Effects of visual-motor combined response ability training on cognitive function and brain plasticity mechanism in different populations: a study protocol for a single-center, open-label, controlled clinical trial.

UNSTRUCTURED: Background: Cognitive impairment is one of the major diseases facing the aging society. The progressive decline of cognitive function will lead to the decline or even loss of life, work and social ability. Exercise and behavioral stimulation can increase neurotransmitters in the brain and improve overall health and cognitive function. Reactivity training can mobilize neuromuscular function and induce changes in brain plasticity, which may effectively improve cognitive dysfunction and delay the occurrence and development of Alzheimer's disease, but the evidence of its effectiveness is still limited. Methods: This study is a single-center, open-label, controlled clinical trial. Seventy-eight participants will be recruited for the study, including an equal number of athletes, average healthy college students, and average older adults in the community. Subjects will receive two weeks of visual-motor response training. The primary outcome of this study was to assess the imaging difference of functional magnetic resonance imaging (fMRI) at 2 weeks. Secondary outcomes are acousto-optic response time, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Mini-mental State Examination (MMSE), Activity of Daily Living Scale (ADL), Subjective Cognitive Decline Questionnaire-9 (SCD-Q9), 10-word memory test and safety. Results: The study was approved by the Shanghai Clinical Research Ethics Committee on January 2, 2024 (ethical reference: SECCR/2023-162-01). As of February 31, 2024, we have recruited 53 participants. We expect to complete recruitment in April 2024 and expect to complete the collection and analysis of study data in July 2024. Discussion: The purpose of this study is to compare improvements in brain perceptual motor functional characteristics and cognitive levels in different populations by response ability training, and to explore the efficacy and safety of exercise-based non- pharmacological therapies in improving cognitive function. Other potential benefits include understanding the functional differences and perceptual characteristics of the brain's perceptual-motor system between athletes and the general population, and exploring the adaptability of the brain for acquiring skills during training in competitive sports, thus providing an evidence base for early sports talent development and broader youth development. Trial registration: Chinese Clinical Trial Registry ID: ChiCTR2400079602. Registered 8 Jan 2024, Available at: www.chictr.org.cn/showproj.html?proj=215669 Abbreviations: AD=Alzheimer's disease (AD), DMC=data Monitoring Committee, fMRI=functional magnetic resonance imaging.

A highly sensitive SERS substrate of porous membrane-Ag NPs for kidney cancer detection.

BACKGROUND: The substrate employed in surface-enhanced Raman spectroscopy (SERS) constitutes an essential element in the cancer detection methodology. In this research, we introduce a three-dimensional (3D) structured SERS substrate that integrates a porous membrane with silver nanoparticles to enhance SERS spectral signals through the utilization of the aggregation effect of silver nanoparticles. This enhancement is crucial because accurate detection results strongly depend on the intensity of specific peaks in Raman spectroscopy. A highly sensitive SERS substrate can significantly improve the accuracy of detection results. RESULTS: We collected 66 plasma samples from individuals with kidney cancer and control individuals, including both bladder cancer patients and healthy individuals. Then, we utilized substrates with and without porous membranes to acquire the SERS spectra of the samples, enabling us to evaluate the enhancement effect of our SERS substrate. The spectral analysis demonstrated enhanced peak intensities in the experimental group (with porous substrate) compared to the control group (without porous substrate). The uniformity and reproducibility of the SERS substrate are also significantly enhanced, which is very helpful for improving the accuracy of detection results. Additionally, the Principal Component Analysis-Linear Discriminant Analysis algorithm (PCA-LDA) was employed to classify the SERS spectra of both groups. In the experimental group, the classification accuracy was 98.5 % for kidney cancer, and 83.3 % for kidney and bladder cancer. Compared to the control group, it improved by 3 % and 12.6 % respectively. SIGNIFICANT: This indicates that our 3D structured SERS substrate combined with multivariate statistical algorithms PCA-LDA can not only improve the accuracy of SERS detection technology in single cancer detection, but also has great potential in multiple cancer detection. This 3D structured SERS substrate is expected to become a new auxiliary means for cancer detection.

