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Ethnopharmacological Relevance: Prinsepia utilis Royle, native to the Himalayan region, has a long history of use in traditional medicine for its heat-clearing, detoxification, anti-inflammatory, and analgesic properties. Oils extracted from P. utilis seeds are also used in cooking and cosmetics. With the increasing market demand, this extraction process generates substantial industrial biowastes. Recent studies have found many health benefits with using aqueous extracts of these biowastes, which are also rich in polysaccharides. However, there is limited research related to the reparative effects of the water extracts of P. utilis oil cakes (WEPUOC) on disruptions of the skin barrier function., Aim of the Study: This study aimed to evaluate the reparative efficacy of WEPUOC in both acute and chronic epidermal permeability barrier disruptions. Furthermore, the study sought to explore the underlying mechanisms involved in repairing the epidermal permeability barrier., Materials and Methods: Mouse models with induced epidermal disruptions, employing tape-stripping (TS) and acetone wiping (AC) methods, were used. The subsequent application of WEPUOC (100 mg/mL) was evaluated through various assessments, with a focus on the upregulation of mRNA and protein expression of Corneocyte Envelope (CE) related proteins, lipid synthase-associated proteins, and tight junction proteins., Results: The polysaccharide was the major phytochemicals of WEPUOC and its content was determined as 32.2% by the anthranone-sulfuric acid colorimetric method. WEPUOC significantly reduced transepidermal water loss (TEWL) and improved the damaged epidermal barrier in the model group. Mechanistically, these effects were associated with heightened expression levels of key proteins such as FLG (filaggrin), INV (involucrin), LOR (loricrin), SPT, FASN, HMGCR, Claudins-1, Claudins-5, and ZO-1., Conclusions: WEPUOC, obtained from the oil cakes of P. utilis, is rich in polysaccharides and exhibits pronounced efficacy in repairing disrupted epidermal barriers through increased expression of critical proteins involved in barrier integrity. Our findings underscore the potential of P. utilis wastes in developing natural cosmetic prototypes for the treatment of diseases characterized by damaged skin barriers, including atopic dermatitis and psoriasis., Competing Interests: Declaration of competing interest This paper has not been published elsewhere in whole or in part. All authors have read and approved the content, and agree to submit it for consideration for publication in your journal. There are no ethical/legal conflicts involved in the article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: There is a growing number of patients suffering from sensitive skin secondary to acne, but its prevalence and influencing factors are not yet well-understood., Objective: The aim of this study is to investigate the nonlinear relationship between air pollutants and secondary sensitive skin in acne patients., Methods: A cross-sectional study comprising 4325 acne outpatients in China was carried out between September 2021 and December 2022, employing a simple random sampling approach. Air pollutants data was derived from the nearest air quality monitoring station corresponding to the subjects' residential locations. Furthermore, socio-economic characteristics, biological attributes, and lifestyle data of patients were acquired via questionnaire surveys. The data were subsequently analyzed utilizing the XGBoost machine learning model., Results: A nonlinear relationship has been observed between secondary sensitive skin in acne patients and various factors, including particulate matter (PM 2.5 ), inhalable particulate matter (PM 10 ), ozone (O 3 ), sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), carbon monoxide (CO), the severity of depression, different levels of exercise intensity, acne grading, frequency of sunscreen application, gender, and age., Conclusion: The occurrence of secondary sensitive skin in acne patients be mitigated through the implementation of measures such as the control of air pollutant emissions, regulation of negative emotions, and improvement of personal lifestyle., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

The involvement of left-behind children (LBC) in school bullying has raised concern in China. However, the susceptibility of LBC to engage in bullying is controversial, and comprehensive, representative studies covering the entire country are lacking. The purpose of this study was to evaluate the prevalence and severity of school bullying among LBC. The Chinese National Knowledge Network, WanFang, VIP, PubMed, Web of Science, EMBASE, and EBSCO databases were searched for literature on being left-behind and bullying before April 2022. The effect size was measured by odds ratio (ORs), standard mean difference (SMD), and 95% confidence interval (CI). Random-effects or fixed-effects models were selected for meta-analysis, and subgroup analysis was used to explore the sources of heterogeneity. The meta-analysis included 25 studies of school bullying among LBC and non-LBC (NLBC). The prevalence of bullying perpetration and victimization among LBC were 18.58% (95% CI [3.72%, 33.44%], p  < .05) and 40.62% (95% CI [25.47%, 55.78%], p  < .05), respectively. Compared with NLBC, the risk of bullying perpetration and victimization among LBC increased 1.97 times (OR = 1.97, 95% CI [1.77, 2.20], p  < .05) and 2.17 times (OR = 2.17, 95% CI [1.43, 3.29], p  < .05), respectively. The severity of bullying experienced by LBC was higher than that of NLBC (SMD = 0.49, 95% CI [0.20, 0.79], p  < .05). The prevalence and severity of school bullying were higher in LBC than in NLBC, and left-behindness was positively associated with school bullying. LBC are a crucial population to protect when developing bullying interventions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In the context of escalating urban heat events due to climate change, air conditioning (AC) has become a critical factor in maintaining indoor thermal comfort. Yet the usage of AC can also exacerbate outdoor heat stress and burden the electricity system, and there is little scientific knowledge regarding how to balance these conflicting goals. To address this issue, we established a coupled modeling approach, integrating the Weather Research and Forecasting model with the building energy model (WRF&#95;BEP + BEM), and designed multiple AC usage scenarios. We selected Chongqing, China's fourth-largest megacity, as our study area due to its significant socioeconomic importance, the severity of extreme heat events, and the uniqueness of its energy infrastructure. Our analysis reveals that AC systems can substantially reduce indoor temperatures by up to 18 °C; however, it also identifies substantial nighttime warming (2-2.5 °C) and a decline in thermal comfort. Particularly for high-density neighborhoods, when we increase 2 °C indoors, the outdoor temperature can be alleviated by up to 1 °C. Besides, despite the limited capacity to regulate peak electricity demand, we identified that reducing the spatial cooled fraction, increasing targeted indoor temperature by 2 °C, and implementing temporal AC schedules can effectively lower energy consumption in high-density neighborhoods, especially the reduction of spatial cooled fraction (up to 50%). Considering the substantial demand for cooling energy, it is imperative to carefully assess the adequacy and continuity of backup energy sources. The study underscores the urgency of reassessing energy resilience and advocates for addressing the thermal equity between indoor and outdoor environments, contributing to the development of a sustainable and just urban climate strategy in an era of intensifying heat events.

Fever and diarrhea are key causes of malnutrition, growth and development disorders, and death among children. At present, most studies on the associated factors of fever and diarrhea in children are concentrated in African and South Asian countries, but relevant research in China is very limited. This study was aimed to analyze the two-week prevalence of fever, diarrhea, and coexisting fever and diarrhea among children aged 6-23 months in rural areas of Hunan Province and to explore the associated factors. The survey data of the Nutrition Improvement Program for Children in Poor Areas (NIPCPA) from 2016 to 2023 was used here. NIPCPA is a cross-sectional survey completed annually in Hunan to collect children's nutrition and health indicators. The two-week prevalence rates of fever, diarrhea, and coexisting fever and diarrhea among children aged 6-23 months were 12.2% (2066/16,985), 9.6% (1634/16,985), and 3.2% (542/16,985), respectively. Multivariate logistic regression analysis showed the risks of fever, diarrhea, and coexisting fever and diarrhea were higher among younger children. The high educational level of caregivers, effective consumption of Yingyangbao (a complementary food supplement containing iron, zinc, calcium, vitamins A, D, B1, B2, B12, folic acid, and other micronutrients), and complementary feeding meeting minimum dietary diversity and meeting minimum acceptable diet were protective factors against fever in children, with adjusted odds ratios (aORs) of 0.87 (95%CI: 0.78-0.98), 0.78 (0.69-0.87), 0.73 (0.65-0.82), and 0.74 (0.66-0.84), respectively. Effective consumption of Yingyangbao, and complementary feeding meeting the minimum dietary diversity and meeting minimum acceptable diet were protective factors against diarrhea in children, with aORs of 0.72 (95%CI: 0.63-0.83), 0.79 (0.70-0.91), and 0.80 (0.70-0.92), respectively. Effective consumption of Yingyangbao, and complementary feeding meeting the minimum dietary diversity and meeting minimum acceptable diet were protective factors against coexisting fever and diarrhea among children, with aORs of 0.53 (95%CI: 0.43-0.66), 0.71 (0.58-0.89), and 0.70 (0.56-0.88), respectively. Fever, diarrhea, and the coexisting fever and diarrhea affect one in eight, one in ten, and one in thirty children respectively in rural areas of Hunan. Effective interventions should be actively taken, such as improving the education level of caregivers, enhancing their scientific feeding skills for children, and promoting children's compliance with Yingyangbao consumption, to further reduce the prevalence of fever and diarrhea in children., (© 2024. The Author(s).)

