contribution to the development of video-based heart rate detection., Competing Interests: The authors declare that there are no conflicts of interest related to this article, (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Background: Gliomas are primary malignant brain tumors. Despite recent advances in surgery and clinical neuro-oncology, the prognosis of patients with glioma is still poor. Therefore, there is an urgent need to find new therapeutic drugs., Methods: Here, we have studied the anticancer effect of maslinic acid in glioma and explored its potential molecular mechanism. CCK-8, Ki67 immunofluorescence, and colony formation tests are used to detect the proliferation of glioma cells. Transwell and migration experiments are used to detect the function of cell invasion and migration, and RNA-seq was performed to identify differentially expressed genes. Western blot analysis helps us identify important signaling pathways. Finally, the anticancer effect of maslinic acid was confirmed in vivo through tumor xenografting experiments., Results: Our experiments obtained high-throughput data on the treatment of maslinic acid in glioma. We found that maslinic acid significantly inhibits the proliferation, invasion, and migration of glioma cells and promotes the apoptosis of glioma cells via suppressing MAPK signaling., Conclusions: This is the first time to analyze the mechanism of maslinic acid against glioma based on transcription. Our experiments show that maslinic acid may be a useful natural product for the treatment of glioma., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yongqiang Wang et al.)

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Enhanced G protein coupled receptor kinase 2 (GRK2) translocation and prostaglandin E4 receptor (EP4) desensitization play a critical role in fibroblast-like synoviocytes (FLS) dysfunction. Paeoniflorin-6'O-benzene sulfonate (CP-25) exerts a protective effect in arthritis in the RA animal models. To demonstrate the role of Gβγ in EP4 desensitization and the mechanisms of CP-25 that protects FLS in RA, RA-FLS and adjuvant-induced arthritis (AA-FLS) were isolated from synovium of RA patients and AA rats. RA-FLS, AA-FLS and MH7A were treated with CP-25, Gβγ agonist and antagonist. The cell membrane expression of EP4, GRK2, and Gβγ were detected using western blot analysis. Co-immunoprecipitation (Co-IP) and immunofluorescence were adopted to detect the interactions of GRK2-Gβγ, GRK2-EP4, and EP4-Gβγ. Cell Counting Kit-8 and Transwell assay were used to analyze the proliferation and migration of the FLS. An increased membrane expression of GRK2 and Gβγ, enhanced GRK2-Gβγ interaction and decreased EP4 membrane expression in the RA synovial tissue were identified. In vitro , prostaglandin E2 (PGE 2 ) enhanced the proliferation and migration of FLS. CP-25 exhibited an inhibition effect similar to Gβγ inhibitor, which downregulated GRK2-EP4 interaction, blocked the translocation of GRK2, and reversed EP4 desensitization, leading to the suppression of the proliferation and migration induced by PGE 2 . These results elucidated that an enhanced GRK2-Gβγ interaction was involved in the EP4 desensitization and dysfunction. CP-25 regulated EP4-GRK2-Gβγ signaling and re-sensitized EP4 by inhibiting GRK2-Gβγ interaction. The regulation of EP4-Gβγ-GRK2 signaling may be a novel potential therapeutic target in RA., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Background and Purpose: Abnormal kynurenine (Kyn) metabolism has been closely linked to the pathogenesis of rheumatoid arthritis (RA). The aims of this study were to investigate the role of tryptophan 2,3-dioxygenase 2 (TDO2), a rate-limiting enzyme that converts tryptophan (Trp) to Kyn, in regulating fibroblast-like synoviocyte (FLS)-mediated synovial inflammation in autoimmune arthritis., Experimental Approach: The expression of TDO2 was determined by immunohistochemistry, confocal laser scanning fluorescence microscopy, imaging flow cytometry and Western blot. TDO2 activity was tested by HPLC and colorimetric assay. TDO2 siRNA and TDO2 inhibitor 680C91 were used to inhibit TDO2 in AA-FLS function in vitro. A rat model of adjuvant-induced arthritis (AA) was used to evaluate the in vivo effect of allopurinol (Allo), a TDO2 inhibitor., Key Results: TDO2 expression was strongly increased in synovial tissue and FLS of RA and AA. Immune cells were found to express high amount of TDO2 proteins at the peak stage of AA. Pharmacological inhibition or knockdown of TDO2 in AA-FLS resulted in a reduced proliferation, secretion, migration and invasion. Kyn restored the inhibitory effect of TDO2 inhibition on activation of AA-FLS. Allo treatment ameliorated the arthritis severity and decreased the activity of TDO2., Conclusion and Implications: Our results suggest that elevated TDO2 expression may contribute to synovial inflammation and joint destruction during arthritis. Therefore, targeting TDO2 activity and the Kyn pathway of Trp degradation may represent a potential therapeutic strategy in RA., (© 2021 The British Pharmacological Society.)

