Indoor/Outdoor airborne microbiome characteristics in residential areas across four seasons and its indoor purification.

Bioaerosols are more likely to accumulate in the residential environment, and long-term inhalation may lead to a variety of diseases and allergies. Here, we studied the distribution, influencing factors and diffusion characteristics of indoor and outdoor microbiota pollution in six residential buildings in Guangzhou, southern China over a period of one year. The results showed that the particle sizes of bioaerosol were mainly in the range of inhalable particle size (<4.7 µm) with a small difference among four seasons (74.61 % ± 2.17 %). The microbial communities showed obvious seasonal differences with high abundance in summer, but no obvious geographical differences. Among them, the bacteria were more abundant than the fungi. The dominant microbes in indoor and outdoor environments were similar, with Anoxybacillu, Brevibacillus and Acinetobacter as the dominant bacteria, and Cladosporium, Penicillium and Alternaria as the dominant fungi. The airborne microbiomes were more sensitive to temperature and particulate matter (PM2.5, PM10) concentrations. Based on the Sloan neutral model, bacteria were more prone to random diffusion than fungi, and the airborne microbiome can be randomly distributed in indoor and outdoor environments and between the two environments in each season. Bioaerosol in indoor was mainly from outdoor. The health risk evaluation showed that the indoor inhalation risks were higher than those outdoor. The air purifier had a better removal efficiency on 1.1-4.7 µm microorganisms, and the removal efficiency on Gram-negative bacteria was better than that on Gram-positive bacteria. This study is of great significance for the risk assessment and control of residential indoor bioaerosol exposure.

Aptamer-Modified Nb2C Multifunctional Nanomedicine for Targeted Photothermal/Chemotherapy Combined Therapy of Tumor.

The poor delivery efficiency of nanotherapeutic drugs and their potential off-target toxicity significantly limit their effectiveness and extensive application. An active targeting system with high efficiency and few side effects is a promising strategy for tumor therapy. Herein, a multifunctional nanomedicine Nb2C-PAA-DOX@Apt-M (NDA-M) was constructed for targeted photothermal/chemotherapy (PTT/CHT) combined tumor therapy. The specific targeting ability of aptamer could effectively enhance the absorption of nanomedicine by the MCF-7 cell. By employing Apt-M, the NDA-M nanosheets demonstrated targeted delivery to MCF-7 cells, resulting in enhanced intracellular drug concentration. Under 1060 nm laser irradiation, a rapid temperature increase of the NDA-M was observed within the tumor region to achieve PTT. Meanwhile, CHT was triggered when DOX release was induced by photothermal/acid stimulation. The experimental results demonstrated that aptamer-mediated targeting achieved enhanced PTT/CHT efficacy both in vitro and in vivo. Notably, NDA-M induced complete ablation of solid tumors without any adverse side effects in mice. This study demonstrated new and promising tactics for the development of nanomaterials for targeted tumor therapy.

A novel efficient strategy to generate liver sinusoidal endothelial cells from human pluripotent stem cells.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells (ECs) that play an important role in liver development and regeneration. Additionally, it is involved in various pathological processes, including steatosis, inflammation, fibrosis and hepatocellular carcinoma. However, the rapid dedifferentiation of LSECs after culture greatly limits their use in vitro modeling for biomedical applications. In this study, we developed a highly efficient protocol to induce LSEC-like cells from human induced pluripotent stem cells (hiPSCs) in only 8 days. Using single-cell transcriptomic analysis, we identified several novel LSEC-specific markers, such as EPAS1, LIFR, and NID1, as well as several previously revealed markers, such as CLEC4M, CLEC1B, CRHBP and FCN3. These LSEC markers are specifically expressed in our LSEC-like cells. Furthermore, hiPSC-derived cells expressed LSEC-specific proteins and exhibited LSEC-related functions, such as the uptake of acetylated low density lipoprotein (ac-LDL) and immune complex endocytosis. Overall, this study confirmed that our novel protocol allowed hiPSCs to rapidly acquire an LSEC-like phenotype and function in vitro. The ability to generate LSECs efficiently and rapidly may help to more precisely mimic liver development and disease progression in a liver-specific multicellular microenvironment, offering new insights into the development of novel therapeutic strategies.