Cascade Nanoreactor Employs Mitochondrial-Directed Chemodynamic and δ-ALA-Mediated Photodynamic Synergy for Deep-Seated Oral Cancer Therapy.

The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggers δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT/CDT-induced apoptosis generates δ-ALA-containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment.

Antitumour mechanisms of traditional Chinese medicine elicited by regulating tumour-associated macrophages in solid tumour microenvironments.

Tumour-associated macrophages (TAMs), particularly M2-TAMs, constitute the largest proportion of immune cells in the solid tumour microenvironment, playing a crucial role in tumour progression and correlating with poor prognosis. TAMs promote the proliferation, invasion, and metastasis of tumour cells by remodelling the extracellular matrix, inhibiting immunity, promoting immune escape and tumour angiogenesis, and affecting cell metabolism. Traditional Chinese medicine (TCM) has been used clinically in China for millennia. Chinese herbs exhibit potent antitumour effects with minimal to no toxicity, substantially contributing to prolonging the lives of patients with cancer and improving their quality of life. TCM has unique advantages in improving the solid tumour microenvironment, particularly in regulating TAMs to further inhibit tumour angiogenesis, reduce drug resistance, reverse immunosuppression, and enhance antitumour immunity. This review highlights the TAM-associated mechanisms within the solid tumour microenvironment, outlines the recent advancements in TCM targeting TAMs for antitumour effects, emphasises the superiority of combining TCM with standard treatments or new nano-drug delivery systems, and evaluates the safety and efficacy of TCM combined with conventional treatments via clinical trials to provide insights and strategies for future research and clinical treatment.

Identification and validation of an H2AZ1-based index model: a novel prognostic tool for hepatocellular carcinoma.

The H2A.Z variant histone 1 (H2AZ1) is aberrantly expressed in various tumors, correlating with an unfavorable prognosis. However, its role in hepatocellular carcinoma (HCC) remains unclear. We aimed to elucidate the pathways affected by H2AZ1 and identify promising therapeutic targets for HCC. Following bioinformatic analysis of gene expression and clinical data from The Cancer Genome Atlas and Gene Expression Omnibus database, we found 6,344 dysregulated genes related to H2AZ1 overexpression in HCC tissues (P < 0.05). We performed weighted gene co-expression network analysis to identify the gene module most related to H2AZ1. The H2AZ1-based index was further developed using Cox regression analysis, which revealed that the poor prognosis in the high H2AZ1-based index group could be attributed to elevated tumor stemness (P < 0.05). Moreover, the clinical model showed good prognostic potential (AUC > 0.7). We found that H2AZ1 knockdown led to reduced superoxide dismutase (SOD) activity, elevated malondialdehyde (MDA) levels, and increased apoptosis rate in tumor cells (P < 0.001). Thus, we developed an H2AZ1-based index model with the potential to predict the prognosis of patients with HCC. Our findings provide initial evidence that H2AZ1 overexpression plays a pivotal role in HCC initiation and progression.

Carbon quantum dots modified and Y3+ doped Ni3(NO3)2(OH)4 nanospheres with excellent battery-like supercapacitor performance.

Supercapacitor is an important energy storage device widely used in the automobile industry, military production, and communication equipment because of its fast charge-discharge rate, and high power density. Herein, carbon quantum dots modified and Y3+ doped Ni3(NO3)2(OH)4 (NiY@CQDs) nanospheres are prepared by a solvothermal method and used as an electrode material. The electrochemical properties of NiY@CQDs were measured in a three-electrode system. An asymmetric supercapacitor (ASC) cell was assembled with activated carbon (AC) as the anode and NiY@CQDs as the cathode. The electrochemical properties of the ASC device were measured in a two-electrode system. Experimental results show the shape of NiY@CQDs is petal-shaped and the introducing carbon quantum dots and doping Y3+ significantly increases the specific surface area, conductivity, and specific capacitance of Ni3(NO3)2(OH)4. The mass-specific capacitance of NiY@CQDs reaches up to 2944 F g-1 at a current density of 1 A g-1. The asymmetric supercapacitor of NiY@CQDs//AC has a high energy density of 138.65 Wh kg-1 at a power density of 1500 W kg-1, displaying a wide range of application prospects in the energy storage area.

