Single-cell RNA-Seq reveals the heterogeneity of fibroblasts within the tympanojugular paraganglioma microenvironment.

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.

Cyclic methylsiloxanes in wastewater treatment plants: Occurrence, emissions, environmental distributions, and occupational exposure.

Cyclic methylsiloxanes (CMSs), widely found in wastewater treatment plants (WWTPs), are potentially hazardous to the environment and human health. In this study, the environmental behavior and human exposure risks of three CMSs (D4-D6) were evaluated in WWTPs located in Beijing and Kunming, Yunnan province. D5 had the highest concentrations in air, water, and sludge, with seasonal variation that consisted of a high concentration in summer and low concentration in winter. The CMS concentrations in air were 3-4-fold higher in the A2/O (Anaerobic-Anoxic-Oxic) treatment units than in the other units. CMS emissions to air, soil, and water from the Beijing WWTP were in the ranges of 3.4 × 104-5.0 × 104 kg·a-1, 4.5 × 102-7.5 × 102 kg·a-1, and 2.5 × 102-2.9 × 102 kg·a-1, constituting 98 %, 1.3 %, and 0.7 % of the total emissions, respectively. Total daily inhalation exposure doses of CMSs (ADDinh,CMSs) associated with four different jobs in WWTPs showed that wastewater treatment technicians had the highest ADDinh,CMSs (51 µg/kg/day), indicating that these people had the highest occupational exposure risk in WWTPs. Therefore, this study identified that atmospheric emission was the main environmental fate of CMSs in WWTPs, and provide a basis for the improvement of WWTP process and risk management decisions. ENVIRONMENTAL IMPLICATION: Assessing the environmental fate and occupational exposure risk of cyclic methylsiloxanes (CMSs) found in wastewater treatment plants (WWTPs) is crucial. This is the first study to identify that atmospheric emission was the main environmental fate of CMSs in WWTPs, especially D5; the inhalation exposure doses of CMSs were all significantly higher in the occupational population working in WWTPs. The results described in our study will help enhance the understanding of current knowledge base of environmental fate and exposure risk of CMSs in WWTPs, and provide a basis for the improvement of WWTP process and risk management decisions.

Targeting NUF2 suppresses gastric cancer progression through G2/M phase arrest and apoptosis induction.

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 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.

[Endothelial cells and fibroblasts mediate the microenvironmental regulatory network of carotid body paraganglioma].

Objective:To explore the gene expression characteristics of endothelial cells and fibroblasts in the microenvironment of SDHD-mutated carotid body tumors（SDHD-CBT）, to fine the functional enrichment of each subcluster, and to further explore the network of cell-cell interactions in the microenvironment of SDHD-CBT. Methods:The bioinformatics analysis was used to download and reanalyze the single-nuclear RNA sequencing data of SDHD-CBT, SDHB mutated thoracic and abdominal paraganglioma（SDHB-ATPGL）, SDHB-CBT, and normal adrenal medulla（NAM）, to clarify the information of cell populations of the samples. We focused on exploring the gene expression profiles of endothelial cells and fibroblasts subclusters, and performed functional enrichment analysis based on Gene Ontology（GO） resources. CellChat was used to compare the cell-cell interactions networks of different clinical samples and predict significant signaling pathways in SDHD-CBT. Results:A total of 7 cell populations were profiled. The main subtypes of endothelial cells in SDHD-CBT are arterial and venous endothelial cells, and the main subtypes of fibroblasts are myofibroblasts and pericytes. Compared to NAM, SDHB-CBT and SDHB-ATPGL, cell communication involving endothelial cells and fibroblasts in SDHD-CBT is more abundant, with significant enrichment in pathways such as FGF, PTN, WNT, PROS, PERIOSTIN, and TGFb. Conclusion:Endothelial cells and fibroblasts in SDHD-CBT are heterogeneous and involved in important cellular interactionprocesses, in which the discovery of FGF，PTN，WNT，PROS，PERIOSTIN and TGFb signals may play an important role in the regulation of microenvironment of SDHD-CBT.

[Advance in HIF expression and immune microenvironment in pseudohypoxic HNPGL].

