- by Chen, P., Bauer, R. J., Li, Y.Population pharmacokinetic (popPK) models are commonly developed using ordinary differential equations (ODEs) to describe deterministic concentration-time profiles, with unexplained variability typically attributed to interindividual variability or residual error. When model misspecification is present, system-level deviations may be absorbed into these conventional variability terms, making the source and magnitude of model inadequacy difficult to assess quantitatively. Stochastic differential equations (SDEs) provide an alternative framework by introducing an explicit system-noise component into the structural model, allowing model-data mismatch to be evaluated more […]
- by Alimoradi, H., Abri Aghdam, M., Fallah, A., Delporte, C.Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective targeted therapies and is frequently associated with chemotherapy resistance and immunosuppression. Inducible nitric oxide synthase (iNOS) is overexpressed in breast cancer and has been strongly correlated with poor clinical outcomes, owing to its role in promoting tumor progression, invasiveness, and resistance to therapy. Although highly selective iNOS inhibitors such as N-(3-(Aminomethyl)benzyl)acetamidine (1400W) exhibit considerable therapeutic promise, their clinical translation has been hindered by unfavorable pharmacokinetic properties. […]
- by Sayers, C. J., Huamani Valdivia, L., Siguas Gonzales, C. P., Pisconte, J. N., Vega, C. M., Yurek, H., Regan, K., Adams, E., Huaraca-Charca, N. R., Cal, R., Reneau, S., Martinez, W., Welch, G., Hartwell, K. S., Evers, D. C., Fernandez, L. E., Tingley, M. W.Abstract 1. Heavy metals are pervasive environmental contaminants that can impair the health of organisms globally. As the largest anthropogenic source of the potent neurotoxin mercury (Hg), gold mining has amplified these threats throughout the tropics. Consequently, there is a mounting need to monitor Hg contamination of the richest biological communities on Earth. Venous whole blood provides a reliable, nonlethal measurement of recent dietary and site-derived contamination, but collecting and cold-storing samples can be impractical in field conditions. 2. To […]
- by Peterson, R., Baldwin, N., Clark, A. J., Kaminski, N. E., Hoberman, A., Pala, R., Lewis, E., Vaden-Harris, A., Malinczak, C.-A.The preclinical safety of human-equivalent lactoferrin alpha (heqLF; effera(R)), produced by Komagataella phaffii, was evaluated to support its use as a food ingredient in infant formula and products for young children. Genotoxicity was assessed using a bacterial reverse mutation (Ames) assay in five strains of Salmonella typhimurium and Escherichia coli, and an in vitro micronucleus assay in TK6 cells. Both studies followed OECD guidelines and were conducted up to the recommended limit concentrations (5000 g/plate and 2000 g/mL, respectively). A […]
- by Martin, N. L., Holmes, S. E., Siegel, J. B.Migraine headaches affect over one billion people internationally and can be defined as episodes of acute severe pain wrapping around the head and are normally accompanied by nausea, blurry vision, and sensitivity to light and sound. While triggers that cause migraines may vary among patients, evidence shows they are involved with the trigeminovascular system (a network of blood vessels in the brain in conjunction with the trigeminal nerve). Activation of the trigeminal neurons triggers the release of vasoactive neuropeptides, such […]
- by Napier Khwaja, F., Mariam, Z., Abdolhay, Y., Poyner, D., Deganutti, G., Wheatley, M., Ayub, H.Small-molecule agonists of class B1 G-protein-coupled receptors (GPCRs) remain rare because these receptors typically require large extracellular peptide ligands for activation. PCO371 is a notable exception: an intracellular agonist, originally developed for osteoporosis treatment, that activates the parathyroid hormone 1 receptor (PTH1R) from the cytoplasmic face of the receptor. In this study, we compared the functional, pharmacological and structural properties of PCO371 with the canonical extracellular peptide PTH1-34 at the PTH1R to define the mechanism underlying PCO371's unusual signalling profile. […]
- by Nguyen, T. D., Gould, C. E., Sanborn, J. T., Tutin, J., Pan, Y., Gao, H., Ruszaj, D., Angevine, D., Bussa, J., Atakora, D., Chen, L., Roach, D. R., Wood, T. D., Smith, N. M.Accurate quantitation of therapeutic bacteriophages (phages) remains a challenge for clinical development. Plaque-based enumeration is the current standard but is laborious, host-dependent, and variable, particularly when distinguishing individual phages in cocktails. Targeted mass spectrometry of virion structural proteins offers an orthogonal, structure-based approach amenable to reproducible and scalable phage quantitation. Here, we describe a targeted proteomic liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for host-independent quantitation of the Pseudomonas aeruginosa podovirus LUZ19. Proteomic characterization was performed on an LTQ Orbitrap XL […]