Iron containing sludge-derived carbon towards efficient peroxymonosulfate activation: Active site synergy, performance and alternation mechanism.

Converting industrial sludge into catalytic materials for water purification is a promising approach to simultaneously realize effective disposal of sludge and resource of water. However, manipulating the high efficiency remains a huge challenge due to the difficulty in the active sites control of the sludge. Herein, we proposed a constitutive modulation strategy by the combination of hydrothermal and pyrolysis (HTP) for the fabrication of defects-assistant Fe containing sludge-derived carbon catalysts on upgrading performance in peroxymonosulfate (PMS) activation for pollutant degradation. Adjustable defects on dyeing sludge-derived carbon catalysts (DSCC) were achieved by introducing oxygen or nitrogen functional precursors (hydroquinone or p-phenylenediamine) during hydrothermal processes and by further pyrolysis, where O was detrimental while N was beneficial to defect generation. Compared to the DSCC with less defects (DHSC-O), the defect-rich sample (DHSC-2N) exhibited superior catalytic performance of PMS activation for bisphenol A (BPA) elimination (k = 0.45 min-1, 2.52 times of DHSC-O), as well as 81.4% total organic carbon (TOC) removal. Meanwhile, the degradation capacity was verified in wide pH range (2.1-8.1) and various aqueous matrices, reflecting the excellent adaptability and anti-interference performance. Furthermore, the continuous-flow experiments on industrial wastewater showed synchronous BPA and chemical oxygen demand (COD) removal, implying great potential for practical application. Solid electron paramagnetic resonance (EPR) and 57Fe Mösssbauer spectra analysis indicated that the defects acted as secondary active sites for Fe sites, which were beneficial to accelerating the electron transfer process. The only Fe active sites preferred the radical pathway. The controllable reaction tendency provides possibilities for the on-demand design of sludge-based catalysts to meet the requirements of practical wastewater treatment under Fenton-like reaction.

Dyeing sludge-derived biochar for efficient removal of antibiotic from water.

Adsorption is one of the most effective methods for ecotoxic antibiotics removal, while developing high-performance adsorbents with excellent adsorption capacity is indispensable. As the unavoidable by-product of wastewater, sewage sludge has dual properties of pollution and resources. In this study, dyeing sludge waste was converted to biochar by KOH activation and pyrolysis, and used as an efficient adsorbent for aqueous antibiotics removal. The optimized dyeing sludge-derived biochar (KSC-8) has excellent specific surface area (1178.4 m2/g) and the adsorption capacity for tetracycline (TC) could reach up to 1081.3 mg/g, which is four and five times higher than those without activation, respectively. The PSO (pseudo-second-order) kinetic model and the Langmuir isotherm model fitted better to the experimental data. The obtained KSC-8 has stabilized adsorption capacity for long-term fixed-bed experiments, and maintained 86.35% TC removal efficiency after five adsorption-regeneration cycles. The adsorption mechanism involves electrostatic attraction, hydrogen bonding, π-π interactions and pore filling. This work is a green and eco-friendly way as converting the waste to treat waste in aiming of simultaneous removal of antibiotics and resource recovery of dyeing sludge.

