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Abstract Efficiently mixed conduction between ionic and electronic charges stands to revolutionize the studies in organic electrochemical transistors (OECTs). However, inefficient ion transport due to the long-range injection and migration process in the bulk film presents challenges for enhancing the steady and transient performance of OECTs. In this work, we proposed a lateral intercalation-assisted ion transport strategy to assist volumetric ion charging, by introducing a striped microstructure in the conductive channel. By precisely adjusting the ratio of lateral area (RoL), the electrical performance, indicated by the maximum transconductance versus response time (G m,max/τ), increases progressively by over 600%. We further unveiled the mechanism for the enhanced doping uniformity and increased volume capacitance at the lateral area. Based on the universality investigation, we uncovered the effects of molecular stacking on ionic lateral intercalation transport, contributing to the high-performance OECTs and the bio-applications in the recording of dynamic electrocardiography (ECG) signals with distinct features.

Abstract. Background:. Gastric cancer (GC), a malignant tumor with poor prognosis, is one of the leading causes of cancer-related deaths worldwide; consequently, identifying novel therapeutic targets is crucial for its corresponding treatment. NUF2, a component of the NDC80 kinetochore complex, promotes cancer progression in multiple malignancies. Therefore, this study aimed to explore the potential of NUF2 as a therapeutic target to inhibit GC progression. Methods:. Clinical samples were obtained from patients who underwent radical resection of GC at Lanzhou University Second Hospital from 2016 to 2021. Cell count assays, colony formation assays, and cell-derived xenotransplantation (CDX) models were used to determine the effects of NUF2 on GC progression. Flow cytometry was used to detect the effect of NUF2 or quercetin on cell cycle progression and apoptosis. A live-cell time-lapse imaging assay was performed to determine the effect of NUF2 on the regulation of mitotic progression. Transcriptomics was used to investigate the NUF2-associated molecular mechanisms. Virtual docking and microscale thermophoresis were used to identify NUF2 inhibitors. Finally, CDX, organoid, and patient-derived xenograft (PDX) models were used to examine the efficacy of the NUF2 inhibitor in GC. Results:. NUF2 expression was significantly increased in GC and was negatively correlated with prognosis. The deletion of NUF2 suppressed GC progression both in vivo and in vitro. NUF2 significantly regulated the mitogen-activated protein kinase (MAPK) pathway, promoted G2/M phase transition, and inhibited apoptosis in GC cells. Additionally, quercetin was identified as a selective NUF2 inhibitor with low toxicity that significantly suppressed tumor growth in GC cells, organoids, CDX, and PDX models. Conclusions:. Collectively, NUF2-mediated G2/M phase transition and apoptosis inhibition promoted GC progression; additionally, NUF2 inhibitors exhibited potent anti-GC activity. This study provides a new strategy for targeting NUF2 to suppress GC progression in clinical settings.

Background: Pesticides may impact children’s neurodevelopment. As children’s metabolic function and neural plasticity change throughout their growth and development, the effects of pesticide exposure may also vary. Objectives: We aimed to identify the trajectories of combined pesticide exposure during childhood, and to examine the associations of the exposure trajectories with children’s neurobehavior at the age of 10. Methods: We involved repeated measurements of three pesticide metabolites [Pentachlorophenol (PCP), 3,5,6-Trichloro-2-pyridinol (TCPy), and Carbofuran phenol (CFP)], in urine samples collected from children in a cohort study at ages 1, 2, 3, 6, 7, 8, 9, and 10 years. The group-based multi-trajectory model (GBMT) and latent class analysis (LCA) were separately utilized to describe the distinct trajectories and patterns of pesticide mixture exposure during childhood. Meanwhile, the Strengths and Difficulties Questionnaire (SDQ) and attention deficit hyperactivity disorder (ADHD) Criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) list were applied to assess behavioral disorders in children. The associations between exposure trajectories and behavioral problem scores were then examined. Results: The GBMT model delineated three distinct trajectories of combined pesticide exposure among children: consistently low, higher levels in early childhood transitioning to lower levels during pre-school age, and lower levels in early childhood followed by higher levels in the middle childhood. The LCA model identified three similar longitudinal exposure patterns. Further, the children in the second trajectory group identified by GBMT, characterized by higher early childhood exposure levels, exhibited significantly elevated hyperactivity/inattention scores of the SDQ compared to the other two groups (β = 0.46, 95 %CI: 0.11, 0.81; β = 0.44, 95 %CI: 0.02, 0.86). Conclusions: Our study revealed that exposure to pesticides during early childhood (especially before the age of two), rather than other age periods, was linked to hyperactivity/inattention problems in children aged 10 years. We also provided a novel perspective on characterizing the fluctuation in repeated measurements of multiple environmental chemicals and identifying the potential critical windows.