Ferroptosis in thyroid cancer: Potential mechanisms, effective therapeutic targets and predictive biomarker.

Thyroid cancer is a prevalent endocrine malignancy whose global incidence has risen over the past several decades. Ferroptosis, a regulated form of cell death distinguished by the excessive buildup of iron-dependent lipid peroxidates, stands out from other programmed cell death pathways in terms of morphological and molecular characteristics. Increasing evidence suggests a close association between thyroid cancer and ferroptosis, that is, inducing ferroptosis effectively suppresses the proliferation of thyroid cancer cells and impede tumor advancement. Therefore, ferroptosis represents a promising therapeutic target for the clinical management of thyroid cancer in clinical settings. Alterations in ferroptosis-related genes hold potential for prognostic prediction in thyroid cancer. This review summarizes current studies on the role of ferroptosis in thyroid cancer, elucidating its mechanisms, therapeutic targets, and predictive biomarkers. The findings underscore the significance of ferroptosis in thyroid cancer and offer valuable insights into the development of innovative treatment strategies and accurate predictors for the thyroid cancer.

Preparation of µ-HMX/C-Based Composite Energy Composite Microspheres by Microdroplet Technology.

Taking µ-HMX particles as the main research subject, a set of microdroplet sphericalization coating technology platforms was designed and constructed to realize the preparation of composite microspheres by sphericalization coating of µ-HMX. The suspension stability of µ-HMX particles and the mechanism of droplet formation were investigated, and the application effect of nanocarbon materials was also analyzed. The results showed that the prepared sample microspheres all showed a better spherical morphology, as well as good dispersibility; the samples with micron-sized particles for spherical coating had a lower thermal decomposition temperature, a higher energy release efficiency, lower mechanical sensibility, and better combustion performance; the incorporation of CNFs changed the combustion mode of the system, which resulted in the microsphere system of µ-HMX having a good safety performance. The stability and feasibility of uniform spheronization when the dispersed phase is a low-concentration particle suspension system in the spheronization encapsulation process by microdroplet technology were verified.

Protein profile of circulating extracellular vesicles reveals biomarker candidates for diagnosis of post-traumatic deep vein thrombosis.

BACKGROUND AND OBJECTIVE: Deep vein thrombosis (DVT) is a common complication after trauma and mostly without specific symptoms. Timely diagnosis and early appropriate treatment measures can prevent further development of thrombosis for patients with traumatic lower extremity fractures. Although extracellular vesicles (EVs) are confirmed as promising disease biomarkers, little is known about the role of altered levels and composition in the diagnosis of post-traumatic DVT. METHOD: The levels of circulating EVs subgroups were measured using flow cytometry. Isolated EVs were characterized and subjected to proteomics analysis to screen for differentially expressed proteins (DEPs) between DVT and non-DVT patients. Regularized logistic regression analysis based on L2 penalty terms using R's caret package was applied to build a model for DVT diagnosis. RESULTS: Compared to non-DVT patients, DVT patients had higher circulating hepatocyte-derived EVs (hEVs) with good predictive value for post-traumatic DVT diagnosis. The results of the proteomic analysis showed that differentially expressed proteins (DEPs) of circulating EVs between the DVT group and non-DVT group were enriched in the complement and coagulation cascade. Finally, an integrated model of five biomarkers including SERPING1, C8G, CFH, FIX, and hEVs level was established for post-traumatic DVT diagnosis with robust identification of the traumatic patients with and without DVT (AUC 0.972). CONCLUSION: Post-traumatic DVT patients had changed levels and composition of circulating EVs compared to non-DVT patients and healthy controls. Circulating EVs may acquire pathological protein signatures and become potential biomarkers for identifying subjects' post-traumatic DVT.

