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The 3rd International Online Conference on Toxins (IOCT 2025) was held online from 10 to 12 September 2025, and chaired by Prof. Dr. Jay W. Fox. There were six areas of focus at IOCT 2025, providing ample opportunities for the written and oral presentation of new, exciting studies in toxinology. The main topics and sessions of the conference were as follows: Plant, Animal, Insect and Microbial Toxins: New Developments; Novel Insights on The Mechanism of Action and/or Pathophysiology of Toxins; Use of Toxins as Tools for Research, Drug Discovery, and Therapeutics; Impact of Toxins on Public Health; Impact of Toxins on Agriculture; Foodborne Toxins. Full article

Background/Objectives: Sarcomatoid or rhabdoid renal cell carcinoma (sRCC) represents an aggressive dedifferentiated phenotype of RCC associated with high metastatic potential. The histologic composition of metastatic lesions arising from clear cell RCC with sarcomatoid/rhabdoid differentiation (ccRCC/sRCC) and its relationship to the primary tumor remain incompletely characterized. Methods: We retrospectively reviewed patients undergoing nephrectomy for ccRCC/sRCC who had at least one resected metastatic lesion between 2013 and 2025 at a single institution. Primary and metastatic lesions were characterized by the percentage of clear cell versus sarcomatoid/rhabdoid histology. Associations between sarcomatoid/rhabdoid percentage in the primary tumor, metastatic histology, metastatic location, and overall survival were examined. Results: Twenty-six patients with 63 metastases were included. Metastatic histology demonstrated substantial heterogeneity, with 27 lesions (43%) showing pure clear cell histology, 21 (33%) mixed, and 15 (24%) pure sarcomatoid/rhabdoid. Some patients had multiple metastases with differing histology. Increasing sarcomatoid/rhabdoid percentage in the primary was associated with a higher likelihood of sarcomatoid/rhabdoid in metastases (p < 0.001). ROC analysis demonstrated primary tumor sarcomatoid/rhabdoid percentage predicted sarcomatoid/rhabdoid differentiation in metastases (AUC 0.84, 95% CI 0.73–0.95). An optimal cutoff of 10% sarcomatoid/rhabdoid differentiation predicted sarcomatoid/rhabdoid features in metastases. Metastatic histology varied by site, with lymph node metastases more frequently demonstrating clear cell morphology and visceral metastases more commonly exhibiting sarcomatoid/rhabdoid features. Conclusions: Metastases arising from ccRCC with sarcomatoid/rhabdoid differentiation exhibit marked histologic heterogeneity. These findings highlight the complex biology of ccRCC/sRCC metastasis and underscore the need for studies examining molecular drivers of metastatic heterogeneity, as well as the relationship between metastatic histology and therapeutic response. Full article

Leadership plays a critical role in promoting equitable and high-quality early care and education (ECE) environments. Within this context, leaders of color bring unique perspectives and experiences that support ECE teachers, children, and families with diverse backgrounds. Despite their importance, there is limited research focusing on the professional experiences and well-being of ECE leaders of color. Drawing on Critical Race Theory (CRT), the current study aims to fill the gap by exploring the well-being, challenges, and strengths of ECE leaders of color. Using applied thematic analysis, we analyzed interview data from 17 leaders of color working in center-based ECE settings. Five themes were identified: (1) Multidimensional and interconnected well-being, (2) structural and racialized challenges in leadership roles and career pathways, (3) strengths and assets drawn from leaders of color’s identities and experiences, (4) interconnections between strengths and burdens, and (5) suggestions for well-being and work conditions improvement. The findings suggest that improving the well-being and work conditions of ECE leaders of color requires both individual and structural support, including more targeted well-being resources, culturally sustaining organizational practices and climate, leadership preparation and development support, and more stable policy environments. Full article