Atrial fibrillation (AF) is the most common arrhythmia, but an estimated 30% of patients with AF are unaware of their conditions. The purpose of this work is to design a model for AF screening from facial videos, with a focus on addressing typical motion disturbances in our real life, such as head movements and expression changes. This model detects a pulse signal from the skin color changes in a facial video by a convolution neural network, incorporating a phase-driven attention mechanism to suppress motion signals in the space domain. It then encodes the pulse signal into discriminative features for AF classification by a coding neural network, using a de-noise coding strategy to improve the robustness of the features to motion signals in the time domain. The proposed model was tested on a dataset containing 1200 samples of 100 AF patients and 100 non-AF subjects. Experimental results demonstrated that VidAF had significant robustness to facial motions, predicting clean pulse signals with the mean absolute error of inter-pulse intervals less than 100 milliseconds. Besides, the model achieved promising performance in AF identification, showing an accuracy of more than 90% in multiple challenging scenarios. VidAF provides a more convenient and cost-effective approach for opportunistic AF screening in the community.

Currently, almost all available cancer biomarkers are based on concentrations of compounds, often suffering from low sensitivity, poor specificity, and false positive or negative results. The stable isotopic composition of elements provides a different dimension from the concentration and has been widely used as a tracer in geochemistry. In health research, stable isotopic analysis has also shown potential as a new diagnostic/prognostic tool, which is still in the nascent stage. Here we discovered that bladder cancer (BCa) could induce a significant variation in the ratio of natural copper isotopes ( 65 Cu/ 63 Cu) in the blood of patients relative to benign and healthy controls. Such inherent copper isotopic signatures permitted new insights into molecular mechanisms of copper imbalance underlying the carcinogenic process. More importantly, to enhance the diagnostic capability, a machine learning model was developed to classify BCa and non-BCa subjects based on two-dimensional copper signatures (copper isotopic composition and concentration in plasma and red blood cells) with a high sensitivity, high true negative rate, and low false positive rate. Our results demonstrated the promise of blood copper signatures combined with machine learning as a versatile tool for cancer research and potential clinical application., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

During the SARS period in 2003 and COVID-19 pandemic period in 2020, unexpected severe particulate matter pollution occurred in northern China, although the anthropogenic activities and associated emissions have assumed to be reduced dramatically. This anomalistic increase in PM 2.5 pollution raises a question about how source emissions impact the air quality during these pandemic periods. In this study, we investigated the stable Cu and Si isotopic compositions and typical source-specific fingerprints of PM 2.5 and its sources. We show that the primary PM 2.5 emissions (PM 2.5 emitted directly from sources) actually had no reduction but redistribution during these pandemic periods, rather than the previous thought of being greatly reduced. This finding provided critical evidence to interpret the anomalistic PM 2.5 increase during the pandemic periods in north China. Our results also suggested that both the energy structure adjustment and stringent regulations on primary emissions should be synergistically implemented in a regional scale for clean air actions in China.

