Biology subjects

Madsen, A.

Publications and source records attributed to Madsen, A..

6 recordsLinked to original sources

bioRxiv2026

Increased Demographic Turnover and Isolation Precede Social Fragmentation in Asian Elephants

Humans and other animals live in interconnected social communities that are essential for survival and well-being. In principle, social communities can persist despite changes in constituent members. However, gradually accumulating changes to membership could push systems past critical thresholds into alternate states. We investigated social network dynamics for 443 wild female Asian elephants over 12 years by tracking community membership and structure. Following accumulated demographic turnover, networks fractured into smaller and more isolated social communities. Connections were changed not only due to turnover of members but also rewired among remaining individuals. This provides the first empirical evidence of a social network state change in a long-lived mammal.

animal behavior and cognition↗

bioRxiv2026

Single-Cell and Tissue-Specific CRISPR Editing Analyses Unveil New Insights to Off-Targets and Translocations

CRISPR-Cas9 holds promise for treating genetic disease, but rare off-target mutations and structural variants remain as key safety concerns, especially at scales relevant to therapy. We established workflows to resolve Cas9 off-target activity in vitro at single-cell resolution and in vivo across different tissues. Using clonally expanded electroporated mouse embryos and embryonic stem cells, we reveal that individual cells exhibit unique off-target and translocation profiles, including events missed in bulk analyses. Integrating single-cell editing with chromatin accessibility, transcription, and DNA methylation measurements suggested that sequence-independent features modulate Cas9 access and cleavage, with preferential editing in regions characterized by open chromatin and lower methylation. In Cas9-inducible mouse models, editing analyses revealed organ-distinct off-target spectra, DNA repair pathway usage, indel patterns, and markedly varying translocation propensity between tissues. These findings demonstrate that off-target activity is heterogeneous across cells and context-dependent across organs, motivating sensitive single-cell analyses and organ-specific evaluation in preclinical development to more accurately assess risk and improve the safety of CRISPR-based genomic medicines.

genomics↗

bioRxiv2025

Pathophysiological remodeling of the skeletal muscle microenvironment in patients with lung cancer

Background Muscle wasting, systemic inflammation, and functional decline are highly prevalent and detrimental in patients with advanced-stage non small cell lung cancer (NSCLC). Methods: In this cross sectional study, we investigated NSCLC associated muscle remodeling by analyzing skeletal muscle biopsies from patients with NSCLC (n = 18) and matched controls (n = 18) using quantitative proteomics, histology, fluorescence-activated cell sorting, gene expression profiling, and high resolution respirometry. Findings: NSCLC muscle was characterized by type II muscle fiber atrophy, greater collagen deposition, and redistribution of lipids to the extracellular matrix (ECM), together with remodeling of the inflammatory, immune, ECM and mitochondrial proteome. Additionally, mitochondrial respiratory capacity and morphology were altered in patients with NSCLC, which was associated with increased oxidative stress and dysregulated calcium handling. Concomitantly, we detected STAT3 activation and immune cell alterations, which may negatively impact skeletal muscle health in patients with NSCLC. Finally, we identified a shift in fibro-adipogenic progenitors (FAPs), favoring the CD90 subtype. Mechanistically, conditioned media from patient-derived FAPs reduced myotube width in vitro, uncovering a novel mechanism by which altered paracrine signaling from the muscle resident stromal compartment drives atrophy in cancer cachexia. Interpretation: These findings provide human evidence that altered FAP composition, mitochondrial homeostasis, calcium handling, and immune cell landscape accompany muscle wasting in NSCLC, which may inform therapeutic strategies to preserve skeletal muscle health in patients with cancer.

molecular biology↗

bioRxiv2025

Dynamic membership drives long-term persistence of sparrow winter social communities

Social groups range from highly stable to highly dynamic over extended periods. Demographic factors like individual lifespans and rates of births, deaths, immigration, and emigration in a population can strongly impact group stability and persistence over time. Highly stable long-term groups are often driven by long-lived core individuals that maintain relationships, kin-structure, or high philopatry. In opposition, fluid groups of individuals that associate repeatedly, called social communities, can persist in populations that have high turnover, lack kin structure, and exhibit high fission-fusion dynamics. However, we lack an understanding of how animal social communities persist amidst highly dynamic membership. We investigated the drivers of persistence of social communities in a winter population of migratory golden-crowned sparrows over 12 years. Sparrows frequently flock with the same individuals over the entire winter, forming social communities that are identified from discrete clusters within a social network. Long-term community membership was highly dynamic due to high annual turnover and the relatively short lifespans of individuals. However, the social fidelity of returning members and recruitment of new members between consecutive years resulted in communities that persisted for multiple years, even when there was a complete turnover of members over time. Our results indicate that groups can persist with consistent short-term membership, overlapping generations, and turnover with balanced rates of recruitment and loss. This dynamic stability of individual membership may be a universal feature of large, long-term groups found in many social systems, from animal societies with fission-fusion dynamics to networks of human collaboration.

animal behavior and cognition↗

bioRxiv2024

mRNA-based influenza vaccine expands breadth of B cell response in humans

Summary paragraphEliciting broad and durable antibody responses against rapidly evolving pathogens like influenza viruses remains a formidable challenge1,2. The germinal center (GC) reaction enables the immune system to generate broad, high-affinity, and durable antibody responses to vaccination3-5. mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines induce persistent GC B cell responses in humans6-9. Whether an mRNA-based influenza vaccine could induce a superior GC response in humans compared to the conventional inactivated influenza virus vaccine remains unclear. We assessed B cell responses in peripheral blood and draining lymph nodes in cohorts receiving the inactivated or mRNA-based quadrivalent seasonal influenza vaccine. Participants receiving the mRNA-based vaccine produced more robust plasmablast responses and higher antibody titers to H1N1 and H3N2 influenza A viruses and comparable antibody titers against influenza B virus strains. Importantly, mRNA-based vaccination stimulated robust recall B cell responses characterized by sustained GC reactions that lasted at least 26 weeks post-vaccination in three of six participants analyzed. In addition to promoting the maturation of responding B cell clones, these sustained GC reactions resulted in enhanced engagement of low-frequency pre-existing memory B cells, expanding the landscape of vaccine-elicited B cell clones. This translated to expansion of the serological repertoire and increased breadth of serum antibody responses. These findings reveal an important role for the induction of persistent GC responses to influenza vaccination in humans to broaden the repertoire of vaccine-induced antibodies.

immunology↗

bioRxiv2021

ACTN2 missense variant causes proteopathy in human iPSC-derived cardiomyocytes

Genetic variants in -actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut present a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2-associated cardiomyopathies.

cell biology↗