- by Kanyo, R., Smith, E., Allison, W. T., Kurata, H. T.Background and PurposeEpilepsy is a neurological condition characterized by recurring seizures and neuronal hyperexcitability. Cell-based high-throughput screening applications have been essential for drug development and discovering novel biological processes. However, cell-based screens do not provide information on how drug-targeted pathways are integrated into a whole animal. Our objective was to develop and evaluate a screening application using zebrafish larvae to identify signalling mechanisms that modulate neural activity. Experimental ApproachWe developed an in vivo automated high-content screening assay using zebrafish larvae […]
- by Forn-Cuni, G., van Lieshout, B., Koch, B., Villellas, C., Van Asten, S., Lanckacker, E., Stoops, B., Vreeken, R. J., Roymans, D., Krekels, E. H. J., van Hasselt, J. G. C., Spaink, H. P., van Wijk, R. C.The development of novel therapeutics for infectious diseases remains a global health priority. To accelerate the treatment development, innovative strategies through new approach methodology (NAM) are needed to bridge speed of in vitro with predictive power of in vivo studies, while reducing mammalian experiments. The zebrafish (Danio rerio), particularly the embryo/larva, has been established as a valuable non-mammalian in vivo model in biomedical research. We developed a standardized and streamlined workflow for the zebrafish as NAM, which consisted of 3 […]
- by Beeralingappa, N. C., Lu, M., Patel, R., Pannala, N., Dhiman, A., Heil, B. N., Imhoff, R. D., Smith, E. G., Bahler, M. B., Marsden, H. L., Allen-Petersen, B. L., Wendt, M. K., Das, C., Flaherty, D. P.The deubiquitinating enzyme, ubiquitin C-terminal hydrolase L3 (UCHL3), has been implicated as a potential therapeutic target for cancer with a role in regulating the DNA damage response pathways. While the target has been studied using genetic methods there is a lack of reliable chemical probes to selectivity target UCHL3. In this study we report hit identification and optimization of a new chemical scaffold that irreversibly inhibits UCHL3. The observed structure-activity relationships are corroborated by ligand-bound crystal structures that confirm covalent […]
- by Park, J., Miller, A. S., Pore, G., Banginwar, M., Lee, S., Li, J., Jung, E., Wagner, A., Smith, J., Malone, C., Brust-Mascher, I., Schoultz, I., Salihovic, S., Reardon, C., Gareau, M. G.Inflammatory bowel diseases (IBD) affect millions of patients worldwide and impair quality of life. Although genetic and environmental factors are known to disrupt the gastrointestinal (GI) epithelial barrier and increase susceptibility to IBD, the precise contribution of specific environmental exposures remains unclear. Per- and polyfluoroalkyl substances (PFAS), or "forever chemicals," are widely used in consumer products and contaminate food and water sources, resulting in chronic oral exposure worldwide. Perfluorooctanoic acid (PFOA), a common PFAS, has been epidemiologically associated with the […]
- by Kang, T., Jiao, Y., Lai, S., Tao, S., Chen, C., Cao, Z., Yan, F., Ding, Y., Li, X., Ke, B.Hydrogen persulfide (H2S2) is an important endogenous signaling molecule, holding significant therapeutic potential across diverse disease models due to its potent antioxidant and redox-regulating properties. Herein, we report the synthesis, characterization, and in vivo evaluation of an esterase responsive H2S2 donor, HPD1. It reduced mechanical and cold allodynia at 14 mg/kg (i.p.) in chronic constriction injury and paclitaxel-induced neuropathic pain models. Moreover, HPD1 exhibited negligible systemic toxicity and behavioral side effects even at 28 mg/kg. Electrophysiological tests showed that HPD1 […]
- by Mslati, H., Wilson, M., Naeinipour, M., Coulombe, G., Ezzine, M., Yuen, T., Bari, O., Singh, H., Tam, R., Sheff, J., Gentile, F., Leyton, J.Antibody-drug conjugates (ADCs) represent a significant advancement in cancer therapy, yet their development remains constrained by high attrition rates driven by an incomplete understanding of how ADC chemical design interconnects with tumor biology. Compounding this challenge, the field has converged on a narrow set of redundant structural components, and current linker-payload systems that do not share a single mechanism of action. Existing drug response prediction frameworks cannot resolve this multidimensional complexity, relying predominantly on genomic inputs while protein-level biology is […]