Enhanced sensitivity of extracellular antibiotic resistance genes (ARGs) to environmental concentrations of antibiotic.

As emerging contaminants, antibiotics are frequently present in various environments, particularly rivers, albeit often at sublethal concentrations (ng/L∼µg/L). Assessing the risk associated with these low levels, which are far below the lethal threshold for most organisms, remains challenging. In this study, using microcosms containing planktonic bacteria and biofilm, we examined how antibiotic resistance genes (ARGs) in different physical states, including intracellular ARGs (iARGs) and extracellular ARGs (eARGs) responded to these low-level antibiotics. Our findings reveal a positive correlation between sub-lethal antibiotic exposure (ranging from 0.1 to 10 µg/L) and increased prevalence (measured as ARG copies/16s rDNA) of both iARGs and eARGs in planktonic bacteria. Notably, eARGs demonstrated greater sensitivity to antibiotic exposure compared to iARGs, with a lower threshold (0.1 µg/L for eARGs versus 1 µg/L for iARGs) for abundance increase. Moreover, ARGs in biofilms demonstrates higher sensitivity to antibiotic exposure compared to planktonic bacteria. To elucidate the underlying mechanisms, we established an integrated population dynamics-pharmacokinetics-pharmacodynamics (PD-PP) model. This model indicates that the enhanced sensitivity of eARGs is primarily driven by an increased potential for plasmid release from cells under low antibiotic concentrations. Furthermore, the accumulation of antibiotic in biofilms induces a greater sensitivity of ARG compared to the planktonic bacteria. This study provides a fresh perspective on the development of antibiotic resistance and offers an innovative approach for assessing the risk of sublethal antibiotic in the environment.

Reliability and Validity of the Chinese Version of the Revised Sociosexual Orientation Inventory.

The Revised Sociosexual Orientation Inventory (SOI-R) is a measurement tool for assessing an individual's willingness to engage in uncommitted sexual relations. Despite its widespread use in various contexts, no studies have validated the use of this instrument in China. Therefore, the current study aimed to assess the reliability and validity of an existing Chinese translation of the SOI-R. A total of 2,209 participants were recruited and randomly divided into two groups: exploratory factor analysis was conducted on one group and confirmatory factor analysis on the other, with 161 participants from the total sample recruited to assess the test-retest reliability. Criterion validity was measured by testing the correlations between sociosexuality and sexual desire, mate value, sexual attitudes, and personality traits. The results confirmed a three-factor structure (sociosexual behaviors, attitudes, and desire) for the SOI-R. Furthermore, the findings demonstrated good reliability (internal consistency and test-retest stability) and validity (criterion validity, convergent validity, and discriminant validity) of the SOI-R, supporting its suitability as an assessment tool for sociosexual orientation in China.

Predicting human epidermal growth factor receptor 2 status of patients with gastric cancer by computed tomography and clinical features.