Background: Prostate cancer is a heterogeneous disease with variable clinical outcomes. If localized, the patient may be cured. However, prostate cancer is lethal if recurrence/progression to metastatic castrate resistant disease occurs. Thus, there is an unmet need to further understand the molecular underpinnings of this progression. Epidemiologic studies show that increased risk of developing and dying from prostate cancer has been associated with elevated serum IGF-1 levels, hyperinsulinemia and metabolic syndrome. Alterations in insulin pathway genes, such as PTEN, FOXO, and PIK3CA, are mutated in up to 32%, 15%, and 11% of localized prostate tumors, respectively. We aimed to further characterize expression of insulin pathway genes in localized prostate cancers in an effort to (1) provide insights into potential mechanisms of progression to metastatic disease and (2) try to further enrich for those prostate tumors that portend worse survival outcomes. Methods: Using the multi-institutional Oncology Research Information Exchange Network (ORIEN) database, gene expression data was analyzed from localized prostate cancer tumors. The raw counts were first normalized, and 176 genes related to the insulin receptor and its downstream pathways were then subset and used for clustering using the non-negative matrix factorization (NMF). The NMF cluster analysis was performed in an attempt to separate gene expression into two groups. Gene Set Enrichment Analysis (GSEA) was then performed between the two groups that had been separated by cluster analysis to determine homology between other GSEA sets. Kaplan–Meier curves were used to assess median overall survival. Cox analysis was performed to generate the adjusted KM curve. Mediation analysis was conducted to determine the relationship between cluster status, TN stage, and survival. Results: Cluster analysis revealed two distinct groups of insulin gene expression, cluster 1 (n = 96) and cluster 2 (n = 337). Compared with cluster 2, cluster 1 consisted of decreased expression of PTEN (p < 0.001) and PIK3R1 (p < 0.001), along with increases in the expression of AKT1 (p < 0.001), IRS1/2 (p < 0.001), FASN (p < 0.001), IGFBP2 (p < 0.001), and MTOR (p < 0.001). GSEA analysis revealed changes in lipid metabolism and WNT secretion pathways in cluster 1. Cluster 2 GSEA showed pathway changes related to DNA damage repair and testosterone. Patient characteristics between clusters differed significantly in the T and N stages of tumor but not in other ways. In unadjusted analysis, median overall survival was estimated at 117 months and 232 months for cluster 1 and cluster 2, respectively (p < 0.05). The proportion of patients who went on to develop metastases (p < 0.05) or need chemotherapy (p < 0.05) was increased in cluster 1 compared to cluster 2. Repeat survival analysis adjusted for confounders (T stage, N stage, age at diagnosis, pathologic grade) showed no difference in survival between clusters. Mediation analysis showed that the contribution of cluster status to survival was independent of T or N stage. Conclusions: A subset of localized prostate cancer patients demonstrated linked insulin pathway changes that are consistent with prior studies describing a pattern of insulin dysregulation. Though the group characterized by insulin dysregulation initially showed worse survival outcomes, this difference disappeared when controlling for confounders. Though baseline differences in tumor stage seemed to most readily explain the difference in survival between clusters, mediation analysis showed that the effect of cluster status on survival was independent of tumor stage. This suggests that other confounders, such as pathologic grade or baseline age, may explain the survival difference. Full article

Thomas Jefferson, the Author of the Declaration of Independence and the Father of the University of Virginia, considered it a self-evident truth that our rights must be secured through government and that the people themselves are the only safe guardians of their liberty in a republican form of government. The civic education of the people is, therefore, imperative, in his view, if they are to be informed citizens. This article examines the ways that the first States sought to institute public universities, through both constitutional and legislative means, and highlights Jefferson’s vision for civic education against the activity of the States in establishing education. Surveying early State constitutions and university charters reveals, for those States instituting public education, a wide range of approaches, particularly with respect to three aspects: authorizing mode (constitutional or legislative mandates); civic rhetoric; and scope (tiered system or single institution). While several of the States recognize education as important to republican government, their commitments to public civic education vary. Against this backdrop, Jefferson’s views on education appear both comprehensive and constant, from his reform Bill for the More General Diffusion of Knowledge and Notes on the State of Virginia, which envision a three-tiered public system, to his efforts in retirement to pass education reform and establish a new university, with his purpose being explicitly civic. While his State never adopted his full system, Jefferson continued to advocate for ward republics and public instruction throughout his life. The founding of the University of Virginia in 1819 partially fulfilled this pursuit, embodying the keystone in his educational architecture. Yet Jefferson’s broader system—grounded in local participation and universal civic instruction—remained unrealized. This survey further reveals that statesmen in early America did not always agree with Jefferson that States must have an enduring institutional commitment to public civic education, as the best means to inform the people and to secure republican self-government. Full article

