Biology subjects

Larsson, M.

Publications and source records attributed to Larsson, M..

At least 19 recordsLinked to original sources

bioRxiv2026

A novel adenovirus 19K/IX protein promotes infection by preventing proteasomal degradation of tyrosine-ubiquitinated capsid protein pIX

Human adenoviruses (HAdVs) are double-stranded DNA viruses that cause a wide range of diseases, including respiratory, ocular, and gastrointestinal infections. HAdVs rely extensively on alternative splicing to expand their coding capacity and regulate gene expression during infection. Using replication-competent epitope-tagged HAdV-C5 viruses, we investigated the function of the newly identified alternatively spliced viral transcript, 19K/IX, derived from E1B19K and pIX genes. We show that 19K/IX binds to and stabilizes the minor capsid protein IX (pIX), thereby preventing its proteasomal degradation and promoting the production of infectious viral progeny. Mechanistically, we demonstrate that pIX degradation is mediated by a non-canonical ubiquitination of conserved tyrosine residues, which also partially mediate pIX interaction with the PSMC3 subunit of the 26S proteasome. Collectively, these findings identify 19K/IX as a novel regulator of HAdV-C5 infection and suggest that non-canonical tyrosine ubiquitination may represent a mechanism by which HAdV-C5 modulates protein degradation during infection. Author summaryHuman adenoviruses (HAdVs) are clinically important pathogens and widely used as therapeutic tools. Because of their compact genomes, HAdVs use their genetic information very efficiently through alternative pre-mRNA processing. Here, we describe and characterize 19K/IX, a novel fusion protein generated by alternative splicing of two virus genes during infection. We demonstrate that 19K/IX stabilizes the capsid protein IX by preventing its degradation, revealing a previously unrecognized strategy by which HAdVs ensure efficient production of new virus particles. These findings deepen our understanding of HAdV-C5 gene regulation and protein homeostasis and highlight the functional importance of non-canonical viral transcripts.

microbiology↗

bioRxiv2026

Genomic Evolution of SARS-CoV-2 Delta Variants Pre- and Post-Omicron Emergence using Alignment-free Machine Learning models

The SARS-CoV-2 Delta variant (B.1.617.2), initially classified as a variant of concern due to its enhanced transmissibility and vaccine-escape mutations, underwent further genomic changes following the emergence of the Omicron variant (B.1.1.529). This study investigates the genomic differences in Delta variant spike gene sequences collected before and after the emergence of Omicron. A total of 190 sequences were analyzed using an alignment-free approach incorporating k-mer-based feature extraction and machine learning models, including convolutional neural networks (CNN), K-means clustering, and random forest classification. The random forest model achieved 93% accuracy, with significant F1 scores, effectively distinguishing the two Delta variant groups. Comparative analysis revealed 157 persistent mutations and four vanished mutations in the post-Omicron group. Cluster analysis showed notable shifts, indicating stable yet evolving genomic patterns over time. The study demonstrates the advantage of alignment-free methods in detecting subtle sequence variations that alignment-based approaches may overlook. These findings enhance our understanding of SARS-CoV-2 evolution and provide a framework for identifying key genomic signatures relevant to public health. The methodology and insights gained offer potential applications in variant surveillance, vaccine design, and viral evolutionary studies, supporting preparedness for future SARS-CoV-2 variant emergence.

genomics↗

bioRxiv2026

Rapid peripheral reprogramming of myelinated afferents drives human hyperalgesia

A small burn can render a large area of skin painfully tender. This widespread hyperalgesia protects injured tissue and is typically attributed to altered spinal cord mechanisms. Whether peripheral sensory afferents directly interact to contribute to hyperalgesia remains unclear. Using single-unit microneurography, we recorded cutaneous afferents before and after inducing localized TRPV1-mediated inflammatory flare. This triggered minutes-scale reweighting of transcriptomically defined TRPV1- afferents, with divergent effects among myelinated (A{beta}-range) classes: tactile receptors showed reduced responsiveness, whereas mechano-nociceptors underwent sensitization. These changes paralleled diminished tactile sensitivity and intensified mechanical pain. Recruitment of mechanically silent branches in A{beta}-range mechano-nociceptors produced wide-field amplification of peripheral nociceptive signaling beyond the inflamed site. These findings suggest that rapid peripheral crosstalk from TRPV1+ afferents reprograms TRPV1- A{beta}-afferents and drives human hyperalgesia.