Background: There have been no studies on predicting human epidermal growth factor receptor 2 (HER2) status in patients with resectable gastric cancer (GC) in the neoadjuvant and perioperative settings. We aimed to investigate the use of preoperative contrast-enhanced computed tomography (CECT) imaging features combined with clinical characteristics for predicting HER2 expression in GC. Methods: We retrospectively enrolled 301 patients with GC who underwent curative resection and preoperative CECT. HER2 status was confirmed by postoperative immunohistochemical analysis with or without fluorescence in situ hybridization. A prediction model was developed using CECT imaging features and clinical characteristics that were independently associated with HER2 status using multivariate logistic regression analysis. Receiver operating characteristic curves were constructed and the performance of the prediction model was evaluated. The bootstrap method was used for internal validation. Results: Three CECT imaging features and one serum tumor marker were independently associated with HER2 status in GC: enhancement ratio in the arterial phase (odds ratio [OR] = 4.535; 95% confidence interval [CI], 2.220-9.264), intratumoral necrosis (OR = 2.64; 95% CI, 1.180-5.258), tumor margin (OR = 3.773; 95% CI, 1.968-7.235), and cancer antigen 125 (CA125) level (OR = 5.551; 95% CI, 1.361-22.651). A prediction model derived from these variables showed an area under the receiver operating characteristic curve of 0.802 (95% CI, 0.740-0.864) for predicting HER2 status in GC. The established model was stable, and the parameters were accurately estimated. Conclusions: Enhancement ratio in the arterial phase, intratumoral necrosis, tumor margin, and CA125 levels were independently associated with HER2 status in GC. The prediction model derived from these factors may be used preoperatively to estimate HER2 status in GC and guide clinical treatment.

Predicting One-year Recurrence of HCC based on Gadoxetic Acid-enhanced MRI by Machine Learning Models.

OBJECTIVE: Accurate prediction of recurrence risk after resction in patients with Hepatocellular Carcinoma (HCC) may help to individualize therapy strategies. This study aimed to develop machine learning models based on preoperative clinical factors and multiparameter Magnetic Resonance Imaging (MRI) characteristics to predict the 1-year recurrence after HCC resection. METHODS: Eighty-two patients with single HCC who underwent surgery were retrospectively analyzed. All patients underwent preoperative gadoxetic acidenhanced MRI examination. Preoperative clinical factors and MRI characteristics were collected for feature selection. Least Absolute Shrinkage and Selection Operator (LASSO) was applied to select the optimal features for predicting postoperative 1-year recurrence of HCC. Four machine learning algorithms, Multilayer Perception (MLP), random forest, support vector machine, and k-nearest neighbor, were used to construct the predictive models based on the selected features. A Receiver Operating Characteristic (ROC) curve was used to assess the performance of each model. RESULTS: Among the enrolled patients, 32 patients experienced recurrences within one year, while 50 did not. Tumor size, peritumoral hypointensity, decreasing ratio of liver parenchyma T1 value (ΔT1), and α-fetoprotein (AFP) levels were selected by using LASSO to develop the machine learning models. The area under the curve (AUC) of each model exceeded 0.72. Among the models, the MLP model showed the best performance with an AUC, accuracy, sensitivity, and specificity of 0.813, 0.742, 0.570, and 0.853, respectively. CONCLUSION: Machine learning models can accurately predict postoperative 1-year recurrence in patients with HCC, which may help to provide individualized treatment.

Bacterial diversity in a continuum from supraglacial habitats to a proglacial lake on the Tibetan Plateau.

Mountain glaciers are frequently assessed for their hydrological connectivity from glaciers to proglacial lakes. Ecological process on glacier surfaces and downstream ecosystems have often been investigated separately, but few studies have focused on the connectivity between the different glacial habitats. Therefore, it remains a limited understanding of bacterial community assembly across different habitats along the glacier hydrological continuum. In this study, we sampled along a glacial catchment from supraglacial snow, cryoconite holes, supraglacial runoff, ice-marginal moraine and proglacial lake on the Tibetan Plateau. The bacterial communities in these habitats were analyzed using high-throughput DNA sequencing of the 16S rRNA gene to determine the bacterial composition and assembly. Our results showed that each habitat hosted unique bacterial communities, with higher bacterial α-diversity in transitional habitats (e.g. runoff and ice-marginal moraine). Null model analysis indicated that deterministic processes predominantly shaped bacterial assembly in snow, cryoconite holes and lake, while stochastic process dominantly governed bacterial community in transitional habitats. Collectively, our findings suggest that local environment play a critical role in filtering bacterial community composition within glacier habitats. This study enhances our understanding of microbial assembly process in glacier environments and provides valuable insights into the factors governing bacterial community compositions across different habitats along the glacial hydrological continuum.

