Biology subjects

Meijer, J.

Publications and source records attributed to Meijer, J..

8 recordsLinked to original sources

bioRxiv2026

Identification of small-molecule enhancers of circadian rhythm amplitude in central and peripheral clocks

The circadian clock regulates daily rhythms in metabolism, behavior, and physiological homeostasis. Damped or disrupted circadian rhythms are linked to physiological malfunctions, including neurodegeneration, metabolic syndrome, and cancers. Enhancing circadian rhythm amplitude can strengthen the processes regulated through the circadian system and offer a potential therapeutic approach. Here, we present eight small-molecule enhancers of circadian amplitude with previously unrecognized roles in circadian regulation. By using a Bmal1 transcription reporter system in NIH3T3 fibroblasts, we screened a drug repurposing library comprising 5,631 diverse compounds. Through which eight molecules were identified to increase circadian amplitude across multiple cycles, in a dose-dependent manner, without significantly perturbing period or phase. We evaluated the physiological potential of these compounds in ex vivo mouse tissues expressing PER2 luminescence reporter. A set of compounds tested in organotypic liver or suprachiasmatic nucleus slices enhanced the circadian amplitude in respective tissues, showing their suitability for peripheral as well as central clocks. Single-cell imaging of suprachiasmatic nucleus slices revealed that amplitude enhancement results from increased expression of clock proteins in individual cells rather than from intercellular synchronization. Together, these compounds and their targets present a new array of circadian amplitude modulators that may present opportunities to pharmacologically enhance clock robustness in physiology and disease. Significance StatementThrough a network of molecular interactions, the circadian clock coordinates rhythms of biochemical and behavioural processes, right from the level of a single cell to organs. Therefore, maintaining a strong circadian clock, through its high-amplitude circadian rhythm, is crucial. However, few pharmacological approaches and targets are known to enhance circadian amplitude. This study presents eight previously uncharacterized amplitude enhancer molecules by conducting a chemical screen on cultured fibroblasts. Identified molecules also induced amplitude enhancement in mouse-derived liver and brain-SCN slices, showing their robust functionality across tissues. In brain-SCN slices, the amplitude enhancement was found to occur on the single-cell level without affecting the synchronization between cells.

biochemistry↗

bioRxiv2023

Morpho-electric and computational properties of three types of human hippocampal CA1 pyramidal neurons

Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal pyramidal neurons, even though human hippocampus underwent strong evolutionary reorganization and shows lower theta rhythm frequencies. To test whether biophysical and computational properties of human CA1 pyramidal neurons can explain observed rhythms, we map the morpho-electric and computational properties of individual CA1 pyramidal neurons in human, non-pathological hippocampal slices from neurosurgery. Human CA1 pyramidal neurons have extensive dendrites and resonate at 2.9 Hz, optimally tuned to human theta frequencies. Morphological and biophysical properties reveal three cell types with distinct dendrite bifurcations and physiology. Data-driven biophysical models show that human CA1 pyramidal neurons use i) computationally independent dendritic compartments, ii) preferential routing of electrical activity towards soma or dendritic tree and iii) non-linear input-output transformations. Across cell types, morpho-electric properties consistently increase computational richness in human CA1 pyramidal neurons. TeaserHuman CA1 pyramidal neurons have large and intricate morphologies, which translates to complex computational properties.

neuroscience↗

bioRxiv2023

Eco-evolutionary dynamics of massive, parallel bacteriophage outbreaks in compost communities

Bacteriophages are important drivers of microbial ecosystems, yet their dynamics in complex natural communities remain poorly understood compared to simplified laboratory systems. To address this gap, we analyzed viral dynamics across 20 compost-derived microbial communities propagated for one year in mesocosms. Communities clustered into two distinct types, each dominated by different cellulose-degraders and comprising hundreds of genera. In one type, we observed massive, parallel outbreaks of Theomophage, a previously undescribed bacteriophage, reaching 74% of metagenomic sequencing reads, the largest bacteriophage outbreak documented to date. Theomophage populations in isolated communities were composed of a single genotype that showed striking evolutionary stability throughout the experiment. In contrast, following experimental viral migration between mesocosms, all Theomophage populations showed rapid evolution via recombination between preexisting genotypes, replacement of ancestral lineages, and, upon successful migration to mesocosms of the alternate community type where Theomophage was initially absent, rapid acquisition of novel mutations that swept local populations and then spread to other mesocosms. Our study reveals the spatial and temporal scales at which bacteriophage microdiversity evolves in complex communities. It further shows that mixing of viral communities -- likely common in natural systems -- can rapidly accelerate bacteriophage evolution.

