Biology subjects

Meijer, L.

Publications and source records attributed to Meijer, L..

9 recordsLinked to original sources

bioRxiv2026

Additive Effects Dominate Legume Responses to Combined Heat and Drought Stress: A Quantitative Review

Concurrent exposure to heat and drought stress compromises legume productivity, yet their combined effects are rarely quantified systematically. We compiled a database of 18 studies covering seven legume species. From these, we extracted 929 physiological, biochemical, and yield-related traits and calculated actual-to-additive ratios to classify heat-drought interactions as antagonistic (ratio < 1), additive (ratio = 1), or synergistic (ratio > 1). Additive heat-drought relationships accounted for 59 % of all classifiable observations, 37% relationships were antagonistic, and 4% synergistic. The relationship varied with species, genotype, trait, and experimental conditions highlighting the complexity of combined abiotic stress effects. The results challenge the common assumption that concurrent stresses invariably exacerbate damage and underscore the need for more realistic, quantitatively defined stress treatments as well as frameworks that integrate trait-level responses into predictive models of crop growth and development. Our synthesis provides a quantitative foundation to understand legume phenotypes under the increasingly frequent co-occurrence of heat and drought stress and identifies research areas where further work is needed to improve insight into combined stress responses. HighlightsO_LICombined heat and drought responses were mainly additive or antagonistic. C_LIO_LIEvidence is biased toward few legumes and controlled environments. C_LIO_LIField-based, multi-species studies are needed to identify adaptive traits. C_LI

plant biology↗

bioRxiv2026

Ciliogenesis associated kinase 1 accumulates in its inactive form during polycystic kidney disease progression

Ciliogenesis associated kinase 1 (CILK1) deficiency in human and mice results in kidney developmental defects including cystogenesis. However, the biology of CILK1 in autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, remains to be investigated. Here, we show that CILK1 is overexpressed in dedifferentiated cells of renal tissue from ADPKD human patients in comparison to normal control tissue samples. We demonstrate that CILK1 overexpression results in protein accumulation in a non-phosphorylated inactive form. Using mouse polycystic kidney disease models, we reveal that inactive CILK1 accumulation is progressive over the course of disease progression. We show that genetic inactivation of the Polycystic Kidney Disease 1 (PKD1) gene is sufficient to trigger CILK1 accumulation. Altogether, these findings demonstrate that CILK1 regulation is altered in ADPKD and it represents a hallmark of disease progression.

biochemistry↗

bioRxiv2026

Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 iPSC-derived neural cells

Dysregulated expression and activity of DYRK1A, dual specificity tyrosine phosphorylation regulated kinase 1A, is a feature of several neurodevelopmental and neurodegenerative diseases, including Down syndrome, DYRK1A syndrome, autism spectrum disorders, Alzheimers disease, and Parkinsons disease. Thus, manipulating DYRK1A activity in the brain has emerged as a potential therapeutic target for neurological disorders. Several DYRK1A inhibitors have shown promise for improving cognition in rodent models of Down syndrome and Alzheimers disease, for example, but the ability to affect DYRK1A levels or activity in relevant human cells has not been established. We filled this gap by testing the effects of a new DYRK1A inhibitor on trisomy 21 induced pluripotent stem cell derived neural progenitor cells and neurons, where DYRK1A expression and activity are increased. Our results demonstrate that Leucettinib-21, a potent and selective low-molecular weight pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in human trisomy 21 neural progenitor cells and cortical neurons. We show for the first time that Leucettinib-21 reduces DYRK1A activity in a relevant human disease model, supporting future human trials. Summary StatementWe show for the first time that Leucettinib-21, a pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in a human iPSC-derived neural cell culture model of Down syndrome.

developmental biology↗

bioRxiv2025

Network Modeling Predicts How DYRK1A Inhibition Promotes Cardiomyocyte Cycling after Ischemic/Reperfusion Injury

The adult mammalian heart has a limited ability to regenerate lost myocardium following myocardial infarction (MI), largely due to the poor proliferative capacity of cardiomyocytes (CMs). Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a known regulator of cell quiescence, though the mechanisms underlying its function remain unclear. Previous studies have shown that pharmacological inhibition of DYRK1A using harmine induces CM cell cycle re-entry after ischemia/reperfusion (I/R) MI. Here, we developed a computational network model of DYRK1A-mediated regulation of the cell cycle, which predicts how DYRK1A inhibition promotes CM re-entry. To validate these predictions, we tested selective DYRK1A inhibitors and observed robust induction of cell cycle activity in neonatal rat cardiomyocytes (NRCMs). Integrating our network model with bulk RNA-sequencing data from DYRK1A inhibitor-treated NRCMs, we identified E2F1 as a key transcriptional driver of cell cycle gene expression. Finally, we demonstrate that both pharmacological and post-developmental inhibition of DYRK1A enhances heart function and increases CM cycling following I/R MI. Our findings suggest that functional recovery induced by small molecule inhibitor of DYRK1A is mediated by the induction of cycling CMs. One Sentence SummaryInhibition of DYRK1A through LCTB-92 induces cardiomyocyte cycling and improved heart function in a mouse model of ischemic/reperfusion injury.

