Biology subjects

Olofsson, P.

Publications and source records attributed to Olofsson, P..

8 recordsLinked to original sources

bioRxiv2025

NOD1 ligand FK565 promotes atherogenesis and accumulation of NOD1high smooth muscle cells in atherosclerotic lesions

AimsNucleotide-binding oligomerization domain-containing protein (NOD)1 is an intracellular pattern recognition receptor that initiates immune responses upon ligation of molecules such as bacterial peptidoglycan containing a D-glutamyl-meso-diaminopimelic acid (iE-DAP) moiety. NOD1 ligation has been shown to promote vascular inflammation and atherosclerosis. In this study, we investigate the functional role of NOD1 in atherosclerotic plaques and characterize the vascular cells responsible for NOD1 expression and function. Methods and resultsNOD1 was mainly expressed in a subtype of vascular smooth muscle cells (SMC) in human atherosclerotic lesions. In ex vivo cultures, human endarterectomy specimens reacted to NOD1 ligand by activation of mitogen-activated protein kinase (MAPK) pathways, leading to cytokine expression. Levels of NOD1 mRNA were higher in carotid endarterectomy specimens obtained from symptomatic patients compared to asymptomatic ones. NOD1high SMC were also found in arteries of atherosclerosis-prone Ldlr-/- mice. Challenging these mice with a NOD1 agonist resulted in transmural vascular inflammation, severe arterial damage, accelerated atherogenesis throughout the aorta, and evidence of occlusive coronary artery disease. In rats, mechanic injury to carotid arteries promoted NOD1high SMC expansion and neointima formation. In vitro, neointima derived NOD1high SMCs responded to NOD1 ligand exposure by enhanced migration, increased iNOS+ cells and amplified CCL5 production. ConclusionOur findings show that NOD1 promotes vascular inflammation, vascular injury responses and atherosclerosis by acting on a NOD1high subtype of SMC.

immunology↗

bioRxiv2023

Highly pathogenic avian influenza causes mass mortality in Sandwich tern (Thalasseus sandvicensis) breeding colonies across northwestern Europe

AO_SCPLOWBSTRACTC_SCPLOWIn 2022, highly pathogenic avian influenza (HPAI) A(H5N1) virus clade 2.3.4.4b became enzootic and caused mass mortality in Sandwich terns and other seabird species across northwestern Europe. We present data on characteristics of the spread of the virus between breeding colonies and the number of dead adult Sandwich terns recorded at breeding sites throughout northwestern Europe. Within two months after the first mortalities were reported, in total 20,531 adult Sandwich terns were found dead, which is >17% of the total northwestern European breeding population. Losses are likely higher, as we expect that many victims were not found (mortality rate might be up to 74% of the breeding population). Inside the colonies almost all chicks died. After the peak of the outbreak, in a colony established by late breeders, 25.7% of adults showed immunity against HPAI subtype H5. Removal of carcasses helped in reducing the spread of the disease and consequently total mortality. More research on the sources and modes of transmission, incubation times, effective containment and immunity is urgently needed to combat this major threat for colonial seabirds.

ecology↗

bioRxiv2021

Noninvasive Stimulation of Peripheral Nerves using Temporally-Interfering Electrical Fields

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation noninvasively without surgically implanted devices is enabling for fundamental research and clinical translation. Here we demonstrate how relatively high frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. We validate this principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, we demonstrate how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve. Our method is simple, relying on repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.

neuroscience↗

bioRxiv2021

A Branching Process Model of Evolutionary Rescue

Evolutionary rescue is the process whereby a declining population may start growing again, thus avoiding extinction, via an increase in the frequency of fitter genotypes. These genotypes may either already be present in the population in small numbers, or arise by mutation as the population declines. We present a simple two-type discrete-time branching process model and use it to obtain results such as the probability of rescue, the shape of the population growth curve of a rescued population, and the time until the first rescuing mutation occurs. Comparisons are made to existing results in the literature in cases where both the mutation rate and the selective advantage of the beneficial mutations are small.