Is it more effective for anhedonia and avolition? A systematic review and meta-analysis of non-invasive brain stimulation interventions for negative symptoms in schizophrenia.

BACKGROUND: Noninvasive brain stimulation (NIBS) techniques are a promising tool for treating the negative symptoms of schizophrenia. Growing evidence suggests that different dimensions of negative symptoms have partly distinct underlying pathophysiological mechanisms. Previous randomized controlled trials (RCTs) have shown inconsistent impacts of NIBS across dimensions. OBJECTIVE: This systematic review and meta-analysis evaluated the effects of NIBS on general negative symptoms, and on specific domains, including blunted affect, alogia, asociality, anhedonia, and avolition. DATA SOURCES: PubMed, Web of Science, Embase, Cochrane CENTRAL, PsycINFO, OpenGrey, and Clinicaltrials.gov from the first date available to October, 2023. RESULTS: Among 1049 studies, we identified eight high-quality RCTs. NIBS significantly affects general negative symptoms (SMD = -0.54, 95% CI [-0.88, -0.21]) and all five domains (SMD = -0.32 to -0.63). Among dimensions, better effects have been shown for improvement of avolition (SMD = -0.47, 95% CI [-0.81, -0.13]) and anhedonia (SMD = -0.63, 95% CI [-0.98, -0.28]). Subgroup analyses of studies that applied once daily stimulation or >10 sessions showed significantly reduced negative symptom severity. CONCLUSION: NIBS exerts distinct effects across multiple dimensions of negative symptom, with treatment effects related to stimulation frequency and total sessions. These results need to be confirmed in dedicated studies.

Walking Dead Macrophage-Based Positive Enhancement MRI for Ultrahighly Efficient Diagnosis of Nephritis.

Nephritis is an inflammatory condition of the glomerulus, and the clinical gold standard for its diagnosis is a kidney biopsy. However, obtaining biopsy results can take several days, which does not meet the requirement of rapid diagnosis, especially for rapidly progressive types. To achieve an effective and noninvasive diagnosis, we propose a nephritis-specific, positive magnetic resonance imaging (MRI) contrast agent based on Gd3+ anchored walking dead macrophage Gd-RAW. Gd-RAW exhibits high selectivity for inflammatory renal parenchyma and provides comparable results to histopathology methods. The Gd-RAW-based MRI contrast agent reduces the diagnostic time of nephritis from 14 days of biopsy to 1 h. Furthermore, in a unilateral nephritis model constructed by increasing the glycerol concentration, the T1WI of renal parenchyma exhibits an increased signal-to-noise ratio, which is crucial for evaluating nephritic severity. This work promotes rapid diagnosis of nephritis and potentially provides sufficient evidence for clinicians to offer timely treatment to patients. The methodology of paramagnetic ion-anchored macrophage corpse also opens up new prospects for designing more specific and biosafe MRI contrast agents.

Prediction of immunocyte infiltration and prognosis in postoperative hepatitis B virus-related hepatocellular carcinoma patients using magnetic resonance imaging.