pharmacology and toxicology↗

bioRxiv2024

Phenotyping the hidden half: Combining UAV phenotyping and machine learning to predict barley root traits in the field

Improving crop root systems for enhanced adaptation and productivity remains challenging due to limitations in scalable non-destructive phenotyping approaches, inconsistent translation of root phenotypes from controlled environment to the field, and a lack of understanding of the genetic controls. This study serves as a proof of concept, evaluating a panel of Australian barley breeding lines and cultivars (Hordeum vulgare L) in two field experiments. Integrated ground-based root and shoot phenotyping was performed at key growth stages. UAV-captured vegetation indices (VIs) were explored for their potential to predict root distribution and above-ground biomass. Machine learning models, trained on a subset of 20 diverse lines, with the most accurate model applied to predict traits across a broader panel of 395 lines. Unlike previous studies focusing on above-ground traits or indirect proxies, this research directly predicts root traits in field conditions using VIs, machine learning and root phenotyping. Root trait predictions for the broader panel enabled genomic analysis using a haplotype-based approach, identifying key genetic drivers, including EGT1 and EGT2 which regulate root gravitropism. This approach offers the potential to advance root research across various crops and integrate root traits into breeding programs, fostering the development of varieties adapted to future environments. HighlightIntegrating UAV phenotyping and machine learning can be used to predict RSA traits non-destructively and offers a new approach to support root research and crop improvement.

physiology↗

bioRxiv2023

Congenital heart defects in Down syndrome are caused by increased dosage of DYRK1A

Down syndrome (DS), trisomy 21, is a gene dosage disorder which results in multiple phenotypes including congenital heart defects (CHD). This clinically important pathology is caused by a third copy of one or more of the [~]230 genes on human chromosome 21 (Hsa21), but the identity of the causative dosage-sensitive genes is unknown and hence pathological mechanisms remain obscure. We show that embryonic hearts from human fetuses with DS and mouse models of DS have reduced expression of mitochondrial respiration and cell proliferation genes correlating with CHD. Using systematic genetic mapping, we determine that three copies of the Dyrk1a gene, encoding a serine/threonine protein kinase, are required to cause CHD. Reducing Dyrk1a copy number from three to two reverses defects in proliferation and mitochondrial respiration in embryonic cardiomyocytes and rescues septation defects in DS hearts. Furthermore, treatment of pregnant mice with a DYRK1A inhibitor developed for clinical use partially reduces the incidence of CHD among Dp1Tyb embryos. Thus, increased dosage of DYRK1A is required to impair mitochondrial function and cause CHD in DS, revealing a therapeutic target for this common human condition. One Sentence SummaryIncreased dosage of DYRK1A causes mitochondrial dysfunction and congenital heart defects in Down syndrome and is ameliorated in utero by a drug.

developmental biology↗

bioRxiv2022

Genetic Impairment of Succinate Metabolism Disrupts Bioenergetic Sensing in Adrenal Neuroendocrine Tumor

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of mitochondrial TCA cycle enzyme, succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect in PC tumors, triggers dysregulation of Ca2+ homeostasis, and aberrantly activates calpain and the protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a cascade of phospho- signaling where GSK3 inhibition inactivates energy sensing by AMP-kinase through dephosphorylation of the AMP-kinase {gamma} subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC tumor formation. A novel Cdk5 inhibitor, MRT3-007, reversed this phospho-cascade, invoking an anti- Warburg effect, cell cycle arrest, and senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important novel mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers. HighlightsO_LILoss of SDHB function in pheochromocytoma causes Ca2+ dysregulation, calpain activation, and aberrant activation of the protein kinase Cdk5. C_LIO_LIHyperactive Cdk5 deregulates a GSK3/PRKAG2/AMPK signaling cascade. C_LIO_LIp25 overexpression and consequent aberrant Cdk5 activity in chromaffin cells causes pheochromocytoma. C_LIO_LIInhibition of Cdk5 activates the PRKAG2/AMPK/p53 signaling to rescue cell senescence and block PC tumor progression. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/475410v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@16f0a48org.highwire.dtl.DTLVardef@10c1c7aorg.highwire.dtl.DTLVardef@21b100org.highwire.dtl.DTLVardef@1eb8674_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Bronchoalveolar lavage affects thorax computed tomography of healthy and SARS-CoV-2 infected rhesus macaques (Macaca mulatta)