Background: Sensitive skin is hypersensitive to various external stimuli and a defective epidermal permeability barrier is an important clinical feature of sensitive skin. Claudin-5 (CLDN5) expression levels decrease in sensitive skin. This study aimed to explore the impact of CLDN5 deficiency on the permeability barrier in sensitive skin and the regulatory role of miRNAs in CLDN5 expression., Materials and Methods: A total of 26 patients were retrospectively enrolled, and the CLDN5 expression and permeability barrier dysfunction in vitro were assessed. Then miRNA-224-5p expression was also assessed in sensitive skin., Results: Immunofluorescence and electron microscopy revealed reduced CLDN5 expression, increased miR-224-5p expression, and disrupted intercellular junctions in sensitive skin. CLDN5 knockdown was associated with lower transepithelial electrical resistance (TEER) and Lucifer yellow penetration in keratinocytes and organotypic skin models. The RNA-seq and qRT-PCR results indicated elevated miR-224-5p expression in sensitive skin; MiR-224-5p directly interacted with the 3`UTR of CLDN5, resulting in CLDN5 deficiency in the luciferase reporter assay. Finally, miR-224-5p reduced TEER in keratinocyte cultures., Conclusion: These results suggest that the miR-224-5p-induced reduction in CLDN5 expression leads to impaired permeability barrier function, and that miR-224-5p could be a potential therapeutic target for sensitive skin., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Urban expansion often occurs at the expense of cropland loss, posing challenges to sustainable urban growth and food security. However, detailed investigations into urban expansion and cropland loss remain limited, particularly in regions with varying levels of urbanization. Here, we take Guangdong Province, China, as a case study to exemplify how urban expansion affects cropland using remotely sensed land use products. We adopted geospatial analysis, correlation indicators, and landscape metrics to uncover their spatial relationships at 10-m spatial resolutions. Results showed that urban areas increased by 6335 km 2 while cropland decreased by 3780 km 2 from 2017 to 2022. Notably, 41 % of newly expanded urban areas were from croplands, and 45 % of lost croplands were converted to urban areas. Western Guangdong experienced the largest extent of urban expansion and cropland loss, emerging as a hotspot region in recent years. Additionally, our analysis observed the increasing compactness of urban areas and the growing fragmentation of cropland landscapes over time. These findings shed light on the intricate dynamics between urban expansion and cropland loss in rapidly urbanizing regions, which provide valuable insights for sustainable urban development, agricultural practice, and land management in the future., Competing Interests: 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., (© 2024 The Authors.)

The interaction between bacteria and the host plays a vital role in the initiation and progression of systemic diseases, including gastrointestinal and oral diseases, due to the secretion of various virulence factors from these pathogens. GroEL, a potent virulence factor secreted by multiple oral pathogenic bacteria, is implicated in the damage of gingival epithelium, periodontal ligament, alveolar bone and other peripheral tissues. However, the underlying biomechanism is still largely unknown. In the present study, we verify that GroEL can trigger the activation of NLRP3 inflammasome and its downstream effector molecules, IL-1β and IL-18, in human periodontal ligament stem cells (hPDLSCs) and resultantly induce high activation of gelatinases (MMP-2 and MMP-9) to promote the degradation of extracellular matrix (ECM). GroEL-mediated activation of the NLRP3 inflammasome requires the participation of Toll-like receptors (TLR2 and TLR4). High upregulation of TLR2 and TLR4 induces the enhancement of NF-κB (p-p65) signaling and promotes its nuclear accumulation, thus activating the NLRP3 inflammasome. These results are verified in a rat model with direct injection of GroEL. Collectively, this study provides insight into the role of virulence factors in bacteria-induced host immune response and may also provide a new clue for the prevention of periodontitis.

Background: Liver progenitor cells (LPCs) are a subpopulation of cells that contribute to liver regeneration, fibrosis and liver cancer initiation under different circumstances., Results: By performing adenoviral-mediated transfection, CCK-8 analyses, F-actin staining, transwell analyses, luciferase reporter analyses and Western blotting, we observed that TGF-β promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-β activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFβ-Smad signaling induced growth inhibition and partial EMT, whereas TGFβ-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-β was mutually restricted in LPCs. Mechanistically, we found that TGF-β activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFβ-MAPK signaling inhibited the phosphorylation of Smad3 but not Smad2 at the C-terminus, and it reinforced the linker phosphorylation of Smad3 at T179 and S213. We then found that overexpression of mutated Smad3 at linker phosphorylation sites intensifies TGF-β-induced cytostasis and EMT, mimicking the effects of MAPK inhibition in LPCs, whereas mutation of Smad3 at the C-terminus caused LPCs to blunt TGF-β-induced cytostasis and partial EMT., Conclusion: These results suggested that TGF-β downstream of Smad3 and MAPK signaling were mutually antagonistic in regulating the viability and partial EMT of LPCs. This antagonism may help LPCs overcome the cytostatic effect of TGF-β under fibrotic conditions and maintain partial EMT and progenitor phenotypes.

Glutamate-NMDAR receptors (GRINs) have been reported to influence cancer immunogenicity; however, the relationship between GRIN alterations and the response to immune checkpoint inhibitors (ICIs) has not been determined. This study combined clinical characteristics and mutational profiles from multiple cohorts to form a discovery cohort (n = 901). The aim of this study was to investigate the correlation between the mutation status of the GRIN gene and the response to ICI therapy. Additionally, an independent ICI-treated cohort from the Memorial Sloan Kettering Cancer Center (MSKCC, N = 1513) was used for validation. Furthermore, this study explored the associations between GRIN2A mutations and intrinsic and extrinsic immunity using multiomics analysis. In the discovery cohort, patients with GRIN2A-MUTs had improved clinical outcomes, as indicated by a higher objective response rate (ORR: 36.8% vs 25.8%, P = 0.020), durable clinical benefit (DCB: 55.2% vs 38.7%, P = 0.005), prolonged progression-free survival (PFS: HR = 0.65; 95% CI 0.49 to 0.87; P = 0.003), and increased overall survival (OS: HR = 0.67; 95% CI 0.50 to 0.89; P = 0.006). Similar results were observed in the validation cohort, in which GRIN2A-MUT patients exhibited a significant improvement in overall survival (HR = 0.66; 95% CI = 0.49 to 0.88; P = 0.005; adjusted P = 0.045). Moreover, patients with GRIN2A-MUTs exhibited an increase in tumor mutational burden, high expression of costimulatory molecules, increased activity of antigen-processing machinery, and infiltration of various immune cells. Additionally, gene sets associated with cell cycle regulation and the interferon response were enriched in GRIN2A-mutated tumors. In conclusion, GRIN2A mutation is a novel biomarker associated with a favorable response to ICIs in multiple cancers., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Direct inhibitor of tau aggregation has been extensively studied as potential therapeutic agents for Alzheimer's disease. However, the natively unfolded structure of tau complicates the structure-based ligand design, and the relatively large surface areas that mediate tau-tau interactions in aggregation limit the potential for identifying high-affinity ligand binding sites. Herein, a group of isatin-pyrrolidinylpyridine derivative isomers (IPP1-IPP4) were designed and synthesized. They are like different forms of molecular "transformers". These isatin isomers exhibit different inhibitory effects on tau self-aggregation or even possess a depolymerizing effect. Our results revealed for the first time that the direct inhibitor of tau protein aggregation is not only determined by the previously reported conjugated structure, substituent, hydrogen bond donor, etc. but also depends more importantly on the molecular shape. In combination with molecular docking and molecular dynamics simulations, a new inhibition mechanism was proposed: like a "molecular clip", IPP1 could noncovalently bind and fix a tau polypeptide chain at a multipoint to prevent the transition from the "natively unfolded conformation" to the "aggregation competent conformation" before nucleation. At the cellular and animal levels, the effectiveness of the inhibitor of the IPP1 has been confirmed, providing an innovative design strategy as well as a lead compound for Alzheimer's disease drug development., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Sensitivity skin (SS) is a common skin disorders, which have a various of clinical manifestation. Facial erythema is common objective symptom of SS. However, the reasons for the occurrence of erythema in sensitive skin are not fully understood., Aims: In this study, we preliminarily explain the possible factors inducing erythema of sensitive skin by evaluating facial erythematous reaction to lactic acid sting test (LAST) and capsaicin test (CAT) in subjects with sensitive skin., Methods: A total of 197 subjects were divided into five groups, that is, normal controls (NC), LAST-positive (LAST + ), both LAST and CAT positive (L + C + ), both LAST and CAT negative (L - C - ) and CAT-positive (CAT + ). Erythema index (EI), a* value, and tissue viability imaging (TIVI) were measured before and after LAST and CAT, The ΔEI, Δa*, and ΔTIVI before and after LAST and CAT were calculated, and the correlation between the scores of CAT, EI values, a* values, and TIVI values were analyzed to clarify the causes of facial erythema., Results: Our results showed that EI values and a* values were significantly higher in the L + C + and CAT + group than in NC group, TIVI values were higher in the L + C + group than in NC group. ΔEI and Δa* values after LAST did not differ significantly among five groups. However, ΔEI values in L + C + group were higher than that in L - C - group, while Δa* values were higher in CAT + group than in NC. Moreover, ΔTIVI values in L + C + group and CAT + group were also significantly higher than that in NC group after capsaicin stimulation. CAT scores correlated positively with EI, a* and TIVI values., Conclusion: Our results suggest that sensitive skin subjects with positive CAT are more likely to experience erythema reactions, and vasodilation is more pronounced after capsaicin stimulation. Reducing vascular and neural hyperreactivity could be therapeutic target in management of facial erythema in subjects with sensitive skin., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Pyroptosis is an inflammatory programmed cell death (PCD) and is reported to be associated with N6-methyladenosine (m6A) modification. This study aimed to investigate the mechanism of m6A demethylase AlkB homolog 5 (ALKBH5) in pyroptosis in the process of chronic actinic dermatitis (CAD). Changes of m6A-related genes were evaluated between CAD and normal samples using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Human keratinocytes (HaCaT cells) exposed to ultraviolet B (UVB; 10, 20, and 30 mJ/cm 2 ), followed by evaluation of cell proliferation, cell apoptosis, inflammatory cytokines (interleukin (IL)-1β, IL-18, and tumor necrosis factor (TNF-α)), and pyroptosis-related proteins (gasdermin D (GSDMD), Caspase-1, and Caspase-4). Small interfering RNA (siRNA) targeting ALKBH5 was transfected into HaCaT cells to assess the effect of si-ALKBH5 on CAD. A CAD mice model was induced after exposure to UVB (250 mJ/cm 2 per day) to confirm the role of ALKBH5 in CAD. AKKBH5 was highly expressed in CAD patients. UVB also promoted ALKBH5 expression, increased cell apoptosis, and induced the release of inflammatory cytokines (IL-1β, IL-18, and TNF-α) as well as pyroptosis-related proteins (GSDMD, Caspase-1, and Caspase-4). Silencing ALKBH5 repressed cell apoptosis and suppressed UVB-induced pyroptosis and inflammatory response. Meanwhile, silencing ALKBH5 attenuated UVB-induced skin damage of CAD mice, accompanied with the reduction in expression of inflammatory cytokines and pyroptosis-related proteins. This study helps to further understand the mechanism of ALKBH5 in CAD-induced pyroptosis and provides novel ideas for the research and management of CAD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To comprehensively delineate the underlying mechanisms for the whole progression from normal skin to AK to invasive cSCC, we performed single-cell RNA sequencing (scRNA-seq) to acquire the transcriptomes of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC, and their matched normal tissues, covering comprehensive clinical courses of cSCC. We identified diverse cell types, including important subtypes with different gene expression profiles and functions in major keratinocytes. In SCCIS, we discovered the malignant subtypes of basal cells with differential proliferative and migration potential. Differentially expressed genes (DEGs) analysis screened out multiple key driver genes including transcription factors along AK to cSCC progression. Immunohistochemistry (IHC)/immunofluorescence (IF) experiments and single-cell ATAC sequencing (scATAC-seq) data verified the expression changes of these genes. The functional experiments confirmed the important roles of these genes in regulating cell proliferation, apoptosis, migration, and invasion in cSCC tumor. Furthermore, we comprehensively described the tumor microenvironment (TME) landscape and potential keratinocyte-TME crosstalk in cSCC providing theoretical basis for immunotherapy. Together, our findings provide a valuable resource for deciphering the progression from AK to cSCC and identifying potential targets for anticancer treatment of cSCC., Competing Interests: DZ, YS, XL, WW, DX, YH, JQ, YT, YT, YT, XW, XL, FL, LH, HL, LH, XL No competing interests declared, (© 2023, Zou, Sun et al.)