Inhalation of respirable silica particles can cause serious lung diseases (e.g., silicosis and lung cancer), and the toxicity of respirable silica is highly dependent on its crystal form. Common combustion processes such as coal and biomass burning can provide high temperature environments that may alter the crystal forms of silica and thus affect its toxic effects. Although crystalline silica (i.e., quartz, tridymite, and cristobalite) were widely found at different temperatures during the burning processes, the sources and crystal transformation pathways of silica in the burning processes are still not well understood. Here, we investigate the crystal transformation of silica in the coal and biomass combustion processes and clarify the detailed transformation pathways of silica for the first time. Specifically, in coal burning process, amorphous silica can transform into quartz and cristobalite starting at 1100 °C, and quartz transforms into cristobalite starting at 1200 °C; in biomass burning process, amorphous silica can transform into cristobalite starting at 800 °C, and cristobalite transforms into tridymite starting at 1000 °C. These transformation temperatures are significantly lower than those predicted by the classic theory due to possibly the catalysis of coexisting metal elements (e.g., aluminum, iron, and potassium). Our results not only enable a deeper understanding on the combustion-induced crystal transformation of silica, but also contribute to the mitigation of population exposure to respirable silica., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Tryptophan 2,3-dioxygenase (TDO2) was an initial rate-limiting enzyme of the kynurenine (Kyn) pathway in tryptophan (Trp) metabolism. We undertook this study to determine a comprehensive analysis of TDO2 expression in immune cells and assess the characterization of immune cell phenotype in TDO2 knockout mice. The expression of TDO2 in various tissues of DBA/1 mice was detected by quantitative real-time PCR (qPCR) and immunohistochemistry. Both flow cytometry and immunofluorescence were used to analyze the expression of TDO2 in immune cells. Furthermore, TDO2 knockout (KO) mice were generated by CRISPR/Cas9 technology to detect immune cell phenotype. TDO2 protein level in liver was tested by western blot. High-performance liquid chromatography was used to detect the level of Trp and Kyn. Flow cytometry was used to test the proportions of splenic lymphocyte subsets in wild-type (WT) and TDO2 KO mice. We found that TDO2 was expressed in various tissues and immune cells, and TDO2 staining was mainly observed in the cytoplasm of cells. There was no difference in the development of immune cells between TDO2 KO mice and WT mice, including T cells, B cells, memory B cells, plasma cells, dendritic cells, and natural killer cells. Interestingly, the reduced M1/M2 ratio was observed in the peritoneal macrophages of TDO2 KO mice. Taken together, these findings enriched the known expression profile of TDO2, especially its expression in immune cells. Our study suggested that TDO2-mediated Trp-Kyn metabolism pathway might be involved in the immune response., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Tumor necrosis factor (TNF)-α inhibitors represented by Etanercept (a fusion protein containing soluble TNF receptor II (sTNFRII) and the Fc segment of human IgG1) play a pivotal role in Rheumatoid arthritis (RA) treatment. However, long-term use increases the risk of infection and tumors for their systemic inhibition of TNF-α, which disrupts the regular physiological function of this molecular. Mesenchymal stem cells (MSCs)-based delivery system provides new options for RA treatment with their "homing" and immune-regulation capacities, whereas inflammatory environment (especially TNF-α) is not conducive to MSCs' therapeutic effects by inducing apoptosis/autophagy. Here, we constructed a strain of sTNFRII-Fc-expressing MSCs (sTNFRII-MSC), aiming to offset the deficiency of those two interventions., Methods: Constructed sTNFRII-Fc lentiviral vector was used to infect human umbilical cord-derived MSCs, and sTNFRII-MSC stable cell line was generated by monoclonal cultivation. In vitro and vivo characteristics of sTNFRII-MSC were assessed by coculture assay and an acute inflammatory model in NOD/SCID mice. The sTNFRII-MSC were transplanted into CIA model, pathological and immunological indicators were detected to evaluate the therapeutic effects of sTNFRII-MSC. The distribution of sTNFRII-MSC was determined by immunofluorescence assay. Apoptosis and autophagy were analyzed by flow cytometry, western blot and immunofluorescence., Results: sTNFRII-Fc secreted by sTNFRII-MSC present biological activity both in vitro and vivo. sTNFRII-MSC transplantation effectively alleviates mice collagen-induced arthritis (CIA) via migrating to affected area, protecting articular cartilage destruction, modulating immune balance and sTNFRII-MSC showed prolonged internal retention via resisting apoptosis/autophagy induced by TNF-α., Conclusion: sTNFRII-Fc modification protects MSCs against apoptosis/autophagy induced by TNF-α, in addition to releasing sTNFRII-Fc neutralizing TNF-α to block relevant immune-inflammation cascade, and thus exert better therapeutic effects in alleviating inflammatory arthritis., (© 2021. The Author(s).)

