Association of thrombocytopenia with immune checkpoint inhibitors: a large-scale pharmacovigilance analysis based on the data from FDA adverse event reporting system database.

Introduction: An increasing number of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been reported during clinical treatment. We aimed to explore the clinical characteristics of patients with ICIs-induced ITP under different therapeutic strategies based on the FAERS database and explore the potential biological mechanisms in combination with TCGA pan-cancer data. Methods: Data from FAERS were collected for ICIs adverse reactions between January 2012 and December 2022. Disproportionality analysis identified ICIs-induced ITP in the FAERS database using the reporting odds ratio (ROR), proportional reporting ratio (PRP), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker algorithms (MGPS). The potential biological mechanisms underlying ITP induced by ICIs were examined using TCGA transcriptome data on cancers. Results: In the FAERS, 345 ICIs-induced ITP reports were retrieved, wherein 290 (84.06%) and 55 (15.94%) were reported as monotherapy and combination therapy, respectively. The median age of the reported patients with ICIs-induced ITP was 69 years (IQR 60-76), of which 62 (18%) died and 47 (13.6%) had a life-threatening outcome. The majority of reported indications were lung, skin, and bladder cancers, and the median time to ITP after dosing was 42 days (IQR 17-135), with 64 patients (43.5%) experiencing ITP within 30 days of dosing and 88 patients experiencing ITP in less than 2 months (59.9%). The occurrence of ICIs-induced ITP may be associated with ICIs-induced dysregulation of the mTORC1 signaling pathway and megakaryocyte dysfunction. Conclusion: There were significant reporting signals for ITP with nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab/ipilimumab, and pembrolizumab/ipilimumab. Patients treated with anti-PD-1 in combination with anti-CTLA-4 are more likely to have an increased risk of ICIs-induced ITP. Patients with melanoma are at a higher risk of developing ITP when treated with ICI and should be closely monitored for this risk within 60 days of treatment. The potential biological mechanism of ICIs-induced ITP may be related to the dysfunction of megakaryocyte autophagy through the overactivation of the mTOR-related signaling pathway. This study provides a comprehensive understanding of ICIs-induced ITP. Clinicians should pay attention to this potentially fatal adverse reaction.

Pharmacological Inhibition or Silencing of TREM1 Restrains HCC Cell Metastasis by Inactivating TLR/PI3K/AKT Signaling.

Hepatocellular carcinoma (HCC), a widely prevalent malignancy strongly linked to inflammation, remains a significant public health concern. Triggering receptor expressed on myeloid cells 1 (TREM1), a modulator of inflammatory responses identified in recent years, has emerged as a crucial facilitator in cancer progression. Despite its significance, the precise regulatory mechanism of TREM1 in HCC metastasis remains unanswered. In the present investigation, we observed aberrant upregulation of TREM1 in HCC tissues, which was significantly linked to poorer overall survival. Inhibition of TREM1 expression resulted in a significant reduction in HCC Huh-7 and MHCC-97H cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process. Furthermore, inhibiting TREM1 decreased protein expressions of toll-like receptor 2/4 (TLR2/4) and major myeloid differentiation response gene 88 (MyD88), leading to the inactivation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. Notably, these effects were reversed by treatment with TLR2-specific agonist (CU-T12-9), indicating a potential crosstalk between TREM1 and TLR2/4. Mechanistic studies revealed a direct interaction between TREM1 and both TLR2 and TLR4. In vivo studies demonstrated that inhibition of TREM1 suppressed the growth of HCC cells in the orthotopic implant model and its metastatic potential in the experimental lung metastasis model. Overall, our findings underscore the role of TREM1 inhibition in regulating EMT and metastasis of HCC cells by inactivating the TLR/PI3K/AKT signaling pathway, thereby providing deeper mechanistic insights into how TREM1 regulates metastasis during HCC progression.

Cross-linked Sodium Hyaluronate Gel with PLLA-b-PEG Microsphere for Facial Contouring in Chinese: A Retrospective Study.

