J Mol Biol. 2025 May 15:169222. doi: 10.1016/j.jmb.2025.169222. Online ahead of print.

NO ABSTRACT

PMID:40381984 | DOI:10.1016/j.jmb.2025.169222

Neurobiol Dis. 2025 May 15:106954. doi: 10.1016/j.nbd.2025.106954. Online ahead of print.

ABSTRACT

Pathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (~40 % of patients) and p.E815K (~25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.

PMID:40381892 | DOI:10.1016/j.nbd.2025.106954

Antiviral Res. 2025 May 15:106190. doi: 10.1016/j.antiviral.2025.106190. Online ahead of print.

ABSTRACT

LP-98 is a lipopeptide-based HIV fusion inhibitor with exceptional potency and long-acting antiviral activity, currently in phase II clinical trials. In this study, we elucidated the structural basis of LP-98's antiviral activity and resistance mechanisms. Using AlphaFold3, we first predicted the six-helical bundle (6-HB) structure formed by LP-98 and the gp41-derived NHR peptide N44, identifying key residues mediating interhelical interactions. Subsequent crystallographic analysis of the LP-98/N44 complex confirmed these binding features, revealing that a cluster of hydrophobic residues in LP-98, along with a network of 15 hydrogen bonds, two electrostatic interactions and a salt bridge, critically stabilizes the 6-HB structure. Superposition analyses of the LP-98/N44 crystal structure with either the predicted 6-HB model or the LP-40/N44 crystal structure provided further mechanistic insights into LP-98's binding mode. Additionally, structural and functional characterization of the N-terminal Tyr-127 residue using a truncated variant (LP-98-Y) demonstrated its essential role in inhibitor binding and antiviral activity. Notably, LP-98 exhibited significantly reduced efficacy against T20-resistant HIV strains harboring single or double mutations in NHR. Our structural models shed light on the molecular basis of this resistance, offering critical insights for drug optimization. Collectively, these findings provide a detailed structural understanding of LP-98's antiviral mechanism, supporting its continued development as a promising next-generation HIV fusion inhibitor.

PMID:40381660 | DOI:10.1016/j.antiviral.2025.106190

Neuron. 2025 May 13:S0896-6273(25)00298-3. doi: 10.1016/j.neuron.2025.04.015. Online ahead of print.

ABSTRACT

We report a role for activity in the development of the primary sensory neurons that detect touch. Genetic deletion of Piezo2, the principal mechanosensitive ion channel in somatosensory neurons, caused profound changes in the formation of mechanosensory end-organ structures. Peripheral-nervous-system-specific deletion of the voltage-gated sodium channel Nav1.6 (Scn8a), which resulted in altered electrophysiological responses to mechanical stimuli, also disrupted somatosensory neuron morphologies, supporting a role for neuronal activity in end-organ formation. Single-cell RNA sequencing of Piezo2 mutants revealed changes in gene expression in sensory neurons activated by light mechanical forces, whereas other neuronal classes were minimally affected, and genetic deletion of Piezo2-dependent genes partially reproduced the defects in mechanosensory neuron structures observed in Piezo2 mutants. These findings indicate that mechanically evoked neuronal activity acts early in life to shape the maturation of mechanosensory end-organs that underlie our sense of gentle touch.

PMID:40381613 | DOI:10.1016/j.neuron.2025.04.015

Pediatr Neurol. 2025 Apr 25;168:67-81. doi: 10.1016/j.pediatrneurol.2025.04.010. Online ahead of print.