This article systematically reviewed the pathological features, molecular mechanisms, and tumor microenvironment of head and neck paraganglioma（HNPGL）, with a focus on pseudohypoxic HNPGL. It was demonstrated that pseudohypoxic HNPGL mainly involves multiple gene mutations, such as SDHx and VHL/EPAS1, which affect the stability and activity of HIF protein and exacerbate the development of the tumor. Meanwhile, the paper also analyzed the expression patterns of HIF-1α and HIF-2α in HNPGL, and found that differences in HIF activation may have an impact on the therapeutic response of specific subtypes. In addition, the paper explored the tumor microenvironment of HNPGL and found that immune cells such as macrophages, CD4⁺T cells, and CD8⁺T cells play an important role in the tumor, and the heterogeneity of the immune microenvironment also affects the choice of therapeutic approaches and responsiveness. Through comprehensive analysis, these findings not only contribute to a deeper understanding of the pathogenesis and developmental process of HNPGL, but also provide clues for future personalized treatments for specific subtypes.

Blocking Metallothionein-2 Expression by Copper-Doped Carbon Dots Induces Cellular Antioxidant System Collapse for Antitumor Therapy.

The insufficient antioxidant reserves in tumor cells play a critical role in reactive oxygen species (ROS)-mediated therapeutics. Metallothionein-2 (MT-2), an intracellular cysteine-rich protein renowned for its potent antioxidant properties, is intricately involved in tumor development and correlates with a poor prognosis. Consequently, MT-2 emerges as a promising target for tumor therapy. Herein, we present the development of copper-doped carbon dots (Cu-CDs) to target MT-2 to compromise the delicate antioxidant reserves in tumor cells. These Cu-CDs with high tumor accumulation and prolonged body retention can effectively suppress tumor growth by inducing oxidative stress. Transcriptome sequencing unveils a significant decrease in MT-2 expression within the in vivo tumor samples. Further mechanical investigations demonstrate that the antitumor effect of Cu-CDs is intricately linked to apolipoprotein E (ApoE)-mediated downregulation of MT-2 expression and the collapse of the antioxidant system. The robust antitumor efficacy of Cu-CDs provides invaluable insights into developing MT-2-targeted nanomedicine for cancer therapies.

Associations of prenatal and concurrent exposure to phenols mixture with anthropometric measures and blood pressure during childhood: A time-varying mixture approach.

BACKGROUND: Environmental phenols were recognized as endocrine disrupting chemicals (EDCs). However, their impact on childhood anthropometric measures and blood pressure (BP) is still inconclusive. Limited studies have simultaneously considered prenatal and childhood exposures in analyzing mixtures of phenols. OBJECTIVE: We investigated the relationships between combined prenatal and childhood exposures (two periodic exposures) to phenol mixtures and anthropometric measure and BP, to further identify the vulnerable periods of phenol exposure and to explore the important individual contribution of each phenol. METHODS: We analyzed 434 mother-child dyads from the Sheyang Mini Birth Cohort Study (SMBCS). The urinary concentrations of 11 phenolic compounds were measured using gas chromatography tandem mass spectrometry. Generalized linear regression models (GLMs) and hierarchical Bayesian Kernel Machine Regression (hBKMR) were used to examine the effects of individual phenolic compounds at each period and of two periodic exposures. RESULTS: In the single-chemical analysis, prenatal or childhood exposure to specific phenols, especially Benzopheone-3 (BP3), 4-tert-Octylphenol (4-tOP), and Benzyl paraben (BePB) were associated with BMI z-scores (BAZ), Waist-to-height ratio (WHtR), and BP. In the hBKMR models, two periodic exposures to phenol mixtures had a U-shaped association with WHtR, primarily driven by childhood BePB exposure. Moreover, among the phenol mixtures analysis, childhood 4-tOP exposure was identified as the primary contributor to the positive association with diastolic BP. Concurrent exposure to phenol mixtures resulted in greater susceptibility. CONCLUSIONS: We found that prenatal and childhood exposure to phenol mixtures might influence childhood obesity and elevate blood pressure levels. Concurrent exposure to 4-tOP may be the primary driver of the positive associations with BP.

Immobile polyanionic backbone enables a 900-µm-thick electrode for compact energy storage with unprecedented areal capacitance.

