- by KIM, C. H., Zhu, Z., Tagmount, A., Barbazuk, W. B., Bacher, R., Stuchal, L. D., Martyniuk, C. J., Vulpe, C. D.Inter-individual and population variability in susceptibility to chemical exposures confounds determination of threshold exposure levels to protect the most vulnerable. Current risk assessment frameworks, in the absence of empiric chemical-specific data, generally recommend default or probabilistic adjustment factors to account for such variability. We present an experimental approach to incorporate common genetic variants potentially impacting population-level differences in toxicant susceptibility into human cell-based models for any cellular apical endpoint of interest. We focus on the genes with the most common […]
- by KIM, C. H., Zhu, Z., Tagmount, A., Barbazuk, W. B., Bacher, R., Vulpe, C. D.Many omics-based approaches in toxicology research primarily rely on correlative data, often lacking functional relationships or causal links between genotypes and phenotypes. CRISPR-based approaches can overcome this limitation by establishing direct causal connections between genes and toxicological phenotypes. Moreover, CRISPR screens enable scalable and systematic interrogation of gene function and associated mechanisms following chemical exposure, predominantly using in vitro models. In line with the paradigm of new approach methodologies (NAMs) in toxicology research, CRISPR screens hold promise to provide an […]
- by KIM, C. H., Tagmount, A., Zhu, Z., Wilson, F., Li, D., Ostrov, D., Barbazuk, W. B., Bacher, R., Vulpe, C. D.Perfluorooctane sulfonate (PFOS) poses significant health and environmental risks due to its persistence and widespread use and has been linked to various adverse outcomes, such as liver toxicity. Although the molecular responses and toxicity effects of PFOS exposure have been extensively studied, considerable uncertainty remains regarding the causal mechanisms leading to PFOS-associated adverse effects. To help bridge this gap, we conducted CRISPR screens in HepG2/C3A human liver cells exposed to IC25 (170 uM) of PFOS to identify genes and pathways […]
- by Fakih, H., Ohara, M., Summers, A., Sarli, S., Kelly, K., Maru, B., Bramato, B., Khvorova, A., Watts, J.Improving siRNA delivery to the central nervous system (CNS) is a major focus for treating the numerous debilitating neurological conditions which have a genetic basis. Here, we present an albumin-binding siRNA based on an amphiphilic dendrimer conjugate (D-siRNA). We demonstrate that D-siRNA achieves effective and homogeneous delivery throughout the CNS following administration into the cerebrospinal fluid (CSF). In mice, a single CSF administration of D-siRNA resulted in potent and durable gene silencing across various brain regions, with effects lasting six […]
- by Shuangxi, T., Zhu, X., Yin, K., Tang, H., Wang, X.As developing obese adipose tissue, adipocytes suffer pathological changes from inert energy storage to excessive and active endocrine organ in association with disease hazard. METTL3, as an RNA methyltransferase of key importance in adipose tissue development, functional preservation and metabolic homeostasis, is remarkably complex. Licoisoflavone A (LIC-A) is a prenylated flavonoid compound of licorice that has been suggested to display antiinflammatory, -hypertrophic, and -proliferative activities; it remains unknown whether it can directly modulate expression of METTL3 and impact functions of […]
- by The Immunogenicity Database Collaborative (IDC),, Agnihotri, S., Gonzalez-Nolasco, B., Monian, B., Pattijn, S., Ackaert, C., Wu, P., Kettenberger, H., Tourdot, S., Hickling, T., Hu, Z., Higgs, R. E., Leventhal, D. S.The incidence and impact of anti-drug antibodies (ADAs) against biotherapeutics remain difficult to predict, limiting efforts to mitigate immunogenicity risk prior to clinical trials. Existing data are fragmented across disparate sources with inconsistent definitions, representing a key barrier to progress in the field. Here, we present the Immunogenicity Database Collaborative (IDC) and its release of the Immunogenicity Database (DB) V1: a structured clinical immunogenicity dataset integrating therapeutic characteristics, sequence, and patient cohort-level data from publicly available sources. The dataset includes […]
- by Keith, M., Stander, C., De Gregorio, D., Huang, A., Townsend, S., Sheybani-Deloui, S., Zigman, J., Hughes, J., Castro, D. C.Most clinically and recreationally used opioids drugs act on the endogenous mu opioid receptor (MOPR). While MOPR is typically studied in the context of addiction and analgesia, decades of evidence indicates that they have a strong modulatory role on metabolism and glycemia. However, whether these effects are directly driven by MOPR actions on pancreatic islets remains poorly understood. Here we sought to comprehensively profile MOPRs on islets to assess how their activity shapes cellular physiology and secretion. First, we used […]