Single-cell RNA sequencing revealed potential targets for immunotherapy studies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a solid tumor prone to chemotherapy resistance, and combined immunotherapy is expected to bring a breakthrough in HCC treatment. However, the tumor and tumor microenvironment (TME) of HCC is highly complex and heterogeneous, and there are still many unknowns regarding tumor cell stemness and metabolic reprogramming in HCC. In this study, we combined single-cell RNA sequencing data from 27 HCC tumor tissues and 4 adjacent non-tumor tissues, and bulk RNA sequencing data from 374 of the Cancer Genome Atlas (TCGA)-liver hepatocellular carcinoma (LIHC) samples to construct a global single-cell landscape atlas of HCC. We analyzed the enrichment of signaling pathways of different cells in HCC, and identified the developmental trajectories of cell subpopulations in the TME using pseudotime analysis. Subsequently, we performed transcription factors regulating different subpopulations and gene regulatory network analysis, respectively. In addition, we estimated the stemness index of tumor cells and analyzed the intercellular communication between tumors and key TME cell clusters. We identified novel HCC cell clusters that specifically express HP (HCC_HP), which may lead to higher tumor differentiation and tumor heterogeneity. In addition, we found that the HP gene expression-positive neutrophil cluster (Neu_AIF1) had extensive and strong intercellular communication with HCC cells, tumor endothelial cells (TEC) and cancer-associated fibroblasts (CAF), suggesting that clearance of this new cluster may inhibit HCC progression. Furthermore, ErbB signaling pathway and GnRH signaling pathway were found to be upregulated in almost all HCC tumor-associated stromal cells and immune cells, except NKT cells. Moreover, the high intercellular communication between HCC and HSPA1-positive TME cells suggests that the immune microenvironment may be reprogrammed. In summary, our present study depicted the single-cell landscape heterogeneity of human HCC, identified new cell clusters in tumor cells and neutrophils with potential implications for immunotherapy research, discovered complex intercellular communication between tumor cells and TME cells.

Exploring the global immune landscape of peripheral blood mononuclear cells in H5N6-infected patient with single-cell transcriptomics.

BACKGROUND: Avian influenza viruses (AIV), particularly H5N6, have risen in infection frequency, prompting major concerns. Single-cell RNA sequencing (scRNA-seq) can illustrate the immune cell landscape present in the peripheral circulation of influenza H5N6-infected individuals at the single-cell level. This study attempted to employ scRNA-seq technology to map the potentially hidden single cell landscape of influenza H5N6. METHODS: High-quality transcriptomes were generated from scRNA-seq data of peripheral blood mononuclear cells (PBMCs), which were taken from a critically-ill child diagnosed with H5N6 avian influenza infection and one healthy control donor. Cluster analysis was then performed on the scRNA-seq data to identify the different cell types. The pathways, pseudotime developmental trajectories and gene regulatory networks involved in different cell subpopulations were also explored. RESULTS: In total, 3,248 single cell transcriptomes were captured by scRNA-seq from PBMC of the child infected with H5N6 avian influenza and the healthy control donor and further identified seven immune microenvironment cell types. In addition, a subsequent subpopulation analysis of innate lymphoid cells (ILC) and CD4+ T cells revealed that subpopulations of ILC and CD4+ T cells were involved in cytokine and inflammation-related pathways and had significant involvement in the biological processes of oxidative stress and cell death. CONCLUSION: In conclusion, characterizing the overall immune cell composition of H5N6-infected individuals by assessing the immune cell landscape in the peripheral circulation of H5N6 avian influenza-infected and healthy control donors at single-cell resolution provides key information for understanding H5N6 pathogenesis.

Agricultural tillage practice and rhizosphere selection interactively drive the improvement of soybean plant biomass.

Rhizosphere microbes play key roles in plant growth and productivity in agricultural systems. One of the critical issues is revealing the interaction of agricultural management (M) and rhizosphere selection effects (R) on soil microbial communities, root exudates and plant productivity. Through a field management experiment, we found that bacteria were more sensitive to the M × R interaction effect than fungi, and the positive effect of rhizosphere bacterial diversity on plant biomass existed in the bacterial three two-tillage system. In addition, inoculation experiments demonstrated that the nitrogen cycle-related isolate Stenotrophomonas could promote plant growth and alter the activities of extracellular enzymes N-acetyl- d-glucosaminidase and leucine aminopeptidase in rhizosphere soil. Microbe-metabolites network analysis revealed that hubnodes Burkholderia-Caballeronia-Paraburkholderia and Pseudomonas were recruited by specific root metabolites under the M × R interaction effect, and the inoculation of 10 rhizosphere-matched isolates further proved that these microbes could promote the growth of soybean seedlings. Kyoto Encyclopaedia of Genes and Genomes pathway analysis indicated that the growth-promoting mechanisms of these beneficial genera were closely related to metabolic pathways such as amino acid metabolism, melatonin biosynthesis, aerobactin biosynthesis and so on. This study provides field observation and experimental evidence to reveal the close relationship between beneficial rhizosphere microbes and plant productivity under the M × R interaction effect.