Background: Although rosacea and seborrheic dermatitis share some symptoms of sensitive skin, whether they respond differently to lactic acid sting and capsaicin tests, common tests for diagnosis of sensitive skin, is unknown., Objectives: To reveal the cutaneous responses to lactic acid sting (LAST) and capsaicin test (CAT) in females with either rosacea vs. seborrheic dermatitis., Methods: A total of 60 patients with rosacea, 20 patients with seborrheic dermatitis and 40 normal controls were enrolled in the study. Their skin sensitivity to stimuli were evaluated following topical application of either 10% lactic acid solution or 0.001% capsaicin solution. Transepidermal water loss (TEWL) rates and erythema indexes were also measured on the face., Results: In comparison to normal controls, the positive rate to either LAST or CAT was significantly higher in subjects with rosacea (p < 0.001), but not in that with seborrheic dermatitis. Similarly, individuals with rosacea displayed a higher positive rate to both LAST and CAT than those with seborrheic dermatitis and normal controls (p < 0.001). In parallel, the LAST scores and CAT scores in individuals with rosacea were significantly higher than in that with either seborrheic dermatitis or normal controls (p < 0.001). The baseline TEWL rates and erythema indexes were higher in individual with rosacea than in normal controls (p < 0.001). But the baseline TEWL rates and erythema indexes did not differ significantly between subjects with rosacea and that with seborrheic dermatitis. Moreover, LAST scores and CAT scores correlated positively with TEWL (p < 0.0001). TEWL rates were higher in CAT positive than in CAT negative subjects (p < 0.0001). Finally, erythema index correlated positively with CAT scores (p < 0.0001), but not with LAST scores (p = 0.0842)., Conclusions: Skin responses to LAST and CAT differ between individuals with rosacea and those with seborrheic dermatitis, possibly due to the differences in epidermal permeability barrier and the neurovascular hyperreactivity. The higher LAST and CAT scores, as well as positive rates of both LAST and CAT can be attributable to inferior permeability barrier and the neurovascular hyperreactivity in subjects with rosacea., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Chronic actinic dermatitis (CAD) is an immune-mediated photodermatosis characterized by a high eosinophil count and total immunoglobulin E (IgE) in the peripheral blood of patients. At present, however, the reasons for their elevation remain unclear., Objective: The current study aimed to detect changes in inflammatory cytokines in CAD and explore their role in this disease., Methods: Enzyme-linked immunosorbent assay and Luminex assay were conducted to measure inflammatory factor levels. Immunohistochemical analysis and quantitative real-time polymerase chain reaction were performed to evaluate the expression levels of interleukin-36γ (IL-36γ), IL-8, chemokine (C-C motif) ligand 17 (CCL17), and CCL18. CCK8 kits were used to assess cell proliferation. Immunofluorescence was used to detect nuclear factor κB (NF-κB) p65 nuclear translocation. Western blot analysis was performed to detect the protein expression level of phosphorylated NF-κB (p-NF-κB) p65. Hematoxylin and eosin and Masson trichrome staining were applied to observe histological changes in a chronic photo-damaged mouse model., Results: Eosinophils, total IgE, IL-36γ, IL-8, tumor necrosis factor α, CCL17, and CCL18 were elevated in CAD. Of note, IL-36γ promoted the proliferation of eosinophilic cells (EOL-1) and the production of IgE in peripheral blood mononuclear cells. IL-36γ also promoted the production of IL-8 and CCL18 in immortalized human keratinocytes (HaCaT cells), while ultraviolet radiation (UVR)-induced IL-36γ via activation of the NF-κB signaling pathway., Conclusions: IL-36γ was involved in the pathogenesis of CAD and UVR contributed to the production of IL-36γ, which may provide a novel therapeutic target for CAD., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Integrin tensions are critical for cell mechanotransduction. By converting force to fluorescence, molecular tension sensors image integrin tensions in live cells with a high resolution. However, the fluorescence signal intensity results collectively from integrin tension magnitude, tension dwell time, integrin density, sensor accessibility, and so forth, making it highly challenging to specifically monitor the molecular force level of integrin tensions. Here, a ratiometric tension sensor (RTS) was developed to exclusively monitor the integrin tension magnitude. The RTS consists of two tension-sensing units that are coupled in series and always subject to the same integrin tension. These two units are activated by tension to fluoresce in separate spectra and with different activation rates. The ratio of their activation probabilities, reported by fluorescence ratiometric measurement, is solely determined by the local integrin tension magnitude. RTS responded sensitively to the variation of integrin tension magnitude in platelets and focal adhesions due to different cell plating times, actomyosin inhibition, or vinculin knockout. At last, RTS confirmed that integrin tension magnitude in platelets and focal adhesions decreases monotonically with the substrate rigidity, verifying the rigidity dependence of integrin tensions in live cells and suggesting that integrin tension magnitude could be a key biomechanical factor in cell rigidity sensing.