neuroscience↗

bioRxiv2025

The aging transcriptome: a condition-dependent response to a deteriorating soma

Organismal function requires precise gene expression, as deviations reduce fitness and can cause disease. The widespread expression changes characteristic of old age therefore suggests that aging itself may partly stem from gene dysregulation. Alternatively, many of these changes may represent a plastic response to somatic decline, tuning the organism to an altered physiological state. We tested the latter hypothesis by experimentally reducing the condition of Drosophila melanogaster females independently of age and comparing the resulting expression changes with those occurring naturally during aging. Consistent with the plasticity hypothesis, we find substantial overlap between genes responding to reduced condition and old age. Downregulated genes are enriched for metabolic functions, with a consistent, albeit weaker, association with mitochondrial function and cytoplasmic translation, while upregulated genes relate to genome maintenance. Both old age and reduced condition also cause downregulation of tissue-specific and female-biased genes, as expected when energy is reallocated to core cellular processes. In line with a coordinated transcriptional response to old age, both down- and upregulated genes within enriched functional categories show reduced expression variability and experience strong purifying selection. Collectively, our results support that the aging soma elicits a plastic transcriptional program that adjusts the organism to a declining physiological condition, implying that many age-related expression changes mitigate rather than accelerate somatic aging. These findings call for a more nuanced view of the causes and consequences of age-related transcriptional change, with implications for both theoretical and applied research on aging and disease.

genetics↗

bioRxiv2025

Hierarchical organization of mechano-nociceptive pathways revealed by activity labeling

Noxious mechanical stimuli give rise to distinct percepts, from sharp cutaneous pain to diffuse visceral discomfort, yet the nociceptor ensembles that underlie these differences remain poorly defined. We mapped the peripheral architecture of nociceptive signaling by combining in vivo activity labeling of pelvic nerve afferents with single-cell RNA sequencing. Noxious stimuli recruited diverse classes of mechano-nociceptors, but stimulus type exerted modest influence on the composition of activated ensembles. Instead, tissue identity imposed the dominant organizational structure: stimulation of cutaneous and deep pelvic tissues engaged distinct subsets of both myelinated and unmyelinated neurons, revealing a clear domain-level division. Within this architecture, we identified a bladder-innervating myelinated nociceptor subtype with distinctive molecular features, illustrating an additional layer of refinement. Functional imaging and anatomical tracing corroborated this multilevel organization. These findings reveal a hierarchical organization of peripheral mechanical pain encoding, in which mechano-nociceptor populations are differentially engaged according to tissue domain and organ context.

neuroscience↗

bioRxiv2025

Central role for fast nociceptors in mechanical nocifensive behavior and sensitization

Nociceptors, primary afferent nerve fibers that signal noxious stimuli, are broadly divided into slowly conducting unmyelinated C fibers and fast-conducting myelinated A fibers. Whereas C-nociceptors have been extensively studied, considerably less is known about the function of A-nociceptors. To address this gap, we developed an intersectional genetic approach for robust and selective interrogation and manipulation of mechanically responsive A-nociceptors (A-MNs) in mice. Optogenetic A-MN stimulation induced rapid and precise withdrawal reflexes as well as place aversion and facial expression changes consistent with pain affect, while inhibition strongly impaired mechanical nociceptive withdrawal reflexes, demonstrating that A-MNs are necessary and sufficient for rapid avoidance of noxious mechanical stimuli. Prolonged A-MN activation induced mechanical allodynia and central sensitization. In a rare individual lacking thickly myelinated A{beta} fibers, mechanical withdrawal reflexes were completely absent, and pain perception reduced. Together, these findings identify fast-conducting mechano-nociceptors as essential drivers of nocifensive behaviors in mice and humans.