Thickening of electrodes is crucial for maximizing the proportion of active components and thus improving the energy density of practical energy storage cells. Nevertheless, trade-offs between electrode thickness and electrochemical performance persist because of the considerably increased ion transport resistance of thick electrodes. Herein, we propose accelerating ion transport through thick and dense electrodes by establishing an immobile polyanionic backbone within the electrode pores; and as a proof of concept, gel polyacrylic electrolytes as such a backbone are in situ synthesized for supercapacitors. During charge and discharge, protons rapidly hop among RCOO- sites for oriented transport, fundamentally reducing the effects of electrode tortuosity and polarization resulting from concentration gradients. Consequently, nearly constant ion transport resistance per unit thickness is achieved, even in the case of a 900-µm-thick dense electrode, leading to unprecedented areal capacitances of 14.85 F cm-2 at 1 mA cm-2 and 4.26 F cm-2 at 100 mA cm-2. This study provides an efficient method for accelerating ion transport through thick and dense electrodes, indicating a significant solution for achieving high energy density in energy storage devices, including but not limited to supercapacitors.

Novel L-(CaP-ZnP)/SA Nanocomposite Hydrogel with Dual Anti-Inflammatory and Mineralization Effects for Efficient Vital Pulp Therapy.

Background: Vital pulp therapy (VPT) is considered a conservative treatment for preserving pulp viability in caries and trauma-induced pulpitis. However, Mineral trioxide aggregate (MTA) as the most frequently used repair material, exhibits limited efficacy under inflammatory conditions. This study introduces an innovative nanocomposite hydrogel, tailored to simultaneously target anti-inflammation and dentin mineralization, aiming to efficiently preserve vital pulp tissue. Methods: The L-(CaP-ZnP)/SA nanocomposite hydrogel was designed by combining L-Arginine modified calcium phosphate/zinc phosphate nanoparticles (L-(CaP-ZnP) NPs) with sodium alginate (SA), and was characterized with TEM, SEM, FTIR, EDX, ICP-AES, and Zeta potential. In vitro, we evaluated the cytotoxicity and anti-inflammatory properties. Human dental pulp stem cells (hDPSCs) were cultured with lipopolysaccharide (LPS) to induce an inflammatory response, and the cell odontogenic differentiation was measured and possible signaling pathways were explored by alkaline phosphatase (ALP)/alizarin red S (ARS) staining, qRT-PCR, immunofluorescence staining, and Western blotting, respectively. In vivo, a pulpitis model was utilized to explore the potential of the L-(CaP-ZnP)/SA nanocomposite hydrogel in controlling pulp inflammation and enhancing dentin mineralization by Hematoxylin and eosin (HE) staining and immunohistochemistry staining. Results: In vitro experiments revealed that the nanocomposite hydrogel was synthesized successfully and presented desirable biocompatibility. Under inflammatory conditions, compared to MTA, the L-(CaP-ZnP)/SA nanocomposite hydrogel demonstrated superior anti-inflammatory and pro-odontogenesis effects. Furthermore, the nanocomposite hydrogel significantly augmented p38 phosphorylation, implicating the involvement of the p38 signaling pathway in pulp repair. Significantly, in a rat pulpitis model, the L-(CaP-ZnP)/SA nanocomposite hydrogel downregulated inflammatory markers while upregulating mineralization-related markers, thereby stimulating the formation of robust reparative dentin. Conclusion: The L-(CaP-ZnP)/SA nanocomposite hydrogel with good biocompatibility efficiently promoted inflammation resolution and enhanced dentin mineralization by activating p38 signal pathway, as a pulp-capping material, offering a promising and advanced solution for treatment of pulpitis.

Discriminative feature analysis of dairy products based on machine learning algorithms and Raman spectroscopy.

