Biology subjects

Wolf, P.

Publications and source records attributed to Wolf, P..

10 recordsLinked to original sources

bioRxiv2026

A metabolic perspective on eIF1A and eIF3B inhibition as a potential therapeutic strategy in psoriasis

Psoriasis is a chronic inflammatory skin disease marked by epidermal hyperplasia and distinct metabolic alterations. Here, we investigated the metabolic impact of targeting translation initiation factors by performing 1H NMR-based metabolomic profiling on polar skin extracts from imiquimod-induced (IMQ) and K5.TGF{beta}1 transgenic (TGF{beta}) mouse models treated with eIF1A or eIF3B siRNA. IMQ-treated skin demonstrated significant, human-like metabolic shifts, including depleted energy substrates (glucose, glycogen, 3-hydroxybutyrate) and elevated phospholipid/nucleotide markers, which correlated strongly with epidermal thickness. In contrast, TGF{beta} skin exhibited no broad baseline polar metabolome changes. eIF1A/eIF3B inhibition selectively attenuated IMQ-associated energy and phospholipid alterations without causing widespread metabolic disruption in TGF{beta} skin. Overall, eIF1A/eIF3B inhibition ameliorated psoriasis-like pathology and mitigated disease-associated metabolic demands in a context-dependent manner.

molecular biology↗

bioRxiv2026

Somatic DNA methylation heterogeneity predicts extreme transgenerational epimutation hotspots in Arabidopsis

Spontaneous epimutations are stochastic and heritable changes in cytosine methylation that arise independently of DNA sequence alterations. In plants, they occur predominantly at CG sites, accumulate across generations at high and clock-like rates, and contribute substantially to constitutive epigenetic diversity. Although these features are well established, the developmental origin of spontaneous epimutations remains poorly understood. One model proposes that they arise during somatic growth in different cell layers of the shoot apical meristem, where lineage bottlenecks enable nascent epimutations to clonally propagate into developing organs. Such layer-specific dynamics are expected to generate spatial mosaics of methylation states within tissues that manifest as heterogeneity in bulk bisulfite sequencing data. Here, we quantified genome-wide CG methylation heterogeneity in single Arabidopsis leaves using read-level methylation discordance metrics adopted from cancer epigenomics. We identified thousands of highly heterogeneous loci and show that they overlap extreme transgenerational epimutation hotspots. Analysis of multiple leaves from the same individuals further revealed that methylation divergence at these loci scales with developmental distance and recapitulates the branching architecture of the shoot. Together, these results support a meristematic origin of spontaneous epimutations and highlight a shared susceptibility to methylation-maintenance errors in both developmental and transgenerational contexts.

genetics↗

bioRxiv2025

Threshold-like transcriptomic responses of European beech to simulated future climates

Beech (Fagus sylvatica) is one of the most important forest tree species in Europe, both in terms of land coverage and ecosystem services. Although it is projected to be strongly affected by climate change, insights into its functional genomic responses to realistic future scenarios are still lacking. We conducted a fully controlled ecotron experiment to examine the transcriptomic responses of 125 young, naturally regenerated beech trees exposed to regionalized dynamic climate series representing a reference period (1987-2016) and two future climate scenarios (Representative Concentration Pathways, RCP2.6 and RCP8.5, for 2071-2100) in Germany. RCPs describe alternative greenhouse gas trajectories established by the IPCC, ranging from strong mitigation (RCP2.6) to high, unmitigated emissions (RCP8.5), the latter representing a worst-case future scenario. Although both scenarios produced substantial transcriptional changes relative to the reference period, RCP8.5 elicited markedly stronger responses than RCP2.6, with nearly twice as many differentially expressed genes and unique transcriptional programs across functional categories that were not predictable from the RCP2.6 transcriptomes. Our study reveals emergent functional responses in European beech under projected late 21st-century climate conditions in Germany and highlights potential biomarkers for monitoring ecosystem responses to climate change.

ecology↗

bioRxiv2025

Targeting the hyperactive STAT3/5 pathway in cutaneous T-cell lymphoma with the multi-kinase nuclear transporter inhibitor IQDMA