ABSTRACT

Developmental and epileptic encephalopathies (DEEs) are severe neurological disorders characterized by childhood-onset seizures and significant developmental impairments. Seizures are often refractory to treatment with traditional antiseizure medications, which fail to address the underlying genetic and molecular mechanisms. This comprehensive review explores the evolving landscape of precision therapeutics for DEEs, focusing on mechanism-driven interventions across key pathophysiologic categories. Targeted approaches for channelopathies include antisense oligonucleotides and gene therapies, such as zorevunersen and ETX101 for SCN1A-related Dravet syndrome, alongside novel small molecules for other ion channel disorders. Advances in targeting neurotransmitter receptor dysfunctions, including γ-aminobutyric acid and glutamate receptor variants, highlight the use of modulators such as gaboxadol, radiprodil, and l-serine, alongside emerging gene therapies. For synaptic dysfunctions, innovative treatments such as chemical chaperones for STXBP1-related disorders and Ras-Raf-MEK-ERK inhibitors for SYNGAP1 pathologies are discussed. The review also examines precision interventions targeting cellular signaling pathways in tuberous sclerosis complex, epigenetic regulation in Rett syndrome, and metabolic interventions like ketogenic diets and targeted supplementation for specific genetic etiologies. Additionally, the importance of enhancing access to genetic testing, conducting robust natural history studies, and employing innovative clinical trial designs is emphasized. Future directions focus on addressing the challenges in developing and implementing gene-based therapies, integrating systems biology, leveraging artificial intelligence for data analysis, and fostering collaboration among stakeholders. The rapidly advancing field of precision therapeutics for DEEs holds promise to improve outcomes through tailored, equitable, and patient-centered care.

PMID:40381457 | DOI:10.1016/j.pediatrneurol.2025.04.010

Neoplasia. 2025 May 16;66:101173. doi: 10.1016/j.neo.2025.101173. Online ahead of print.

ABSTRACT

Obesity-related oesophageal adenocarcinoma (OAC), arising from Barrett's oesophagus (BO), incidence rates are rising coincident with high-fat diets. However, adipose tissue phenotype drives metabolic characteristics. Prior feeding studies demonstrated that obesogenic diets enriched in saturated fatty acids (SFA) induce a more adverse metabolic and pro-inflammatory adipose phenotype, compared to monounsaturated fatty acids (MUFA) enriched high-fat diets, despite equal obesity. We hypothesise that different fatty acids may alter the progression of BO to OAC, wherein SFA may be more pathogenic compared to MUFA. Proteomic analysis shows that SFA, not MUFA, increases fatty acid metabolism, oncogenic signalling, and mitochondrial respiratory chain to a greater extent in BO but not in OAC cells. Cellular metabolic analysis validated proteomic findings to show mitochondrial dysfunction in BO but showed an increase in glycolysis in OAC following SFA treatment compared to MUFA. Additionally, it showed a decrease in mitochondrial ATP production following treatment of SFA in BO and OAC cells. Reduction of SFA intake may be beneficial as a supplementary treatment approach to manage and/or prevent OAC progression.

PMID:40381373 | DOI:10.1016/j.neo.2025.101173

ISME J. 2025 May 17:wraf096. doi: 10.1093/ismejo/wraf096. Online ahead of print.

ABSTRACT

Phytoplankton account for nearly half of global photosynthetic carbon fixation, and the fate of that carbon is regulated in large part by microbial food web processing. We currently lack a mechanistic understanding of how interactions among heterotrophic bacteria impact the fate of photosynthetically fixed carbon. Here, we used a set of bacterial isolates capable of growing on exudates from the diatom Phaeodactylum tricornutum to investigate how bacteria-bacteria interactions affect the balance between exudate remineralization and incorporation into biomass. With exometabolomics and genome-scale metabolic modeling, we estimated the degree of resource competition between bacterial pairs. In a sequential spent media experiment, we found that pairwise interactions were more beneficial than predicted based on resource competition alone, and 30% exhibited facilitative interactions. To link this to carbon fate, we used single-cell isotope tracing in a custom cultivation system to compare the impact of different "primary" bacterial strains in close proximity to live P. tricornutum on a distal "secondary" strain. We found that a primary strain with a high degree of competition decreased secondary strain carbon drawdown by 51% at the single-cell level, providing a quantitative metric for the "cost" of competition on algal carbon fate. Additionally, a primary strain classified as facilitative based on sequential interactions increased total algal-derived carbon assimilation by 7.6 times, integrated over all members, compared to the competitive primary strain. Our findings suggest that the degree of interaction between bacteria along a spectrum from competitive to facilitative is directly linked to algal carbon drawdown.