- by Hoegeman, K. M., Wotring, J. W., Fursmidt, R., Gaetz, J., Khalil, E. M., Selinger, D. W., Schultz, T. L., McCarty, S. M., O'Meara, M. J., Clasby, M. C., Sexton, J. Z.BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent condition characterized by fat build-up in the liver and ranges from benign steatosis to progression to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and end-stage liver disease including hepatocellular carcinoma, representing a significant cause of chronic liver disease globally.1,2 Current treatment options are limited, primarily relying on lifestyle modifications, highlighting an urgent need for novel therapeutic strategies. MethodsA Cell Painting-style high-content screening phenotypic assay was employed using the PH5CH8 human hepatocyte […]
- by Payne, N. R., Scott, S. M., Scalf, M., Dobbelmann, R. F., Engel, S., Lee, A. M.Acute alcohol withdrawal encompasses somatic withdrawal signs and increased negative affect. In prolonged alcohol withdrawal the somatic withdrawal signs have resolved but the increased negative affect persists. We investigated acute and prolonged alcohol withdrawal after 9 daily injections of 2.5 g/kg alcohol plus 4-methypyrazole, an alcohol dehydrogenase inhibitor, in male and female C57BL/6J mice, and examined whether nicotinic acetylcholine receptor (nAChR) drugs could attenuate withdrawal-induced negative affect. Male mice showed changing somatic withdrawal signs over time and negative affect that […]
- by Gomez, K., Efimenko, K., Genzer, J., San Miguel, A.Polydimethylsiloxane (PDMS), often assumed to be biocompatible, is widely used in microfluidic devices and biomedical research. Here, we systematically assess the organismal effects of PDMS network components and their leachates using Caenorhabditis elegans as a whole-animal model. We demonstrate that uncrosslinked vinyl-terminated PDMS (v-PDMS) chains, which comprise the majority of a PDMS network and are known to diffuse into aqueous environments, exhibit acute, environmentally-dependent toxicity. Low-molecular-weight v-PDMS (6 kDa) caused mild lethality in nutrient-rich S-Medium but significantly higher mortality in […]
- by Kirchhofer, S., Jelinek, V., Klingelhoefer, K., Krett, A.-L., Buenemann, M.G-Protein coupled receptors (GPCRs) mediate intracellular signaling by selectively activating heterotrimeric G-proteins. While certain GPCRs exhibit a high specificity toward particular G-protein subtypes, other GPCRs display promiscuous signaling by engaging interaction with multiple G-protein families. Molecular determinants underlying the selectivity or promiscuity of the receptors remain incompletely understood. In the present study, we investigate various structural motifs within the intracellular domains of Muscarinic receptors to assess their role in both G subunit binding and activation. To this end, we generated […]
- by Eilertsen, J., Schnell, S., Walcher, S.Drug-target occupancy time–the cumulative duration a target remains bound–critically influences therapeutic efficacy. While Copelands widely-used residence time (1/koff) emphasizes dissociation kinetics, it neglects association rates, rebinding events, and drug elimination that affect in vivo outcomes. Returning to Paul Ehrlichs 1913 principle that drugs act only when bound ("Corpora non agunt nisi fixata"), we develop a mathematically rigorous framework defining Ehrlich occupancy time as the integral of fractional target occupancy over time. Our approach explicitly incorporates association (kon) and dissociation (koff) […]
- by Martinez, M., Longstaff, D. G.PurposeTo explore the utility of the Matrix of Chemistry, Manufacturing and Control (MoCMC) approach for evaluating product physicochemical (Q3) similarity as part of a product bioequivalence assessment. MethodologyEach Q3 parameter was converted to a radius of a polygon using a mathematical equation that converted each reference Q3 parameter to a value of "5". That equation was applied to the corresponding test product Q3 parameter and the areas of the treatment polygons determined. The ratio of the product area/outer area [Matrix […]