Single-cell RNA sequencing reveals cell subpopulations in the tumor microenvironment contributing to hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is among the deadliest cancers worldwide, and advanced HCC is difficult to treat. Identifying specific cell subpopulations in the tumor microenvironment and exploring interactions between the cells and their environment are crucial for understanding the development, prognosis, and treatment of tumors. Methods: In this study, we constructed a tumor ecological landscape of 14 patients with HCC from 43 tumor tissue samples and 14 adjacent control samples. We used bioinformatics analysis to reveal cell subpopulations with potentially specific functions in the tumor microenvironment and to explore the interactions between tumor cells and the tumor microenvironment. Results: Immune cell infiltration was evident in the tumor tissues, and BTG1 + RGS1 + central memory T cells (Tcms) interact with tumor cells through CCL5-SDC4/1 axis. HSPA1B may be associated with remodeling of the tumor ecological niche in HCC. Cancer-associated fibroblasts (CAFs) and macrophages (TAMs) were closely associated with tumor cells. APOC1 + SPP1 + TAM secretes SPP1, which binds to ITGF1 secreted by CAFs to remodel the tumor microenvironment. More interestingly, FAP + CAF interacts with naïve T cells via the CXCL12-CXCR4 axis, which may lead to resistance to immune checkpoint inhibitor therapy. Conclusion: Our study suggests the presence of tumor cells with drug-resistant potential in the HCC microenvironment. Among non-tumor cells, high NDUFA4L2 expression in fibroblasts may promote tumor progression, while high HSPA1B expression in central memory T cells may exert anti-tumor effects. In addition, the CCL5-SDC4/1 interaction between BTG1 + RGS1 + Tcms and tumor cells may promote tumor progression. Focusing on the roles of CAFs and TAMs, which are closely related to tumor cells, in tumors would be beneficial to the progress of systemic therapy research.

The Conformational Transitions and Dynamics of Burkholderia cepacia Lipase Regulated by Water-Oil Interfaces.

Structural dynamics and conformational transitions are crucial for the activities of enzymes. As one of the most widely used industrial biocatalysts, lipase could be activated by the water-oil interfaces. The interface activations were believed to be dominated by the close-to-open transitions of the lid subdomains. However, the detailed mechanism and the roles of structure transitions are still under debate. In this study, the dynamic structures and conformational transitions of Burkholderia cepacia lipase (LipA) were investigated by combining all-atom molecular dynamics simulations, enhanced sampling simulation, and spectrophotometric assay experiments. The conformational transitions between the lid-open and lid-closed states of LipA in aqueous solution are directly observed by the computational simulation methods. The interactions between the hydrophobic residues on the two lid-subdomains are the driven forces for the LipA closing. Meanwhile, the hydrophobic environment provided by the oil interfaces would separate the interactions between the lid-subdomains and promote the structure opening of LipA. Moreover, our studies demonstrate the opening of the lids structure is insufficient to initiate the interfacial activation, providing explanations for the inability of interfacial activation of many lipases with lid structures.

Functional Hearing Impairment, Psychological Resilience, and Social Well-Being Among Chinese Older Adults in Low-Income Households.

PURPOSE: Hearing loss (HL) is prevalent and relates to social health in old age. This study aims to examine the association between functional HL and social well-being (SWB) in older adults and to investigate whether psychological resilience mediates this association. METHOD: The analytical sample of 4,531 older adults aged ≥ 60 years was from the Sample Survey on Vulnerable Populations from Poor Families in Urban/Rural China (2018). SWB was measured by social networks and social engagement using the Lubben Social Network Scale and Index of Social Engagement Scale, respectively. Functional hearing impairment was defined by a dichotomized measure of self-perceived hearing difficulty. Psychological resilience was assessed by a 25-item Connor-Davidson Resilience Scale. Structural equation modeling was performed to determine associations of HL with SWB and the mediating roles of psychological resilience. RESULTS: Functional HL was associated with reduced SWB among older adults living in low-income households. Hearing-impaired individuals were more likely to be socially isolated and less socially engaged compared to those with normal hearing. The association persisted in gender subsamples and in non-low-income households but not in older adults aged ≥ 70 years. Psychological resilience partially mediated the association of hearing impairment with SWB, accounting for 50.9% of the variance in the change of SWB. CONCLUSIONS: Functional hearing impairment may be a modifiable risk factor for social restrictions and downstream older adults' health. Promotion of hearing health care and accessibility to coping resources including psychological support may improve social wellness among the older adults and benefit healthy aging. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.22750736.