neuroscience↗

bioRxiv2025

Unheralded high MHC Class II polymorphism in the abundant Atlantic herring resolved by long-read sequencing

Major Histocompatibility Complex (MHC) genes are the most polymorphic in vertebrate genomes due to their important function of presenting a diversity of peptides from pathogens to initiate an adaptive immune response. Here, we have characterized MHC class II genes and explored their polymorphism and evolution in one of the most abundant vertebrates in the world, Atlantic herring (Clupea harengus). The vast population size and schooling behavior make Atlantic herring an attractive target for pathogens. Hence, we hypothesized that it would maintain exceptionally high MHC polymorphism. We used PacBio HiFi long-read whole genome sequencing data of 14 individuals from three different geographic regions in the Atlantic Ocean and Baltic Sea. The analysis identified nine MHC class II loci distributed across four chromosomes. We found two distinct lineages of class II genes, a highly polymorphic one denoted DA and a non-polymorphic DB lineage, arranged as alpha-beta gene pairs (DAA-DAB or DBA-DBB). The DA genes showed extremely high nucleotide diversity in exon 2, strong signatures of positive selection (dN/dS >> 1) as well as copy number variation. Structure prediction revealed that all highly polymorphic amino acid residues occurred in the predicted peptide binding cleft. Two of the most polymorphic loci showed distinct allelic groupings (supertypes), with high sequence similarity within supertypes and high sequence divergence between supertypes. Most of the haplotypes had genes from different supertypes, thus maintaining diverse class II repertoire in a single individual. There was also a highly significant nonrandom association of DAA and DAB alleles within supertypes, strongly suggesting coevolution of DAA and DAB alleles forming the peptide binding domain. This study reveals that the herring MHC class II genes are among the most, if not the most, polymorphic so far described in vertebrates. Their exceptional polymorphism surpasses that of human due to a larger gene repertoire, copy number variation, and pronounced sequence divergence among alleles. This unheralded polymorphism is most likely explained by the combined effects of the vast population size, minimizing genetic drift, and strong pathogen-driven balancing selection.

immunology↗

bioRxiv2025

Genetic targeting of myelinated primary afferent neurons using a new NefhCreERT2 knock-in mouse

Primary afferent neurons that convey somatosensory modalities comprise two large, heterogeneous populations: small-diameter neurons that give rise to slowly conducting unmyelinated axonal C fibers and medium-to-large diameter neurons with fast myelinated A fibers. Despite these two major groupings, tools to differentiate between unmyelinated and myelinated primary afferent fibers by genetic targeting have not been available; in particular, whereas numerous mouse driver lines exist to target different C fiber populations, genetic tools that target myelinated primary afferent populations are scarce. Here we describe a knock-in mouse line expressing tamoxifen-dependent CreERT2 under control of the Nefh gene, which encodes neurofilament heavy chain (NFH or NF200), a protein that is highly enriched in myelinated fibers. This mouse enables highly selective and efficient recombination of Cre-dependent reporters for functional and anatomical interrogation of myelinated fibers while excluding unmyelinated C fibers. In combination with other recombinase-expressing mouse lines, this genetic tool will be valuable for intersectional targeting of subpopulations of myelinated primary afferent fibers.

neuroscience↗

bioRxiv2025

A NaV1.8FlpO mouse enabling selective intersectional targeting of low threshold C fiber mechanoreceptors and nociceptors