- by SARENG, H. R., Dutta, N., Manna, A., chandel, s., Goswami, R. K., Pal, M., Chakrabarti, S., Mukhopadhyay, j., Ravichandiran, V., Ghosh, N., Kamal, I. M.Parkinsons disease (PD) is a major debilitating health concern for millions of the elderly population all over the world. This progressive neurodegenerative disorder also poses a severe mental and financial burden to caregivers and society. Despite a major thrust on research for therapy development, no significant progress has been made; only temporary management options are currently available. To this end, we have reported azadiradione (AZD), a triterpenoid that we isolated from neem seed extract using a cell-based assay. AZD showed […]
- by Lee, T., Liu, J., Park, Y., Rakotondraibe, H. L., Cheng, X., Piermarini, P. M.TRPA1 channels are multi-modal receptors in animals for sensing noxious physical and chemical factors. They are considered promising biochemical targets for developing repellents of arthropod disease vectors and drugs to treat a variety of medical conditions including pain, inflammation, and itch. Recently, we discovered that cinnamodial (CDIAL), a natural drimane sesquiterpene produced by the medicinal plant Cinnamosma fragrans, agonizes mosquito TRPA1 channels and is antifeedant and repellent to Aedes aegypti. However, the selectivity of CDIAL for mosquito vs. human TRPA1 […]
- by El Sayed, A., Kluzek, M., Serwa, R., Azzi, A.Masitinib is an oral tyrosine kinase inhibitor developed initially for the treatment of mastocytosis. Preclinical studies suggest that masitinib can modulate mast cell activity and neuroinflammation, making it a potential therapeutic candidate for neurodegenerative diseases. However, clinical outcomes remain inconclusive, which may be linked to a lack of understanding of its molecular mechanism of action and potential off-target effects. Using a panel of cancer cell lines, we found that masitinib suppresses mTORC1 activity while simultaneously inducing AKT phosphorylation. Interestingly, thermal […]
- by Menon, K., Davasam, A., Chen, G., Bryant, C., Lam, B., Yang, C., Barcelos, D., Liu, Y., Liu, F., Alon, A., Lyu, J.Deep-learning methods for protein structure prediction, such as AlphaFold2 (AF2) and RosettaFold (RF), have transformed structural biology and accelerated downstream biological discovery. More recent models, including AlphaFold3 (AF3) and RosettaFold All-Atom (RFAA), extend this capability to protein-ligand co-folding, enabling direct prediction of bound complexes from sequence and ligand inputs. This advance has raised the possibility that such models could function not only as structure predictors but also as AI-based molecular docking engines for virtual screening. Yet their true impact on […]
- by Hao, X., Vincelle-Nieto, A., Reyes Palomares, A., Salumets, A., Reyes-Palomares, A., Rodriguez-Wallberg, K. A.The alkylating chemotherapeutic cyclophosphamide (CPA) is gonadotoxic, commonly resulting in depletion of ovarian primordial follicles and leading to infertility and premature menopause in female cancer patients. However, the mechanisms underlying the early stages of CPA-induced ovarian damage are unclear, limiting our ability to prevent gonadotoxicity. This study provides a comprehensive temporal exploration of the transcriptomic profiles of ex vivo intact mouse ovaries exposed to CPA. Analyses of CPA responses from 8 to 36 hours revealed an important early role of […]
- by Ottosson, N. E., Frampton, D. J. A., Pipatpolkai, T., Norman, C., Karlsson, U., Miguel, A. J., Venter, M., Sridhar, A., Green, H., Liin, S. I.Synthetic cannabinoid receptor agonists (SCRAs) is a large group of structurally diverse designer drugs (analogues of controlled substances) associated with intense and sometimes fatal intoxication. Cardiac symptoms including tachycardia and arrhythmia are common consequences of SCRA consumption. However, little is known about the mechanisms through which SCRAs may perturb cardiac rhythm. Here we used electrophysiological techniques to screen 36 SCRAs on two ion channels responsible for cardiomyocyte repolarization, hERG (also called KV11.1) and KV7.1/KCNE1. We report that the majority of […]
- by Powell, A. J., Griggs, N., Iniguez-Lluhi, J., Traynor, J. R.The conformational selection model of G-protein coupled receptor (GPCR) activation suggests that, by binding to a high affinity site, an agonist will shift receptor equilibrium in favor of active state (R*) conformations that recruit heterotrimeric G proteins over inactive state (R) conformations. Agonist binding to the -opioid receptor is highly sensitive to sodium ions which stabilize an inactive receptor state. Higher efficacy opioid agonists, such as DAMGO and fentanyl, are sensitive to Na+ compared to lower efficacy ligands at the […]
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