Biology subjects

Classen, A.

Publications and source records attributed to Classen, A..

10 recordsLinked to original sources

bioRxiv2026

Accumulation of FAM98B and tRNA-Splicing Ligase Complex Proteins in Neuronal Intranuclear Inclusions in Spinocerebellar ataxia type 4.

Background and Objectives: Spinocerebellar ataxia type 4 (SCA4) is caused by a GGC-repeat expansion in ZFHX3 encoding an expanded polyglycine tract causing p62- and ubiquitin-positive neuronal intranuclear inclusions (NIIs). In multiple polyglycine diseases NIIs sequester tRNA-splicing ligase complex (tRNA-LC) proteins, causing downstream functional defects linked to neurodegeneration. We assessed the localization of tRNA-LC proteins in SCA4 pontine neurons. Methods: Postmortem brain tissue from a genetically confirmed SCA4 patient was examined across multiple regions using immunofluorescence confocal microscopy for p62, ubiquitin and tRNA-LC proteins FAM98B, RTRAF, and RTCB. Results: In pontine neurons, FAM98B, RTRAF, and RTCB were incorporated into NII, accumulating in a distinct outer layer respective to a ubiquitin inner layer. This redistribution was accompanied by depletion of all three proteins from the soluble nucleoplasm. Discussion: Our findings link SCA4 to a tRNA-LC dysfunction phenotype shared by multiple GGC-repeat disorders, further supporting a unified pathological mechanism in polyglycine diseases.

neuroscience↗

bioRxiv2026

Maternal Folate Nutrition Programs Adult Hematopoietic Stem Cell Function Through Mitochondrial Remodeling

Folic acid fortification for the prevention of neural tube defects has been a cornerstone of public health policy for nearly three decades, but its broader consequences for other developing organ systems, particularly the hematopoietic system, are poorly studied. Hematopoietic stem cell (HSC) emergence overlaps developmentally with neural tube closure, and folate-dependent one-carbon metabolism is critical for nucleotide synthesis, cellular methylation, and redox balance, positioning folate as a candidate regulator of HSC programming. Using dietary models of maternal folate deficiency or supplementation in mice, we demonstrate that maternal folate acts as a dose-dependent developmental tuner of hematopoiesis, programming adult offspring HSC function through divergent mitochondrial and chromatin states. Maternal folate deficiency impaired adult HSC self-renewal, associated with mitochondrial defects, disrupted cristae, elevated proteotoxic stress and a stress-adapted chromatin landscape. In contrast, maternal folate supplementation enhanced HSC self-renewal accompanied by improved mitochondrial quality control and CDC42-associated organelle remodeling, and established chromatin states permissive for stem cell maintenance. Fetal HSC metabolomics identified shifts in one-carbon intermediates, pyruvate and lipid pools, suggesting that divergent fetal metabolic states provide substrate-level inputs that drive persistent and opposing chromatin programs in offspring HSCs. Our findings establish maternal folate availability as an unappreciated regulator of lifelong hematopoietic output demonstrating that a single maternal micronutrient, folate, is sufficient to program adult HSC function and regenerative capacity through persistent metabolic and mitochondrial programming.

cell biology↗

bioRxiv2026

Forest biodiversity benefits from warmer microclimate, but only in colder regions

The diversity of many forest-dwelling organisms depends on forest structure, but it remains unknown to which degree this is mediated by microclimatic temperature, and whether microclimatic buffering is universally beneficial for forest biodiversity. In 234 broad-leaved forest plots across nine climatically differing regions in Germany, we measured micro- and macroclimatic temperatures, canopy cover, and deadwood volume after experimental manipulations of forest structure through thinning operations and gap cuts. We surveyed 21 taxonomic groups, representing plants, bacteria, fungi, and animals, to assess how their diversity depended on the predictors. Multi-taxon diversity, and diversity of ten separate taxonomic groups, increased from closed to open canopies. Only necrophagous beetles were more diverse in closed stands. These effects of canopy cover on diversity were partly mediated by microclimatic temperatures. Thereby, diversity responses to microclimatic temperature depended on the macroclimatic context. In regions with colder summers, locally warmer microclimates in canopy gaps had strong positive effects on biodiversity, while these effects were not found in regions with warmer summers. Consequently, management strategies aimed at multi-taxon forest diversity conservation should be chosen based on the regional climate, favoring canopy gaps primarily in colder regions, and taking future climate warming into consideration.