Background: Neonicotinoid insecticides (NNIs) were reported to be endocrine disruptors and cause adverse health effects in human. However, epidemiological evidence about the effect of prenatal NNIs exposure on birth outcome and hormones remains limited. Objectives: This study aimed to explore the effects of prenatal NNIs exposure on neonatal birth size and endocrine hormones, and assess the potential mediating role of hormones. Methods: The study included 860 mother–child pairs from the Sheyang Mini Birth Cohort Study. 12 parent NNIs (p-NNIs) and 6 metabolites of NNIs (m-NNIs) were measured in maternal urine samples collected on their delivery days, and 5 thyroid hormones and 2 sex hormones were analyzed in cord serum. The concentrations of p-NNIs and its specific metabolite(s) were summed to characterize the role of each class of NNIs. Generalized linear model and weighted quantile sum regression were used to examine the impact of prenatal NNIs exposure on birth size and endocrine hormones, and potential mediating roles of hormones were further explored using mediation analysis. Results: Higher detection frequencies of m-NNIs were observed than those in p-NNIs. A decrease in neonatal head circumference for gestation age z-score was associated with a 10-fold increase in 5-OH-IMI (β = -0.15, 95 %CI: −0.26, −0.03), ∑DIN (β = -0.22, 95 %CI: −0.40, −0.03), ∑IMI (β = -0.20, 95 %CI: −0.35, −0.06) and ∑NNIs (β = -0.23, 95 %CI: −0.42, −0.04). ∑IMI and ∑DIN were the major contributors to the significantly negative mixture effect and no sex-specific effect was observed. Negative associations were observed between ∑DIN and TT3 (β = -0.013, 95 %CI: −0.025, −0.002), ∑IMI and T (β = -0.035, 95 %CI: −0.065, −0.004), respectively. Furthermore, TT3 and T demonstrated 6.7 % and 6.1 % mediating effects on the negative association of prenatal ∑DIN and ∑IMI exposure with head circumference. Conclusions: Our findings suggested the potential endocrine disruptive properties of NNIs and their impacts on head circumference. Endocrine hormones may partly mediate these associations.

Background: Per- and polyfluoroalkyl substances (PFAS) have been suspected as potential environmental obesogens, with several mechanisms being proposed, including the role of metabolomics. However, current epidemiological studies have yielded inconclusive findings. Objectives: We aimed to estimate the associations of prenatal exposure to PFAS with offspring adiposity measures, and to explore the potential metabolic pathways underlying these associations. Methods: A total of 464 mother–child pairs from the Sheyang Mini Birth Cohort Study (SMBCS) were included in this study. Cord serum concentrations of 12 PFAS and urine metabolite profiles at age 10 were obtained from the SMBCS database. Adiposity-related anthropometric measurements and body composition estimates of children aged 10 were used to assess offspring obesity. Multiple linear regression models and quantile g-computation were conducted to estimate the associations of prenatal exposure to individual and multiple PFAS with obesity at 10 years old. Metabolomics analysis was performed to characterize the biological pathways associated with PFAS exposure or obesity, subsequently identifying the overlapping metabolic pathways underlying the PFAS-obesity relationship. Results: Prenatal exposure to several PFAS was significantly associated with elevated obesity-related markers in 10-year-old children. After stratification by sex, the effects were more pronounced in girls. Quantile g-computation results indicated that exposure to higher levels of PFAS mixtures during pregnancy was associated with increased odds of obesity in girls, with PFNA emerging as the predominant driving compound. Untargeted metabolomics results showed that several amino acid metabolic pathways were characterized as the overlapping pathways underlying the above associations. Conclusions: Taken together, our findings suggested the potential obesogenic effects of prenatal exposure to PFAS and offered insight into the possible metabolic mechanisms underlying PFAS-related offspring obesity.