Objective: The mental health of sexual minorities has received increasing attention, but there are few studies on the risk of psychotic-like experiences (PLEs) among sexual minorities. The purpose of this study is to explore the relationship between different sexual orientations and PLEs among college students and the moderating effect of gender., Methods: A total of 4,460 college students from seven provinces participated in this cross-sectional survey. The χ 2 test and logistic regression were used to investigate the relationship between sexual orientation and PLEs., Results: Of the participants, 4.9% identified as bisexual, 1.1% as lesbian/gay, and 5.6% were questioning/unsure; 60.1% of the sample experienced at least one PLE item, 59.2% reported delusional experiences (DEs), and 20.6% had hallucinatory experiences (HEs). Compared with heterosexual college students, bisexual and questioning students showed a higher risk of PLEs, DEs, and HEs, and lesbian/gay students showed a higher risk of HEs. Stratified analysis indicated that sexual orientation was significantly associated with PLEs only for female college students., Conclusion: Sexual orientation is a predictive factor of PLEs. In particular, different sexual minority subgroups show the different effects on PLEs between male and female college students. Mental health interventions for PLEs could employ distinct strategies based on different sexual orientations and gender disparity., 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 Lu, Qing, Tu and Liu.)

Amyloid-β oligomers (AβO) have been identified as core biomarkers for early diagnosis of Alzheimer's disease (AD). For the first time, a "turn-on" unlabeled colorimetric aptasensor based on aptamer-polythymine (polyT)-polyadenine (polyA)-gold nanoparticles (pA-pT-apt@AuNPs) was developed for highly sensitive and specific detection of amyloid-β 1-40 oligomers (Aβ40-O). In this system, polyA sequence could preferentially anchor onto AuNPs surface as well as reduce the non-specific adsorption, and the aptamer could form upright conformation for the specific recognition of Aβ40-O. The aggregation of pA-pT-apt@AuNPs was induced by MgCl 2 . However, the addition of Aβ40-O enabled the aptamer fold adaptively upon recognition and aptamer-Aβ40-O complex formed surrounding AuNPs, effectively stabilizing pA-pT-apt@AuNPs against salt-induced aggregation, therefore the color of pA-pT-apt@AuNPs solution still retained red. Based on this principle, the proposed aptasensor exhibited high sensitivity with the limit of detection of 3.03 nM and a linear detectable range from 10.00 nM to 100.0 nM. The superb sensitivity was achieved via the optimization of the length of polyA and polyT spacer. This pA-pT-apt@AuNPs based colorimetric aptasensor provides a rapid, cost-effective, highly sensitive detection method for Aβ40-O, which is valuable for the early diagnosis of AD., 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.)

Background: Chronic actinic dermatitis (CAD) is an immune-mediated photo-allergic skin disease. In the clinic, the treatment of this disease is hampered by the lack of proper understanding of the skin barrier dysfunction mechanism., Objective: To illuminate the mechanism of skin barrier dysfunction in CAD., Methods: Transcriptome sequencing and protein profiling were used to detect skin barrier injury-related genes. RNA pull down, a promoter-reporter gene assay, and chromatin isolation by RNA purification-sequencing were used to elucidate the effect of WAKMAR2 in skin barrier functionality., Results: Transcriptome sequencing from patient's tissues showed a significantly decreased expression of WAKMAR2. Down-regulation of WAKMAR2 destroyed the keratinocyte barrier. Moreover, WAKMAR2 can directly bind to the c-Fos protein. This novel long non-coding RNA (LncRNA)-protein complexes were targeted to the CLDN1 promotor. Overexpression of WAKMAR2 enhanced the promoter activity of CLDN1, while the addition of AP-1 inhibitor could reverse this phenomenon. Furthermore, our in vivo results suggested that expression of WAKMAR2 was required for the repair of skin damage in mice induced by ultraviolet irradiation., Conclusions: We identified a crucial LncRNA (WAKMAR2) for the protection of the skin barrier in vitro and in vivo. Mechanically, it can specifically interact with c-Fos protein for the regulation of CLDN1, a finding which could be applied for CAD treatment., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Here, sulfonated polyaniline (SPAN) was decorated on the surface of copper-based metal organic frame (HKUST-1) and the composite was functionalized by luminol to construct a chemiluminescence (CL) hybrids (SPAN/HKUST-1@Luminol). The as-prepared SPAN/HKUST-1@Luminol demonstrated a great dispersion and stability performance in aqueous solution. Moreover, the resultant SPAN/HKUST-1@Luminol hybrids exhibited extremely strong CL properties, and the CL quantum yield was 136 times higher than that of luminol. In particular, it exhibited outstanding CL activity not only under alkaline conditions, but also under neutral conditions. The sensitive response of the hybrid to hydrogen peroxide was used to construct CL methods for the detection of hydrogen peroxide at a wide range of pH, with the detection limit of 60 nM at a neutral condition and 25 pM at alkaline condition. Due to strong and stable signal of the SPAN/HKUST-1@Luminol, the CL method provides a viable tool for determination of H 2 O 2 in biological systems and enabled the monitoring of stimulated production of H 2 O 2 released by living cells., 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.)

Focal adhesions (FAs) transmit force and mediate mechanotransduction between cells and the matrix. Previous studies revealed that integrin-transmitted force is critical to regulate FA formation. As vinculin is a prominent FA protein implicated in integrin tension transmission, this work studies the relation among integrin tensions (force), vinculin (protein), and FA formation (structure) by integrin tension manipulation, force visualization and vinculin knockout (KO). Two DNA-based integrin tension tools are adopted: tension gauge tether (TGT) and integrative tension sensor (ITS), with TGT restricting integrin tensions under a designed T tol (tension tolerance) value and ITS visualizing integrin tensions above the T tol value by fluorescence. Results show that large FAs (area >1 μm 2 ) were formed on the TGT surface with T tol of 54 pN but not on those with lower T tol values. Time-series analysis of FA formation shows that focal complexes (area <0.5 μm 2 ) appeared on all TGT surfaces 20 min after cell plating, but only matured to large FAs on TGT with T tol of 54 pN. Next, we tested FA formation in vinculin KO cells on TGT surfaces. Surprisingly, the T tol value of TGT required for large FA formation is drastically decreased to 23 pN. To explore the cause, we visualized integrin tensions in both wild-type and vinculin KO cells using ITS. The results showed that integrin tensions in FAs of wild-type cells frequently activate ITS with T tol of 54 pN. With vinculin KO, however, integrin tensions in FAs became lower and unable to activate 54 pN ITS. Force signal intensities of integrin tensions reported by 33 and 43 pN ITS were also significantly reduced with vinculin KO, suggesting that vinculin is essential to transmit high-level integrin tensions and involved in transmitting intermediate-level integrin tensions in FAs. However, the high-level integrin tensions transmitted by vinculin are not required by FA formation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Cell adhesive force transmitted by integrins or other mechanosensitive receptors is critical for many cellular functions and biological development. Visualization and quantification of such force have been long desired and practiced in cell mechanobiology. Here we describe integrative tension sensor (ITS), a dsDNA-based tension sensor that coverts invisible force signal to fluorescence and enables cell adhesive force imaging with ultra-sensitivity. ITS can be selectively implemented at two imaging modes: a cumulative mode that maps cell adhesive force at a high signal-to-noise ratio even with a low-end fluorescence microscope, and a real-time mode that images the force at the single molecular tension level., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Bullying is a serious public health concern affecting the physical and mental health of children. Migrant children are at higher risk of developing health problems. We conducted this study to investigate the prevalence of school bullying and its possible influencing factors of migrant children., Methods: A cross-sectional study was carried out in Hunan Province, China from April to July 2018. Multi-stage cluster sampling was adopted to achieve a representative sample covering both urban and rural areas. Migrant children are defined as those who migrate with one or both parents to other places and who do not have a hukou in their city of residence. The Chinese version of Olweus Bully/Victim Questionnaire was applied to measure children's involvement in school bullying., Results: A total of 7,607 students were surveyed, including 995 migrant children and 6,612 non-migrant children. The prevalence of school bullying was significantly higher in migrant children than in non-migrant children ( χ 2  = 22.740; p  < 0.001). Binary regression analysis showed that male, middle school identity, more times of playing violent games, more social friends owning and being beaten by parents or caregivers may increase the risk of involvement of school bullying in migrant children., Conclusion: Migrant children showed a higher prevalence of school bullying than non-migrant children. Gender, grade, frequency of playing violent games, number of social friends and being beaten by parents or caregivers were associated with school bullying in migrant children., 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 © 2022 Yang, Tu, Qin, Liu and Lu.)

