Biology subjects

von Elverfeldt, D.

Publications and source records attributed to von Elverfeldt, D..

9 recordsLinked to original sources

bioRxiv2025

Gene expression reveals the pancreas of Aselli as a critical organ for plasma cell differentiation in the common shrew

Almost all mammals rely on the thymus and bone marrow to generate and differentiate B- and T cells essential for adaptive immunity. A few members of the family Soricidae, or true shrews, have also evolved the pancreas of Aselli, a kidney-sized organ hypothesized to serve this primary immune role, and whose gene expression profile is unknown. Here we introduce transcriptomes of juvenile Sorex araneus pancreas of Aselli, compare them to those of the spleen and chick bursa of Fabricius, an analogous and bird-specific organ, and explore differential expression overlaps with positively selected genes. While differential gene expression analyses revealed overexpression of genes that regulate the differentiation of B cells into long-term plasma cells (e.g., IRF4, XBP1, PRDM1) compared to the spleen and more convergent expression with the bursa of Fabricius than expected by chance (including IRF4), overlaps with positive selection were as expected and included PTPRCAP, which regulates both T and B cell antigen responses and lymph node size. Our results support the specialized role of the pancreas of Aselli in adaptive immunity, and we propose this unique organ evolved at the intersection between extreme metabolic demands and high parasite burdens in tiny yet very active shrews.

evolutionary biology↗

bioRxiv2025

Seasonal brain regeneration and chromosome instability are linked to selection on DNA repair in Sorex araneus

Sorex araneus, the Eurasian common shrew, has seasonal brain size plasticity (Dehnels phenomenon) and abundant intraspecific chromosomal rearrangements, but genomic contributions to these traits remain unknown. We couple a chromosome-scale genome assembly with seasonal brain transcriptomes to discover relationships between molecular changes and both traits. Positively selected genes enriched the Fanconi anemia DNA repair pathway, which prevents the accumulation of chromosomal aberrations, and is likely involved in chromosomal rearrangements (FANCI, FAAP100). Genes involved in neurogenesis show either signatures of positive selection (PCDHA6), seasonal differential expression in the cortex and hippocampus (Notch signaling), or both (SOX9), suggesting a role for cellular proliferation in seasonal brain shrinkage and regrowth. Both positive selection and evolutionary upregulation in the shrew hypothalamus of VEGFA and SPHK2 indicate adaptations in hypothalamic metabolic homeostasis have evolved together with Dehnels phenomenon. These findings reveal genomic changes central to the evolution of both chromosomal instability and cyclical patterns in brain gene expression that characterizes mammalian brain size plasticity. TeaserGenomic and expression variations are key to chromosomal instability and seasonal brain plasticity in the common shrew.

evolutionary biology↗

bioRxiv2025

Vertical RAS-pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations

Background & AimsOncogenic KRAS mutations drive metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC). Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity and promising dual SHP2/mitogen-activated protein kinase (MAPK) inhibition is currently being tested in clinical trials. Exploitable metabolic adaptations may contribute to an invariably evolving resistance. MethodsTo understand the metabolic changes induced by dual inhibition, we comprehensively tested cell lines, endogenous tumor models, and patient-derived organoids representing the full spectrum of PDAC molecular subtypes. ResultsWe find that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major mitochondrial alterations, elevates reactive oxygen species (ROS) levels and triggers a lipid peroxidase dependency. While anabolic pathways, glycolysis and autophagy were also affected, mitochondrial alterations persisted longterm into a therapy resistant state. ConclusionsThe resulting vulnerability to induction of ferroptotic cell death via combined SHP2/MEK1/2 and glutathione peroxidase (GPX4) inhibition provides a metabolic lever to reinforce RAS-pathway inhibition for targeted PDAC treatment.

cancer biology↗

bioRxiv2024

Seasonal and comparative evidence of adaptive gene expression in mammalian brain size plasticity