Genetic targeting of select populations of cells in the mouse nervous system is often hampered by a lack of selectivity, as candidate genes for such targeting are commonly expressed by multiple cell populations, also in the same region. Intersectional targeting using two or more genes has been enabled by the development of reporter tools dependent on more than one recombinase or gene regulator. Still, widespread adoption of intersectional tools is complicated by a scarcity of driver mice expressing recombinases otherthan Cre. Here we report the generation and characterization of a new driver mouse that expresses the FlpO recombinase from the endogenous locus of the Scn10a gene encoding NaV1.8, a voltage-gated sodium channel that is almost exclusively expressed in the afferent limb of the peripheral nervous system. Moreover, among sensory neurons the channel is preferentially expressed in nociceptors and in low-threshold C-fiber mechanoreceptors (C-LTMRs). The mouse showed high recombination efficiency (97 %) and selectivity (93 %) in dorsal root ganglia. Reporter-expressing fibers were observed in a variety of peripheral tissues, including skin, skeletal muscle, genitalia, bladder and intestines. To validate the suitability of the FlpO mouse line for intersectional targeting, we crossed it with a mouse line expressing CreERT2 from the Th (tyrosine hydroxylase) locus. This approach resulted in strikingly selective and efficient targeting of C-LTMRs, showing robust visualization of nerve endings of these fibers in skin and spinal cord at the light and electron microscopic level. Thus, the NaV1.8Flpo mouse line presented here constitutes a selective and versatile tool for intersectional genetic targeting of NaV1.8 expressing primary afferent neurons.

neuroscience↗

bioRxiv2025

The Disc1 deletion common to many inbred mouse strains has negligible effects on social behavior of 129S4 mice in a semi-natural environment

Numerous mouse models have been engineered to carry alterations to the Disrupted in Schizophrenia 1 (Disc1) gene, thought to be involved in neurodevelopmental conditions. However, most Swiss and probably all 129 mouse substrains, which are widely used in biological research, naturally carry a 25 bp deletion in Disc1 exon 6. Despite the prevalence of these strains, little has been done to characterize the extent to which this natural mutation affects behavioral output and may unintentionally impact studies. Here, we report on experiments to test the effects of this deletion on social and exploratory behaviors. To model natural conditions, we designed a seminatural environment to house groups of mice (4 females and 1 male; 3 groups per strain) for prolonged periods and then employed this model to study social behaviors. First, we compared behavioral phenotypes in C57Bl/6Jrj (B6) mice and 129S4 (S4Disc1-/-) natural mutants to validate our setup. Then, to assess the contribution of the naturally mutated Disc1 to social behavior differences, the wild-type (WT) Disc1 allele was crossed into S4 mice (S4Disc1+/+). S4 and B6 lines were drastically different, with S4 mice being hypoactive, less explorative, and less social than B6 mice. However, S4 mice expressing WT Disc1 only marginally differed from S4Disc1-/- mice, showing little to no contribution of Disc1 to their behavioral phenotype. Thus, this mutation holds little significance for natural exploratory and social behaviors in the seminatural environment.

animal behavior and cognition↗

bioRxiv2025

A fast nociceptive subsystem mediating rapid reflexive behavior but not affective pain

Spinal nociceptive withdrawal reflexes are widely believed to rely on unmyelinated and thinly myelinated nociceptive fibers that also signal affective and motivational aspects of pain. Here we discover a population of myelinated mechanoreceptive nociceptor that forms free nerve endings as well as circumferential endings around hair follicles, and exclusively terminate in the deep spinal dorsal horn. Optogenetic activation of these fibers triggers rapid withdrawal reflexes that are precise and selective for the targeted limb, while silencing increases the threshold of mechanical nociceptive withdrawal reflexes. By contrast, optogenetic stimulation of the fibers is not associated with place aversion nor with changes in facial expression. Thus, we conclude that this nerve fiber population is uniquely positioned to rapidly respond to mechanical threats via selective withdrawal of the targeted body part, whereas other fast and slow nociceptive pathways are required for affective-motivational aspects of pain.

neuroscience↗

bioRxiv2025

HIV-1 derived replication intermediates/oligonucleotides induce a type I IFN-dependent immune suppression via STING activation that can be restored by targeting IFNARI