PMID:40381217 | DOI:10.1093/ismejo/wraf096

Cell Rep. 2025 May 15;44(5):115710. doi: 10.1016/j.celrep.2025.115710. Online ahead of print.

ABSTRACT

The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

PMID:40381195 | DOI:10.1016/j.celrep.2025.115710

Funct Integr Genomics. 2025 May 17;25(1):103. doi: 10.1007/s10142-025-01611-3.

ABSTRACT

Epitranscriptomic changes in the transcripts of cancer related genes could modulate protein levels. RNA editing, particularly A-to-I(G) editing catalyzed by ADAR1, has been implicated in cancer progression. RNA editing events in the 3' untranslated region (3'UTR) can regulate mRNA stability, localization, and translation, underscoring the importance of exploring their impact in cancer. Here, we performed an in silico analysis to detect breast cancer enriched RNA editing sites using the TCGA breast cancer RNA-seq dataset. Notably, the majority of differential editing events mapped to 3' untranslated regions (3'UTRs). We confirmed A-to-I(G) editing in the 3'UTRs of MDM2 (Mouse Double Minute 2 homolog), GINS1 (GINS Complex Subunit 1), and F11R (Junctional Adhesion Molecule A) in breast cancer cells. RNA immunoprecipitation with ADAR1 antibody confirmed the interaction between ADAR1 and MDM2, GINS1, and F11R 3'UTRs. ADAR1 knockdown revealed decreased editing levels, establishing ADAR1 as the editing enzyme. A reporter assay for MDM2, an oncogene overexpressed mostly in luminal breast cancers, demonstrated that RNA editing enhances protein expression, in agreement with reduced MDM2 protein levels in ADAR1 knockdown cells. Further exploration into the mechanisms of 3'UTR editing events revealed an interaction between ADAR1 and CSTF2, a core component of the polyadenylation machinery, as identified through biotin-based proximity labeling mass spectroscopy, and co-immunoprecipitation experiments. Furthermore, CSTF2 knockdown reduced both ADAR1 and MDM2 protein levels. Our findings highlight implications for MDM2 regulation by ADAR1-dependent 3'UTR RNA editing and present an interplay between RNA editing on 3'UTRs and the mRNA polyadenylation machinery. These results improve our understanding of ADAR1's role in cancer-associated 3' UTR RNA editing and its potential as a therapeutic target.

PMID:40381037 | DOI:10.1007/s10142-025-01611-3

Stud Health Technol Inform. 2025 May 15;327:487-491. doi: 10.3233/SHTI250385.

ABSTRACT

BACKGROUND: Patient similarity analysis is pivotal in cancer research and clinical oncology, aiding in identifying patterns among patients with similar clinical and molecular profiles to guide therapeutic decisions, particularly in Molecular Tumor Boards (MTB), where therapy decisions are frequently informed by the treatment experiences of previously treated similar patients. However, the lack of standardized tools for automation and visualization limits efficiency here, especially in individualized MTB decisions.

OBJECTIVE: This study aims to develop a graphical user interface that aligns with clinician preferences to enhance patient similarity assessments and support decision-making in MTBs.

METHODS: Visualization concepts were developed through iterative design and evaluation cycles involving clinical experts. Mock-ups were created to represent various approaches for displaying patient similarities, focusing on molecular data relevant to MTB decisions.

RESULTS: Various designs were developed for visualizing patient similarity in cBioPortal. These include tabular views, network representations, and radar plots.

CONCLUSIONS: These visualizations offer promise in enhancing decision-making in MTBs by making patient similarity assessments more accessible. Future development will focus on additional functionalities and better integration into clinical workflows.

PMID:40380495 | DOI:10.3233/SHTI250385

Stud Health Technol Inform. 2025 May 15;327:98-102. doi: 10.3233/SHTI250281.