Contrasting almost all other mammalian wintering strategies, Eurasian common shrews, Sorex araneus, endure winter by shrinking their brain, skull, and most organs, only to then regrow to breeding size the following spring. How such tiny mammals achieve this unique brain size plasticity while maintaining activity through the winter remains unknown. To discover potential adaptations underlying this trait, we analyzed seasonal differential expression in the shrew hypothalamus, a brain region that both regulates metabolic homeostasis and drastically changes size, and compared hypothalamus expression across species. We discovered seasonal variation in suites of genes involved in energy homeostasis and apoptosis, shrew-specific upregulation of genes involved in the development of the hypothalamic blood brain barrier and calcium signaling, as well as overlapping seasonal and comparative gene expression divergence in genes implicated in the development and progression of human neurological and metabolic disorders, including CCDC22. With high metabolic rates and facing harsh winter conditions, Sorex araneus have evolved both adaptive and plastic mechanisms to sense and regulate their energy budget. Many of these expression changes mirrored those identified in human neurological and metabolic disease, highlighting the interactions between metabolic homeostasis, brain size plasticity, and longevity.

evolutionary biology↗

bioRxiv2023

Large captivity effect based on gene expression comparisons between captive and wild shrew brains

Compared to their free-ranging counterparts, wild animals in captivity experience different conditions with lasting physiological and behavioral effects. Although shifts in gene expression are expected to occur upstream of these phenotypes, we found no previous gene expression comparisons of captive vs. free-ranging mammals. We assessed gene expression profiles of three brain regions (cortex, olfactory bulb, and hippocampus) of wild shrews (Sorex araneus) compared to shrews kept in captivity for two months and undertook sample drop-out to examine robustness given limited sample sizes. Consistent with captivity effects, we found hundreds of differentially expressed genes in all three brain regions, 104 overlapping across all three, that enriched pathways associated with neurodegenerative disease, oxidative phosphorylation, and genes encoding ribosomal proteins. In the shrew, transcriptomic changes detected under captivity resemble responses in several human pathologies, including major depressive disorder and neurodegeneration. While interpretations of individual genes are tempered by small sample sizes, we propose captivity influences brain gene expression and function and can confound analyses of natural processes in wild individuals under captive conditions.

genetics↗

bioRxiv2023

Probing hippocampal stimulation in experimental temporal lobe epilepsy with functional MRI

BackgroundElectrical neurostimulation is a potentially effective therapy in epilepsy but the optimal approach is not yet clear. The parameter space is wide and the effects of different stimulations are not immediately obvious. Functional MRI (fMRI) can reveal which brain areas are affected by stimulation and help understand the induced effects. However, simultaneous deep brain stimulation (DBS)-fMRI examinations in patients are rare and the possibility to investigate multiple stimulation protocols is limited. Preclinical stimulation-fMRI studies can provide predictive value and help identify optimal neurostimulation parameters. ObjectiveTo systematically investigate the brain-wide responses to hippocampal electrical stimulations in a mouse model of mesial temporal lobe epilepsy (mTLE) using fMRI. MethodsWe applied electrical stimulation in the intrahippocampal kainate mouse model of mTLE and assessed the effect of different stimulation amplitudes (80-230 {micro}A) and frequencies (1-100 Hz). In addition, the effect of prolonged 1 Hz stimulation was explored. Saline-injected mice served as controls. ResultsVarying the stimulation amplitudes had little effect on the resulting activation patterns. Low frequency stimulation led to a local response at the stimulation site only, whereas high frequency resulted in a spread of activation from the hippocampal formation into cortical and frontal areas. Prolonged low frequency stimulation reduced excitability. ConclusionsWhile the amplitude parameter offers little opportunity to vary the outcome, the frequency represented the key parameter and determined whether the induced activation remained local or spread across the brain. This is in line with the few DBS-fMRI results obtained in epilepsy patients demonstrating the translational value of fMRI.

neuroscience↗

bioRxiv2020

DTI reveals whole-brain microstructural changes in the P301L mouse model of tauopathy