Abstract Due to the complexity of the biomedical domain, the ability to capture semantically meaningful representations of terms in context is a long-standing challenge. Despite important progress in the past years, no evaluation benchmark has been developed to evaluate how well language models represent biomedical concepts according to their corresponding context. Inspired by the Word-in-Context (WiC) benchmark, in which word sense disambiguation is reformulated as a binary classification task, we propose a novel dataset, BioWiC, to evaluate the ability of language models to encode biomedical terms in context. BioWiC comprises 20’156 instances, covering over 7’400 unique biomedical terms, making it the largest WiC dataset in the biomedical domain. We evaluate BioWiC both intrinsically and extrinsically and show that it could be used as a reliable benchmark for evaluating context-dependent embeddings in biomedical corpora. In addition, we conduct several experiments using a variety of discriminative and generative large language models to establish robust baselines that can serve as a foundation for future research.

BackgroundPer- and polyfluoroalkyl substances (PFAS) are a class of persistent organic pollutants that possess potential toxicity to the human body. The production and utilization of diverse emerging PFAS have resulted in widespread human exposure. Therefore, it is imperative to establish a quantitative methodology encompassing a wide range of PFAS for a comprehensive assessment of human exposure to these compounds. ObjectiveTo establish a high-throughput quantitative method for the simultaneous determination of 53 PFAS in human serum based on ultra-high-performance liquid chromatography-Q Exactive high resolution mass spectrometry (UPLC-Q Exactive HRMS). MethodsThe extraction recoveries of hydrophilic-lipophilic balance (HLB) column, weak anionexchange (WAX) column, and 96-well WAX μElution plate were compared to select the SPE column with the highest recovery. The retention time and peak shape of the target compounds were compared between ACQUITY UPLC BEH C18 column and Accucore aQ column, and the more cost-effective column was chosen. The effects of adding different levels of ammonium formate (0, 2, 5 and 10 mmol·L−1) in mobile phase on peak shape and target response were compared to determine the optimal buffer salt concentration. The optimal spray voltage was obtained by comparing −2 kV and −4 kV. The proposed method was validated from the aspects of selectivity, standard curve, limits of detection, precision, accuracy, and matrix effect. The method was applied to 142 umbilical serum samples. ResultsThe best recovery rate (64%-118%) was achieved by using 96-well WAX μElution plate. The optimal separation and peak shape were obtained by utilizing Accucore aQ column with H2O-methanol (containing 5 mmol·L−1 ammonium formate) as the mobile phase. Less in-source collision and better target response were observed when the spray voltage was set to −2 kV. All target analytes had a good linearity, with R2 > 0.99. The limits of detection ranged from 0.01 to 0.50 μg·L−1, and the recovery ranged from 69% to 127% with the precision less than 26%. A total of 31 PFAS were detected in the 142 actual samples, among which 14 PFAS had a detection frequency over 50%. Perfluorooctanoic acid showed the highest median concentration of 4.16 μg·L−1, followed by 6:2 chlorinated polyfluorinated ether sulfonate and perfluorooctane sulfonates (3.50 μg·L−1 and 1.59 μg·L−1, respectively). ConclusionIn this study, we establish a UPLC-Q Excative HRMS method for simutanious determination of 53 PFAS concentrations in serum. This method has the advantages of wide coverage of PFAS, good selectivity, and easy operation, and is suitable for biological detection with a large sample size.

Abstract A major question in developmental and regenerative biology is how organ size and architecture are controlled by progenitor cells. While limb bones exhibit catch-up growth (recovery of a normal growth trajectory after transient developmental perturbation), it is unclear how this emerges from the behaviour of chondroprogenitors, the cells sustaining the cartilage anlagen that are progressively replaced by bone. Here we show that transient sparse cell death in the mouse fetal cartilage is repaired postnatally, via a two-step process. During injury, progression of chondroprogenitors towards more differentiated states is delayed, leading to altered cartilage cytoarchitecture and impaired bone growth. Then, once cell death is over, chondroprogenitor differentiation is accelerated and cartilage structure recovered, including partial rescue of bone growth. At the molecular level, ectopic activation of mTORC1 correlates with, and is necessary for, part of the recovery, revealing a specific candidate to be explored during normal growth and in future therapies.