ecology↗

bioRxiv2026

Biotic modulators of global change effects on plant communities

Understanding and predicting future plant biodiversity and productivity is critical for prioritizing global change mitigation, conservation, and restoration efforts. One major challenge is that we know remarkably little of how interspecific interactions may modulate the effects of global change factors on diversity and productivity. Here, we develop and test a synthetic conceptual framework about how different biotic modulators (herbivory, plant-plant interactions, pathogens, mycorrhiza) can either amplify or mitigate the effects of global change drivers (nutrient and CO2 enrichment, changes in rainfall and temperature) on plant community biomass and diversity. We report that herbivores mitigated both biomass increment and diversity decline caused by different global change drivers, while plant competition did not significantly alter global change impacts due to mixed effects (both amplification and mitigation). Pathogens tended to function similarly to herbivores, while mycorrhiza both amplified and mitigated community responses. Our conceptual framework further identifies mechanisms by which species interactions can modify global change effects, provides new testable hypotheses, and identifies research gaps and future research directions. We conclude that plant consumers can be important agents stabilizing plant productivity and safeguarding plant biodiversity in the Anthropocene, while more research is urgently needed to understand the role of other biotic modulators.

ecology↗

bioRxiv2026

Direct fluorescence detection and volume electron microscopy reveal a role for antibiotic biosynthesis in the bacterial cell envelope

Secondary metabolites support the environmental fitness of a broad taxonomic diversity of bacteria and fungi, yet the cellular biology that supports secondary metabolism is little understood. This study focuses on the linearmycin antibiotics from Streptomyces sp. Mg1. These membrane-disruptive metabolites are packaged into extracellular vesicles, which in turn require the linearmycins for their biogenesis. This connection suggests that for some secondary metabolites, their biosynthesis is an integral function of cell organization and physiology. In this study, we employed simultaneous multi-photon fluorescence microscopy to directly detect linearmycins, enabling us to follow their biosynthesis and accumulation. We found that linearmycin fluorescence localizes to membrane-dense regions that also coincide with localization with a fluorescent fusion protein, LnyI-Ypet, that is essential for biosynthesis. Genetic disruption of linearmycin biosynthesis led to changes in the cell membrane visible using lipophilic dyes. To resolve differences between wild type and linearmycin-deficient membranes, we used serial FIB milling and scanning electron microscopy (FIB-SEM) to generate 3D volume reconstructions of S. Mg1 filaments. Using this approach, we identified granular subcellular compartments that require linearmycins. Disruption of linearmycin synthesis causes, in addition to disappearance of the compartments, visible distortions in the cell envelope, suggesting an integral role for the metabolites in membrane dynamics of the producer bacteria. We propose that the subcellular compartments coalesce near hyphal cell division and branch points and are regions for linearmycin biosynthesis. This study demonstrates the combined use of advanced microscopy to reveal an intrinsic role for antibiotics in the cell biology of the producing organism.

microbiology↗

bioRxiv2025

Experimental enhancement of structural heterogeneity in forest landscapes promotes multidimensional hoverfly diversity.

O_LIThe homogenization of temperate forests due to intensive management has led to biodiversity loss at local and landscape scales, threatening species persistence and ecosystem functions. However, experimental evidence on how structural heterogeneity among forest patches influences diversity at the landscape scale is lacking. Here, we test whether enhancing structural heterogeneity, via diverse deadwood enrichment and canopy gap creation treatments (Enhancement of Structural Beta Complexity, ESBC), can increase hoverfly diversity within landscapes, and elucidate the contributions of local (-) diversity enrichment and turnover ({beta}-diversity) to this effect. C_LIO_LIWe conducted a large-scale forest experiment in 11 regions across Germany. Each region included two districts, representing small forest landscapes. In one district, we implemented patches with ESBC treatments, while in the other, serving as the control, we established patches without ESBC. Hoverflies were sampled in three seasonal intervals and across, in total, 234 forest patches (50 x 50 m) using pan traps. We applied a new integrative meta-analytic framework that incorporates sample completeness to quantify taxonomic, functional, and phylogenetic diversity (TD, FD, PD) using Hill numbers at , {beta}, and {gamma} scales. C_LIO_LIAll three {gamma}-diversity dimensions - TD, FD, and PD - were significantly higher in structurally heterogeneous forest landscapes than in homogeneous ones. The strongest effects were observed for TD, indicating functional and phylogenetic redundancy among species. Effect sizes declined with increasing order of Hill numbers, suggesting that rare species benefit most from structural heterogeneity. C_LIO_LIIn most regions, {gamma}-diversity gains were driven by increases in -diversity rather than {beta}-diversity, highlighting the importance of interventions to increase local structural complexity. However, several regions also showed elevated {beta}-diversity, indicating context-dependent effects of spatial heterogeneity. C_LIO_LIOur results provide the first experimental evidence that enhancing structural heterogeneity at the landscape scale can restore multi-dimensional insect diversity in temperate forests. They underscore the management value of ESBC as a scalable tool to restore biodiversity, increase ecological resilience, and counteract biotic homogenization in production forests. C_LI

ecology↗

bioRxiv2025

Longitudinal single-cell analysis reveals RUNX1T1 as an early driver in treatment-induced neuroendocrine transdifferentiation