BACKGROUND: In Asia, the demand for cosmetic facial treatments has surged due to technological advancements, increased social acceptability, and affordability. Poly-L-lactic acid (PLLA) fillers, known for their biocompatibility and biodegradability, have emerged as a popular choice for facial contouring, yet studies specifically addressing their use in Asian populations are scarce. METHODS: This retrospective study examined 30 Chinese patients who underwent facial contouring with PLLA fillers, focusing on product composition, injection techniques, and safety measures. A comprehensive clinical evaluation was performed, including the Global Aesthetic Improvement Scale (GAIS) and Global Impression of Change Scale (GICS) for effectiveness and patient satisfaction, respectively. RESULTS: No significant difference in GAIS scores was observed between injectors and blinded evaluators over a 12-month period, indicating consistent effectiveness. Patient satisfaction remained high, with GICS scores reflecting positive outcomes. The safety profile was favorable, with no serious adverse events reported. The study highlighted the importance of anatomical knowledge to avoid complications, particularly in areas prone to blindness. CONCLUSIONS: PLLA fillers offer a safe, effective option for facial contour correction in the Asian population, achieving high patient satisfaction and maintaining results over time. The study underscores the need for tailored approaches in cosmetic procedures for Asians, considering their unique facial structures and aesthetic goals. Further research with larger, multicenter cohorts is recommended to validate these findings and explore long-term effects. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Impact of Detrusor Muscle Activity on Short-term Prognosis Following 1470 nm Semiconductor Laser Surgery in Elderly Patients with Benign Prostatic Hyperplasia.

Objective: To investigate the influence of preoperative detrusor muscle activity on the short-term prognosis of elderly patients diagnosed with benign prostatic hyperplasia (BPH) undergoing 1470 nm semiconductor laser surgery. Methods: A retrospective study was conducted on clinical data from 165 elderly BPH patients who underwent 1470 nm semiconductor laser surgery between May 2019 and April 2023. Patients were stratified based on preoperative urodynamic study findings, specifically their bladder contractility index (BCI). Patients with a BCI ≤100 constituted the detrusor underactivity (DU) group (n=64), while those with a BCI >100 formed the non-DU group (n=101). Surgical parameters, including duration, intraoperative blood loss, postoperative hospital stay, bladder irrigation, and catheterization duration, were compared. Additionally, changes in International Prostate Symptom Score (IPSS), Quality of Life (QOL) score, residual urine volume, and peak urinary flow rate (Qmax) were assessed before and three months after surgery in both groups. Results: There were no statistically significant differences observed between the DU and non-DU groups concerning surgical duration, intraoperative blood loss, postoperative hospitalization duration, bladder irrigation duration, and postoperative catheterization duration (P > .05). Similarly, no significant disparities were noted in the IPSS and QOL scores preoperatively and at the three-month follow-up in both groups (P > .05). Both cohorts exhibited no significant differences in residual urine volume before surgery and at the three-month mark postoperatively (P > .05). However, the postoperative Qmax was significantly reduced in the DU group compared to the non-DU group (P < .05). Conclusions: Detrusor muscle activity does not exert a significant impact on clinical symptom improvement and quality of life in elderly BPH patients treated with 1470 nm semiconductor laser surgery. However, patients with DU exhibited inferior postoperative recovery in Qmax, underscoring the importance of preoperative urodynamic studies for early intervention and enhanced surgical outcomes in this patient population.

A strategy for inhibitors screening of xanthine oxidase based on colorimetric sensor combined with affinity chromatography technology.

The discovery of enzyme inhibitors from natural products is a crucial aspect in the development of therapeutic drugs. However, the complexity of natural products presents a challenge in developing simple and efficient methods for inhibitor screening. Herein, we have developed an integrated analytical model for screening xanthine oxidase (XOD) inhibitors that combines simplicity, accuracy, and efficiency. This model utilizes a colorimetric sensor and affinity chromatography technology with immobilized XOD. The colorimetric sensor procedure can quickly identify whether there are active components in complex samples. Subsequently, the active components in the samples identified by the colorimetric sensor procedure were further captured, separated, and identified through affinity chromatography. The integrated analytical model can significantly enhance the efficiency and accuracy of inhibitor screening. The proposed method was applied to screen for an activity inhibitor of XOD in five natural medicines. As a result, a potential active ingredient for XOD, polydatin, was successfully identified from Polygoni Cuspidati Rhizoma et Radix. This work is anticipated to offer new insights for the screening of enzyme inhibitors from natural medicines.

Can digital financial inclusion help reduce migrant workers' overwork? Evidence from China.