Cutaneous T-cell lymphoma (CTCL), particularly its tumor stage mycosis fungoides (MF) subtype, presents considerable therapeutic challenges since current treatment modalities show limited efficacy. This study addresses the unmet need for novel targeted therapies that inhibit the STAT3/5 pathway, which is hyperactive in CTCL. Utilizing a murine model with intradermally grafted malignant T-cell lymphoma cells, we compared the efficacy of the multi-kinase inhibitor IQDMA with the conventional, topical psoralen + UV-A (PUVA) phototherapeutic regimen. Our data show that IQDMA reduced tumor volume by 90.7% (p = 0.0001) and was significantly more effective than PUVA, which reduced the tumor volume by only 46.2% (p = 0.0074). Results of an immunobiological analysis reveal that IQDMA treatment decreased tumor cell infiltration by 29.8% (p = 0.03) and the percentage of Ki67+ cells by 25.3% (p = 0.03), indicating a reduced tumor cell proliferation rate. Moreover, remarkable 40.0% and 45.6% reductions were observed in the total STAT5 (p = 0.047) and STAT3 (p = 0.01) levels of the infiltrating tumor cells upon IQDMA treatment. STAT5 levels are directly correlated with CD3+ tumor cell infiltration, confirming the role of the STAT3/5 pathway in the disease pathogenesis. Intriguingly, while phospho-STAT5 and total STAT5 levels directly correlated in the vehicle-treated group, a negative correlation was observed in the IQDMA-treated group, indicating IQDMA action in blocking STAT5 hyperactivation. IQDMA targets PAK kinase, a nuclear transporter for phospho-STAT5; in turn, we observed a compartmental shift of phospho-STAT5 from the nucleus to the cytoplasm. These key findings establish the properties of IQDMA as a potent targeted therapy for CTCL and offer compelling evidence for its clinical evaluation.

cancer biology↗

bioRxiv2024

Molecular Tracking and Cultivation Reveal Ammonia Oxidizing Archaea as Integral Members of the Human Skin Microbiome

BackgroundAmmonia-oxidizing archaea (AOA) have repeatedly been detected on human skin, yet their persistence, physiological traits, and adaptations remain poorly understood. Here, we identify Nitrosocosmicus species as integral members of the healthy skin microbiome using two complementary approaches. ResultsThrough cultivation, we enriched two autotrophic strains, Candidatus Nitrosocosmicus epidermidis and Ca. Nitrosocosmicus unguis, from human skin samples. Genomic analyses revealed specific adaptations for skin colonization, including genomic islands and expanded gene families linked to interactions with host proteins and signaling pathways, distinguishing these AOA from their soil-dwelling relatives. Parallel molecular profiling in cross-sectional and longitudinal cohorts (n=47) consistently detected Nitrosocosmicus particularly in sebaceous areas. Co-occurrence patterns with specific bacterial taxa reinforce their role as stable components of the skin microbiome. ConclusionsThese findings indicate that Nitrosocosmicus species are emerging commensals, evolutionarily capable of transitioning from soil to human skin, where they likely play a critical role in the skin ecosystem.

microbiology↗

bioRxiv2024

Chromosome Numbers and Reproductive Life Cycles in Green Plants: A Genomic Perspective

The strong correlation between reproductive life cycle type and chromosome numbers in green plants has been a long-standing mystery in evolutionary biology. Within green plants, the derived condition of heterosporous reproduction has emerged from the ancestral condition of homospory in disparate locations on the phylogenetic tree at least 11 times, of which 3 lineages are extant. In all green plant lineages where heterospory has emerged, there has been a significant downsizing in chromosome numbers (refer to figure 1). This dynamic has been investigated without clear answers for many decades. In this study, we combine known ideas from existing literature with novel methods, tools, and data to generate fresh insights into an old question. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/604804v3_fig1.gif" ALT="Figure 1"> View larger version (8K): org.highwire.dtl.DTLVardef@fcc574org.highwire.dtl.DTLVardef@10759bforg.highwire.dtl.DTLVardef@1950e33org.highwire.dtl.DTLVardef@d7718d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:-C_FLOATNO A simplified phylogeny of green plants/Embryophytes with the respective group and their average chromosome numbers in each group. Heterosporous lineages highlighted in green. C_FIG Using gene family evolution models and selection analyses, we identified gene families that have undergone significant expansion, contraction, or selection in heterosporous lineages. Our results reveal both shared and lineage-specific genomic changes associated with the evolution of heterospory. We found expansions in gene families related to developmental regulation, signaling pathways, and stress responses across heterosporous groups. Notably, the MATE efflux family showed consistent expansion and evidence of selection in heterosporous lineages, suggesting a potentially conserved role in heterospory evolution. These findings highlight novel insights that may underpin the association between heterospory and reduced chromosome numbers. The general importance of chromosome numbers, structure, and sizes in cellular biology notwithstanding, the association between the emergence of heterosporous reproduction and chromosome number reduction/genome downsizing is not fully understood. It remains unclear why there exists an association between aspects of biology at such disparate levels as reproductive life-cycles and chromosome numbers/genome size. Exploring and answering this conundrum of evolutionary biology can add to our broader understanding of life sciences and of biology at different levels. Applying the novel tools and methods emerging from ongoing progress in biotechnology and computational sciences presents an opportunity to make new inroads into this long-standing question.

