Biology subjects

Eklund, M.

Publications and source records attributed to Eklund, M..

5 recordsLinked to original sources

bioRxiv2025

Estrogen Impacts Nod2-Dependent Regulation of Intestinal Homeostasis

Mutations in the innate immune receptor NOD2 are the greatest single genetic risk factor for Crohns disease, yet the mechanisms by which NOD2 regulates intestinal homeostasis remain unclear. We used a CRISPR-generated zebrafish model to determine the impacts of NOD2 deficiency on intestinal health. In cellular, molecular, and transcriptomic studies, we uncovered substantial effects of NOD2 deficiency on epithelial and immune compartments, including deregulated expression of developmental pathways that establish and maintain the gut epithelium, and an unexpected increase in the expression of multiple estrogen-response genes. In functional assays, we uncovered a mechanistic link between estrogenic signals and NOD2-deficiency phenotypes, whereby exposure to estrogen alone replicated the effects of NOD2-deficiency, and treatment with the estrogen receptor modulator tamoxifen reverted the epithelial defects observed in nod2 mutants. Our findings identify a NOD2-estrogen regulatory axis that supports intestinal homeostasis and suggest that hormonal signaling may contribute to sex-specific aspects of Crohns disease.

immunology↗

bioRxiv2025

Conformational dynamics in the membrane interactions of bispecific targeted degrader therapeutics

Proteolysis targeting chimeras (PROTACs) offer vast new therapeutic opportunities, however their physicochemical properties are difficult to combine with optimal cell permeability and exposure at the target sites. We have systematically analyzed a dataset of more than 3500 PROTACs to investigate how the choice of ubiquitin E3 ligase ligands, linker design, and global molecular properties can be optimized to achieve the desired cell permeability and intracellular exposure. We find that conformational flexibility leads to environment-dependent shielding of polar functions and improved interactions with cell membranes, but that at the same time extended, linear conformations within the membrane are beneficial. Linker composition was a major factor in determining the folding propensity. Collectively, our results suggest that strategies to rationally design linkers and to shield polarity selectively within the protein-of-interest (POI) ligand and/or E3 ligand domains, rather than more extensive folding, may be beneficial in the design of permeable and effective PROTACs.

pharmacology and toxicology↗

bioRxiv2023

SINGLE CELL RESOLUTION OF THE ADULT ZEBRAFISH INTESTINE UNDER CONVENTIONAL CONDITIONS, AND IN RESPONSE TO AN ACUTE VIBRIO CHOLERAE INFECTION.

Vibrio cholerae is an aquatic bacterium that primarily infects the gastrointestinal tract, causing the severe and potentially deadly diarrheal disease, cholera. Despite the impact of Vibrio on global health, our understanding of host mucosal responses to the pathogen at the site of infection remains limited, highlighting a critical knowledge gap that must be addressed to develop more effective prevention and treatment strategies. Using a natural infection model, we combined physiological and single-cell transcriptomic studies to characterize adult zebrafish guts raised under conventional conditions and after a challenge with Vibrio. We discovered that Vibrio causes a mild mucosal immune response characterized by T cell activation and enhanced antigen capture in the epithelium. Additionally, we discovered that Vibrio suppresses host interferon signaling, and that ectopic activation of interferon significantly alters the course of infection. Notably, we also found that the adult zebrafish gut shares many similarities with mammalian counterparts, including the presence of previously undescribed Best4+ cells, tuft cells, and a population of basal cycling cells. These discoveries provide important insights into host-pathogen interactions and emphasize the utility of zebrafish as a natural model of Vibrio infection.