microbiology↗

bioRxiv2023

Identifying and tracking mobile elements in evolving compost communities yields insights into the nanobiome

Microbial evolution is driven by rapid changes in gene content mediated by horizontal gene transfer (HGT). While mobile genetic elements (MGEs) are important drivers of gene flux, the nanobiome - the zoo of Darwinian replicators that depend on microbial hosts - remains poorly characterised. New experimental approaches and analyses are necessary to advance our understanding beyond simple pairwise MGE-host interactions. To detect horizontal transfer, a bioinformatic pipeline (xenoseq) was developed to cross-compare metagenomic samples, which was then applied to metagenomic data from evolving compost communities. These communities were routinely exposed to an "MGE cocktail" derived from allopatric communities. We show that this results in horizontal transfer of a multitude of previously undetected MGEs, including bacteriophages, phage-plasmids, megaplasmids, and even nanobacteria. Sequences that spread from one community to another are shown to disproportionally carry characteristics of phages and insertion-sequences, i.e., traits of canonically parasitic MGEs. We also show that one particularly prolific mobile element - a 313 kb plasmid - correlates substantially with rates of ammonia production, which under nitrogen limitation is likely beneficial. Taken together, our data show that new experimental strategies combined with bioinformatic analyses of metagenomic data stand to provide insight into the drivers of microbial community evolution.

microbiology↗

bioRxiv2022

Behavioral activity increases neuronal activity in the circadian clock of diurnal Arvicanthis ansorgei

2.The central circadian clock, located in the suprachiasmatic nucleus (SCN) within the brain, regulates daily patterns of activity and physiology. Many studies indicate that exercise at specific times throughout the day can help maintain proper circadian rhythms. In nocturnal animals, even moderate levels of physical activity suppress the neuronal discharge rate of the SCN. Given that such a mechanism would likely be counter-effective in diurnal animals, we measured the firing rate of SCN neurons in freely moving diurnal Arvicanthis ansorgei using implanted microelectrodes. We found that SCN firing was acutely increased rather than decreased both during brief (seconds) and long (hours) bouts of activity, and returned to baseline levels after behavioral activity ceased. We also found that daytime activity increases the strength of the SCN rhythm, as expected for day-active animals. To determine whether the acute increases in firing are produced within the SCN or in response to input from outside the SCN, we performed ex vivo recordings in which afferent inputs are severed. We found no intrinsic increment occurring in the isolated SCN. These findings suggest that the excitatory effect on the SCNs neuronal firing rate comes from areas that lie outside the SCN, presumably those that are affected by the animals activity. We conclude that exercise has opposite effects on the clock between nocturnal and diurnal rodents, and identified how exercise strengthens the neuronal discharge rhythm in the clock of a diurnal animal. 3. Significance statementOur biological clock controls behavioral activity rhythms by generating a 24-pattern of electrical activity. The electrical activity serves as output of the clock and is high during the day and low during the night. Physical activity, being under strong control of the clock, acts vice versa, and affects the electrical activity of the clock. In nocturnal animals, behavioral activity inhibits the clocks firing rate. Here, we examined the effect of behavioral activity on the brains clock in the diurnal rodent, Arvicanthis. When the animal is active, the clocks electrical activity is enhanced, rather than decreased. Thus, a diurnal animal can increase the strength of its own clock, by being active during the day. Preprint ServersThe manuscript was deposited as a preprint in bioRxiv preprint doi: https://doi.org/10.1101/2022.05.31.493966; this version posted June 1, 2022. The copyright holder for this preprintin bioRxiv, made available under aCC-BY-NC-ND 4.0 International license (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ClassificationBiological Sciences, Physiology

neuroscience↗

bioRxiv2021

Reduced plasticity in coupling strength in the SCN clock in aging as revealed by Kuramoto modelling