ABSTRACT

Molecular tumor boards present special challenges when it comes to information collection for case preparation. It is one of the most time-consuming tasks participating pathologists and oncologists face, limiting the number of cases that can be discussed in these specialized tumor boards and in turn can profit from a potential highly personalized therapy. Digital support is a necessity to enable medical professionals to efficiently make use of the vast amount of data available for each patient and their genomic and clinical profile. This includes historically recommended therapies for patients with molecularly similar tumors. To combat this issue, we developed an extension for the MTB-cBioPortal in collaboration with clinicians, enabling users to access previously documented therapy recommendations combined with corresponding follow-up data based on HL7 FHIR profiles and modules established in the Medical Informatics Initiative (MII). The information is made available through an additional annotation in the MTB-cBioPortal patient view. In doing so we intend to improve the efficiency of the case preparation process for molecular tumor boards and lay the groundwork for a potential multicentric exchange of therapy recommendations and follow-up data.

PMID:40380393 | DOI:10.3233/SHTI250281

BMC Psychiatry. 2025 May 16;25(1):498. doi: 10.1186/s12888-025-06951-9.

ABSTRACT

BACKGROUND: Observational studies reported altered levels of plasma metabolites in attention-deficit/hyperactivity disorder (ADHD). We aim to explore the causal link between plasma metabolites and ADHD.

METHODS: We utilized Mendelian randomization (MR) analysis to assess the causal relationship between plasma metabolites and ADHD and the Genome-wide association study (GWAS) summary datasets were sourced from public databases. GWAS summary datasets were used in the study, including ADHD (n = 292,548) and 871 plasma metabolites (n = 8,299). Moreover, we used DrugBank and ChEMBL to evaluate whether the identified metabolites are potential therapeutic targets, and in addition, Bayesian colocalization analyses were conducted to assess the shared genetic signals between these metabolites and ADHD.

RESULTS: Our MR analysis identified 20 plasma metabolites that conferred protective effects against the risk of ADHD, including dimethylglycine, 3-methoxytyramine sulfate, and adenosine 3',5'-cyclic monophosphate (OR: 0.97-0.98). Additionally, 22 metabolites were associated with an increased risk of ADHD, including N-acetylneuraminate and 3-indoleglyoxylic acid (OR:1.01-1.03). Druggability evaluation showed that 12 of the ADHD-related metabolites have been targeted by pharmacological interventions. For example, doconexent has been used to increase the levels of docosahexaenoic acid. Our reverse MR analysis showed that genetic liability to ADHD may affect the abundance of 91 metabolites. Notably, several plasma metabolites had bidirectional causal associations with ADHD, including docosahexaenoate (DHA; 22:6n3), docosatrienoate (22:3n3), N1-methyladenosine, S-adenosylhomocysteine, and 4-allylcatechol sulfate.

CONCLUSIONS: Our study supported a causal role of plasma metabolites in the susceptibility to ADHD, and the identified metabolites may provide a new avenue for the prevention and treatment of ADHD.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:40380147 | DOI:10.1186/s12888-025-06951-9

Geroscience. 2025 May 16. doi: 10.1007/s11357-025-01698-3. Online ahead of print.

ABSTRACT

Functional ability and intrinsic capacity (IC) have been proposed as determinants of healthy aging, but the extent to which these indicators are affected by biological aging remains unknown. We explored the association of biological age acceleration (BAA) with functional ability and IC in older adults with physical and cognitive impairments. This cross-sectional study used data from 163 individuals (84.0 ± 5.2 years [range 72-99], 61.8% women) of the COGFRAIL cohort. Functional ability on basic (BADL-Katz Index) and instrumental activities of daily living (IADL-Lawton Index) was assessed. IC was measured as a composite score (0-100, higher is better) including the locomotion, cognition, psychology, sensory, and vitality domains. BAA was assessed by Horvath's, Hannum's, PhenoAge, and GrimAge epigenetic clocks. In the fully adjusted model, higher BAAPhenoAGe was associated to lower functional ability in BADLs (β = - 0.021, 95% confidence interval = - 0.038 to - 0.003, p = 0.022), with no significant results observed for the remaining clocks. No significant association was found between BAA and IC, but some associations were found with specific IC domains. Particularly, BAAGrimAge was associated with lower locomotion scores (β = - 1.179, 2.286 to - 0.072, p = 0.037), while BAAPhenoAge tended to be associated with lower scores in vitality (β = - 0.257, - 0.539 to 0.025, p = 0.073). Higher BAAPhenoage was associated with lower functional ability in very old adults with frailty and cognitive impairment. Although no biological clock was associated with a composite IC score, some associations were found between second-generation epigenetic clocks and specific IC domains.

