Biology subjects

Arner, A.

Publications and source records attributed to Arner, A..

5 recordsLinked to original sources

bioRxiv2026

Rhodopsin is a tunable capacitor buffering the toxic, desensitizing retinoids of the vertebrate eye

The eye is a marvel of evolution, but visual sensitivity introduces the risk of blinding photodamage. Here we reveal that the locus of sensitivity--the visual pigment rhodopsin --moonlights as a tunable mechanism of retinal photoprotection. Independent of signaling, light activated rhodopsin (R*) serves as an overflow capacitor buffering all-trans retinal (atRAL), a toxic and desensitizing retinoid agonist that accumulates as lipofuscin--a clinical marker of macular degeneration. Across mammals, R* stability reflects binding affinity and sequestration of atRAL (capacitance), thereby mitigating phototoxicity to a degree proportional to species photodamage risk, with human R* uniquely non-protective. A mouse model of defective atRAL clearance treated with a synthetic R* of unnaturally high atRAL capacitance preserved retinal function following light damage. This gene therapy also provided supra-physiological scotopic sensitivity despite being a signal-silent receptor, shielding neighboring dark-state receptors from agonist interference during regeneration, while also enhancing the signaling of endogenous R*. While the consensus human rhodopsin is not photoprotective, during recent evolution, mutations that protect against light damage emerged in high irradiance human environments and are now significantly associated with a 38% reduced risk of blindness and low vision. Together, our findings redefine rhodopsin as a tunable light buffer that can be leveraged to enhance photoreceptor function beyond natural limits.

biochemistry↗

bioRxiv2026

Divergent Biological Consequences of APOE Isoforms Across Industrialized and Non-Industrial Environments

The apolipoprotein {varepsilon}4 (APOE {varepsilon}4) isoform directly alters cholesterol and immune biology and is associated with an increased risk of neurodegenerative and cardiometabolic disease in industrialized settings; nevertheless, APOE {varepsilon}4--which is ancestral in humans--has persisted over evolutionary time. One potential explanation is that the costs and benefits of APOE {varepsilon}4 were significantly different in the environments in which humans evolved compared to those we experience today. In support, previous work has suggested that living in a high pathogen environment, engaging in high levels of physical activity, or eating a low fat diet can dampen the detrimental effects of APOE {varepsilon}4, and has revealed positive effects for fertility. However, direct tests of whether APOE isoforms are associated with different biological outcomes in non-industrial versus industrialized contexts are lacking. Working with the Turkana of Kenya and the Orang Asli of Peninsular Malaysia--two Indigenous groups in which individuals of shared ancestry span a continuum of subsistence, non-industrial to urban, industrialized lifestyles--we investigated how APOE genotypes impact cholesterol, immunological, and reproductive traits and tested for genotype x environment (GxE) interactions. First, we confirmed established genotype effects across lifestyles, showing that more APOE {varepsilon}4 alleles are associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol. Second, we tested for lifestyle interactions, finding lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli but not Turkana. Finally, we show that more APOE {varepsilon}4 alleles are correlated with an extended reproductive lifespan, however this effect is relatively weak, is not consistent across populations, and does not correspond with a higher reproductive output. Together, our study provides evidence that industrialized environments can modify the biology of APOE {varepsilon}4; however, we find that APOE {varepsilon}4 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits.

evolutionary biology↗

bioRxiv2023

fhl2b expression ameliorates muscular dystrophy

In muscular dystrophies, muscle fibers loose integrity and die, leading to significant suffering and a shorter life. Strikingly, the extraocular muscles (EOMs), controlling eye movements, are spared and function well despite the disease progression. Although EOMs have been shown to have important differences compared to body musculature the mechanisms underlying this inherent resistance to muscle dystrophies remain largely unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscle in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is upregulated in response to knockout of desmin, plectin and obscurin, intermediate filament proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival rate. Therefore, fhl2 is a protective agent and a candidate target gene for therapy of muscle dystrophies.

cell biology↗

bioRxiv2020

In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets

High-throughput sequencing describes multiple alterations in each tumor (1), but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient (2). Here, we established a Cre-ERT2-loxP based inducible RNAi-mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition was initiated in mice harboring orthotopic tumors. Fluorochrome guided, competitive in vivo trials identified a major tumor-maintaining potency of the MLL-AF4 fusion protein and validated MCL1 as vulnerability in some, but not all patients tumors. We could prove DUX4 to play an essential role in patients leukemias carrying the recently described DUX4-IGH translocation. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future.

cancer biology↗

bioRxiv2017

Long-term cardiovascular re-programming by short-term perinatal exposure to nicotine‘s main metabolite cotinine

BackgroundCotinine - a nicotine by-product and biomarker of passive perinatal tobacco smoke exposure - is historically considered to lack significant health effects. We challenged this notion and sought \"proof-of-concept\" evidence of the adverse developmental potential of exposure to this substance at real-life levels.\n\nMethodsPregnant C57 mice drank nicotine or cotinine-laced water for 6wks from conception (NPRE = 2% saccharin+100g nicotine/ml; CPRE = 2% saccharin + 10g cotinine/ml) or for 3wks after birth (CPOST = 2% saccharin + 30g cotinine/ml). Controls drank 2% saccharin (CTRL). At 17{+/-}1weeks male pups (CTRL n=6; CPOST n=6; CPRE n=8; NPRE n=9) were instrumented for EEG and blood pressure (BP) telemetry. We evaluated (i) cardiovascular control during sleep (at rest / during stress); (ii) arterial reactivity ex vivo; (iii) expression of genes involved in arterial constriction/dilation.\n\nResultsBlood cotinine levels (ELISA) recapitulated passive smoker mothers-infants. Pups exposed only to cotinine exhibited (i) mild bradycardia - hypotension at rest (p<0.001); (ii) attenuated (CPRE, p<0.0001) or reverse (CPOST; p<0.0001) BP reactivity to asphyxia; (iii) pronounced adrenergic hypo-contractility (p<0.0003), low Protein Kinase C (p<0.001) and elevated adrenergic receptor mRNA (p<0.05) (all drug-treated arteries). NPRE pups also exhibited endothelium-mediated dysfunction.\n\nConclusionsCotinine has subtle, enduring developmental consequences. Some cardiovascular effects of nicotine can plausibly arise via conversion to cotinine. Low-level exposure to this metabolite may pose unrecognized perinatal risks. Adults must avoid inadvertently exposing a fetus or infant to cotinine as well as nicotine.

physiology↗