Differential expression profiles of plasma exosomal microRNAs in dilated cardiomyopathy with chronic heart failure.

As one of the most prevalent heritable cardiovascular diseases, dilated cardiomyopathy (DCM) induces cardiac insufficiency and dysfunction. Although genetic mutation has been identified one of the causes of DCM, the usage of genetic biomarkers such as RNAs for DCM early diagnosis is still being overlooked. In addition, the alternation of RNAs could reflect the progression of the diseases, as an indicator for the prognosis of patients. Therefore, it is beneficial to develop genetic based diagnostic tool for DCM. RNAs are often unstable within circulatory system, leading to the infeasibility for clinical application. Recently discovered exosomal miRNAs have the stability that is then need for diagnostic purpose. Hence, fully understanding of the exosomal miRNA within DCM patients is vital for clinical translation. In this study, we employed the next generation sequencing based on the plasma exosomal miRNAs to comprehensively characterize the miRNAs expression in plasma exosomes from DCM patients exhibiting chronic heart failure (CHF) compared to healthy individuals. A complex landscape of differential miRNAs and target genes in DCM with CHF patients were identified. More importantly, we discovered that 92 differentially expressed miRNAs in DCM patients undergoing CHF were correlated with several enriched pathways, including oxytocin signalling pathway, circadian entrainment, hippo signalling pathway-multiple species, ras signalling pathway and morphine addiction. This study reveals the miRNA expression profiles in plasma exosomes in DCM patients with CHF, and further reveal their potential roles in the pathogenesis of it, presenting a new direction for clinical diagnosis and management of DCM patients with CHF.

Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer.

Mapping tumor metabolic remodeling and their spatial crosstalk with surrounding non-tumor cells can fundamentally improve our understanding of tumor biology, facilitates the designing of advanced therapeutic strategies. Here, we present an integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics to hierarchically visualize the intratumor metabolic heterogeneity and cell metabolic interactions in same gastric cancer sample. Tumor-associated metabolic reprogramming is imaged at metabolic-transcriptional levels, and maker metabolites, lipids, genes are connected in metabolic pathways and colocalized in the heterogeneous cancer tissues. Integrated data from spatial multi-omics approaches coherently identify cell types and distributions within the complex tumor microenvironment, and an immune cell-dominated "tumor-normal interface" region where tumor cells contact adjacent tissues are characterized with distinct transcriptional signatures and significant immunometabolic alterations. Our approach for mapping tissue molecular architecture provides highly integrated picture of intratumor heterogeneity, and transform the understanding of cancer metabolism at systemic level.

Atherosclerosis: The Involvement of Immunity, Cytokines and Cells in Pathogenesis, and Potential Novel Therapeutics.

As a leading contributor to coronary artery disease (CAD) and stroke, atherosclerosis has become one of the major cardiovascular diseases (CVD) negatively impacting patients worldwide. The endothelial injury is considered to be the initial step of the development of atherosclerosis, resulting in immune cell migration and activation as well as inflammatory factor secretion, which further leads to acute and chronic inflammation. In addition, the inflammation and lipid accumulation at the lesions stimulate specific responses from different types of cells, contributing to the pathological progression of atherosclerosis. As a result, recent studies have focused on using molecular biological approaches such as gene editing and nanotechnology to mediate cellular response during atherosclerotic development for therapeutic purposes. In this review, we systematically discuss inflammatory pathogenesis during the development of atherosclerosis from a cellular level with a focus on the blood cells, including all types of immune cells, together with crucial cells within the blood vessel, such as smooth muscle cells and endothelial cells. In addition, the latest progression of molecular-cellular based therapy for atherosclerosis is also discussed. We hope this review article could be beneficial for the clinical management of atherosclerosis.