Background: The immune microenvironment (IME) is closely associated with prognosis and therapeutic response of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). Multi-parametric magnetic resonance imaging (MRI) enables non-invasive assessment of IME and predicts prognosis in HBV-HCC. We aimed to construct an MRI prediction model of the immunocyte-infiltration subtypes and explore its prognostic significance. Methods: HBV-HCC patients at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) with radical surgery (between 1 October and 30 December 2021) were prospectively enrolled. Patients with pathologically proven HCC (between 1 December 2013 and 30 October 2019) were retrospectively enrolled. Pearson correlation analysis was used to examine the relationship between the immunocyte-infiltration counts and MRI parameters. An MRI prediction model of immunocyte-infiltration subtypes was constructed in prospective cohort. Kaplan-Meier survival analysis was used to analyse its prognostic significance in the retrospective cohort. Results: Twenty-four patients were prospectively enrolled to construct the MRI prediction model. Eighty-nine patients were retrospectively enrolled to determine its prognostic significance. MRI parameters (relative enhancement, ratio of the apparent diffusion coefficient value of tumoral region to peritumoral region [rADC], T1 value) correlated significantly with the immunocyte-infiltration counts (leukocytes, T help cells, PD1+Tc cells, B lymphocytes). rADC differed significantly between high and low immunocyte-infiltration groups (1.47 ± 0.36 vs 1.09 ± 0.25, P = 0.009). The area under the curve of the MRI model was 0.787 (95% confidence interval 0.587-0.987). Based on the MRI model, the recurrence-free time was longer in the high immunocyte-infiltration group than in the low immunocyte-infiltration group (P = 0.026). Conclusions: MRI is a non-invasive method for assessing the IME and immunocyte-infiltration subtypes, and predicting prognosis in post-operative HBV-HCC patients.

Sulfonate-modified fullerenes mimicking tentacle structures for humidity sensors.

In this work, a straightforward method for synthesizing fullerene derivatives with tentacle structures has been explored for monitoring environmental humidity, which involves introducing sulfonate onto the fullerenes. The structure and number of polar groups in three fullerene derivatives determined by a series of structural tests greatly affect their hydrophilicity and morphology, resulting in changes in humidity sensitive properties. In particular, the hysteresis and response time of the sensors display a great correlation with hydrophilicity. C60-Ho, the best performing derivative of this work, has exhibited high response values (∼3500 times), good linearity (R2 = 97.3 %), and rapid response/recovery times (0.3/4.4 s), making it suitable for various applications such as non-contact detection of respiration, finger distance, and soil humidity.

Visualization and correlation of drug release of risperidone/clozapine microspheres in vitro and in vivo based on FRET mechanism.

This study addresses the challenging task of quantitatively investigating drug release from PLGA microspheres after in vivo administration. The objective is to employ Förster resonance energy transfer (FRET) to visualize drug-encapsulated microspheres in both in vitro and in vivo settings. The primary goal is to establish a quantitative correlation between FRET fluorescence changes and microsphere drug release. The study selects drugs with diverse structures and lipid solubility to explore release mechanisms, using PLGA as the matrix material. Clozapine and risperidone serve as model drugs. FRET molecules, Cy5 and Cy5.5, along with Cy7 derivatives, create FRET donor-acceptor pairs. In vitro results show that FRET fluorescence changes align closely with microsphere drug release, particularly for the Cy5.5-Cy7 pair. In vivo experiments involve subcutaneous administration of microspheres to rats, tracking FRET fluorescence changes while collecting blood samples. Pharmacokinetic studies on clozapine and risperidone reveal in vivo absorption fractions using the Loo-Riegelman method. Correlating FRET and in vivo absorption data establishes an in vitro-in vivo relationship (IVIVR). The study demonstrates that FRET-based fluorescence changes quantitatively link to microsphere drug release, offering an innovative method for visualizing and monitoring release in both in vitro and in vivo settings, potentially advancing clinical applications of such formulations.

Cucurbitacin B suppresses hepatocellular carcinoma progression through inducing DNA damage-dependent cell cycle arrest.