Introduction: Migrant workers in China are migrants from the rural to the urban areas who usually work in the cities and return to the countryside after a certain period. Due to China's strict household registration system, they differ significantly from urban residents' access to public services. However, at the same time, China's workers are facing a severe phenomenon of overwork, and the group of migrant workers is even more hard-hit by overwork, which will cause various adverse effects on workers and society and should attract the attention of all sectors of society. Methods: This paper focuses on the impact of digital financial inclusion on the overwork of migrant workers. This study considered cross-sectional data containing 98,047 samples based on the 2017 China Migrants Dynamic Survey 2017 (CMDS) and China Municipal Statistical Yearbook after robustness tests and heterogeneity analysis using probit models. Results: (1) digital financial inclusion can effectively alleviate overwork among migrant workers; (2) the impact of digital finance on overwork is more significant for the new generation, digitized industries, and self-employed migrant workers; it is also more significant for the South, East, and small and medium-sized cities than for the North, the Midwest, and large cities; (3) job quality and income are crucial factors in how digital financial inclusion affects overwork among migrant workers. Digital financial inclusion can improve the quality of employment for migrant workers and alleviate overwork. However, the income substitution effect partially reduces the inhibitory impact of digital financial inclusion on overwork. Conclusion: Continuously promote the development of digital inclusive finance, improve laws and regulations, and protect the labor rights and interests of migrant workers. At the same time, vocational training and skills upgrading for rural migrant workers should be strengthened to improve the quality of their employment so that they can leave the secondary labor market and enter the primary labor market.

Assessment and Comparison of Early Developmental Toxicity of Six Per- and Polyfluoroalkyl Substances with Human Embryonic Stem Cell Models.

Per- and polyfluoroalkyl substances (PFAS) are extensively utilized in varieties of products and tend to accumulate in the human body including umbilical cord blood and embryos/fetuses. In this study, we conducted an assessment and comparison of the potential early developmental toxicity of perfluorooctanoic acid (PFOA), undecafluorohexanoic acid (PFHxA), heptafluorobutyric acid, perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate, and perfluorobutyric acid at noncytotoxic concentrations relevant to human exposure using models based on human embryonic stem cells in both three-dimensional embryoid body (EB) and monolayer differentiation configurations. All six compounds influenced the determination of cell fate by disrupting the expression of associated markers in both models and, in some instances, even led to alterations in the formation of cystic EBs. The expression of cilia-related gene IFT122 was significantly inhibited. Additionally, PFOS and PFOA inhibited ciliogenesis, while PFOA specifically reduced the cilia length. Transcriptome analysis revealed that PFOS altered 1054 genes and disrupted crucial signaling pathways such as WNT and TGF-ß, which play integral roles in cilia transduction and are critical for early embryonic development. These results provide precise and comprehensive insights into the potential adverse health effects of these six PFAS compounds directly concerning early human embryonic development.

Establishment and application of a screening method for α-glucosidase inhibitors based on dual sensing and affinity chromatography.

α-Glucosidase plays a direct role in the metabolic pathways of starch and glycogen, any dysfunction in its activity could result in metabolic disease. Concurrently, this enzyme serves as a target for diverse drugs and inhibitors, contributing to the regulation of glucose metabolism in the human body. Here, an integrated analytical method was established to screen inhibitors of α-glucosidase. This step-by-step screening model was accomplished through the biosensing and affinity chromatography techniques. The newly proposed sensing program had a good linear relationship within the enzyme activity range of 0.25 U mL-1 to 1.25 U mL-1, which can quickly identify active ingredients in complex samples. Then the potential active ingredients can be captured, separated, and identified by an affinity chromatography model. The combination of the two parts was achieved by an immobilized enzyme technology and a microdevice for reaction, and the combination not only ensured efficiency and accuracy for inhibitor screening but also eliminated the occurrence of false positive results in the past. The emodin, with a notable inhibitory effect on α-glucosidase, was successfully screened from five traditional Chinese medicines using this method. The molecular docking results also demonstrated that emodin was well embedded into the active pocket of α-glucosidase. In summary, the strategy provided an efficient method for developing new enzyme inhibitors from natural products.

ART1 knockdown decreases the IL-6-induced proliferation of colorectal cancer cells.