The gut–heart axis plays a role in cardiac injury due to the disruption of barriers, endotoxemia, and inflammatory signaling; yet, it is not clear whether sodium butyrate (SB) is capable of alleviating isoprenaline-induced myocardial injury through coordinated intestinal, microbial, and metabolic restoration. This study used male Sprague-Dawley rats, which were grouped into control, control + SB, isoprenaline (ISO)-induced myocardial injury, and ISO + SB groups. We evaluated cardiac biomarkers of injury, oxidative stress, histopathologic, intestinal barrier (16S rRNA sequencing), and serum metabolomics (LC-MS). SB treatment decreased serum cardiac troponin I, creatine kinase-MB, and lactate dehydrogenase; relieved oxidative stress; and lowered myocardial necrosis and fibrosis. It re-established colonic architecture, upregulated the expression of ZO-1 (zonula occludens-1) and claudin-1, and reduced endotoxin in the bloodstream. SB also prevented the production of proinflammatory cytokines such as TNF-α, IL-6, and IL-1β; cardiac TLR4; IκBα degradation; and NF-κB p 65 phosphorylation. In addition, SB altered the gut microbiota in favor of beneficial commensals, including Ligilactobacillus and Bifidobacterium, and reduced Desulfovibrio. It normalized key circulating metabolites and enriched cardiometabolic pathways, and the patterns of correlation suggested the coordinated remodeling of the microbiome–metabolome. These findings reveal that SB prevents myocardial injury caused by ISO through strengthening gut barrier protection, alleviating endotoxemia, inhibiting TLR4/NF-κB, and remodeling the microbiome–metabolome axis, indicating its potential for use as a gut-targeted cardioprotective intervention. Full article

Regulated cell death is essential for development, tissue homeostasis, host defense, and disease. Beyond apoptosis, it is now clear that other forms of cell death, including ferroptosis, pyroptosis, and necroptosis, also contribute to pathology, often in interconnected rather than isolated ways. Within this broader framework, the transcriptional intermediary factor 1 (TIF1) family, comprising TRIM24, TRIM28, TRIM33, and TRIM66, has emerged as an important group of regulators linking stress adaptation, cell-state control, and cell death susceptibility. Although these proteins belong to the same family, they influence cell death through distinct and context-dependent mechanisms. Across the TIF1 family, apoptosis is by far the most extensively studied cell death phenotype, whereas links to ferroptosis, pyroptosis, and necroptosis remain more limited, more context dependent, and more unevenly distributed across individual members. Cell death often becomes evident when TIF1-dependent stress-buffering programs are disrupted, highlighting both their biological importance and potential therapeutic relevance. At the same time, family-level differences are emerging, while the underlying mechanisms remain incompletely understood, and recent advances in this field have not been synthesized. This review summarizes how TIF1 family members intersect with different cell death programs, discusses emerging translational opportunities and challenges, and highlights key mechanistic questions for future study. Full article

In this paper we aim to conduct inference on the “lift” effect generated by an online advertisement display: specifically we want to analyze if the presence of the brand ad among the advertisements on the page increases the overall number of consumer clicks on that page. A distinctive feature of online advertising is that the ad displays are highly targeted—the advertising platform evaluates the (unconditional) probability of each consumer clicking on a given ad, which leads to a higher probability of displaying the ads that have a higher a priori estimated probability of click. As a result, inferring thecausal effect of the ad display on the page clicks by a given consumer from typical observational data is difficult. To address this we propose a multi-step estimator that focuses on the tails of the consumer distribution to estimate the true causal effect of an ad display. This “identification at infinity” approach alleviates the need for independent experimental randomization but results in nonstandard asymptotic theory, motivating our novel inference method. To validate our results, we use a set of large-scale randomized controlled experiments that Microsoft has run on its advertising platform. Our dataset has a large number of observations and a large number of variables and we employ LASSO to perform variable selection. Providing a basis for comparison with our estimates, we use a study conducted by Microsoft with approximately 9.3 million search sessions focusing on consumer click behavior across search result pages of a major search engine. Randomized experiments indicate that displaying a brand advertisement increases the probability of visiting the advertiser’s website by about 2.27 percentage points relative to a baseline visit rate of roughly 78 percent. Our non-experimental estimates exhibit broadly similar patterns to those obtained from randomized controlled trials, suggesting that the proposed observational estimator can recover qualitatively comparable treatment effects in large-scale advertising data. Full article