evolutionary biology↗

bioRxiv2020

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

Two formyl peptide receptors (FPR1 and FPR2), abundantly expressed by neutrophils, regulate both pro-inflammatory tissue recruitment of neutrophils and resolution of inflammatory reactions. This dual functionality of the FPRs, opens for a possibility to develop receptor selective therapeutics as mechanism for novel anti-inflammatory treatments. In line with this, high throughput screening studies have identified numerous FPR ligands belonging to different structural classes, but a potent FPR1 agonist with defined biased signaling and functional selectivity has not yet been reported. In this study, we used an FPR1 selective small compound agonist (RE) that represents a chemical entity developed from NOX2 activators identified from our earlier screening studies (WO2012127214). This FPR1 agonist potently activates neutrophils to produce reactive oxygen species (ROS, EC50 ~1 nM), whereas it is a weaker chemoattractant than the prototype FPR1 agonist fMLF. At the signaling level, RE has a strong bias towards the PLC-PIP2-Ca2+ pathway and ERK1/2 activation but away from {beta}-arrestin recruitment and the ability to recruit neutrophils chemotactically. In addition, FPR1 when activated by RE could cross-regulate other receptor-mediated neutrophil functions. In comparison to the peptide agonist fMLF, RE is more resistant to oxidization-induced inactivation by the MPO-H2O2-halide system. In summary, this study describes as a novel FPR1 agonist displaying a biased signaling and functional selectivity when activating FPR1 in human blood neutrophils. RE could possibly be a useful tool compound not only for further mechanistic studies of the regulatory role of FPR1 in inflammation in vitro and in vivo, but also for developing FPR1specific drug therapeutics.

cell biology↗

bioRxiv2019

Antibody responses to immunization require sensory neurons

Mammals store memories in the nervous and immune systems. Sensory neurons have been implicated in enhancing neurological memory, but whether neurons participate during immunity to novel antigens is unknown. Here, mice rendered deficient in transient receptor potential vanilloid 1 (TRPV1)-expressing sensory neurons, termed "nociceptors," fail to develop competent antibody responses to KLH and hapten-NP. Moreover, selective optogenetic stimulation of TRPV1 neurons during immunization significantly enhanced antibody responses to antigens. Thus, TRPV1 nociceptors mediate antibody responses to novel antigen, and stimulating TRPV1 nociceptors enhances antibody responses during immunization. This is the first genetic and selective functional evidence that nociceptors are required during immunization to produce antigen-specific antibodies. SummaryThe first genetic and selective functional evidence showing that TRPV1-expressing nociceptors are required for competent antibody responses to novel antigen, and stimulating TRPV1 nociceptors enhances antibody responses to novel antigen.

immunology↗

bioRxiv2019

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study. To gain more insights into FPR2 recognition of this first-in-class compound for future utility of the agonist, we have in this study determined the receptor preference and down-stream signaling characteristics induced by Act-389949 in human blood neutrophils isolated from healthy donors. Our data demonstrate that Act-389949 is an agonist for FPR2 that triggers functional/signaling repertoires comparable to what has been earlier described for other FPR2 agonists, including neutrophil chemotaxis, granule mobilization and activation of the NADPH-oxidase. In fact, Act-389949 was found to be as potent as the prototype FPR2 peptide agonist WKYMVM and had the advantage of being resistant to oxidation by the MPO-H2O2-halide derived oxidants, as compared to the sensitive WKYMVM. The down-stream signals generated by Act-389949 include an FPR2-dependent and Gq-independent transient rise in intracellular Ca2+ and recruitment of {beta}-arrestin. In summary, our data show that Act-389949 serves as an excellent tool-compound for further dissection of FPR2-regulated activities in vitro and in vivo. Potent and stable FPR ligands such as Act-389949 may therefore be used to develop the next generation of FPR signaling regulating anti-inflammatory therapeutics.

pharmacology and toxicology↗

bioRxiv2018

Muller’s Ratchet in Asexual Populations Doomed to Extinction

Asexual populations are expected to accumulate deleterious mutations through a process known as Mullers ratchet. Lynch and colleagues proposed that the ratchet eventually results in a vicious cycle of mutation accumulation and population decline that drives populations to extinction. They called this phenomenon mutational meltdown. Here, we analyze mutational meltdown using a multi-type branching process model where, in the presence of mutation, populations are doomed to extinction. We analyse the change in size and composition of the population and the time of extinction under this model.

evolutionary biology↗