Colorectal cancer (CRC) is a worldwide health concern. Chronic inflammation is a risk factor for CRC, and interleukin-6 (IL-6) plays a pivotal role in this process. Arginine-specific mono-ADP-ribosyltransferase-1 (ART1) positively regulates inflammatory cytokines. ART1 knockdown reduces the level of glycoprotein 130 (gp130), a key transducer in the IL-6 signalling pathway. However, the relationship between ART1 and IL-6 and the resulting effects on IL-6-induced proliferation in CRC cells remain unclear. The aims of this study were to investigate the effects of ART1 knockdown on IL-6-induced cell proliferation in vitro and use an in vivo murine model to observe the growth of transplanted tumours. The results showed that compared with the control, ART1-sh cancer cells induced by IL-6 exhibited reduced viability, a lower rate of colony formation, less DNA synthesis, decreased protein levels of gp130, c-Myc, cyclin D1, Bcl-xL, and a reduced p-STAT3/STAT3 ratio (P < 0.05). Moreover, mice transplanted with ART1-sh CT26 cells that had high levels of IL-6 displayed tumours with smaller volumes (P < 0.05). ART1 and gp130 were colocalized in CT26, LoVo and HCT116 cells, and their expression was positively correlated in human CRC tissues. Overall, ART1 may serve as a promising regulatory factor for IL-6 signalling and a potential therapeutic target for human CRC.

Assessing developmental neurotoxicity of emerging environmental chemicals using multiple in vitro models: A comparative analysis.

Newly synthesized chemicals are being introduced into the environment without undergoing proper toxicological evaluation, particularly in terms of their effects on the vulnerable neurodevelopment. Thus, it is important to carefully assess the developmental neurotoxicity of these novel environmental contaminants using methods that are closely relevant to human physiology. This study comparatively evaluated the potential developmental neurotoxicity of 19 prevalent environmental chemicals including neonicotinoids (NEOs), organophosphate esters (OPEs), and synthetic phenolic antioxidants (SPAs) at environment-relevant doses (100 nM and 1 µM), using three commonly employed in vitro neurotoxicity models: human neural stem cells (NSCs), as well as the SK-N-SH and PC12 cell lines. Our results showed that NSCs were more sensitive than SK-N-SH and PC12 cell lines. Among all the chemicals tested, the two NEOs imidaclothiz (IMZ) and cycloxaprid (CYC), as well as the OPE tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), generated the most noticeable perturbation by impairing NSC maintenance and neuronal differentiation, as well as promoting the epithelial-mesenchymal transition process, likely via activating NF-κB signaling. Our data indicate that novel NEOs and OPEs, particularly IMZ, CYC, and TDCIPP, may not be safe alternatives as they can affect NSC maintenance and differentiation, potentially leading to neural tube defects and neuronal differentiation dysplasia in fetuses.

Alterations in degree centrality and functional connectivity in tension-type headache: a resting-state fMRI study.

Previous studies have provided evidence of structural and functional changes in the brains of patients with tension-type headache (TTH). However, investigations of functional connectivity alterations in TTH have been inconclusive. The present study aimed to investigate abnormal intrinsic functional connectivity patterns in patients with TTH through the voxel-wise degree centrality (DC) method as well as functional connectivity (FC) analysis. A total of 33 patients with TTH and 30 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning and were enrolled in the final study. The voxel-wise DC method was performed to quantify abnormalities in the local functional connectivity hubs. Nodes with abnormal DC were used as seeds for further FC analysis to evaluate alterations in functional connectivity patterns. In addition, correlational analyses were performed between abnormal DC and FC values and clinical features. Compared with HCs, patients with TTH had higher DC values in the left middle temporal gyrus (MTG.L) and lower DC values in the left anterior cingulate and paracingulate gyri (ACG.L) (GRF, voxel-wise p < 0.05, cluster-wise p < 0.05, two-tailed). Seed-based FC analyses revealed that patients with TTH showed greater connections between ACG.L and the right cerebellum lobule IX (CR-IX.R), and smaller connections between ACG.L and ACG.L. The MTG.L showed increased FC with the ACG.L, and decreased FC with the right caudate nucleus (CAU.R) and left precuneus (PCUN.L) (GRF, voxel-wise p < 0.05, cluster-wise p < 0.05, two-tailed). Additionally, the DC value of the MTG.L was negatively correlated with the DASS-depression score (p = 0.046, r=-0.350). This preliminary study provides important insights into the pathophysiological mechanisms of TTH.

Unraveling the ecological mechanisms of Aluminum on microbial community succession in epiphytic biofilms on Vallisneria natans leaves: Novel insights from microbial interactions.