- by Zuo, R., Wang, M., Wang, Y., Hu, J. Z., Moura, A. K., Wang, D., Li, P.-L., Wu, M., Hussain, T., Gao, W., Li, X., Zhang, Y.Liver sinusoidal endothelial cells (LSECs) are increasingly recognized as a critical yet underexplored cell type in anti-fibrotic drug development. This study presents a computational drug screening platform integrating LSEC-specific transcriptomic analysis across simple steatosis, fibrotic nonalcoholic steatohepatitis (NASH), and cirrhosis, with tiered gene signature selection combining machine learning, large language model-assisted curation, gene safety assessment, and Connectivity Map-based screening using human endothelial perturbational profiles. The platform identifies 6 clinical-stage and 8 preclinical candidates with LSEC-protective potential. Among these, vorinostat (SAHA), […]
- by Process, A., Chamorro-Garcia, R., Diaz-Castillo, C.IntroductionIt is now widely recognized that environmental exposures can predispose unexposed descendants to disease across multiple generations without inducing genetic mutations. Among the numerous unknowns that multigenerational effects still hold, identifying the most probable windows of susceptibility for multigenerational environmental disease predisposition remains a crucial challenge in preventing such effects. We have proposed that multigenerational environmental effects can be mediated by perturbations in chromatin organization that originate from environmental exposures causing alterations in gamete elements necessary for establishing chromatin organization […]
- by Chen, J., Wang, J., Du, S., Chen, Y., Li, K., Song, J., Liu, D.Clinical pharmacokinetic (PK) modelling is constrained by sparse sampling, limited general-isability of single-drug models, and labour-intensive workflows, making it difficult to infer complete drug exposure from limited concentration observations. We present the Pharmacokinetic Foundation Model (PKFM), a grey-box Transformer framework pre-trained across 32 drugs that reconstructs concentration-time profiles from sparse concentration observations, dosing events, molecular descriptors, and physiological covariates while preserving output interpretability. In representative oral PK curves, three sparse input points recovered the principal absorption-elimination trajectory, achieving coefficient of […]
- by Xu, Y., Liang, R., Xia, P., Luo, S., Jiang, B., Wang, A., Liang, K., Wang, Y., Jing, W., Wang, S.Gut microbiota metabolic remodeling is a pivotal determinant in irinotecan-induced enterotoxicity and epithelial damage, although the underlying mechanisms remain unclear. Herein, we discovered that Daikenchuto (DKT), a traditional Chinese prescription for intestinal disorders, alleviated irinotecan-induced enterotoxicity without compromising its anti-tumor efficacy by improving weight loss, diarrhea, intestinal inflammation, and barrier damage, and these effects were partially dependent on gut microbiota. DKT significantly restored microbial tryptophan metabolism in irinotecan-treated rats, which was characterized by the enrichment of Limosilactobacillus reuteri, and elevated […]
- by Bans Burtchaell, P., Santiago, M., Wang, C., Hagdoost, M., Clay, E. J. M., Mohnot, D., Connor, M.3:(-)-trans-Cannabidiol ((-)-CBD) is a principal phytocannabinoid from Cannabis sativa. (-)-CBD has complex pharmacology but is a relatively weak inhibitor of CB1 and CB2 receptor signalling. Cannabidiol has two chiral centres and thus four stereoisomers. (+)-trans-CBD ((+)-CBD) has a higher affinity than (-)-CBD at CB1 and CB2, but its pharmacodynamic effects at these receptors are incompletely described. We examined the activity of (+)-CBD at human CB1 and CB2 receptors using a fluorescence-based assay of membrane potential in AtT20 cells stably expressing […]
- by Alahmadi, H., Harbolic, A., De Oliveria-Cordova, C., Reynolds, R., Jojy, M., Potts, C., Doan, S., Mathur, T., Islam, M. S., Andrade, M. J., Smith, Q., Stapleton, P., Mitra, S., Warner, G. R.Plastic production has been increasing exponentially. Throughout their lifespan, plastics degrade into smaller particles that accumulate in our bodies and the environment. Recent studies found these plastic particles can cross the placental barrier and reach the fetus. However, the impact of plastic particles on placental function is still unknown. We hypothesized that nanoplastics would disrupt placental growth and function, specifically focusing on transforming growth factor beta (TGF{beta}) signaling. To understand the impact of plastic particles on the placenta, we orally […]
- by LaCroix, A. S., Coungeris, N. S., Alstat, V. K., Rountree, C., Botta, P., Maaz, M., Butt, C. M.Drug-induced seizures remain a major safety concern in drug development, yet human seizure liability is difficult to predict using conventional preclinical models. Here, we evaluated whether spontaneous calcium network activity in human induced pluripotent stem cell-derived CNS-3D Brain Organoids could predict clinically observed seizure risk across a pharmacokinetically anchored drug set. CNS-3D organoids contained neuronal and astrocytic populations, expressed neuroactive receptor and ion-channel gene programs that aligned with human cortical tissue, and exhibited reproducible spontaneous calcium oscillations across production batches. […]
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