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal form of advanced prostate cancer that can emerge from adenocarcinoma under androgen receptor pathway inhibition, but the tumor-cell states and regulators underlying this transition remain incompletely defined. Here, we analyzed longitudinal single-cell RNA sequencing data from the LTL331/331R patient-derived xenograft model across seven disease stages, comprising 32,269 tumor-cell transcriptomes from treatment-naive adenocarcinoma, post-castration regression, and relapsed NEPC. We identified an AR-low/NE-low intermediate state that emerged after castration and before overt relapse, as well as two transcriptionally distinct terminal NEPC states marked by ASCL1high/FOXA2low and ASCL1low/FOXA2high programs. RUNX1T1 was induced in the intermediate state and remained elevated across both terminal states. RUNX1T1 enhanced NE-associated features and cell viability during enzalutamide treatment in adenocarcinoma cells, whereas its knockdown in NCI-H660 cells reduced NE-associated transcriptional programs, proliferation, and survival and shifted the transcriptome toward an intermediate-like state. Chromatin interactome analysis and co-immunoprecipitation linked RUNX1T1 to G9A/LASP1-containing chromatin repressor complexes. These findings define a temporal framework for treatment-induced NEPC progression and identify RUNX1T1 as an early-induced and sustained regulator of NE lineage transition and maintenance of established NEPC.

cancer biology↗

bioRxiv2025

Earlier snowmelt reduces the strength of carbon sink in montane meadows

O_LIWarming temperatures are changing winters, leading to earlier snowmelt. This shift can lead to an earlier and potentially longer growing season, which in turn may affect various plant-mediated ecosystem functions. Despite its relevance in the carbon cycle, we still know little about how earlier snowmelt impacts the carbon balance in ecosystems over the growing season, e.g., does it only shift phenology, or does it affect the overall carbon uptake? Most studies rely on interannual variability in snowmelt timing, making it difficult to isolate snowmelt effects from other confounding variables, e.g, temperature and moisture anomalies. To address this uncertainty, we investigated how experimentally advancing snowmelt affects the carbon cycling of montane meadows across the growing season. C_LIO_LIWe experimentally advanced the snowmelt date in a montane meadow by approximately 12 days and collected data every two weeks throughout the growing season, including net ecosystem exchange (NEE), gross primary productivity (GPP), ecosystem respiration (ER), plant composition, and shrub, graminoid, and forb biomass. C_LIO_LIEarly in the growing season, GPP was higher in the early snowmelt plots, though this effect decreased as the growing season progressed. Our modeling of cumulative NEE showed that earlier snowmelt increased the carbon sink strength by 22%, with the strongest effect in the early spring and the effect diminishing as the growing season progressed, with control plots being a greater carbon sink in the later season. Graminoid biomass was 47% higher in plots with earlier snowmelt, but there was no change in total biomass. C_LIO_LISynthesis: As winters warm and snowmelt occurs earlier, plant productivity will shift earlier in the growing season, and montane meadows will become a stronger carbon sink. However, this effect will differ seasonally, altering the carbon balance in montane meadows. C_LI

ecology↗

bioRxiv2023

Microbially-conjugated Bile Salts Found in Human Bile Activate the Bile Salt Receptors TGR5 and FXR.

Background & AimsBile salts of hepatic and microbial origin mediate inter-organ crosstalk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs), activate the main host bile salt receptors (TGR5 and FXR) and enter the human systemic and enterohepatic circulation. Approach & ResultsN-amidates of (chenodeoxy)cholic acid and leucine, tyrosine and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gs protein, activation of a cAMP-driven reporter, and diminution of LPS-induced cytokine release from macrophages. Intestine- and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. Affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (i.e. <2.5 nmol/L) in human mesenteric or portal blood, but Leu- and Phe-variants were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. ConclusionsMBSCs activate the cell surface receptor TGR5 and the transcription factor FXR, and are substrates for intestinal (ASBT) and hepatic (NTCP) transporters. Their entry into the human circulation is, however, non-substantial. Given low systemic levels and surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. Origin and function of biliary MBSCs remain to be determined. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/556292v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@72f57borg.highwire.dtl.DTLVardef@1526fe8org.highwire.dtl.DTLVardef@130fd89org.highwire.dtl.DTLVardef@155603f_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender.com

molecular biology↗

bioRxiv2019

A global synthesis reveals biodiversity-mediated benefits for crop production

Human land use threatens global biodiversity and compromises multiple ecosystem functions critical to food production. Whether crop yield-related ecosystem services can be maintained by few abundant species or rely on high richness remains unclear. Using a global database from 89 crop systems, we partition the relative importance of abundance and species richness for pollination, biological pest control and final yields in the context of on-going land-use change. Pollinator and enemy richness directly supported ecosystem services independent of abundance. Up to 50% of the negative effects of landscape simplification on ecosystem services was due to richness losses of service-providing organisms, with negative consequences for crop yields. Maintaining the biodiversity of ecosystem service providers is therefore vital to sustain the flow of key agroecosystem benefits to society.

ecology↗