The hallmark of HIV-1 infection is the progressive development of multicellular and systemic immune dysfunction, culminating in AIDS. Dendritic cells (DCs) play a pivotal role in HIV dissemination to CD4+ T cells, which are subsequently depleted by the virus leading to HIV disease progression. Type I interferons (IFNs) are critical for host defense during acute infection but contribute to chronic immune activation during the later stages of HIV disease. This persistent activation leads to immune cell exhaustion. HIV-1 can activate type I IFN responses via several pathways, including the STING pathway, which is activated by e.g., virus-derived oligonucleotides. Here, we investigated the underlying mechanisms creating HIV-1-mediated immune dysfunction and role of type I IFNs using a DC and T cell co-culture model. HIV-1 exposure in the DC-T cell co-culture promoted the expansion of suppressive T cells with diminished proliferation and effector functions. The impairment required type I IFNs and subsequent IFN-/{beta} receptor signaling, initiated by HIV-derived ssDNA activation of IFI16/cGAS followed by STING signaling in the DCs. Targeting IFNAR1 with Anifrolumab restored the immune functions of both DCs and T cells, as well as T cell proliferation and T cell effector functions, including their secretion of IL-2, IFN-{gamma}, and granzyme B. Our findings support that the immune impairments existing in untreated or antiretroviral therapy (ART) treated HIV-infected individuals are mediated, if not fully in part by type I IFNs negative effect on DC and T cells. Therapeutics targeting IFN-/{beta} receptors, such as Anifrolumab, hold potential as combination treatment alongside ART, to achieve a more complete immune restoration and contribute to improved quality of life among people living with HIV.

immunology↗

bioRxiv2025

Lithography-free Water Stable Conductive Polymer Nanowires

Free-standing nanowires can gain intracellular access without causing cellular stress or apoptosis. Current approaches to generate nanowires focus on lithographic patterning and inorganic materials (Si, GaAs, Al2O3, etc.) while organic materials are less explored. Use of organic conductive polymers allows for creation of soft mixed ion-electron conducting nanowires. Processing conductive polymers into nanowires is challenging due to the harsh chemicals and processing conditions used. Here, we demonstrate a lithography-free and scalable method to generate all-organic water-stable nanowires composed of conductive polymers. A nanoporous membrane is filled with conductive polymer in solution followed by a cross-linking step to make the polymer water stable. The surface of the membrane is anisotropically etched using a reactive ion etcher to reveal the polymer inside the pores, which extend from the membrane as nanowires. We interface the nanowires with model algal cells and human primary hematopoietic stem and progenitor cells. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/631660v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@bf44b3org.highwire.dtl.DTLVardef@13782baorg.highwire.dtl.DTLVardef@1679366org.highwire.dtl.DTLVardef@fe1677_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

Altered DNA methylation pattern contributes to differential epigenetic immune signaling in the upper respiratory airway of COVID-19 patients

The emergence of SARS-CoV-2 has had a profound adverse impact on global health and continues to remain a threat worldwide. The disease spectrum of COVID-19 ranges from asymptomatic to fatal clinical outcomes especially in the elderly population and in individuals with underlying medical conditions. The impact of COVID-19 on host immune responses and immune cells at the protein and DNA levels remains largely ambiguous. In a case-control study, here we explored the impact of COVID-19 on DNA methylation patterns in the upper respiratory airway to determine how SARS-CoV-2 infection altered the immune status of individuals requiring hospitalization for COVID-19. We performed DNA methylation arrays on nasopharyngeal swabs at inclusion/hospitalization as well as 6 weeks post-inclusion. Our study reveals a distinct DNA methylation pattern in COVID-19 patients compared to healthy controls, characterized by 317 779 differentially methylated CpGs. Notably, within the transcription start sites and gene body, COVID-19 patients exhibited a higher number of genes/CpGs with elevated methylation levels. Enrichment analysis of methylated genes at transcription start sites highlighted the impact on genes associated with inflammatory responses and immune functions. Some SARS-CoV-2 -induced CpG methylations were transient, returning to normal levels by 6 weeks post-inclusion. Enriched genes of interest included IL-17A, a pivotal cytokine implicated with inflammation and healing, and NUP93, associated with antiviral innate immunity. Further, six genes in our data set, OAS1, CXCR5, APP, CCL20, CNR2, and C3AR1, were found in enrichment analysis with previous COVID-19 studies. Additionally, RNAse1 and RNAse2 emerged as key regulators, while IL-18 played a role in various biological processes in COVID-19 patients. Overall, our results demonstrates that COVID-19 has a major impact on the upper airway by modifying the methylation pattern of many genes and this could have implications for the conditioning of the airways and how the individual response to future airway infections.