Single-cell and spatial dissection of precancerous lesions underlying the initiation process of oral squamous cell carcinoma.

Precancerous lesions of the oral mucosa, especially those accompanied by moderate to severe dysplasia, contribute to the initiation of oral squamous cell carcinoma (OSCC). However, the cellular compositions and spatial organization of the precancerous stage and how these factors promote human OSCC initiation remain unclear. Here, we built a single-cell transcriptome atlas and a spatial transcriptome map after obtaining data from pairwise human oral mucosal biopsies of 9 individuals consisting of very early-stage OSCC, adjacent precancerous lesions with moderate to severe dysplasia, as well as a matched normal region. An altered epithelial gene-expression profile was identified which favored OSCC initiation. This observation was coupled with distinct fibroblast, monocytic, and regulatory T-cell subclusters involved in reshaping the microenvironment. In particular, a unique immune-inhibitory monocyte subtype and spatial-switching regulation of VEGF signaling were observed surrounding precancerous lesions, concertedly strengthening activities in promoting cancer initiation. Collectively, our work elucidated the cellular landscapes and roles of precancerous lesions underlying OSCC initiation, which is essential for understanding the entire OSCC initiation process and helps inform therapeutic strategies for cancer intervention.

Impacts of the hearing aid intervention on healthcare utilization and costs among middle-aged and older adults: results from a randomized controlled trial in rural China.

Background: Hearing impairment has become a major global health issue. To reduce the burden of hearing impairment, we explored impacts of the hearing aid intervention on healthcare utilization and costs. Methods: In this randomized controlled trial, participants aged 45+ were allocated with a ratio of 1:1.5 (intervention: control). Neither the investigators nor the assessors were blinded to the allocation status. Those in the intervention group were fitted with hearing aids, and those in the control group received no care. We applied the difference-in-difference (DID) approach to examine the impacts on healthcare utilization and costs. Given that social network and age can be significant variables affecting effectiveness of the intervention, subgroup analyses by social network and age were used to explore the heterogeneity. Findings: 395 subjects were successfully recruited and randomized. 10 subjects did not meet the inclusion criteria and therefore, 385 eligible subjects (150 in the treatment group and 235 in the control group) were analyzed. The intervention significantly reduced their total healthcare costs (average treatment effect (ATE) = -1.26, 95% CI = -2.39, -0.14, p = 0.028) and total out-of-pocket (OOP) healthcare costs (ATE = -1.29, 95% CI = -2.37, -0.20, p = 0.021) in the 20-month follow-up. To be exact, it reduced self-medication costs (ATE = -0.82, 95% CI = -1.49, -0.15, p = 0.016) and OOP self-medication costs (ATE = -0.84, 95% CI = -1.46, -0.21, p = 0.009). Subgroup analysis showed that the impacts on self-medication costs and OOP self-medication costs varied by social network (ATE for self-medication costs = -0.26, 95% CI = -0.50, -0.01, p = 0.041; ATE for OOP self-medication costs = -0.27, 95% CI = -0.52, -0.01, p = 0.038). The impacts also varied by age groups (ATE for self-medication costs = -0.22, 95% CI = -0.40, -0.04, p = 0.019; ATE for OOP self-medication costs = -0.17, 95% CI = -0.29, -0.04, p = 0.010). There were no adverse events or side effects during the trial. Interpretation: Hearing aid use significantly lowered self-medication costs and total healthcare costs, but had no impacts on inpatient or outpatient services utilization or costs. The impacts were manifested among people with active social network or younger age. It can be speculated that the intervention may be adapted to other similar settings in developing countries to reduce healthcare costs. Funding: P.H. reports grants from National Natural Science Foundation of China (No. 71874005) and Major Project of the National Social Science Fund of China (No. 21&ZD187). Trial registration: Chinese Clinical Trial Registry: ChiCTR1900024739.