An individual’s host genetics influence its susceptibility to both COVID-19 and coronary artery disease (CAD). We analyzed large-scale GWAS datasets encompassing 7.7 million SNPs to identify shared genetic architecture between the two diseases. We identified 24 pleiotropic risk loci for both COVID-19 and CAD, with three loci (1p31.1, 8p21.3, and 18q11.2) showing strong evidence for a single shared causal variant. Loci in the 8p21.3 and 18q11.2 regions showed a bidirectional causal association: COVID-19 to CAD or vice versa, while the 1p31.1 locus only showed a CAD to COVID-19 unilateral casual association in a Mendelian randomization analysis (GSMR). A fine mapping analysis of the three loci identified three lead pleiotropic variants (rs7515509, rs8192330, and rs4800403). The variant rs7515509 was spatially associated with AK5, PIGK, USP33, and ZZZ3; rs8192330 with DMTN, PIWIL2, and several other genes; and rs4800403 with GATA6 and CTAGE1. Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients validated proxitropic variants (rs8192330 and rs4800403) with distinct expression signatures and prioritized DMTN and PIWIL2 as the likely causal genes. Overexpression of DMTN has been linked to the heme metabolism hallmark, disrupted iron distribution in COVID-19 patients with comorbid CAD, and subsequent stress erythropoiesis, oxidative stress, immunological dysfunction, and altered wound healing, while a lower expression of PIWIL2 has been observed in the cytoplasmic translation and regulation of mRNA metabolism. In conclusion, we identified shared genetic components for COVID-19 and CAD and prioritized DMTN and PIWIL2 as the likely causal genes for the observed shared genetic risk. COVID-19 may act as an acute stressor that unmask or accelerates underlying CAD. Full article

Comparative, experimentally grounded evidence for selecting smart city IoT data-layer architectures remains limited, complicating practical design decisions. This study provides an applied architecture decision-making guide by evaluating seven serverless data-layer architectures within a clearly defined service boundary (The Things Network, Azure-managed ingestion services, and Delta Lake persistence on object storage). Using a 21-day pilot deployment with nine LoRaWAN sensors, we compare ingestion completeness, median ingestion latency (estimated from TTN receive timestamps to Delta Lake commit times), cloud costs within an explicit boundary (ingestion, compute, and storage), and implementation/operational complexity proxies. Under the observed workload, TTN Storage Integration offers the lowest-cost archival ingestion via batching, Event Grid provides the most cost-effective near-real-time option among reliable pipelines, and Event Hubs demonstrates the highest ingestion completeness. The results are synthesized into practical guidance that maps common smart city application requirements to appropriate serverless ingestion patterns. Full article

The utilization of immunomodulatory nanomaterials, i.e., leveraging their unique properties to enhance immune responses, represents a transformative approach for the treatment of various diseases. Recent advancements in nanotechnology have enabled the design of nanomaterials capable of delivering immunomodulatory agents in a targeted manner, such as cytokines, antibodies, and nucleic acids, to specific cells or tissues involved in immune regulation. These nanomaterials, including nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, MXenes and extracellular vesicles, have been increasingly tailored to modulate immune responses with precision and efficacy. This targeted approach not only enhances therapeutic outcomes but also reduces off-target effects, minimizing systemic toxicity. In this review, an overview of immunomodulatory nanomaterials and their biomedical applications are highlighted. Herein, we have discussed different types of nanomaterials and their design strategies, interactions with different immune system components (macrophages, dendritic cells (DCs), neutrophils, T lymphocytes (CD4⁺ helper T-cells, CD8⁺ cytotoxic T-cells, regulatory T-cells/Tregs, and memory T-cells), and B lymphocytes), and immunomodulation mechanisms. Furthermore, nanomaterial-based immunomodulation strategies to enhance cancer immunotherapy, wound healing, and bone regeneration and the treatment of infectious diseases, autoimmune diseases, and allergy and are discussed in detail. In addition to therapeutic applications, selected nanomaterial platforms demonstrate significant potential in pharmaceutical formulations by improving drug stability, controlled release, and bioavailability, as well as in cosmetology through skin-targeted delivery, anti-inflammatory activity, immune protection, and enhanced tissue regeneration. Finally, clinical trial updates, challenges and future prospects are outlined. Key findings indicate that lipid-based, polymeric, inorganic nanoparticles and dendrimers provide complementary advantages for immunomodulation, including efficient delivery, controlled release, multifunctionality, and precise immune targeting. Despite safety, regulatory, and scalability challenges, these systems show strong potential for advancing precision and personalized medicine. Taken together, these innovations hold great promise for personalized medicine approaches, wherein nanomaterials can be tailored to individual patient profiles for more effective and precise disease treatment and prevention strategies. This review focuses primarily on the mechanistic interactions between immunomodulatory nanomaterials and immune cells, including macrophages, dendritic cells, neutrophils, T lymphocytes, and B lymphocytes, rather than providing an exhaustive treatment of physicochemical optimization parameters such as particle size or surface modification chemistry, which fall outside the defined scope of this work. Full article