There is an urgent need for reliable and effective models to study air pollution health effects on human lungs. Here, we report the utilization of human pluripotent stem cell (hPSC) induction models for human lung progenitor cells (hLPs) and alveolar type 2 epithelial cell-like cells (ATLs) for the toxicity assessment of benzo(a)pyrene, nano-carbon black, and nano-SiO 2 , as common air pollutants. We induced hPSCs to generate ATLs, which recapitulated key features of human lung type 2 alveolar epithelial cells, and tested the induction models for cellular uptake of nanoparticles and toxicity evaluations. Our findings reveal internalization of nano-carbon black, dose-dependent uptake of nano-SiO 2 , and interference with surfactant secretion in ATLs exposed to benzo(a)pyrene/nano-SiO 2 . Thus, hLP and ATL induction models could facilitate the evaluation of environmental pollutants potentially affecting the lungs. In conclusion, this is one of the first studies that managed to adopt hPSC pulmonary induction models in toxicology studies.

Stable isotopic analysis is an important branch of analytical chemistry. Accurate determination of the stable isotopic compositions of substances is critical for tracing their sources and investigating their transformation processes. The new generation of mass spectrometry technology has greatly facilitated the development of high-precision stable isotopic analysis methods. In particular, multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) has emerged as a powerful tool for isotopic composition determination. However, isotopic analysis by MC-ICP-MS is highly sensitive to the sample matrix, which may compromise the precision and accuracy of the analysis. Therefore, it is particularly important to reduce the sample matrix effect using efficient sample purification techniques. This article summarizes the recent progress in sample purification and instrument hyphenation methods for MC-ICP-MS, and provides perspectives on the future application of MC-ICP-MS in different fields.

Objective: Modern consumer-level cameras can detect subtle changes in human facial skin color due to varying blood flow; they are beginning to be used as noncontact devices to detect pulse waves. Little, however, do we know about their capacity to perform pulse wave detection when the recorded faces are unstable., Methods: Here, we propose a novel method that can extract pulse waves from videos with drastic facial unsteadiness such as head twists and alternating expressions. The method first uses chrominance characteristics in multiple facial sub-regions to construct a raw pulse matrix. Subsequently, it employs a disturbance-adaptive orthogonal matching pursuit (DAOMP) algorithm to recover the underlying pulse matrix corrupted by facial unsteadiness., Results: To evaluate the efficacy of the method, we perform analyses on two datasets including 268 samples from 67 testing subjects. The results demonstrate that the proposed method outperforms state-of-the-art algorithms, especially in the terrain where drastic facial unsteadiness is present., Conclusion: The proposed framework shows promise to achieve videos-based noncontact pulse wave detection from both steady and unsteady faces recorded by consumer-level cameras., Significance: By employing the proposed method, disturbance robustness in noncontact pulse wave detection can be significantly improved.