The extensive use of aluminum (Al) poses an escalating ecological risk to aquatic ecosystems. The epiphytic biofilm on submerged plant leaves plays a crucial role in the regulation nutrient cycling and energy flow within aquatic environments. Here, we conducted a mesocosm experiment aimed at elucidating the impact of different Al concentrations (0, 0.6, 1.2, 2.0 mg/L) on microbial communities in epiphytic biofilms on Vallisneria natans. At 1.2 mg/L, the highest biofilms thickness (101.94 µm) was observed. Al treatment at 2.0 mg/L significantly reduced bacterial diversity, while micro-eukaryotic diversity increased. Pseudomonadota and Bacteroidota decreased, whereas Cyanobacteriota increased at 1.2 mg/L and 2.0 mg/L. At 1.2 and 2.0 mg/L. Furthermore, Al at concentrations of 1.2 and 2.0 mg/L enhanced the bacterial network complexity, while micro-eukaryotic networks showed reduced complexity. An increase in positive correlations among microbial co-occurrence patterns from 49.51% (CK) to 57.05% (2.0 mg/L) was indicative of augmented microbial cooperation under Al stress. The shift in keystone taxa with increasing Al concentration pointed to alterations in the functional dynamics of microbial communities. Additionally, Al treatments induced antioxidant responses in V. natans, elevating leaf reactive oxygen species (ROS) content. This study highlights the critical need to control appropriate concentration Al concentrations to preserve microbial diversity, sustain ecological functions, and enhance lake remediation in aquatic ecosystems.

Assessment of dynamic corneal response parameters in Chinese patients of different ages with myopia and orthokeratology lenses using the Corvis ST.

OBJECTIVE: To investigate the effects of orthokeratology lenses (OK lenses) on corneal biomechanics in subjects of different ages. METHODS: Fifty subjects with mild to moderate myopia were categorized into three groups (Group I-III) based on their age. Corvis ST was used to collect dynamic corneal response parameters (DCRs) at different follow-up time points. Repeated measures analysis of variance combined with simple effect analysis was used to analyze the changes in DCRs in different groups during the follow-up period. Multiple linear regression analysis was used to analyze the correlations between axial length growth (ALG) at 6 months (ALG-6M) or 12 months (ALG-12M) and sex, baseline spherical equivalent refraction (SER), and DCRs. RESULTS: The DCRs changed in all three groups after wearing OK lenses. Most DCRs showed significant differences between baseline and 6 months after wearing OK lenses, while the differences between DCRs at 6 months and 12 months were not statistically significant. No significant differences in DCRs were observed among the three groups at the same follow-up time point. Additionally, at 6 months post-OK lens wear, ALG-6M was significantly correlated with velocity of the corneal apex at the first applanation (A1V-6M) (P = 0.002), Corvis biomechanical index (CBI-6M) (P = 0.004), the maximum amount of corneal movement (DAM-6M) (P = 0.010), deformation amplitude ratio of 2 mm (DAR2-6M) (P = 0.010), and stress-strain index (SSI-6M) (P = 0.038) in Group I. Furthermore, ALG-12M showed significant correlations with SSI-6M (P = 0.031), peak distance at the DAM (PD)-6M (P = 0.037), baseline Ambrósio Relational Thickness to the horizontal profile (P = 0.013) in Group I. CONCLUSIONS: The majority of DCRs displayed significant changes within the initial 6 months of OK lens wear. Minimal variation in DCRs was observed across different age groups at the same follow-up time point. Certain DCR parameters exhibited correlations with ALG, suggesting their potential in predicting ALG in myopic children undergoing OK lenses correction.

Interactions between tDCS treatment and COMT Val158Met in poststroke cognitive impairment.

OBJECTIVE: This study aimed to explore the effect of catechol-O-methyltransferase (COMT) Val158Met and brain-derived neurotrophic factor (BDNF) Val66Met to post-stroke cognitive impairment (PSCI) and the interaction with transcranial direct current stimulation (tDCS). METHODS: Seventy-six patients with PSCI were randomly assigned to Group (1) (n = 38) to receive anodal tDCS of left dorsolateral prefrontal cortex or Group (2) (n = 38) to receive sham stimulation. The intensity of the tDCS was 2 mA, and the stimulations were applied over the left DLPFC for 10 sessions. The Montreal Cognitive Assessment (MoCA) and backward digit span test (BDST) were assessed before, immediately after, and one month after stimulation. RESULTS: After stimulation, patients in the tDCS group showed better improvement in both MoCA and BDST than those in the sham group. The results of GLMs also supported the main effects of tDCS on general cognitive function and working memory. Then we found that COMT genotype may have a main effect on the improvement of MoCA and BDST, and there may be an interaction between COMT genotype and tDCS in enhancing BDST. In contrast, BDNF genotype showed no significant main or interaction effects on any scales. CONCLUSIONS: These findings demonstrate that tDCS can improve cognition after stroke. Gene polymorphisms of COMT can affect the efficacy of tDCS on PSCI, but BDNF may not. SIGNIFICANCE: This study found that COMT Val158Met has an interaction on the efficacy of prefrontal tDCS in cognitive function, which provides reference for future tDCS research and clinical application.