Neurodevelopmental exposure to chlorpyrifos (CPF) could increase risks for neurological disorders, such as autism spectrum disorder, cognitive impairment, or attention deficit hyperactivity disorder. The potential involvement of microglia reactive to inflammatory stimuli in these neurological disorders has been generally reported. However, the concrete effects and potential mechanisms of microglia dysfunction triggered by developmental CPF exposure remain unclear. Therefore, we established mouse and human embryonic microglial cells (HMC3 cell) models of developmental CPF exposure to evaluate the effects of developmental CPF exposure on neuroinflammation and underlying mechanisms. The results showed that developmental exposure to CPF enhanced the expression of Iba1 in hippocampus. CPF treatment increased inflammatory cytokines levels and TSPO expression in hippocampus and HMC3 cells. The levels of necroptosis and necroptosis-related signaling RIPK/MLKL were increased in hippocampus and HMC3 cells following CPF exposure. Furthermore, the expression of TLR4/TRIF signaling was increased in hippocampus and HMC3 cells subjected to CPF exposure. Notably, the increased levels of TLR4/TRIF signaling, RIPK/MLKL signaling, necroptosis and pro-inflammatory cytokines induced by CPF treatment were remarkably inhibited by TAK-242 (a specific TLR4 inhibitor). Additionally, the necroptosis and pro-inflammatory cytokines production induced by CPF treatment were significantly relieved by Nec-1 (a specific RIPK1 inhibitor). In general, the above results suggested that activated microglia in hippocampus subjected to developmental CPF exposure underwent RIPK1/MLKL-mediated necroptosis regulated by TLR4/TRIF signaling., 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 Ltd. All rights reserved.)

Cinnamaldehyde (CA) is a promising antimicrobial agent for the preservation of fruits and vegetables due to its excellent antibacterial activity. The application is however, limited by its unstable and volatile properties. A biocompatible carbon dots hybrid γ-cyclodextrin-based metal organic framework (CD/MOF) was developed by the seed-mediated method to improve the encapsulation and sustained continuous release of CA. CD/MOF-0.5 exhibited a CA loading efficiency of 28.42% and a sustained release duration time of more than 15 days at 8  o C. The release kinetics results showed that the release behavior of CD/MOF-0.5 fitted well with the Korsmeyer-Peppas release kinetics model, indicating that its sustained release is mainly controlled by diffusion. Both the Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy analyses revealed that CD/MOF-0.5 and CA molecules were linked by hydrogen bonds. Due to the high sustained release performance, CA-loaded CD/MOF-0.5 considerably inhibited the growth of Escherichia coli , hence preventing the spoilage of fresh-cut cantaloupes. CD/MOF-0.5/CA treatment also maintained the qualities of the fresh-cut cantaloupes, prolonging their edibility to five days. This work provides a promising strategy for the prevention of spoilage in food industry., Competing Interests: 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., (© 2022 The Authors.)

Filopodia are narrow cell extensions involved in various physiological processes. Integrins mediate filopodia adhesion and likely transmit adhesive force to regulate filopodia formation and functions, but the force is extremely weak to study and remains poorly understood. Using integrative tension sensor (ITS), we imaged filopodia adhesive force at the single molecular tension level and investigated the force dynamics and sources. Results show that filopodia integrin tension (FIT) is generated in discrete foci (force nodes) along single filopodia with a spacing of ∼1 μm. Inhibitions of actin polymerization or myosin II activity markedly reduced FIT signals in force nodes at filopodia tips and at filopodia bases, respectively, suggesting differential force sources of FIT in the distal force nodes and proximal ones in filopodia. Using two ITS constructs with different force thresholds for activation, we showed that the molecular force level of FIT is greater at filopodia bases than that at filopodia tips. We also tested the role of vinculin and myosin X in the FIT transmission. With vinculin knockout in cells, filopodia and associated force nodes were still formed normally, suggesting that vinculin is dispensable for the formation of filopodia and force nodes. However, vinculin is indeed required for the transmission of strong FIT (capable of rupturing DNA in a shear conformation), as the strong FIT vanished in filopodia with vinculin knockout. Co-imaging of FIT and myosin X shows no apparent co-localization, demonstrating that myosin X is not directly responsible for generating FIT, despite its prominent role in filopodium elongation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Foliar stable nitrogen (N) isotopes (δ 15 N) generally reflect N availability to plants and have been used to infer about changes thereof. However, previous studies of temporal trends in foliar δ 15 N have ignored the influence of confounding factors, leading to uncertainties on its indication to N availability. In this study, we measured foliar δ 15 N of 1811 herbarium specimens from 12 plant species collected in southern China forests from 1920 to 2010. We explored how changes in atmospheric CO 2 , N deposition and global warming have affected foliar δ 15 N and N concentrations ([N]) and identified whether N availability decreased in southern China. Across all species, foliar δ 15 N significantly decreased by 0.82‰ over the study period. However, foliar [N] did not decrease significantly, implying N homeostasis in forest trees in the region. The spatiotemporal patterns of foliar δ 15 N were explained by mean annual temperature (MAT), atmospheric CO 2 ( P CO 2 ), atmospheric N deposition, and foliar [N]. The spatiotemporal trends of foliar [N] were explained by MAT, temperature seasonality, P CO 2 , and N deposition. N deposition within the rates from 5.3 to 12.6 kg N ha -1  year -1 substantially contributed to the temporal decline in foliar δ 15 N. The decline in foliar δ 15 N was not accompanied by changes in foliar [N] and therefore does not necessarily reflect a decline in N availability. This is important to understand changes in N availability, which is essential to validate and parameterize biogeochemical cycles of N., (© 2022 John Wiley & Sons Ltd.)

Dibutyl phthalate (DBP) and Benzo(a)pyrene (BaP) are ubiquitous contaminants in environment and foodstuffs, which increase the chance of their combined exposure to humans in daily life. However, the combined effects of DBP and BaP on liver and the underlying mechanisms are still unclear. In this study, we explored the combined effects of DBP and BaP on liver and the potential mechanisms in a rat model. We found that DBP and BaP co-exposure activated the MyD88/NF-κB pathway through increasing TLR4 acetylation (TLR4ac) level, leading to the imbalance of pro-inflammatory factors (CXCL-13, IL-6 and TNF-α) and anti-inflammatory factors (IL-10), ultimately resulting in liver tissue damage and functional changes. Sporoderm-broken spores of Ganoderma lucidum (SSGL) had strong alleviating effects on liver injury induced by DBP and BaP co-exposure. Our study found that SSGL suppressed TLR4ac-regulated MyD88/NF-κB signaling to reduce the release of pro-inflammatory factors, and promote the secretion of IL-10, thus alleviating liver injury caused by DBP and BaP co-exposure. In conclusion, SSGL contributed to liver protection against DBP and BaP-induced liver injury in rats via suppressing the TLR4ac-regulated MyD88/NF-κB signaling., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Greenspace exposure metrics can allow for comparisons of green space supply across time, space, and population groups, and for inferring patterns of variation in opportunities for people to enjoy the health and recreational benefits of nearby green environments. A better understanding of greenspace exposure differences across various spatial scales is a critical requirement for lessening environmental health disparities. However, existing studies are typically limited to a single city or across selected cities, which severely limits the use of results in measuring systemic national and regional scale differences that might need policy at above individual city planning level. To close this knowledge gap, our study aims to provide a holistic assessment of multi-scale greenspace exposure across provinces, cities, counties, towns, and land parcels for the whole of China. We mapped the nationwide fractional greenspace coverage at 10 m with Sentinel-2 satellite imagery, and then modeled population-weighted greenspace exposure to examine variation of greenspace exposure across scales. Our results show a prominent scaling effect of greenspace exposure across multi-scale administrative divisions in China, suggesting, as expected, an increase in heterogeneity with finer spatial scales. We also identify an asymmetric pattern of the difference between greenspace exposure and greenspace coverage, across a geo-demographic demarcation boundary (i.e., along the Heihe-Tengchong Line). In general, the greenspace coverage rate will overestimate more realistic human exposure to greenspace in East China while underestimating in West China. We further found that, in China, more recently urbanized areas have much better greenspace exposure than older urban areas. Our study provides a spatially explicit greenspace exposure metric for discovering multi-scale greenspace exposure difference, which will enhance governments' capacity to quantify environmental justice, detect vulnerable greenspace exposure risk hotspots, prioritize greenspace management at the supra-city scale, and monitor the balance between greenspace supply and demand., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Ultraviolet radiation (UVR) is one of the exogenous stimuli increasing melanogenesis. UV light, especially UVB, is also a potent inducer of epidermal cytokine release. This study is aimed at determining the underlying mechanisms by which UVB-induced cytokines in keratinocytes regulate melanin production in vitro ., Methods: Expression levels of mRNA for interleukin- (IL-) 1, IL-1 β , IL-6, IL-10, IL-17, and tumor necrosis factor-alpha (TNF- α ) were measured using RT-qPCR at various time points after UVB irradiation in C57BL/6 mice and HaCaT cells. NaOH lysis and L-dihydroxyphenylalanine (L-DOPA) oxidation method were used to measure melanin content and tyrosinase (TYR) activity, respectively, in melanoma B16 cells. RT-qPCR and Western blot were used to assess mRNA and protein levels of microphthalmia-associated transcription factor (MITF), TYR, tyrosine-related protein-1 (TRP-1), and tyrosine-related protein-2 (TRP-2) in B16 cells. Finally, expression levels of cyclooxygenase-2 (COX-2) mRNA and stem cell factor (SCF) in HaCaT cells were measured following knockdown of IL-1 β using siRNA (siIL-1 β )., Results: UVB irradiation increased IL-1 β mRNA expression levels in both C57BL/6 mice and HaCaT cells. The melanin content, TYR activity, and expression levels of TYR and TRP-1 were all raised when B16 cells were treated with 4 pg/l of IL-1. Moreover, IL-1 β also upregulated the expression levels of SCF and COX-2 in nonirradiated HaCaT cells. Conversely, knockdown of IL-1 β attenuated UVB irradiation-induced upregulation of SCF and COX-2 expression in keratinocytes., Conclusions: UVB-induced melanogenesis is mediated in part by IL-1 β , leading to upregulation of the TYR/TRP1 expression in melanoma B16 cells. IL-1 β can also stimulate the expression of COX-2 and SCF in HaCaT cells, which in turn increase melanin synthesis in melanocytes. These results suggest that anti-inflammatory approaches could possibly mitigate UVB-induced hyperpigmentation., Competing Interests: The authors report no conflicts of interest in this work., (Copyright © 2022 Chun-Yan Yang et al.)