PMID:40380021 | DOI:10.1007/s11357-025-01698-3

Nat Struct Mol Biol. 2025 May 16. doi: 10.1038/s41594-025-01559-9. Online ahead of print.

ABSTRACT

DEK is a highly conserved chromatin-associated oncoprotein that has important roles in regulating chromatin dynamics and stem cell fate. Dysregulation of DEK is associated with stem cell dysfunction and cancers, including acute myeloid leukemia. Despite its importance in chromatin regulation, the structural mechanisms underlying DEK's interaction with chromatin and its influence on gene regulation remain poorly understood. Here we combined cryogenic electron microscopy (cryo-EM), biochemical and cellular approaches to investigate the molecular mechanisms and functional importance of DEK's interaction with chromatin. Our cryo-EM structures reveal the structural basis of the DEK-nucleosome interaction. Biochemical and cellular results demonstrate that this interaction is crucial for DEK deposition onto chromatin. Furthermore, our results reveal that DEK safeguards mouse embryonic stem cells from acquiring primitive endoderm fates by modulating the repressive histone mark H3K27me3. Together, our study provides crucial molecular insights into the structure and function of DEK, establishing a framework for understanding its roles in chromatin biology and cell fate determination.

PMID:40379883 | DOI:10.1038/s41594-025-01559-9

Sci Data. 2025 May 16;12(1):800. doi: 10.1038/s41597-025-05082-w.

ABSTRACT

In oilseed crops, e.g. oilseed rape (OSR; Brassica napus), a key developmental process is seed maturation, during which the embryo transitions from the early, globular state to the mature state. Seed development involves cell division, differentiation, and oil accumulation in specific tissue types (embryo, endosperm, and seed coat). These developmental processes impact seed quality and oil yield. High quality RNA from Brassica spp. seed tissues, from heart to mature developmental stages, was obtained using previously reported methods for five Brassica genotypes comprising winter, semi-winter and spring OSR varieties, a B. napus heritage kale and a rapid-cycling double-haploid Brassica oleracea line. RNA-seq was performed on 240 sets of samples. The resulting dataset contains detailed spatio-temporal expression profiles during seed development. In addition to the repository data, we provide easy access to this through the Seed Oilseed Rape Developmental Expression Resource (SeedORDER), which enables users to search for genes of interest and visualise expression patterns. Knowledge of where and when genes are expressed during seed development will inform future breeding efforts.

PMID:40379636 | DOI:10.1038/s41597-025-05082-w

Cell Genom. 2025 May 13:100878. doi: 10.1016/j.xgen.2025.100878. Online ahead of print.

ABSTRACT

Emerging evidence suggests that MYC interacts with RNAs. Here, we performed an integrative characterization of MYC as an RNA-binding protein in six cell lines. We found that MYC binds to a myriad of RNAs with high affinity for guanosine-rich RNAs. Global and specific depletion of RNAs reduces MYC chromatin occupancy. Mechanistically, two highly conserved sequences, amino acids 355-357 KRR and 364-367 RQRR, within the basic region of MYC are necessary for its RNA binding. Notably, alanine substitution of KRR abolishes MYC's RNA-binding ability both in vitro and in vivo, without affecting its ability to bind E-box DNA as part of the MYC:MAX dimer in vitro. The loss of RNA-binding function decreases MYC chromatin binding in vivo and attenuates its ability to promote gene expression, cell-cycle progression, and proliferation. Our study lays a foundation for future investigation into the role of RNAs in MYC-mediated transcriptional activation and oncogenic functions.

PMID:40378850 | DOI:10.1016/j.xgen.2025.100878

Cell Syst. 2025 May 12:101294. doi: 10.1016/j.cels.2025.101294. Online ahead of print.