Background: Left atrial enlargement (LAE) was reported to be associated with ischemic stroke and its recurrence. Limited data are available on the relationship of LAE and cardiogenic cerebral embolism (CCE). Our aim is to access the association of left atrial size and the recurrence of ischemic stroke in CCE., Methods: We prospectively included 303 CCE patients who underwent transthoracic echocardiography (TTE). Left atrial size was estimated with left atrial diameter (LAD), diameter/height (LAD/H), and left atrial diameter/body surface area (LAD/BSA). The endpoint was one-year recurrent ischemic stroke. Cox proportional hazard models were performed to access the association between left atrial size and recurrent ischemic stroke., Results: During follow-up, 27 patients suffered recurrent ischemic stroke. In multivariate COX regression models adjusted for confounders including age, gender, hypertension, diabetes, and history of stroke or transient ischemic attack (TIA), platelet count, fasting blood glucose (FBG), antithrombotic drugs at discharge, stroke volume, and cardiac output, LAD, LAD/H, and LAD/BSA all were independent risk factors of recurrent ischemic stroke [LAD: HR 1.065, 95% CI (1.006-1.128), p = .029; LAD/H: HR 1.157, 95% CI (1.066-1.255), p < .001; LAD/BSA: HR 1.128, 95% CI (1.059-1.202), p < .001]. Receiver-operator characteristic curves showed that LAD/BSA had better predicting effect. The area under the curve (AUC) was 0.543 [95%CI (0.444-0.642), p = .461) for LAD, 0.626 [95%CI (0.530-0.723), p = .03] for LAD/H, and 0.655 [95%CI (0.558-0.752), p = .008] for LAD/BSA., Conclusion: LAE is an independent risk factor for one-year recurrence of ischemic stroke in patients with CCE., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Nanosized magnetite is a highly toxic material due to its strong ability to generate reactive oxygen species in vivo, and the presence of magnetite NPs in the brain has been linked with aging and neurodegenerative diseases such as Alzheimer's disease. Recently, magnetite pollution nanoparticles (NPs) were found to be present in the human brain, heart, and blood, which raises great concerns about the health risks of airborne magnetite NPs. Here, we report the abundant presence and chemical multifingerprints (including high-resolution structural and elemental fingerprints) of magnetite NPs in the urban atmosphere. We establish a methodology for high-efficiency retrieving and accurate quantification of airborne magnetite NPs. We report the occurrence levels (annual mean concentration 75.5 ± 33.2 ng m -3 in Beijing with clear season variations) and the pollution characteristics of airborne magnetite NPs. Based on the chemical multifingerprints of the NPs, we identify and estimate the contributions of the major emission sources for airborne magnetite NPs. We also give an assessment of human exposure risks of airborne magnetite NPs. Our findings support the identification of airborne magnetite NPs as a threat to human health.

Objective: To evaluate the efficacy of the extract from Ganjiangdazao recipe (EGR) on functional dyspepsia in rats with spleen-stomach deficiency cold pattern (SSDCP) in terms of Traditional Chinese Medicine, and to investigate its pharmacodynamics., Methods: Sixty Sprague-Dawley rats were randomly divided into the control group, SSDCP group, low-EGR SSDCP group, high-EGR SSDCP group, probiotics group, EGR group. SSDCP model was induced by gavage with the 0 ?edible vinegar. The symptoms and manifestations were scored by method from the relative literature, the ecological changes in cecal microflora was analyzed by 16SrRNA high-throughput sequencing technology, gastric tissues were treated by immunohistochemistry, the levels of related biochemical components related to the gastrointestinal functions were detected by enzyme-linked immunosorbent assay and colorimetry, gastric juice was measured by pH meter, blood pressure measurement by trapping tail method, surface temperature measured by infrared thermal imaging, and the content of 6-gingerol in the serum was determined by liquid-mass chromatography before and after EGR was given., Results: It was found that EGR could effectively relieve the symptoms and manifestations of the SSDCP rats (P < 0.05); the value of the relative abundance of Lactobacillus, Streptococcus, Enterococcus and Coprobacillus increased, while the value of the relative abundance of Clostridium decreased (P < 0.05) in the cecal microflora in the SSDCP rats after high-EGR administration; It was also found that EGR had no substantial effect on the related biochemical components related to the gastrointestinal functions of in the SSDCP rats; and a certain amount of 6-gingerol was detected in the serum of EGR group., Conclusion: The pharmacodynamic site of EGR is the intestinal tract, and the mechanism behind the effect of EGR on SSDCP rats, involves increasing the beneficial bacteria and decreasing the proinflammatory bacteria in the intestinal tract. The blood pharmacodynamics of EGR remains to be further studied in the future.