Abstract Background Liver uptake in [68Ga]Ga-PSMA-11 PET is used as an internal reference in addition to clinical parameters to select patients for [177Lu]Lu-PSMA-617 radioligand therapy (RLT). Due to increased demand, [68Ga]Ga-PSMA-11 was replaced by [18F]F-PSMA-1007, a more lipophilic tracer with different biodistribution and splenic uptake was suggested as a new internal reference. We compared the intra-patient tracer distribution between [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007. Methods Fifty patients who underwent PET examinations in two centers with both [18F]F-PSMA-1007 and [68Ga]Ga-PSMA-11 within one year were included. Mean standardized uptake values (SUVmean) were obtained for liver, spleen, salivary glands, blood pool, and bone. Primary tumor, local recurrence, lymph node, bone or visceral metastasis were also assessed for intra- and inter-individual comparison. Results Liver SUVmean was significantly higher with [18F]F-PSMA-1007 (11.7 ± 3.9) compared to [68Ga]Ga-PSMA-11 (5.4 ± 1.7, p

In order to explore the effect of polydimethylsiloxane (PDMS) membrane pervaporation technology on the concentration of freeze-dried rose hydrolat (Rosa damascene), headspace solid phase microextraction (HS-SPME) and gas chromatography-mass spectrometry (GC-MS) were used to analyze the volatile aroma components of freeze-dried rose hydrolat, and its sensory properties and applicability were evaluated by sensory analysis. The results showed that 54 aroma components were detected in rose hydrolat, and its characteristic aroma components including phenylethyl alcohol, citronellol and geraniol accounted for more than 90% of the total, indicating great utilization value. After two osmotic concentration cycles, the rose aroma became more intense and typical, and the content of benzene ring compounds significantly increased, characterized by total odor activity value (OAV) of rose aroma substances increased by 20.47%. The sensory flavor profile analysis also showed similar results: the proportion of floral aroma intensity (M value) increased from 37% to 51%, which was consistent with the result of partial least squares regression (PLSR) validation analysis. Additionally, it was found that the aroma intensity of freeze-dried rose hydrolat obtained after secondary osmosis was similar to that of rose essence sold in the market, and still higher than that of rose soda water sold in the market after 100-fold dilution, demonstrating its potential as a flavor enhancer in daily chemicals and beverages.

Abstract Volumetric super-resolution microscopy typically encodes the 3D position of single-molecule fluorescence into a 2D image by changing the shape of the point spread function (PSF) as a function of depth. However, the resulting large and complex PSF spatial footprints reduce biological throughput and applicability by requiring lower labeling densities to avoid overlapping fluorescent signals. We quantitatively compare the density dependence of single-molecule light field microscopy (SMLFM) to other 3D PSFs (astigmatism, double helix and tetrapod) showing that SMLFM enables an order-of-magnitude speed improvement compared to the double helix PSF by resolving overlapping emitters through parallax. We demonstrate this optical robustness experimentally with high accuracy ( > 99.2 ± 0.1%, 0.1 locs μm−2) and sensitivity ( > 86.6 ± 0.9%, 0.1 locs μm−2) through whole-cell (scan-free) imaging and tracking of single membrane proteins in live primary B cells. We also exemplify high-density volumetric imaging (0.15 locs μm−2) in dense cytosolic tubulin datasets.

Tympanojugular paragangliomas (TJP) originate from the parasympathetic ganglia in the lateral base of the skull. Although the cellular composition and oncogenic mechanisms of paragangliomas have been evaluated, a comprehensive transcriptomic atlas specific to TJP remains to be established to facilitate further investigations. In this study, single-cell RNA sequencing and whole-exome sequencing were conducted on six surgically excised TJP samples to determine their cellular composition and intratumoral heterogeneity. Fibroblasts were sub-classified into two distinct groups: myofibroblasts and fibroblasts associated with bone remodeling. Additionally, an elaborate regulatory and cell–cell communication network was determined, highlighting the multifaceted role of fibroblasts, which varies depending on expression transitions. The Kit receptor (KIT) signaling pathway mediated interactions between fibroblasts and mast cells, whereas robust connections with endothelial and Schwann cell-like cells were facilitated through the platelet-derived growth factor signaling pathway. These findings establish a foundation for studying the mechanisms underlying protumor angiogenesis and the specific contributions of fibroblasts within the TJP microenvironment. IL6 signaling pathway of fibroblasts interacting with macrophages and endothelial cells may be involved in tumor regrowth. These results enhance our understanding of fibroblast functionality and provide a resource for future therapeutic targeting of TJP.