BACKGROUND: The mortality rate of liver cancer ranks third in the world, and hepatocellular carcinoma (HCC) is a malignant tumor of the digestive tract. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae spp., is the main active component of Chinese patent medicine the Cucurbitacin Tablet, which has been widely used in the treatment of various malignant tumors in clinics, especially HCC. PURPOSE: This study explored the role and mechanism of CuB in the suppression of liver cancer progression. METHODS: Cell Counting Kit-8 (CCK-8) and colony formation assays were used to detect the inhibitory function of CuB in Huh7, Hep3B, and Hepa1/6 hepatoma cells. Calcein-AM/propidium iodide (PI) staining and lactate dehydrogenase (LDH) measurement assays were performed to determine cell death. Mitochondrial membrane potential (Δψm) was measured, and flow cytometry was performed to evaluate cell apoptosis and cell cycle. Several techniques, such as proteomics, Western blotting (WB), and ribonucleic acid (RNA) interference, were utilized to explore the potential mechanism. The animal experiment was performed to verify the results of in vitro experiments. RESULTS: CuB significantly inhibited the growth of Huh7, Hep3B, and Hepa1/6 cells and triggered the cell cycle arrest in G2/M phage without leading to cell death, especially apoptosis. Knockdown of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a target of CuB, did not reverse CuB elicited cell cycle arrest. CuB enhanced phosphorylated ataxia telangiectasia mutated (p-ATM) and phosphorylated H2A histone family member X (γ-H2AX) levels. Moreover, CuB increased p53 and p21 levels and decreased cyclin-dependent kinase 1 (CDK1) expression, accompanied by improving phosphorylated checkpoint kinase 1 (p-CHK1) level and suppressing cell division cycle 25C (CDC25C) protein level. Interestingly, these phenomena were partly abolished by a deoxyribonucleic acid (DNA) protector methylproamine (MPA). Animal studies showed that CuB also significantly suppressed tumor growth in BALB/c mice bearing Hepa1/6 cells. In tumor tissues, CuB reduced the expression levels of proliferating cell nuclear antigen (PCNA) and γ-H2AX but did not change the terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) level. CONCLUSION: This study demonstrated for the first time that CuB could effectively impede HCC progression by inducing DNA damage-dependent cell cycle arrest without directly triggering cell death, such as necrosis and apoptosis. The effect was achieved through ataxia telangiectasia mutated (ATM)-dependent p53-p21-CDK1 and checkpoint kinase 1 (CHK1)-CDC25C signaling pathways. These findings indicate that CuB may be used as an anti-HCC drug, when the current findings are confirmed by independent studies and after many more clinical phase 1, 2, 3, and 4 testings have been done.

Integrative single-cell transcriptomic analyses reveal the cellular ontological and functional heterogeneities of primary and metastatic liver tumors.

BACKGROUND: The global cellular landscape of the tumor microenvironment (TME) combining primary and metastatic liver tumors has not been comprehensively characterized. METHODS: Based on the scRNA-seq and spatial transcriptomic data of non-tumor liver tissues (NTs), primary liver tumors (PTs) and metastatic liver tumors (MTs), we performed the tissue preference, trajectory reconstruction, transcription factor activity inference, cell-cell interaction and cellular deconvolution analyses to construct a comprehensive cellular landscape of liver tumors. RESULTS: Our analyses depicted the heterogeneous cellular ecosystems in NTs, PTs and MTs. The activated memory B cells and effector T cells were shown to gradually shift to inhibitory B cells, regulatory or exhausted T cells in liver tumors, especially in MTs. Among them, we characterized a unique group of TCF7+ CD8+ memory T cells specifically enriched in MTs that could differentiate into exhausted T cells likely driven by the p38 MAPK signaling. With regard to myeloid cells, the liver-resident macrophages and inflammatory monocyte/macrophages were markedly replaced by tumor-associated macrophages (TAMs), with TREM2+ and UBE2C+ TAMs enriched in PTs, while SPP1+ and WDR45B+ TAMs in MTs. We further showed that the newly identified WDR45B+ TAMs exhibit an M2-like polarization and are associated with adverse prognosis in patients with liver metastases. Additionally, we addressed that endothelial cells display higher immune tolerance and angiogenesis capacity, and provided evidence for the source of the mesenchymal transformation of fibroblasts in tumors. Finally, the malignant hepatocytes and fibroblasts were prioritized as the pivotal cell populations in shaping the microenvironments of PTs and MTs, respectively. Notably, validation analyses by using spatial or bulk transcriptomic data in clinical cohorts concordantly emphasized the clinical significance of these findings. CONCLUSIONS: This study defines the ontological and functional heterogeneities in cellular ecosystems of primary and metastatic liver tumors, providing a foundation for future investigation of the underlying cellular mechanisms.