ABSTRACT

Effective exploration and analysis tools are vital for the extraction of insights from single-cell data. However, current techniques for modeling single-cell studies performed across experimental conditions (e.g., samples) require restrictive assumptions or do not adequately deconvolute condition-to-condition variation from cell-to-cell variation. Here, we report that reduction and insight in single-cell exploration (RISE), an adaptation of the tensor decomposition method PARAFAC2, enables the dimensionality reduction and analysis of single-cell data across conditions. We demonstrate the benefits of RISE across distinct examples of single-cell RNA-sequencing experiments of peripheral immune cells: pharmacologic drug perturbations and systemic lupus erythematosus patient samples. RISE enables associations of gene variation patterns with patients or perturbations while connecting each coordinated change to single cells without requiring cell-type annotations. The theoretical grounding of RISE suggests a unified framework for many single-cell data modeling tasks while providing an intuitive dimensionality reduction approach for multi-sample single-cell studies across biological contexts. A record of this paper's transparent peer review process is included in the supplemental information.

PMID:40378843 | DOI:10.1016/j.cels.2025.101294

Cancer Cell. 2025 May 12:S1535-6108(25)00172-2. doi: 10.1016/j.ccell.2025.04.013. Online ahead of print.

ABSTRACT

MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth in vivo in multiple group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill group-3 MB by cuproptosis.

PMID:40378837 | DOI:10.1016/j.ccell.2025.04.013

Chemosphere. 2025 May 15;381:144430. doi: 10.1016/j.chemosphere.2025.144430. Online ahead of print.

ABSTRACT

The presence of emerging pollutants in aquatic ecosystems due to human activities poses substantial concerns. While many studies explore detection and removal techniques for these compounds, conventional treatment methods often fail to address emerging pollutants. Moreover, there is a lack of legislation defining safe thresholds for these substances in water. Consequently, caffeine and N,N-diethyl-meta-toluamide (DEET) persist in surface waters, including treated sources, with limited understanding of their genomic effects on human cells. This study aimed to assess the cytotoxic and genotoxic effects of caffeine and DEET, individually and in combination, at concentrations detected in drinking water, using HepG2 cells. Additionally, through systems biology, we sought to understand the underlying molecular mechanisms of both substances. Cytotoxicity was evaluated using MTT and Trypan Blue assays, while genotoxicity was assessed using the comet assay. The chemoproteomic interaction network was constructed using STITCH and STRING databases, with subnetworks analyzed using Cytoscape plugins (MCODE, CentiScaPe, and BiNGO). Both compounds reduced HepG2 cell viability in a dose-dependent manner in both assays. Caffeine and DEET also induced DNA damage at all tested concentrations, including in co-exposure. Proteins related to the inflammatory response, signaling pathways, and xenobiotic metabolism were the main hub-bottlenecks of the chemoproteomic interaction network. These findings underscore the urgent need for further investigations into the presence of emerging pollutants in drinking water and their potential risks to human health.

PMID:40378806 | DOI:10.1016/j.chemosphere.2025.144430

Sci Adv. 2025 May 16;11(20):eadu2079. doi: 10.1126/sciadv.adu2079. Epub 2025 May 16.

ABSTRACT

The impact of SARS-CoV-2 in the lung has been extensively studied, yet the molecular regulators of host-cell programs hijacked by the virus in distinct human airway epithelial cell populations remain poorly understood. Some of the reasons include overreliance on transcriptomic profiling and use of nonprimary cell systems. Here we report a network-based analysis of single-cell transcriptomic profiles able to identify master regulator (MR) proteins controlling SARS-CoV-2-mediated reprogramming in pathophysiologically relevant human ciliated, secretory, and basal cells. This underscored chromatin remodeling, endosomal sorting, ubiquitin pathways, as well as proviral factors identified by CRISPR assays as components of the viral-host response in these cells. Large-scale drug perturbation screens revealed 11 candidate drugs able to invert the entire MR signature activated by SARS-CoV-2. Leveraging MR analysis and perturbational profiles of human primary cells represents an innovative approach to investigate pathogen-host interactions in multiple airway conditions for drug prioritization.

PMID:40378209 | DOI:10.1126/sciadv.adu2079