Recent research by Yucel and colleagues suggests that children perceive equality-based fairness violations (resources being distributed unequally) as less serious than prototypical moral harms, but that making the harmful consequences of unfairness salient shifts these judgments toward the moral domain. We examined whether merit-based fairness violations (someone receiving less than they earned) would similarly shift judgments toward the moral domain by making the injustice more salient. Replicating prior work, 4-year-old children (N = 62) rated prototypical moral violations as significantly more severe than equality-based fairness violations, which were rated as similar in severity to conventional violations. Contrary to predictions, merit-based fairness violations also showed this pattern: They were judged as less severe than prototypical moral violations and similarly severe as both equality-based fairness violations and conventional violations. Children also did not consistently group either type of fairness violation with moral or conventional violations. These findings contribute to a growing body of evidence that children’s (and adults’) perceptions of fairness—whether equality-based or merit-based—are more nuanced than previously thought and that unfairness may not spontaneously be treated like other, more prototypical moral norm violations. Full article

Bottom sediments in anthropogenically impacted freshwater systems represent a dynamic and poorly constrained source of secondary pollution, where heavy metal mobility, rather than total concentration, controls the release of contaminants into the water column under changing physicochemical conditions. This issue is particularly pronounced in small and medium-sized freshwater systems subjected to sustained anthropogenic pressure, where local hydrochemical conditions and sediment composition strongly influence metal speciation and remobilization dynamics. This study aims to quantitatively assess heavy metal speciation, mobility, and associated ecological risk in bottom sediments of anthropogenically impacted freshwater systems using complementary analytical approaches. The data obtained indicate a pronounced spatial heterogeneity in the total metal content, due to varying degrees of anthropogenic impact on the water bodies. The highest level of pollution was recorded in the bottom sediments of the Chizhovskoye reservoir, where Zn concentrations reach 755 mg/kg, Cr—379 mg/kg, Ni—106 mg/kg, and Cu—158 mg/kg, indicating intense technogenic influence. The bottom sediments of the Loshitsa River are characterized by elevated, but less extreme values: the content of Cu is up to 77 mg/kg, Zn—up to 263 mg/kg, and Mn—up to 418 mg/kg. In contrast to urbanized water bodies, the background site—Lake Sergeevskoye—is characterized by significantly lower concentrations of heavy metals, which confirms its representativeness as a control object. Analysis of the fractional composition showed that Zn and Mn have the largest share of mobile forms, with their concentrations in the mobile phase reaching 12–92 mg/kg and 60–116 mg/kg, respectively, especially under conditions of increased anthropogenic load. A significant portion of Cu and Zn (up to 60–70% of the total content) is associated with organic matter, indicating the important role of the organic matrix in retaining metals and their potential mobilization under changing environmental conditions. Calculation of the geoaccumulation index showed that most of the studied bottom sediments belong to the from uncontaminated to moderately contaminated class, while for Cr and Ni in the Chizhovskoye reservoir, I_geo values up to 1.9 are characteristic, corresponding to a moderate level of pollution. The results obtained indicate a significant impact of anthropogenic load on the forms of occurrence and mobility of heavy metals and highlight the role of bottom sediments as an active factor in the secondary pollution of freshwater ecosystems. Full article