Discriminant analysis of similar food samples is an important aspect of achieving food quality control. The effective combination of Raman spectroscopy and machine learning algorithms has become an extremely attractive approach to develop intelligent discrimination techniques. Feature spectral analysis can help researchers gain a deeper understanding of the data patterns in food quality discrimination. Herein, this work takes the discrimination of three brands of dairy products as an example to investigate the Raman spectral feature based on the support vector machines (SVM), extreme learning machines (ELM) and convolutional neural network (CNN) algorithms. The results show that there are certain differences in the optimal spectral feature interval corresponding to different machine learning algorithms. Selecting the appropriate spectral feature interval can maintain high recognition accuracy and improve the computational efficiency of the algorithm. For example, the SVM algorithm has a recognition accuracy of 100% in the 890-980 cm-1, 1410-1500 cm-1 fusion spectral range, which takes about 200 s. The ELM algorithm also has a recognition accuracy of 100% in the 890-980 cm-1, 1410-1500 cm-1 fusion spectral range, which takes less than 0.3 s. The CNN algorithm has a recognition accuracy of 100% in the 890-980 cm-1, 1050-1180 cm-1, 1410-1500 cm-1 fusion spectral range, which takes about 80 s. In addition, by analyzing the distribution of spectral feature intervals based on Euclidean distance, the distribution of experimental samples based on feature spectra is visually displayed. Through the spectral feature analysis process of similar samples, a set of analysis strategies is provided to deeply reveal the data foundation of classification algorithms, which can provide reference for the analysis of relevant discriminative research patterns.

Online Health Search Via Multidimensional Information Quality Assessment Based on Deep Language Models: Algorithm Development and Validation.

BACKGROUND: Widespread misinformation in web resources can lead to serious implications for individuals seeking health advice. Despite that, information retrieval models are often focused only on the query-document relevance dimension to rank results. OBJECTIVE: We investigate a multidimensional information quality retrieval model based on deep learning to enhance the effectiveness of online health care information search results. METHODS: In this study, we simulated online health information search scenarios with a topic set of 32 different health-related inquiries and a corpus containing 1 billion web documents from the April 2019 snapshot of Common Crawl. Using state-of-the-art pretrained language models, we assessed the quality of the retrieved documents according to their usefulness, supportiveness, and credibility dimensions for a given search query on 6030 human-annotated, query-document pairs. We evaluated this approach using transfer learning and more specific domain adaptation techniques. RESULTS: In the transfer learning setting, the usefulness model provided the largest distinction between help- and harm-compatible documents, with a difference of +5.6%, leading to a majority of helpful documents in the top 10 retrieved. The supportiveness model achieved the best harm compatibility (+2.4%), while the combination of usefulness, supportiveness, and credibility models achieved the largest distinction between help- and harm-compatibility on helpful topics (+16.9%). In the domain adaptation setting, the linear combination of different models showed robust performance, with help-harm compatibility above +4.4% for all dimensions and going as high as +6.8%. CONCLUSIONS: These results suggest that integrating automatic ranking models created for specific information quality dimensions can increase the effectiveness of health-related information retrieval. Thus, our approach could be used to enhance searches made by individuals seeking online health information.

Morphology-Controlled Ion Transport in Mixed-Orientation Polymers.

Advancing iontronics with precisely controlled ion transport is fundamentally important to bridge external organic electronics with the biosystem. This long-standing goal, however, is thus far limited by the trade-off between the active ion electromigration and idle diffusion leakage in the (semi)crystalline film. Here, we presented a mixed-orientation strategy by blending a conjugated polymer, allowing for simultaneously high ion electromigration efficiency and low leakage. Our studies revealed that edge-on aggregation with a significant percolative pathway exhibits much higher ion permeability than that of the face-on counterpart but encounters pronounced leakage diffusion. Through carefully engineering the mixed orientations, the polymer composite demonstrated an ideal switchable ion-transport behavior, achieving a remarkably high electromigration efficiency exceeding one quadrillion ions per milliliter per minute and negligible idle leakage. This proof of concept, validated by drug release in a skin-conformable organic electronic ion pump (OEIP), offers a rational approach for the development of multifunctional iontronic devices.

APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

Butylparaben induces glycolipid metabolic disorders in mice via disruption of gut microbiota and FXR signaling.