- Invited Review - Understanding the functionality of the rumen microbiota: searching for better opportunities for rumen microbial manipulation.

Rumen microbiota play a central role in the digestive process of ruminants. Their remarkable ability to break down complex plant fibers and proteins, converting them into essential organic compounds that provide animals with energy and nutrition. Research on rumen microbiota not only contributes to improving animal production performance and enhancing feed utilization efficiency but also holds the potential to reduce methane emissions and environmental impact. Nevertheless, studies on rumen microbiota face numerous challenges, including complexity, difficulties in cultivation, and obstacles in functional analysis. This review provides an overview of microbial species involved in the degradation of macromolecules, the fermentation processes, and methane production in the rumen, all based on cultivation methods. Additionally, the review introduces the applications, advantages, and limitations of emerging omics technologies such as metagenomics, metatranscriptomics, metaproteomics, and metabolomics, in investigating the functionality of rumen microbiota. Finally, the article offers a forward-looking perspective on the new horizons and technologies in the field of rumen microbiota functional research. These emerging technologies, with continuous refinement and mutual complementation, have deepened our understanding of rumen microbiota functionality, thereby enabling effective manipulation of the rumen microbial community.

Understanding the effects of per- and polyfluoroalkyl substances on early skin development: Role of ciliogenesis inhibition and altered microtubule dynamics.

Per- and polyfluoroalkyl substances (PFAS) are a class of highly stable chemicals, widely used in everyday products, and widespread in the environment, even in pregnant women. While epidemiological studies have linked prenatal exposure to PFAS with atopic dermatitis in children, little is known about their toxic effects on skin development, especially during the embryonic stage. In this study, we utilized human embryonic stem cells to generate non-neural ectoderm (NNE) cells and exposed them to six PFAS (perfluorooctanoic acid (PFOA), undecafluorohexanoic acid (PFHxA), heptafluorobutyric acid (PFBA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorobutyric acid (PFBS)) during the differentiation process to assess their toxicity to early skin development. Our results showed that PFOS altered the spindle-like morphology of NNE cells to a pebble-like morphology, and disrupted several NNE markers, including KRT16, SMYD1, and WISP1. The six PFAS had a high potential to cause hypohidrotic ectodermal dysplasia (HED) by disrupting the expression levels of HED-relevant genes. Transcriptomic analysis revealed that PFOS treatment produced the highest number (1156) of differentially expressed genes (DEGs) among the six PFAS, including the keratinocyte-related genes KRT6A, KRT17, KRT18, KRT24, KRT40, and KRT81. Additionally, we found that PFOS treatment disturbed several signaling pathways that are involved in regulating skin cell fate decisions and differentiation, including TGF-ß, NOTCH, Hedgehog, and Hippo signaling pathways. Interestingly, we discovered that PFOS inhibited, by partially interfering with the expression of cytoskeleton-related genes, the ciliogenesis of NNE cells, which is crucial for the intercellular transduction of the above-mentioned signaling pathways. Overall, our study suggests that PFAS can inhibit ciliogenesis and hamper the transduction of important signaling pathways, leading potential congenital skin diseases. It sheds light on the underlying mechanisms of early embryonic skin developmental toxicity and provides an explanation for the epidemiological data on PFAS. ENVIRONMENTAL IMPLICATION: We employed a model based on human embryonic stem cells to demonstrate that PFOS has the potential to elevate the risk of hypohidrotic ectodermal dysplasia. This is achieved by targeting cilia, inhibiting ciliogenesis, and subsequently disrupting crucial signaling pathways like TGF-ß, NOTCH, Hedgehog, and Hippo, during the early phases of embryonic skin development. Our study highlights the dangers and potential impacts of six PFAS pollutants on human skin development. Additionally, we emphasize the importance of closely considering PFHxA, PFBA, PFHxS, and PFBS, as they have shown the capacity to modify gene expression levels, albeit to a lesser degree.