The mammalian circadian clock is located in the suprachiasmatic nucleus (SCN) and consist of a network of coupled neurons, which are entrained to the environmental light-dark cycle. The phase coherence of the neurons is plastic and driven by the length of the day. With aging the capacity to behaviorally adapt to changes in the light regime reduces. The mechanisms underlying photoperiodic adaptation are largely unknown, but are important to unravel for the development of novel interventions to improve the quality of life of the elderly. We analyzed the neuronal synchronization of PER2::LUC protein expression in the SCN of young and old mice entrained to either long or short photoperiod and used the synchronization levels as input for a two-community noisy Kuramoto model. With the Kuramoto model we estimated the coupling strength between and within neuronal subpopulations. The model revealed that the coupling strength between and within subpopulations contributes to photoperiod induced changes in the phase relationship among neurons. We found that the SCN of young mice adapts in coupling strength over a large range, with low coupling strength in long photoperiod and higher coupling strength in short photoperiod. In aged mice we also found low coupling strength in long photoperiod, but strongly reduced capacity to reach high coupling strength in short photoperiod. The inability to respond with an increase in coupling strength shows that manipulation of photoperiod is not a suitable strategy to enhance clock function with aging. We conclude that the inability of aged mice to reach high coupling strength makes aged mice less capable to seasonal adaptation than young mice. Author SummaryCircadian clocks drive daily rhythms in physiology and behavior. In mammals the clock resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN consist of a network of coupled neurons which are synchronized to produce a coherent rhythm. Due to plasticity of the network, seasonal adaptation to short winter days and long summer days occurs. Disturbances in circadian rhythmicity of the elderly have negative health effects, such as neurodegenerative diseases. With the rise in life expectancy this is becoming a major issue. In our paper, we used a model to compare the neuronal coupling in the SCN between young and old animals. We investigated whether exposure to short photoperiod can strengthen coupling among clock cells, and thereby clock function, in old animals. We observed that this is not possible, indicating that simple environmental manipulations are not an option. We suggest that receptor targeted interventions are required, setting the path for further investigation.

neuroscience↗

bioRxiv2020

Global trends in biodiversity and ecosystem services from 1900 to 2050

Despite the scientific consensus on the extinction crisis and its anthropogenic origin, the quantification of historical trends and of future scenarios of biodiversity and ecosystem services has been limited, due to the lack of inter-model comparisons and harmonized scenarios. Here, we present a multi-model analysis to assess the impacts of land-use and climate change from 1900 to 2050. During the 20th century provisioning services increased, but biodiversity and regulating services decreased. Similar trade-offs are projected for the coming decades, but they may be attenuated in a sustainability scenario. Future biodiversity loss from land-use change is projected to keep up with historical rates or reduce slightly, whereas losses due to climate change are projected to increase greatly. Renewed efforts are needed by governments to meet the 2050 vision of the Convention on Biological Diversity. One Sentence SummaryDevelopment pathways exist that allow for a reduction of the rates of biodiversity loss from land-use change and improvement in regulating services but climate change poses an increasing challenge.

ecology↗

bioRxiv2019

Anticipation of a serial transfer protocol through the evolution of fine-tuned growth dynamics

BackgroundExperimental evolution of microbes often involves a serial transfer protocol, where microbes are repeatedly diluted by transfer to a fresh medium, starting a new growth cycle. This protocol has revealed that evolution can be remarkably reproducible, where microbes show parallel adaptations both on the level of the phenotype as well as the genotype. However, these studies also reveal a strong potential for divergent evolution, leading to diversity both between and within replicate populations. We here study how in silico evolved Virtual Microbe "wild types" (WTs) adapt to a serial transfer protocol to investigate both the generic evolutionary adaptation to such an environment which are independent of prior evolution, and the variety of ways in which the adaptation is implemented at the individual and ecosystem level. ResultsWe show that all pre-evolved WTs evolve to anticipate the regularity of the serial transfer protocol by adopting a fine-tuned balance of growth and survival. We find that this anticipation can be done in a variety of ways, either by a single lineage or by several lineages in consort. Interestingly, replicate populations of the same WT initially show similar trajectories, but may subsequently diverge along a growth rate versus yield trade-off. ConclusionsWe find that all our in silico WTs show the same anticipation effects -- fitting the periodicity of a serial transfer protocol -- but do so by a variety of mechanisms. Our results reveal new insights into the dynamics and relevant selection pressures in experimental evolution, but also highlight how, in an eco-evolutionary context, numerous mechanisms can evolve to the same end.

evolutionary biology↗