Objective: To investigate the effect of RUNX2 gene overexpression vector modified exosomes derived from bone marrow mesenchymal stem cells (BMSCs) combined with calcium carbonate scaffold system in bone defect., Methods: Rabbit BMSCs were used as the research object, and BMSCs were identified by flow cytometry. Construct RUNX2 gene overexpression vector, transfect BMSCs with lentivirus, and collect exosomes by ultracentrifugation. The morphology of exosomes was observed by transmission electron microscope, the expression of exosome marker CD63 was detected by Western blot, and the calcium carbonate scaffold was constructed by three chamber parallel automatic temperature control reaction system. According to whether the RUNX2 gene overexpression vector was transfected or not, the complex of BMSCs and calcium carbonate scaffold was divided into three groups, namely BMSCs group, RUNX2 overexpression group and exosome group. The osteogenic differentiation of BMSCs was detected by oil red O staining and RT-PCR. There were 9 clean adult healthy male New Zealand white rabbits, aged (12.97±1.21) months, with a body weight of (19.3±3.6) kg, with 3 rabbits in each group. The animal model of skull defect was constructed by surgical method, and the repair of bone defect was evaluated by imaging, he staining and Masson staining., Results: The results of flow cytometry showed that the expression of CD29 protein, CD44 protein, CD11b protein and CD45 protein on the surface of BMSCs were 99.5%, 100%, 0.1% and 0.1%, respectively. Transmission electron microscopy showed that the exosomes were bilayer vesicles with a diameter of 50 to 150 nm. Western blot showed that the molecular marker CD63 of exosomes was positive. Oil red O staining showed that the osteogenic differentiation of BMSCs in exosome group was significantly higher than that in RUNX2 overexpression group and BMSCs group. The results of RT-PCR showed that the relative expressions of RUNX2, BMP-2 and ALP mRNA in BMSCs in exosome group were significantly higher than those in RUNX2 overexpression group and BMSCs group ( P <0.05). The imaging results showed that the repair effect of skull defect in exosome group was better than that in RUNX2 overexpression group. HE staining and Masson staining showed that the repair effect of skull defect in exosome group was better than that in RUNX2 overexpression group ( P <0.05). MSCs in exosome group was significantly higher than that in RUNX2 overexpression group and BMSCs group. The results of RT-PCR showed that the relative expressions of RUNX2, BMP-2 and ALP mRNA in BMSCs in exosome group were significantly higher than those in RUNX2 overexpression group and BMSCs group( P <0.05). The imaging results showed that the repair effect of skull defect in exosome group was better than that in RUNX2 overexpression group. HE staining and Masson staining showed that the repair effect of skull defect in exosome group was better than that in RUNX2 overexpression group( P <0.05)., Conclusion: Compared with RUNX2 gene overexpression vector transfection, extraction of exosomes directly can promote the differentiation of BMSCs into osteoblasts more efficiently, and the combination with calcium carbonate scaffold can better promote the healing of bone defects. So as to provide new ideas and methods for the clinical treatment of bone defects.

The instinctive protective stress responses of tumor cells hamper low-temperature photothermal therapy (LTPTT), resulting in tumor recurrence and metastasis. The rapid blood clearance and low-efficiency tumor enrichment of nanomedicines also decrease the efficacy of LTPTT. In this study, we fabricated coassembled photothermal agents (indocyanine green, ICG) and autophagy inhibitors (chloroquine, CQ) and red blood cell and cancer cell hybrid membrane (RCm)-camouflaged ICGCQ@RCm nanoparticles (ICGCQ@RCm NPs) to enhance tumor LTPTT. The ICGCQ@RCm NPs exhibited prolonged blood drug circulation and markedly enhanced drug accumulation in tumor tissues. The ICGCQ@RCm NPs reduced the thermal tolerance of tumor cells to sensitize ICG-mediated LTPTT by inhibiting protective autophagy. The ICGCQ@RCm NPs exerted strong immunogenic cell death (ICD) after efficient LTPTT to activate antitumor immunity. In addition, ICGCQ@RCms optimized the therapeutic efficacy by imaging-guided LTPTT, taking advantage of the near-infrared (NIR) fluorescence of ICG. Consequently, the ICGCQ@RCm NPs effectively inhibited tumors under mild LTPTT, significantly suppressed tumor metastasis and prolonged the survival time of tumor-bearing mice. Furthermore, the ICGCQ@RCm NPs showed high biosafety in vitro and in vivo . The ICGCQ@RCm NPs demonstrated tumor-targeting and imaging-guided autophagy inhibition-sensitized LTPTT using two Food and Drug Administration (FDA)-approved drugs, which have great potential for clinical application.

Podosomes are integrin-mediated cell adhesion units involved in many cellular and physiological processes. Integrins likely transmit tensions critical for podosome functions, but such force remains poorly characterized. DNA-based tension sensors are powerful in visualizing integrin tensions but subject to degradation by podosomes which ubiquitously recruit DNase. Here, using a DNase-resistant tension sensor based on a DNA/PNA (peptide nucleic acid) duplex, we imaged podosomal integrin tensions (PIT) in the adhesion rings of podosomes on solid substrates with single molecular tension sensitivity. PIT was shown to be generated by both actomyosin contractility and actin polymerization in podosomes. Importantly, by monitoring PIT and podosome structure in parallel, we showed that extracellular integrin-ligand tensions, despite being critical for the formation of focal adhesions, are dispensable for podosome formation, as PIT reduction or elimination has an insignificant impact on structure formation and FAK (focal adhesion kinase) phosphorylation in podosomes. We further verified that even integrin-ligand interaction is dispensable for podosome formation, as macrophages form podosomes normally on passivated surfaces that block integrin-ligand interaction but support macrophage adhesion through electrostatic adsorption or Fc receptor-immunoglobin G interaction. In contrast, focal adhesions are unable to form on these passivated surfaces.

In this study, two types of the fluoroamphiphile analogs were synthesized and self-assembled into the "core-shell" micellar nanocarriers for intracellular delivery and organelle targeting. Using the fluorescent dyes or vitamin E succinate as the cargo, the drug delivery and targeting capabilities of the fluoroamphiphiles and their micelles were evaluated in the cell lines, tumor cell spheroids, and tumor-bearing mice. The "core-fluorinated" micelles exhibited favorable physicochemical properties and improved the cellular uptake of the cargo by around 20 times compared to their "shell-fluorinated" counterparts. The results also indicated that the core-fluorinated micelles underwent an efficient clathrin-mediated endocytosis and a rapid endosomal escape thereafter. Interestingly, the internalized fluoroamphiphile micelles preferentially accumulated in mitochondria, by which the efficacy of the loaded vitamin E succinate was boosted both in vitro and in vivo . Unlike the popularly used cationic mitochondrial targeting ligands, as a charge-neutral nanocarrier, the fluoroamphiphiles' mitochondrial targeting was potential independent. The mechanism study suggested that the strong binding affinity with the phospholipids, particularly the cardiolipin, played an important role in the fluoroamphiphiles' mitochondrial targeting. These charge-neutral fluoroamphiphiles might have great potential to be a simple and reliable tool for intracellular drug delivery and mitochondrial targeting.