Medical imaging as method to assess the longitudinal process of a SARS-CoV-2 infection in non-human primates is commonly used in research settings. Bronchoalveolar lavage (BAL) is also regularly used to determine the local virus production and immune effects of SARS-CoV-2 in the lower respiratory tract. However, the potential interference of those two diagnostic modalities with each other is unknown in non-human primates. The current study investigated the effect and duration of BAL on computed tomography (CT) in both healthy and experimentally SARS-CoV-2-infected female rhesus macaques (Macaca mulatta). In addition, the effect of subsequent BALs was reviewed. Thorax CTs and BALs were obtained from four healthy animals and 11 experimentally SARS-CoV-2-infected animals. From all animals, CTs were obtained just before BAL, and 24 hours post-BAL. Additionally, from the healthy animals, CTs immediately after and four hours post-BAL were obtained. Thorax CTs were evaluated for alterations in lung density, measured in Hounsfield units, and a visual semi-quantitative scoring system. An increase in the lung density was observed on the immediately post-BAL CT but resolved within 24 hours in the healthy animals. In the infected animals, a significant difference in both the lung density and CT score was still found 24 hours after BAL. Furthermore, the differences between timepoints in CT score were increased for the second BAL. These results indicate that the effect of BAL on infected lungs is not completed within the first 24 hours. Therefore, it is of importance to acknowledge the interference between BAL and CT in rhesus macaques.

biophysics↗

bioRxiv2020

Comparison of SARS-CoV-2 infection in two non-human primate species: rhesus and cynomolgus macaques

The post-acute phase of SARS-CoV-2 infection was investigated in rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis). During the acute phase of infection, SARS-CoV-2 was shed via nose and throat, and viral RNA was occasionally detected in feces. This phase coincided with a transient change in systemic immune activation. Even after the alleged resolution of the infection, as suggested by the absence of viral RNA in nasal and tracheal swabs, computed tomography (CT) and positron emission tomography (PET)-CT were able to reveal pulmonary lesions and activated tracheobronchial lymph nodes in all animals. Post-mortem histological examination of the lung tissue revealed mostly marginal or resolving minimal lesions that were indicative of SARS-CoV-2 infection. Evidence for SARS-CoV-2-induced histopathology was also found in extrapulmonary tissue samples, like conjunctiva, cervical and mesenteric lymph nodes. However, 5-6 weeks after SARS-CoV-2 exposure, upon necropsy, viral RNA was still detectable in a wide range of tissue samples in 50% of the macaques and included amongst others the heart, the respiratory tract and surrounding lymph nodes, salivary gland, and conjunctiva. Subgenomic messenger RNA was detected in the lungs and tracheobronchial lymph nodes, indicative of ongoing virus replication during the post-acute phase. These results could be relevant for understanding the long-term consequences of COVID-19 in humans. Author summaryMore than a year after the start of the pandemic, the long-term consequences of SARS-CoV-2 infection start to surface. The variety of clinical manifestations associated with post-acute COVID-19 suggests the involvement of multiple biological mechanisms. In this study, we show that rhesus and cynomolgus macaques shed virus from their respiratory tract, generate virus-specific humoral immune responses, and show signs of SARS-CoV-2-induced lung pathology. PET-CT revealed that both species showed ongoing mild to moderate pulmonary disease, even after the virus was no longer detectable in nasal and tracheal swabs. Five to six weeks after infection, necropsy confirmed minimal to mild histopathological manifestations in various tissues, like the lungs, heart, lymph nodes, and conjunctiva. We detected Viral RNA in the heart, respiratory tract, and tracheobronchial lymph nodes, and subgenomic messenger RNA in the lungs and surrounding lymph nodes, indicative of ongoing virus replication. We show widespread tissue dissemination of SARS-CoV-2 in infected macaques and the presence of replicating virus in lungs and surrounding lymph nodes after alleged convalescence of infection. This finding is intriguing in the light of long-COVID disease symptoms seen in humans as it has been hypothesized that persistent infection may contribute to this phenomenon.

microbiology↗