Revealing the response characteristics of periphyton biomass and community structure to sulfamethoxazole exposure in aquaculture water: The perspective of microbial network relationships.

The widespread application of sulfonamide antibiotics in aquaculture has raised concerns about their adverse environmental impacts. Periphyton plays a crucial role in the aquatic ecosystem. In this study, we examined sulfamethoxazole (SMX) effects on the community structure and interactions of periphyton in simulated aquaculture water. Our findings indicated that the total biomass of periphyton decreased, while the biomass of periphytic algae and the secretion of extracellular polymeric substances (EPS) increased at 0.7 × 10-3 mg/L. Under higher SMX concentrations (5 mg/L and 10 mg/L), periphyton growth was severely inhibited, the microbial community structure of periphyton were sharply altered, characterized by the cyanobacteria growth suppression and decrease in the diversity index of community. Furthermore, elevated SMX concentrations (5 mg/L and 10 mg/L) increased the ratio of negative relationships from 45.4% to 49.4%, which suggested that high SMX concentrations promoted potential competition among microbes and disrupted the microbial food webs in periphyton. The absolute abundance of sul1 and sul2 genes in T2 and T3 groups were 2-3 orders of magnitude higher than those in control group after 30 days of SMX exposure, which elevated the risk of resistance gene enrichment and dissemination in the natural environment. The study contributes to our understanding of the detrimental effects of antibiotic pollution, which can induce changes in the structure and interaction relationship of microbial communities in aquaculture water.

Typical neonicotinoids and organophosphate esters, but not their metabolites, adversely impact early human development by activating BMP4 signaling.

Recent studies have highlighted the presence of potentially harmful chemicals, such as neonicotinoids (NEOs) and organophosphate esters (OPEs), in everyday items. Despite their potential threats to human health, these dangers are often overlooked. In a previous study, we discovered that NEOs and OPEs can negatively impact development, but liver metabolism can help mitigate their harmful effects. In our current research, our objective was to investigate the toxicity mechanisms associated with NEOs, OPEs, and their liver metabolites using a human embryonic stem cell-based differentiation model that mimics early embryonic development. Our transcriptomics data revealed that NEOs and OPEs significantly influenced the expression of hundreds of genes, disrupted around 100 biological processes, and affected two signaling pathways. Notably, the BMP4 signaling pathway emerged as a key player in the disruption caused by exposure to these pollutants. Both NEOs and OPEs activated BMP4 signaling, potentially impacting early embryonic development. Interestingly, we observed that treatment with a human liver S9 fraction, which mimics liver metabolism, effectively reduced the toxic effects of these pollutants. Most importantly, it reversed the adverse effects dependent on the BMP4 pathway. These findings suggest that normal liver function plays a crucial role in detoxifying environmental pollutants and provides valuable experimental insights for addressing this issue.

Robust All-Solid-State Lithium Metal Batteries Enabled by a Composite Lithium Anode with Improved Bulk Li Diffusion Kinetics Properties.

All-solid-state batteries (ASSBs) with a Li metal anode are expected to be one of the most promising energy storage systems to achieve high energy density. However, the interfacial instability between the Li metal anode and solid-state electrolyte (SSE) limits the rate capability and cycling stability of ASSBs. The main issue is the formation of voids at the Li/SSE interface during Li stripping due to the slow diffusion of Li within the bulk Li metal, then increasing internal cell resistance and inducing the formation of lithium dendrites. To address these issues, a composite Li anode (LAO) composed by Li-Ag alloy and Li2O is constructed by mixing the stoichiometric metal Li and Ag2O directly. LAO anode is capable of improving bulk Li diffusion kinetics and inhibiting the formation of interfacial voids effectively, achieving a high critical current density over 1.5 mA cm-2 and long stable cycling over 1000 h at 1 mA cm-2. The ASSBs, employing LAO as the anode, Li6PS5Cl as the SSE, and LiCoO2 as the cathode, exhibit superior rate capability and stable cycling over 4000 cycles at 5 C. Moreover, ASSBs can operate stably with a high LiCoO2 loading of 17.8 mg cm-2 for more than 100 cycles at 0.2 C.