Butylparaben, a common preservative, is widely used in food, pharmaceuticals and personal care products. Epidemiological studies have revealed the close relationship between butylparaben and diabetes; however the mechanisms of action remain unclear. In this study, we administered butylparaben orally to mice and observed that exposure to butylparaben induced glucose intolerance and hyperlipidemia. RNA sequencing results demonstrated that the enrichment of differentially expressed genes was associated with lipid metabolism, bile acid metabolism, and inflammatory response. Western blot results further validated that butylparaben promoted hepatic lipogenesis, inflammation, gluconeogenesis, and insulin resistance through the inhibition of the farnesoid X receptor (FXR) pathway. The FXR agonists alleviated the butylparaben-induced metabolic disorders. Moreover, 16 S rRNA sequencing showed that butylparaben reduced the abundance of Bacteroidetes, S24-7, Lactobacillus, and Streptococcus, and elevated the Firmicutes/Bacteroidetes ratio. The gut microbiota dysbiosis caused by butylparaben led to decreased bile acids (BAs) production and increased inflammatory response, which further induced hepatic glycolipid metabolic disorders. Our results also demonstrated that probiotics attenuated butylparaben-induced disturbances of the gut microbiota and hepatic metabolism. Taken collectively, the findings reveal that butylparaben induced gut microbiota dysbiosis and decreased BAs production, which further inhibited FXR signaling, ultimately contributing to glycolipid metabolic disorders in the liver.

Source-Specific Air Pollution and Loss of Independence in Older Adults Across the US.

Importance: Air pollution is a recognized risk factor associated with chronic diseases, including respiratory and cardiovascular conditions, which can lead to physical and cognitive impairments in later life. Although these losses of function, individually or in combination, reduce individuals' likelihood of living independently, little is known about the association of air pollution with this critical outcome. Objective: To investigate associations between air pollution and loss of independence in later life. Design, Setting, and Participants: This cohort study was conducted as part of the Environmental Predictors Of Cognitive Health and Aging study and used 1998 to 2016 data from the Health and Retirement Study. Participants included respondents from this nationally representative, population-based cohort who were older than 50 years and had not previously reported a loss of independence. Analyses were performed from August 31 to October 15, 2023. Exposures: Mean 10-year pollutant concentrations (particulate matter less than 2.5 µm in diameter [PM2.5] or ranging from 2.5 µm to 10 µm in diameter [PM10-2.5], nitrogen dioxide [NO2], and ozone [O3]) were estimated at respondent addresses using spatiotemporal models along with PM2.5 levels from 9 emission sources. Main Outcomes and Measures: Loss of independence was defined as newly receiving care for at least 1 activity of daily living or instrumental activity of daily living due to health and memory problems or moving to a nursing home. Associations were estimated with generalized estimating equation regression adjusting for potential confounders. Results: Among 25 314 respondents older than 50 years (mean [SD] baseline age, 61.1 [9.4] years; 11 208 male [44.3%]), 9985 individuals (39.4%) experienced lost independence during a mean (SD) follow-up of 10.2 (5.5) years. Higher exposure levels of mean concentration were associated with increased risks of lost independence for total PM2.5 levels (risk ratio [RR] per 1-IQR of 10-year mean, 1.05; 95% CI, 1.01-1.10), PM2.5 levels from road traffic (RR per 1-IQR of 10-year mean, 1.09; 95% CI, 1.03-1.16) and nonroad traffic (RR per 1-IQR of 10-year mean, 1.13; 95% CI, 1.03-1.24), and NO2 levels (RR per 1-IQR of 10-year mean, 1.05; 95% CI, 1.01-1.08). Compared with other sources, traffic-generated pollutants were most consistently and robustly associated with loss of independence; only road traffic-related PM2.5 levels remained associated with increased risk after adjustment for PM2.5 from other sources (RR per 1-IQR increase in 10-year mean concentration, 1.10; 95% CI, 1.00-1.21). Other pollutant-outcome associations were null, except for O3 levels, which were associated with lower risks of lost independence (RR per 1-IQR increase in 10-year mean concentration, 0.94; 95% CI, 0.92-0.97). Conclusions and Relevance: This study found that long-term exposure to air pollution was associated with the need for help for lost independence in later life, with especially large and consistent increases in risk for pollution generated by traffic-related sources. These findings suggest that controlling air pollution could be associated with diversion or delay of the need for care and prolonged ability to live independently.

A Dataset for Evaluating Contextualized Representation of Biomedical Concepts in Language Models.

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.

Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) influences neurodevelopment. Thyroid homeostasis disruption is thought to be a possible underlying mechanism. However, current epidemiological evidence remains inconclusive. OBJECTIVES: This study aimed to explore the effects of prenatal PFAS exposure on the intelligence quotient (IQ) of school-aged children and assess the potential mediating role of fetal thyroid function. METHODS: The study included 327 7-year-old children from the Sheyang Mini Birth Cohort Study (SMBCS). Cord serum samples were analyzed for 12 PFAS concentrations and 5 thyroid hormone (TH) levels. IQ was assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models (GLM) and Bayesian Kernel Machine Regression (BKMR) were used to evaluate the individual and combined effects of prenatal PFAS exposure on IQ. Additionally, the impact on fetal thyroid function was examined using a GLM, and a mediation analysis was conducted to explore the potential mediating roles of this function. RESULTS: The molar sum concentration of perfluorinated carboxylic acids (ΣPFCA) in cord serum was significantly negatively associated with the performance IQ (PIQ) of 7-year-old children (ß = -6.21, 95 % confidence interval [CI]: -12.21, -0.21), with more pronounced associations observed among girls (ß = -9.57, 95 % CI: -18.33, -0.81) than in boys. Negative, albeit non-significant, cumulative effects were noted when considering PFAS mixture exposure. Prenatal exposure to perfluorooctanoic acid, perfluorononanoic acid, and perfluorooctanesulfonic acid was positively associated with the total thyroxine/triiodothyronine ratio. However, no evidence supported the mediating role of thyroid function in the link between PFAS exposure and IQ. CONCLUSIONS: Increased prenatal exposure to PFASs negatively affected the IQ of school-aged children, whereas fetal thyroid function did not serve as a mediator in this relationship.

Liraglutide Protects Pancreatic Islet From Ischemic Injury by Reducing Oxidative Stress and Activating Akt Signaling During Cold Preservation to Improve Islet Transplantation Outcomes.

BACKGROUND: Islet transplantation is a promising therapy for patients with type 1 diabetes. However, ischemic injury to the donor islets during cold preservation leads to reduced islet quality and compromises transplant outcome. Several studies imply that liraglutide, a glucagon-like peptide-1 receptor agonist, has a positive effect on promoting islet survival, but its impact on islet cold-ischemic injury remains unexplored. Therefore, the aim of this study was to investigate whether liraglutide can improve islet transplantation efficacy by inhibiting cold-ischemic injury and to explore the underlying mechanisms. METHODS: Liraglutide was applied in a mouse pancreas preservation model and a human islets cold-preservation model, and islet viability, function, oxidative stress levels were evaluated. Furthermore, islet transplantation was performed in a syngeneic mouse model and a human-to-nude mouse islet xenotransplantation model. RESULTS: The supplementation of liraglutide in preservation solution improved islet viability, function, and reduced cell apoptosis. Liraglutide inhibited the oxidative stress of cold-preserved pancreas or islets through upregulating the antioxidant enzyme glutathione levels, inhibiting reactive oxygen species accumulation, and maintaining the mitochondrial membrane integrity, which is associated with the activation of Akt signaling. Furthermore, the addition of liraglutide during cold preservation of donor pancreas or donor islets significantly improved the subsequent transplant outcomes in both syngeneic mouse islet transplantation model and human-to-nude mouse islet xenotransplantation model. CONCLUSIONS: Liraglutide protects islets from cold ischemia-related oxidative stress during preservation and hence improved islet transplantation outcomes, and this protective effect of liraglutide in islets is associated with the activation of Akt signaling.

Adaptive functions of structural variants in human brain development.

Quantifying the structural variants (SVs) in nonhuman primates could provide a niche to clarify the genetic backgrounds underlying human-specific traits, but such resource is largely lacking. Here, we report an accurate SV map in a population of 562 rhesus macaques, verified by in-house benchmarks of eight macaque genomes with long-read sequencing and another one with genome assembly. This map indicates stronger selective constrains on inversions at regulatory regions, suggesting a strategy for prioritizing them with the most important functions. Accordingly, we identified 75 human-specific inversions and prioritized them. The top-ranked inversions have substantially shaped the human transcriptome, through their dual effects of reconfiguring the ancestral genomic architecture and introducing regional mutation hotspots at the inverted regions. As a proof of concept, we linked APCDD1, located on one of these inversions and down-regulated specifically in humans, to neuronal maturation and cognitive ability. We thus highlight inversions in shaping the human uniqueness in brain development.