Abstract Bone and mineral metabolism homeostasis accounts for the maintenance of normal skeletal remodeling. However, with aging and changes in hormone levels, over-activated osteoclasts disrupt homeostasis, induce osteoporosis, and even cause osteoporotic fractures, leading to an enormous economic burden. Despite the rapid development of pharmacological therapy for osteoporosis, safer and more effective treatments remain to be explored. Here, we demonstrate that Mulberroside A (Mul-A), a natural component extracted from mulberry bark and branches, effectively suppresses osteoclastogenesis in vitro and counteracts bone loss caused by ovariectomy (OVX). The mechanism underlying this effect involves the repression of autophagic flux during osteoclastogenesis by Mul-A, which can be attributed to the restrained expression of microphthalmia-related transcription factor (Mitf) and its nuclear translocation. Importantly, Mitf overexpression partially reverses the inhibitory effects of Mul-A on autophagy and osteoclastogenesis. Moreover, applying two autophagy agonizts, rapamycin and Torin 1, attenuates the osteoclastogenic regulatory role of Mul-A. Collectively, our study demonstrates that Mul-A damages osteoclast differentiation and ameliorates osteoporosis caused by estrogen deficiency by modulation of Mitf-associated autophagy, indicating its therapeutic potential against osteoporosis.

In order to explore the effects of different combinations of spice essential oils on the quality and safety of air-dried catfish sausages, sausages were prepared from marinated catfish surimi added with a 1:1 (m/m) blend of clove and star anise (CA), clove and perilla (CP), star anise and perilla (AP) or clove, star anise and perilla essential oil (CAP) at 0.03% or none as a control. Moisture content, water activity (aw), pH, color difference, thiobarbituric acid reactive substance (TBARS) value, biological amine content, N-nitrosamine content, and microbial load were measured. Microbial community structure was analyzed by 16S rDNA high-throughput sequencing. The results showed that the moisture content of the AP group was 27.13%, and the aw value was 0.765. The L* and a* values of the CA group were high, indicating typical characteristics of air-dried sausages. The pH of the four treatment groups was higher than that of the control group, and followed the descending order of CAP > AP > CA > CP. There was no significant difference in the inhibition of fat oxidation among different essential oil combinations (P > 0.05), but the TBARS value of air-dried sausages was significantly reduced by all combinations (P < 0.05). The contents of biogenic amine and N-nitrosamine in the AP group were low. The total number of bacteria, and the number of Enterobacteriaceae and Aeromonas were significantly lower in the AP group than in the control group (P < 0.05). High-throughput sequencing results showed low species richness in the AP and CAP groups and low relative abundance of pathogenic bacteria in the AP group. Overall analysis showed that AP was superior to the other groups in improving the quality and safety of air-dried catfish sausages.

Coastal mangrove forests provide numerous ecosystem services, which can be disrupted by natural disturbances, mainly hurricanes. Canopy height (CH) is a key parameter for estimating carbon storage. Airborne Light Detection and Ranging (LiDAR) is widely viewed as the most accurate method for estimating CH but data are often limited in spatial coverage and are not readily available for rapid impact assessment after hurricane events. Hence, we evaluated the use of systematically acquired space-based Synthetic Aperture Radar (SAR) and optical observations with airborne LiDAR to predict CH across expansive mangrove areas in South Florida that were severely impacted by Category 3 Hurricane Irma in 2017. We used pre- and post-Irma LiDAR-derived canopy height models (CHMs) to train Random Forest regression models that used features of Sentinel-1 SAR time series, Landsat-8 optical, and classified mangrove maps. We evaluated (1) spatial transfer learning to predict regional CH for both time periods and (2) temporal transfer learning coupled with species-specific error correction models to predict post-Irma CH using models trained by pre-Irma data. Model performance of SAR and optical data differed with time period and across height classes. For spatial transfer, SAR data models achieved higher accuracy than optical models for post-Irma, while the opposite was the case for the pre-Irma period. For temporal transfer, SAR models were more accurate for tall trees (>10 m) but optical models were more accurate for short trees. By fusing data of both sensors, spatial and temporal transfer learning achieved the root mean square errors (RMSEs) of 1.9 m and 1.7 m, respectively, for absolute CH. Predicted CH losses were comparable with LiDAR-derived reference values across height and species classes. Spatial and temporal transfer learning techniques applied to readily available spaceborne satellite data can enable conservation managers to assess the impacts of disturbances on regional coastal ecosystems efficiently and within a practical timeframe after a disturbance event.