immunology↗

bioRxiv2021

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

ObjectivesInvestigate how WNK1 inhibition modulates glucotoxicity, mitochondrial/peroxisomal protein regulation and metabolism, and right ventricular (RV) function in pulmonary arterial hypertension (PAH). Determine how hypochloremia impacts RV function in PAH patients. BackgroundIn PAH-induced RV failure, GLUT1/GLUT4 expression is elevated, which increases glucose uptake and glycolytic flux to compensate for mitochondrial dysfunction. However, the resultant consequences of the glucose-mediated post-translational modifications (PTM), protein O-GlcNAcylation/glycation in RV failure are understudied. WNK1, a chloride-sensitive kinase, increases GLUT1/GLUT4 expression in skeletal muscle, but its regulation in RV dysfunction is unexplored. MethodsRats were treated with WNK463 (small molecule WNK inhibitor) or vehicle starting two weeks after monocrotaline injection. Immunoblots quantified protein abundance/PTMs. Mitochondrial/peroxisomal proteomics and global metabolomics evaluated glucose metabolism and mitochondrial/peroxisomal function. Pulmonary vascular and cardiac histology, echocardiography, and pressure-volume loop analysis quantified RV function and PAH severity. Finally, the relationship between hypochloremia, a WNK1-activating state, and RV function was evaluated in 217 PAH patients. ResultsWNK463 decreased WNK1/GLUT1/GLUT4 expression, normalized glucose metabolite levels, which dampened excess protein O-GlcNAcylation/glycation. Integration of RV mitochondrial/peroxisomal proteomics and metabolomics identified fatty acid oxidation (FAO) as the most dysregulated metabolic pathway. WNK463 enhanced FAO as demonstrated by increased expression of mitochondrial FAO proteins and normalization of RV acylcarnitines. WNK463 reduced glutaminolysis induction and lipotoxicity, two secondary consequences of diminished FAO. WNK463 augmented RV systolic and diastolic function independent of pulmonary vascular disease severity. In PAH patients, hypochloremia resulted in more severe RV dysfunction. ConclusionsWNK463 combated RV glucotoxicity and impaired FAO, which directly improved RV function. HighlightsO_LISmall molecule inhibition of WNK1 (WNK463) signaling mitigates upregulation of the membrane glucose channels GLUT1 and GLUT4, restores levels of several glucose metabolites, and normalizes protein O-GlcNAcylation and glycation in the RV. C_LIO_LIQuantitative proteomics of RV mitochondrial enrichments shows WNK463 treatment prevents downregulation of mitochondrial enzymes in the tricarboxylic acid cycle, fatty acid oxidation pathway, and the electron transport chain complexes. C_LIO_LIIntegration of proteomics and metabolomics analysis reveals WNK463 reduces glutaminolysis induction and lipotoxicity due to impaired fatty acid oxidation C_LIO_LIWNK463 augments RV systolic and diastolic function independent of PAH severity. C_LIO_LIHypochloremia, a condition of predicted WNK1 activation, in PAH patients results in more severe RV dysfunction. C_LI

physiology↗

bioRxiv2018

A natural history model for planning prostate cancer testing: calibration and validation using Swedish registry data

Recent prostate cancer screening trials have given conflicting results and it is unclear how to reduce prostate cancer mortality while minimising overdiagnosis and overtreatment. Prostate cancer testing is a partially observable process, and planning for testing requires either extrapolation from randomised controlled trials or, more flexibly, modelling of the cancer natural history.\n\nAn existing US prostate cancer natural history model (Gulati et al, Biostatistics 2010;11:707-719) did not model for differences in survival between Gleason 6 and 7 cancers and predicted too few Gleason 7 cancers for contemporary Sweden. We re-implemented and re-calibrated the US model to Sweden. We extended the model to more finely describe the disease states, their time to biopsy-detectable cancer and prostate cancer survival. We first calibrated the model to the incidence rate ratio observed in the European Randomised Study of Screening for Prostate Cancer (ERSPC) together with age-specific cancer staging observed in the Stockholm PSA (prostate-specific antigen) and Biopsy Register; we then calibrated age-specific survival by disease states under contemporary testing and treatment using the Swedish National Prostate Cancer Register.\n\nAfter calibration, we were able to closely match observed prostate cancer incidence trends in Sweden. Assuming that patients detected at an earlier stage by screening receive a commensurate survival improvement, we find that the calibrated model replicates the observed mortality reduction in a simulation of ERSPC.\n\nUsing the resulting model, we predicted incidence and mortality following the introduction of regular testing. Compared with a model of the current testing pattern, organised 8 yearly testing for men aged 55-69 years was predicted to reduce prostate cancer incidence by 0.11% with no increase in the mortality rate. The model is open source and suitable for planning for effective prostate cancer screening into the future.\n\nAuthor summaryA naive perspective is that cancer screening is simple: people are screened, some cancers are detected early, and cancer mortality rates decline. However, the mathematics for screening becomes difficult quickly, it is hard to infer causation from observational data, and even large randomised screening studies provide limited evidence. Simulations are therefore important for planning cancer screening.\n\nWe found an older US prostate cancer natural history model to be poorly suited for contemporary Sweden. We therefore re-implemented and re-calibrated the US model using data from Swedish registries.\n\nOur revised model, the Stockholm \"Prostata\" model, provides predictions similar to those observed in the detailed Swedish registers on prostate cancer incidence and mortality. By modelling the mechanisms of the screening effect, we can predict the benefits and harms under a range of screening interventions.

epidemiology↗