Metallodrug resistance has attracted a great deal of attention in cancer treatment. According to the cisplatin (cis-Pt) anticancer mechanism, a new strategy to overcome cis-Pt resistance through mitochondrial dysfunction is proposed. Two mitochondria-targeted aggregation-induced emission fluorogens (AIEgens) were first synthesized, named DP-PPh 3 and TPE-PPh 3 , which showed superior capacities to overcome the cis-Pt resistance of lung cancer cells (A549R) by the alteration of drug metabolism (up-regulation of influx CTR1 and down-regulation of efflux MRP2) and blockage of autophagic flux (failure of the degradation of autophagosomes). This study is the first time that AIEgens are utilized in the treatment of cis-Pt resistant cancer cells. Moreover, the underlying molecular mechanism was fully revealed. Triphenylphosphonium (PPh 3 )-decorated AIEgens DP-PPh 3 and TPE-PPh 3 not only successfully realized aggregation and the imaging of mitochondria in A549R cells, but also activated cytotoxicity towards A549R cells. DP-PPh 3 and TPE-PPh 3 could induce ROS production, disrupt the mitochondrial structure, and impair mitochondrial and glycolytic metabolism. Furthermore, the anticancer efficacy of these drugs was demonstrated in 3D multicellular tumor spheroids (MCTSs) of A549R cells in vitro and in tumor-bearing nude mice in vivo . This AIE-PPh 3 strategy not only promoted cytotoxicity towards cancer cells but also provided a new pathway for the treatment of metallodrug resistance., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Agricultural pesticides have been one of the most extensively used compounds throughout the world. The main sources of contamination for humans are dietary intake and occupational exposure. The impairments caused by agricultural pesticide exposure have been a significant global public health problem. Recent studies have shown that low-level agricultural pesticide exposure during the critical period of neurodevelopment (pregnancy and lactation) is closely related to autism spectrum disorder (ASD). Inhibition of acetylcholinesterase, gut microbiota, neural dendrite morphology, synaptic function, and glial cells are targets for the effects of pesticides during nervous system development. In the present review, we summarize the associations between several highly used and frequently studied pesticides (e.g., glyphosate, chlorpyrifos, pyrethroids, and avermectins) and ASD. We also discusse future epidemiological and toxicological research directions on the relationship between pesticides and ASD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Theranostic anticancer agents with dual functions of diagnosis and therapy are in highly demand for breast cancer. Herein, a triphenylphosphonium (TPP)-decorated aggregation-induced emission (AIE)-based Pt(IV) prodrug ACPt was developed, which exhibited superior anticancer performance with novel anticancer mechanism of dual modulation of apoptosis and autophagy inhibition. The experimental data showed that ACPt induced increased reactive oxygen species (ROS), and decreased mitochondrial membrane potential (MMP). The morphology and function of mitochondria were also severely damaged and ACPt showed strong inhibition to both mitochondrial and glycolytic bioenergetics. Moreover, DNA damage and cell cycle arrest in the S-phase were also observed after the ACPt treatment, eventually leading to the apoptosis and autophagy inhibition of cancer cells. Furthermore, ACPt also indicated excellent anti-proliferation activity in 3D multicellular tumor spheroids (MCTSs), suggesting the potential to inhibit solid tumors in vivo. Our observation demonstrated that ACPt could serve as a promising anticancer theranostic agent toward breast cancers for prodrug activation monitoring and image-guided chemotherapy., (Copyright © 2021. Published by Elsevier Inc.)

Conventional cell migration assays require time-lapse imaging of live cells to trace cell migration paths, consequently demanding cumbersome hardware setup and suffering from low data throughput. In this work, we developed an assay named Tracking Cells by Footprint (TCF) based on a mechano-optical biosensor that irreversibly becomes fluorescent when sensing local cell adhesive force. Cell migration paths are visualized and recorded as fluorescent footprints on glass or elastic substrates coated with such biosensor. From the footprints, cell migration ranges, speeds and persistence are analyzed and quantified without the need of time-lapse imaging. The feasibility of TCF assays was demonstrated with three types of cells with different migratory capabilities. TCF was then applied to evaluating cell motility affected by biochemical or biomechanical cues. The results show that fibroblast motility is reduced by blebbistatin and vinblastine but promoted by bFGF (basic fibroblast growth factor), and the motility correlates with the substrate rigidity. TCF is also compatible with 96-well plates which, combined with static imaging and large-area scanning, provides high data throughput with minimal additional effort., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A molecular inhibitor of tau protein aggregation offers an attractive therapeutic possibility as disease-modifying treatment of Alzheimer's disease. However, the ineffectiveness as well as adjoint toxicity due to superficial understanding of the inhibition mechanism has hindered drug development. Conventional approaches for screening drug ligands rely on compatible docking with the well-defined structure of a protein receptor. Therefore, the design of tau aggregation inhibitors has been inevitably hindered by the unstructured, highly dynamic nature of the tau protein. This paper suggested a new strategy for reducing tau aggregation through a dynamic process of conformational isomerization. A group of glucose gallate derivatives were selected as tau aggregation inhibitors. These star-shaped molecules have a biocompatible glucose core surrounded by several gallic acid polyphenol arms, which can bind to peptide chains at different sites, probably through hydrogen bonds and π-π stacking. Theoretically, by elevating the saddle point on the potential energy surfaces (PES) of proteins, the barrier in the dynamic pathway of peptide isomerization, glucose gallates effectively inhibit tau aggregation through a dynamic mechanism. A tau cell model based on human neurons was constructed. For the first time, we confirmed that the moderate thermodynamic binding of the molecular ligand to the tau peptide chain can not only prevent the isomerization of the peptide chain leading to aggregation but also avoid toxicity resulting from the dissociation of tau from microtubules.

Background: Rosacea is a common chronic inflammatory dermatosis with uncertainty of etiology. Although clinical features and risk factors of the disease in Caucasians have been reported, this information in Chinese is largely unavailable., Aims: To analyze the clinical features and associated risk factors of rosacea in Chinese., Methods: A questionnaire was given to outpatients with rosacea who visited the dermatology department of the first affiliated hospital of Kunming Medical University from June 2018 to March 2019. Analyses included demographic characteristics of subjects, clinical characteristics, and risk factors of rosacea., Results: A total of 254 outpatients completed the questionnaire. The ratio of female to male was 5.68:1.00. The mean age at onset was 31.18 ± 10.23 years. Erythematotelangiectatic subtype accounted for 51.60%, while 39% of the subjects were of papulopustular subtype. The rest were phymatous type (9.40%). Subjects with flushing, persistent facial erythema, and telangiectasia accounted for 91.73%, 90.55%, and 83.07%, respectively. One hundred and thirteen subjects (44.49%) had papules or pustules, and 24 subjects (9.40%) were with phymatous changes. The most commonly involved sites were the cheeks (93.31%), followed by the nose (82.68%), the perioral area (61.42%), and the forehead (51.97%). The clinical symptoms included burning (93.70%), dryness (90.55%), and itching (75.59%). The main risk factors were sun exposure (90.94%), temperature change (87.40%), etc. Fifty-one (20.08%) patients had comorbidities., Conclusions: Rosacea mainly affects young females. The common signs and symptoms include flushing, persistent facial erythema, and burning. Sun exposure and temperature changes are the common risk factors. Patients can have comorbidities of systemic disorders., (© 2021 Wiley Periodicals LLC.)

Background: For evaluating the severity of coronary heart disease (CHD), coronary arteriography may not be available everywhere due to technical limitations. MicroRNA-101a (miR-101a) associated with inflammation and cholesterol homeostasis. However, whether it related to presence and stratification of CHD is still unknown., Aim: We aim to evaluate the value of miR-101a in stratifying CHD patients., Methods: We enrolled 200 CHD patients and 100 controls, and 200 CHD patients were divided into two groups of low and high SYNTAX score (SYNTAX score ≤ 22 versus SYNTAX score ≥ 33). Intergroup comparisons of miR-101a level were compared among the controls and two groups of low and high SYNTAX score. Correlation between miR-101a and blood lipid profiles was analyzed. The logistic regression analysis were conducted to evaluate the risk factors of CHD., Results: Relative level of miR-101a in the controls, SYNTAX score ≤ 22 and SYNTAX score ≥ 33 group were 4.61 (1.24-8.91), 3.28 (0.58-6.75) and 2.29 (1.04-3.62), respectively (p < 0.001). All lipid profiles significantly associated with miR-101a expression (all p < 0.001). The odds ratio (OR) of miR-101a in univariate analysis was 0.41 (95% CI, 0.33-0.52). After adjusting for the traditional risk factors, such as blood profiles and history of smoking, the odds ratio of miR-101a was 0.63 (95% CI, 0.47-0.43), which closely associated with CHD (p = 0.002)., Conclusions: Circulating miR-101a may be considered as a novel biomarker for evaluating the presence and severity of CHD., (© 2021. Royal Academy of Medicine in Ireland.)