bioinformatics↗

bioRxiv2024

Inhibition of eukaryotic translation initiation factor 1A (eIF1A) and 3B (eIF3B) diminishes the psoriatic phenotype in two mouse models and human 3D model samples

BackgroundPsoriasis is a systemic inflammatory disease for which new topical treatments are required. Psoriatic inflammation is associated with overexpression of eukaryotic translation initiation factors (eIFs), which critically regulate gene expression in many important cellular processes, including proliferation, apoptosis, and differentiation. However, the exact link between overexpression of eIF and psoriasis is unknown. Here, we investigated the role of eIFs, particularly eIF1A and eIF3B, and the impact of their inhibition on the pathophysiology of psoriasis. MethodsWe used two mouse models reflecting the pathophysiology of psoriasis: (i) BALB/c mice topically treated with the immune activator imiquimod (IMQ) and (ii) K5.TGF{beta} transgenic mice. eIF1A and eIF3B were inhibited by either topical or systemic application of specific small interfering RNA (siRNA). In addition, we employed commercial human 3D psoriatic skin model samples. Importantly, in situ mRNA detection-based padlock probes against transcript variants of eIF1A und eIF3B was performed. ResultsTopical and systemic inhibition of eIF1A and eIF3B inhibited inflammation in both imiquimod and TGF{beta} mouse models as well as in a human 3D psoriasis model. Downregulation of eIF1A and eIF3B was associated with normalization of cell proliferation, restoration of the inflammatory milieu and epidermal hyperplasia of psoriasis, and normalization of levels of proinflammatory cytokines (e.g., TNF, IL-1b, IL-17, and IL-22) and keratinocyte differentiation markers (e.g., KRT16 and FLG). ConclusionThese results reveal an imbalance in translation and emphasize the crucial role of eIF1A and eIF3B in the pathophysiology of psoriasis. Targeting eIFs opens new avenues for the development of novel therapeutic treatment strategies against psoriasis.

molecular biology↗

bioRxiv2024

Cell-autonomous GP130 activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment

Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles GP130-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. Here, we find that genetic cell-autonomous activation of the GP130 receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of GP130 signaling mediates senescence via the STAT3/ARF/p53 axis and anti-tumor immunity via recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high GP130 mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. Our findings reveal a context-dependent role of GP130/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development. We challenge the prevailing concept of blocking GP130/STAT3 signaling as functional prostate cancer treatment and instead propose cell-autonomous GP130 activation as a novel therapeutic strategy.

cancer biology↗

bioRxiv2021

Pronounced genetic separation among varieties of the Primula cusickiana species complex, a Great Basin endemic

Distinguishing between unique species and populations with strong genetic structure is a common challenge in population genetics, especially in fragmented habitats where allopatric speciation may be widespread and distinct groups may be morphologically similar. Such is often the case with species complexes across sky island environments. In these scenarios, biogeography may help to explain the relations between species complex members, and RADseq methods are commonly used to compare closely related species across thousands of genetic loci. Here we use RADseq to clarify the relations between geographically distinct but morphologically similar varieties of the Primula cusickiana species complex, and to contextualize past findings of strong genetic structure among populations within varieties. Our genomic analyses demonstrate pronounced separation between isolated populations of this Great Basin endemic, indicating that the current varietal classification of complex members is inaccurate and emphasizing their conservation importance. We discuss how these results correspond to recent biogeographical models used to describe the distribution of other sky island taxa in western North America. Our findings also fit into a wider trend observed for alpine Primula species complexes, and we consider how heterostylous breeding systems may be contributing to frequent diversification via allopatric speciation in this genus.

evolutionary biology↗

bioRxiv2020

Live cell PNA labelling enables erasable fluorescence imaging of membrane proteins

DNA nanotechnology is an emerging field, which promises fascinating opportunities for the manipulation and imaging of proteins on a cell surface. The key to progress in the area is the ability to create the nucleic acid-protein junction in the context of living cells. Here we report a covalent labelling reaction, which installs a biostable peptide nucleic acid (PNA) tag. The reaction proceeds within minutes and is specific for proteins carrying a 2 kDa coiled coil peptide tag. Once installed the PNA label serves as a generic landing platform that enables the recruitment of fluorescent dyes via nucleic acid hybridization. We demonstrate the versatility of this approach by recruiting different fluorophores, assembling multiple fluorophores for increased brightness, and achieving reversible labelling by way of toehold mediated strand displacement. Additionally, we show that labelling can be carried out using two different coiled coil systems, with EGFR and ETBR, on both HEK293 and CHO cells. Finally, we apply the method to monitor internalization of EGFR on CHO cells.

biophysics↗