IntroductionIncreased expression of hyperphosphorylated tau and the formation of neurofibrillary tangles are associated with neuronal loss and white matter damage. Using high resolution ex vivo diffusion tensor imaging (DTI), we investigated microstructural changes in the white and grey matter in the P301L mouse model of human tauopathy at 8.5 months-of-age. For unbiased computational analysis, we implemented a pipeline for voxel-based analysis (VBA) and atlas-based analysis (ABA) of DTI mouse brain data. MethodsHemizygous and homozygous transgenic P301L mice and non-transgenic littermates were used. DTI data were acquired for generation of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) maps. VBA on the entire brain were performed using SPM8 and SPM Mouse toolbox. Initially, all DTI maps were co-registered with Allen mouse brain atlas to bring them to one common coordinate space. In VBA, co-registered DTI maps were normalized and smoothed in order to perform two-sample t-tests to compare hemizygotes with non-transgenic littermates, homozygotes with non-transgenic littermates, hemizygotes with homozygotes on each DTI parameter map. In ABA, the average values for selected regions-of-interests were computed with co-registered DTI maps and labels in Allen mouse brain atlas. After, the same two-sample t-tests were executed on the estimated average values. ResultsWe made reconstructed DTI data and VBA and ABA pipeline publicly available. With VBA, we found microstructural changes in the white matter in hemizygous P301L mice compared to non-transgenic littermates. In contrast, more pronounced and brain-wide spread changes were observed in VBA when comparing homozygous P301L mice with non-transgenic littermates. Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA. FA was found to be decreased in most brain regions, while MD, RD and AD were increased compared to hemizygotes and non-transgenic littermates. Discussion/ConclusionHigh resolution ex vivo DTI demonstrated brain-wide microstructural changes in the P301L mouse model of human tauopathy. The comparison between hemizygous and homozygous P301L mice revealed a gene-dose dependent effect on DTI metrics. The publicly available computational data analysis pipeline can provide a platform for future mechanistic and longitudinal studies.

neuroscience↗

bioRxiv2019

Mapping the living mouse brain neural architecture: strain specific patterns of brain structural and functional connectivity

Mapping the structural and functional brain connectivity fingerprints became an essential approach in neurology and experimental neuroscience because network properties can underlie behavioral phenotypes. In mouse models, revealing strain related patterns of brain wiring have a tremendous importance, since these animals are used to answer questions related to neurological or neuropsychiatric disorders. C57BL/6 and BALB/cJ inbred strains are primary \"genetic backgrounds\" for brain disease modelling and for testing therapeutic approaches. Nevertheless, extensive literature describes basal differences in the behavioral, neuroanatomical and neurochemical profiles of the two strains, which raises the question whether the observed effects are pathology specific or depend on the genetic background. Here we performed a systematic comparative exploration of brain structure and function of C57BL/6 and BALB/cJ mice via Magnetic Resonance Imaging (MRI). We combined voxel-based morphometry (VBM), diffusion MRI and high resolution fiber mapping (hrFM) and resting state functional MRI (rs-fMRI) and depicted brain-wide dissimilarities in the morphology and \"connectome\" features in the two strains. Particularly C57BL/6 animals show bigger and denser frontal cortical areas, cortico-striatal tracts and thalamic and midbrain pathways, and higher density of fibers in the genu and splenium of the corpus callosum. These features are fairly reflected in the functional connectograms that emphasize differences in \"hubness\", frontal cortical and basal forbrain connectivity. We demonstrate strongly divergent reward-aversion circuitry patterns and some variations of the default mode network features. Inter-hemispherical functional connectivity showed flexibility and adjustment regarding the structural patterns in a strain specific manner. We further provide high-resolution tractograms illustrating also inter-individual variability across inter-hemispherical callosal pathways in the BALB/cJ strain.

neuroscience↗

bioRxiv2019

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories world-wide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a murine default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

neuroscience↗