Objective: To explore the effects of siRNA hsa-circ-0000885 modified bone marrow mesenchymal stem cells (BMSCs) on osteogenic differentiation, cell proliferation and apoptosis in order to provide new ideas and methods for the clinical treatment of osteoporosis (OP)., Methods: From September 2018 to February 2020, 13 patients with osteoporosis admitted to our hospital were selected as the research objects, including 11 females and 2 males, with an age of (65.45±10.77) years old. After obtaining the informed consent of patients, peripheral blood tissues were extracted. Then the expression level of cir-cRNA in peripheral blood mononuclear cells(PBMC) was detected by circ RNA chip. The expression of circ RNA was silenced by siRNA technology. The BMSCs were transfected with lentivirus. According to the siRNA interference plasmid hsa-circ-0000885, the cells were divided into the blank group, the empty vector group and the siRNA interference group. After 72 hours of treatment, the cell cycle was detected by flow cytometry, the apoptosis level was detected by AV-PI kit, and the osteogenic differentiation ability of BMSCs was detected by ALP staining., Results: The expression of hsa-circ-0000885 in PBMC of patients with osteoporosis was significantly higher than that of healthy controls ( t =2.119, P <0.05). ALP staining showed that siR-NA hsa-circ-0000885 could promote the osteogenic differentiation of BMSCs, which was obviously too much in the blank group and blank plasmid group ( F =9.132, q =2.995, 2.897; P =0.009, 0.012<0.05). The results of CCK-8 showed that siRNA hsa-circ-0000885 could promote the proliferation of BMSCs, which was significantly higher than that of the blank group and blank plasmid group ( F =9.881, q =2.457, 2.904; P =0.032, 0.016<0.05). The results of AV-PI showed that the apoptosis rate of siRNA interference group was significantly lower than that of blank group and blank plasmid group( F =10.208; q =2.885, 3.001; P =0.019, 0.011<0.05)., Conclusion: The lentivirus mediated siRNA hsa-circ-0000885 plasmid transfected into BMSCs and osteoclast co culture system can promote cell proliferation, inhibit apoptosis and promote osteogenic differentiation of BMSCs, which can be used as a potential therapeutic target for OP patients.

The antioxidant defense system in malignant cells, which involves antioxidant enzymes and antioxidant molecules, is an innate barrier to photodynamic therapy (PDT). Because of the complexity of the endogenous antioxidant mechanisms of these cells, simply inhibiting individual antioxidant pathways has a limited effect on improving the lethality of ROS. To enhance the efficacy of PDT for tumor treatment, a versatile nanoparticle (NP)-based drug is developed, which the authors call PZB NP, containing the glutathione inhibitor l-buthionine sulfoximine (BSO) and the heme oxygenase 1 (HO-1) inhibitor protoporphyrin zinc(II) (ZnPP) to suppress the innate antioxidant defense system of cancer cells in a two-pronged manner. BSO reduces intracellular glutathione levels to minimize ROS elimination and protein protection during PDT, and ZnPP inhibits the ROS-stimulated upregulation of the antioxidant HO-1, thus preventing ROS removal by cells after PDT. Thus, BSO and ZnPP synergistically suppress the antioxidant defense systems of cancer cells both during and after protoporphyrin-IX-mediated PDT in a two-pronged manner, resulting in tumor cell death through excess oxidative pressure. The results demonstrate that the construction of nanodrugs having dual antioxidation defense suppression properties is a promising route for the development of highly efficient ROS-based therapies., (© 2021 Wiley-VCH GmbH.)

Background: Chronic actinic dermatitis (CAD) is a photoallergic skin disease with abnormal hyperplasia. At present, the mechanism of abnormal proliferation is not clear., Objective: To explore possible mechanism of CAD proliferative lesions., Methods: Immunohistochemistry (IHC) assay and small RNA sequencing were carried out. Quantitative real-time PCR (qRT-PCR) analysis was performed to evaluate expression levels of hsa-miR-221-3p and FOS. The interaction between hsa-miR-221-3p and FOS was identified by dual-luciferase reporter assay. Expression of hsa-miR-221-3p also was detected by qRT-PCR after UVB irradiation. Influences of hsa-miR-221-3p and FOS on cell viability and apoptosis were assessed through a series of functional experiments and rescue experiments. Western blot analysis was used to detect protein expression of fos, Bax, Bcl-xL, and caspase-3., Results: Patients with CAD had marked epidermal hyperplasia. The expression of hsa-miR-221-3p was up-regulated in CAD while FOS was significantly down-regulated. Dual-luciferase reporter assay confirmed that hsa-miR-221-3p targeted FOS 3'UTR. Hsa-miR-221-3p induced by UVB ranged from 0 to 30 mJ. Moreover, hsa-miR-221-3p overexpression or FOS knockdown promoted cell proliferation and reduced cell apoptosis. Western blot showed that hsa-miR-221-3p negatively regulated fos, which regulated Bcl-xL/Bax. Cell proliferation caused by hsa-miR-221-3p overexpression or FOS knockdown could be reversed by Bcl-xL inhibitor., Conclusion: Hsa-miR-221-3p induced by UVB targeted FOS 3'UTR, which played an important role in regulating proliferation and apoptosis of keratinocytes via Bcl-xL/Bax pathway; this may provide a new insight for CAD proliferative lesions., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Single-cell sequencing (SCS) is a promising new technique used to assess the genomics, transcriptomics, epigenetics, and other multi-omics at the single-cell level. In addition to elucidating the immune microenvironment and revealing the pathomechanisms of disease and drug resistance, SCS can profile the actual state of an individual cell and identify a novel cell type and differentiation trajectories, which cannot be achieved by bulk tissue sequencing technique. SCS technique serves as powerful tools to explore more meaningful biomarkers of diagnosis, prognosis, and new therapeutic targets in clinical practice. The SCS technique has been widely applied in the field of dermatology. In this review, we summarize the advances of SCS in dermatology.

Objective: Androgens acting through the androgen receptor play a crucial role in the pathogenesis of acne. This study aimed to identify whether two key genes ( CYP21A2 and CYP19A1 ) involved in the synthesis and metabolism of androgens were associated with Pillsbury III-IV severe acne vulgaris., Methods: We carried out a standard questionnaire survey about acne and enlisted 600 Pillsbury III-IV severe acne vulgaris patients and 652 healthy controls of Han Chinese descent from Yunnan, China in the study. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped by SNaPshot assay and analyzed for association with severe acne., Results: There was no significant difference in gender between the two groups ( P = 0.085), and the age of the acne case group was significantly lower than that of the control group ( P < 0.001). Our results revealed that only two SNPs, rs6474 (p.Arg102Lys) ( P = 0.001) and rs6465 ( P = 0.025) of the CYP21A2 gene were significantly associated with severe acne among the Han Chinese. When subjects were divided into males and females, significant associations were observed only in male patients with severe acne vulgaris for four variants: CYP21A2 rs6474 (p.Arg102Lys) ( P = 0.002); CYP21A2 rs6465 ( P = 0.012); CYP19A1 rs8023263 ( P = 0.037); and CYP19A1 rs2470152 ( P = 0.007). Haplotype analyses showed that the distribution of CYP21A2 haplotypes was significantly associated with male patients, while no association of CYP19A1 haplotypes was observed. The structure of the human CYP21A2 consists of two substrate binding sites and one substrate access channel., Conclusion: This study shed a light on a potentially important effect of CYP21A2 and CYP19A1 genes in severe acne vulgaris in the Han Chinese, especially for male patients. Future studies using independently verified datasets from a broader geographical spectrum will be valuable in identifying the causal and functional variants responsible for severe acne vulgaris within the CYP19A1 and CYP21A2 genes., Competing Interests: The authors declare that they have no competing interests., (© 2021 Yang et al.)

Cell adhesive force, exerting on the local matrix or neighboring cells, plays a critical role in regulating many cell functions and physiological processes. In the past four decades, significant efforts have been dedicated to cell adhesive force detection, visualization and quantification. A recent important methodological advancement in cell adhesive force visualization is to adopt force-to-fluorescence conversion instead of force-to-substrate strain conversion, thus greatly improving the sensitivity and resolution of force imaging. This review summarizes the recent development of force imaging techniques (collectively termed as cell adhesive force microscopy or CAFM here), with a particular focus on the improvement of CAFM's spatial resolution and the biomaterial choices for constructing the tension sensors used in force visualization. This review also highlights the importance of DNA-based tension sensors in cell adhesive force imaging and the recent breakthrough in the development of super-resolution CAFM.

Conventional metal oxide semiconductor (MOS) gas sensors have been investigated for decades to protect our life and property. However, the traditional devices can hardly fulfill the requirements of our fast developing mobile society, because the high operating temperatures greatly limit their applications in battery-loaded portable systems that can only drive devices with low power consumption. As ammonia is gaining importance in the production and storage of hydrogen, there is an increasing demand for energy-efficient ammonia detectors. Hence, in this work, a Schottky diode resulting from the contact between zinc oxide nanorods and gold is designed to detect gaseous ammonia at room temperature with a power consumption of 625 μW. The Schottky diode gas sensors benefit from the change of barrier height in different gases as well as the catalytic effect of gold nanoparticles. This diode structure, fabricated without expensive interdigitated electrodes and displaying excellent performance at room temperature, provides a novel method to equip mobile devices with MOS gas sensors.