microbiology↗

bioRxiv2023

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare A{beta} deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on A{beta} input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

neuroscience↗

bioRxiv2023

Social avoidance of mice in pain in naturalistic conditions

Pain and social behavior are subject to reciprocal modulation. Both humans and rodents experience emotional contagion from afflicted conspecifics, and may act to relieve the afflicted state of these. Little has been done to investigate the motivation of such prosocial behavior in rodents in naturalistic conditions. Here, we analyzed social interactions in mice group-housed in a seminatural environment (SNE). Social buffering reduced nocifensive behavior in formalin-injected mice. These mice were also both socially withdrawn and avoided by other mice. These findings appear counter to those showing empathy in mouse pain models. It is possible that in naturalistic conditions, healthy mice simply avoid individuals in pain and the cost associated with emotional contagion. Interestingly, behaviors involving direct body contact were not different between saline- and formalin-treated mice, and thus may carry a prosocial, altruistic component. These findings unveil new patterns of social modulation by pain in a naturalistic laboratory setting holding high translational value. TeaserIn a new, ethological assay, mice in pain are socially withdrawn and avoided by others, challenging findings of empathy in rodent models.

neuroscience↗

bioRxiv2023

Ecological genomics in the Northern krill uncovers loci for local adaptation across ocean basins

Krill is a vital food source for many marine animals but also strongly impacted by climate change. Genetic adaptation could support populations, but remains uncharacterized. We assembled the 19 Gb Northern krill genome and compared genome-scale variation among 74 specimens from the colder Atlantic Ocean and warmer Mediterranean Sea. The genome is dominated by methylated transposable elements and contains many duplicated genes implied in molting and vision. Analysis of 760 million SNPs indicates extensive homogenizing gene-flow among populations. Nevertheless, we detect extreme divergence across hundreds of genes, governing ecophysiological functions like photoreception, circadian regulation, reproduction and thermal tolerance. Such standing variation may be essential for resilience in zooplankton, necessitating insight into adaptive variation to forecast their roles in future marine ecosystems and support ocean conservation. One-Sentence SummaryGenome-scans of Northern krill link genes for photoreception, reproduction and thermal tolerance to ecological adaptation.

evolutionary biology↗

bioRxiv2023

ZC3H11A interacts with PABPN1 and alters polyadenylation of viral transcripts

Nuclear mRNA metabolism is regulated by multiple proteins, which either directly bind to RNA or form multi-protein complexes. The RNA-binding protein ZC3H11A is involved in nuclear mRNA export, and NF-{kappa}B signaling and is essential during mouse embryo development. Furthermore, previous studies have shown that ZC3H11A is important for nuclear-replicating viruses. However, detailed biochemical characterization of the ZC3H11A protein has been lacking. In this study, we established the ZC3H11A protein interactome in human and mouse cells. We demonstrate that the nuclear poly(A)-binding protein PABPN1 interacts specifically with the ZC3H11A protein and controls ZC3H11A localization into nuclear speckles. We report that ZC3H11A specifically interacts with the human adenovirus type 5 (HAdV-5) capsid mRNA in a PABPN1-dependent manner. Notably, ZC3H11A uses the same zinc finger motifs to interact with PABPN1 and mRNA, with a single zinc finger motif responsible for these functions. Further, we demonstrate that the lack of ZC3H11A alters the polyadenylation of HAdV-5 capsid mRNA. Taken together, our results suggest that the ZC3H11A protein acts as a novel regulator of polyadenylation of nuclear mRNA.

molecular biology↗