Zinc oxide nanoparticles exacerbate skin epithelial cell damage by upregulating pro-inflammatory cytokines and exosome secretion in M1 macrophages following UVB irradiation-induced skin injury.

BACKGROUND: Zinc oxide nanoparticles (ZnONPs) are common materials used in skin-related cosmetics and sunscreen products due to their whitening and strong UV light absorption properties. Although the protective effects of ZnONPs against UV light in intact skin have been well demonstrated, the effects of using ZnONPs on damaged or sunburned skin are still unclear. In this study, we aimed to reveal the detailed underlying mechanisms related to keratinocytes and macrophages exposed to UVB and ZnONPs. RESULTS: We demonstrated that ZnONPs exacerbated mouse skin damage after UVB exposure, followed by increased transepidermal water loss (TEWL) levels, cell death and epithelial thickness. In addition, ZnONPs could penetrate through the damaged epithelium, gain access to the dermis cells, and lead to severe inflammation by activation of M1 macrophage. Mechanistic studies indicated that co-exposure of keratinocytes to UVB and ZnONPs lysosomal impairment and autophagy dysfunction, which increased cell exosome release. However, these exosomes could be taken up by macrophages, which accelerated M1 macrophage polarization. Furthermore, ZnONPs also induced a lasting inflammatory response in M1 macrophages and affected epithelial cell repair by regulating the autophagy-mediated NLRP3 inflammasome and macrophage exosome secretion. CONCLUSIONS: Our findings propose a new concept for ZnONP-induced skin toxicity mechanisms and the safety issue of ZnONPs application on vulnerable skin. The process involved an interplay of lysosomal impairment, autophagy-mediated NLRP3 inflammasome and macrophage exosome secretion. The current finding is valuable for evaluating the effects of ZnONPs for cosmetics applications.

Quantitative assessment of inflammation and evaluation of spatial heterogeneity for non-alcoholic fatty liver disease in mice based on iron-adjustive T1.

Background: A sensitive and non-invasive method is necessary to diagnose non-alcoholic fatty liver disease (NAFLD). We explored the iron-adjustive T1 (aT1) ability to quantify the degree of liver inflammation and evaluate the spatial heterogeneity. Methods: Male C57BL/6J mice were randomly categorized as the NAFLD model (n=40), NAFLD-related liver cirrhosis model (n=20), and normal mice (n=10). T1 and T2* maps were acquired using a 3.0T scanner of magnetic resonance imaging (MRI) and aT1 maps through post-processing corrected iron's effect on T1 using T2*. Pathological changes in the left and right liver lobes were assessed using the Non-alcoholic Steatohepatitis-Clinical Research Network scoring system, though hepatic ballooning lesion were rare in models. Spearman's and partial correlation analyses were used to evaluate correlations, and the receiver operating characteristic curve was used to analyze the diagnostic performance. Results: aT1 was highly correlated with NAFLD activity score (NAS) (r=0.747, P<0.001) but not with the fibrosis stage when adjusted by NAS (r=-0.135, P=0.147). The area under the curve (AUC) of the aT1 value distinguishing groups with 0< NAS <4 and NAS ≥4 was 0.802. On analyzing the histogram features of aT1, the entropy, interquartile range, range, and variance were significantly different between the groups with 0< NAS <4 and NAS ≥4 (P<0.05). The entropy was the risk factor of NAS ≥4. Conclusions: aT1 could help evaluate the inflammatory activity in NAFLD mice unaffected by mild fibrosis, and the higher the degree of inflammation, the higher the heterogeneity of the aT1 map.