Macrophages maintain a dynamic balance in physiology. Various known or unknown microenvironmental signals influence the polarization, activation and death of macrophages, which creates an imbalance that leads to disease. Rheumatoid arthritis (RA) is characterized by the massive infiltration of a variety of chronic inflammatory cells in synovia. Abundant activated macrophages found in RA synovia are an early hallmark of RA, and the number of these macrophages can be decreased after effective treatment. In RA, the proportion of M1 (pro-inflammatory macrophages) is higher than that of M2 (anti-inflammatory macrophages). The increased pro-inflammatory ability of macrophages is related to their excessive activation and proliferation as well as an enhanced anti-apoptosis ability. At present, there are no clinical therapies specific to macrophages in RA. Understanding the mechanisms and functional consequences of the heterogeneity of macrophages will aid in confirming their potential role in inflammation development. This review will outline RA-related macrophage properties (focus on polarization, metabolism and apoptosis) as well as the origin of macrophages. The molecular mechanisms that drive macrophage properties also be elucidated to identify novel therapeutic targets for RA and other autoimmune disease., (© 2020 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

Since the implementation of the "Air Pollution Prevention and Control Action Plan" (APPCAP) in 2013, the air quality in China has been greatly improved but still much exceeded the WHO guideline limit. Here we employed a novel approach, two-dimensional Si fingerprints, including stable Si isotopic composition (δ 30 Si and Si abundance (Si%), to investigate the annual variations in both primary and secondary sources of PM 2.5 in Beijing during the APPCAP period (2013-2017). The δ 30 Si and Si% values were used as tracers to reflect the variations in primary and secondary sources, respectively. For primary sources, the mean δ 30 Si value of PM 2.5 in 2015-2017 (>-0.5‰) was significantly more positive than that of 2013 (-1.24‰), indicating a dramatic decline in the contribution of 30 Si-depleted sources (i.e., coal burning and industrial emission). For secondary sources, the mean Si% of PM 2.5 increased from 1.2% in 2013 to 4.6% in 2017, suggesting a large decrease in the secondary aerosol contribution from 83% to 42%. It is worth noting that we found the 30 Si-depleted sources showed a rebound trend during 2015-2017. This study reveals the responses of anthropogenic emission sources under strong regulation policies and provides a reference for future policymaking in Beijing and other polluted regions and countries.

Ambient particulate matter pollution is one of the leading causes of global disease burden. Epidemiological studies have revealed the connections between particulate exposure and cardiovascular and respiratory diseases. However, until now, the real species of ambient ultrafine particles (UFPs) in humans are still scarcely known. Here we report the discovery and characterization of exogenous nanoparticles (NPs) in human serum and pleural effusion (PE) samples collected from non-occupational subjects in a typical polluted region. We show the wide presence of NPs in human serum and PE samples with extreme diversity in chemical species, concentration, and morphology. Through chemical multi-fingerprinting (including elemental fingerprints, high-resolution structural fingerprints, and stable iron isotopic fingerprints) of NPs, we identify the sources of the NPs to be abiogenic, particularly, combustion-derived particulate emission. Our results provide evidence for the translocation of ambient UFPs into the human circulatory system, and also provide information for understanding their systemic health effects.

Inhaled atmospheric fine particulate matter (PM 2.5 ) includes soluble and insoluble fractions, and each fraction can interact with cells and cause adverse effects. PM 2.5 samples were collected in Jinan, China, and the soluble and insoluble fractions were separated. According to physiochemical characterization, the soluble fraction mainly contains water-soluble ions and organic acids, and the insoluble fraction mainly contains kaolinite, calcium carbonate and some organic carbon. The interaction between PM 2.5 and model cell membranes was examined with a quartz crystal microbalance with dissipation (QCM-D) to quantify PM 2.5 attachment on membranes and membrane disruption. The cytotoxicity of the total PM 2.5 and the soluble and insoluble fractions, was investigated. Negatively charged PM 2.5 can adhere to the positively charged membranes and disrupt them. PM 2.5 also adheres to negatively charged membranes but does not cause membrane rupture. Therefore, electrostatic repulsion does not prevent PM 2.5 attachment, but electrostatic attraction induces remarkable membrane rupture. The human lung epithelial cell line A549 was used for cytotoxicity assessment. The detected membrane leakage, cellular swelling and blebbing indicated a cell necrosis process. Moreover, the insoluble PM 2.5 fraction caused a higher cell mortality and more serious cell membrane damage than the soluble fraction. The levels of reactive oxygen species (ROS) enhanced by the two fractions were not significantly different. The findings provide more information to better understand the mechanism of PM 2.5 cytotoxicity and the effect of PM 2.5 solubility on cytotoxicity., Competing Interests: Conflict of interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2020. Published by Elsevier B.V.)