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Müller, J.

Publications and source records attributed to Müller, J..

At least 19 recordsLinked to original sources

Molecular and phenotypic footprints of climate in native Arabidopsis thaliana

Climate change poses a major threat to humanity by driving biodiversity loss and reducing crop yields1,2. To understand the molecular and developmental impacts of rising temperatures, plant science has relied heavily on the model organism Arabidopsis thaliana. Despite decades of research, its development under fully natural conditions remains poorly understood, and only [~]30% of genes have experimental functional annotations, largely because many functions are subtle or manifest only in specific laboratory or ecological contexts3. Here, we address this gap with a landscape transcriptomic approach that integrates intensive phenotyping and transcriptomic profiling of naturally occurring plants in their native habitats4. Across two contrasting field sites and five growing seasons (2021-2025), we phenotyped more than 3,000 A. thaliana plants and generated >1,600 matching transcriptomes. The resulting >30,000 quantitative trait measurements provide a unique opportunity to link climate fluctuations with plant traits and gene expression. Seasons characterized by extreme temperature anomalies directly influenced plant traits, and climatic variables together explained up to 17% of phenotypic variation. In situ transcriptomes carried clear temperature and local environmental signatures, closely matching temperature-response programs known from the laboratory. Leveraging paired per-plant transcriptomes and phenotypes, we applied machine learning to predict regulators of climate-relevant and other plant traits under natural conditions. The models recovered canonical thermomorphogenesis regulators, including PHYTOCHROME INTERACTING FACTOR 4 (PIF4)5,6, providing ecological evidence that temperature signaling pathways defined in controlled environments operate in the wild, and expanded this regulatory landscape by identifying hormonal receptors, signaling components, and previously uncharacterized genes, some of which we functionally validated. Together, this work demonstrates that landscape transcriptomics, by integrating natural field transcriptomes with phenotypes, and thus, capturing environmental and regulatory states, enables the predictive identification of genetic regulators of temperature responses and broader plant traits. This makes landscape transcriptomics a scalable framework for climate-aware functional genomics in plants.

plant biology↗

A CK2-FBXW11 kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating Tryptophan 2,3-dioxygenase stability

Small molecules toggling the ubiquitin-proteasome system (UPS) are powerful regulators of protein degradation. Yet, mechanistic knowledge of how endogenous ligands gate UPS decisions remains rudimentary. Here, we define control of UPS access to Tryptophan-2,3-dioxygenase (TDO2), which converts the essential amino acid tryptophan (Trp) to N-formylkynurenine. When Trp concentrations are limiting, TDO2 is degraded to avert tryptophanemia. Using CRISPRi screening and biochemistry, we identify a CK2-FBXW11 kinase-E3 ligase cascade that generates and recognizes tandem TDO2 phosphodegrons when not protected by Trp. Trp binding to an exosite safeguards TDO2 from phosphorylation-dependent ubiquitylation. Effects of Trp analogs on CK2-FBXW11-dependent ubiquitylation indicated that the indole, amino, and carboxylate groups are necessary for substrate shielding. Cryo-EM reveals how these moieties order a region proximal to the phosphodegrons; without Trp, this segment is flexible, enabling phosphorylation-coupled ubiquitylation. Overall, our data uncovered an endogenous small molecule allosterically stabilizing its own metabolizing enzyme through protection from a phosphorylation-ubiquitylation cascade.

biochemistry↗

From forest decline to salvage logging: cascading impacts on saproxylic beetle diversity

Understanding the cascading effects of forest decline on saproxylic communities is fundamental for optimizing the management of disturbed forests toward biodiversity conservation objectives. We postulated that the nature and intensity of cascading pathways would vary along decline gradients, encompassing stages from stand decline to mortality and subsequent salvage logging, as mediated by shifts in habitat conditions and resource availability. This study was conducted across three representative European forest contexts: fir forests in the French Pyrenees, spruce forests in the Bavarian Alps, and oak forests in the lowlands of the Loire Valley. Within these systems, we assessed how the taxonomic and functional -diversity of saproxylic beetles responded to variations in both the diversity and density of deadwood and tree-related microhabitats (TreMs). Our analyses identified key cascading effects of stand decline and mortality that were shaped by the considered beetle guild and by the forest type, reflecting tree species-specific disturbance legacies. Stand decline and mortality produced distinct responses within saproxylic beetle assemblages, as different successional guilds preferentially utilized either dying or dead trees. The overall influence of decline processes was positive in conifer-dominated forests. TreMs played a central role in mediating cascading processes structuring saproxylic beetle communities throughout the forest decline continuum. The increase in TreM heterogeneity associated with stand decline or mortality enhanced saproxylic diversity, with exposed wood and trunk injuries identified as particularly influential microhabitats. Snags and large deadwood elements, especially in spruce forests, and deadwood diversity further contributed to sustaining high levels of beetle diversity. Conversely, salvage logging exerted detrimental effects on numerous guilds, primarily through reductions in TreM diversity, decreased TreM trait dispersion, and the depletion of saproxylic TreMs. Given the pronounced context dependency of the processes driving these cascading community dynamics, and considering the increasing frequency, severity, and spatial extent of forest disturbances and global forest decline, it is imperative to integrate this complexity into management and conservation frameworks. Addressing these mechanisms with greater precision will be critical for maintaining functional biodiversity within rapidly changing forest ecosystems.

ecology↗

Experimentally manipulating forest structure to mimic management strategies: effects on deadwood fungal diversity and related ecosystem processes

Understanding the relationships between forest management, biodiversity, and ecosystem processes is necessary for achieving multifunctionality. Deadwood fungi are extremely diverse and important for carbon turnover in forests. However, how forest structure, resulting from management, affects deadwood fungal diversity and decomposition is not well known. We experimentally tested the effects of microclimate (via canopy cover) and deadwood enrichment (snags, logs, tree crowns, and habitat trees) on fungal diversity. Further, we assessed the effects of the treatments and fungal diversity on wood mass loss. We characterized the fungal communities of Fagus sylvatica (European beech) and Pinus sylvestris (Scots pine) deadwood via metabarcoding and measured wood mass loss after 3 years. We found that the host tree species was more important than canopy cover or deadwood enrichment for fungal alpha and beta diversity. Fungal alpha diversity of beech was mainly related to canopy cover; diversity of beech was higher under closed canopies. While alpha diversity of pine was related only to deadwood enrichment as diversity increased where habitat trees and crowns remained. Furthermore, while mass loss of beech was significantly higher in patches where trees were removed and patches where crowns remained, pine mass loss was neither affected by canopy cover nor deadwood enrichment. Host tree diversity is more important than environmental variability as a determinant of fungal diversity, underpinning the importance of maintaining diverse hosts in forests. However, contrasting diversity and decomposition effects between beech and pine suggest the need for forest management strategies tailored to tree species to maintain fungal diversity and ecosystem processes.

ecology↗

Direct evidence of acid-driven protein desolvation

Water and its ability to modulate the protonation states of biomolecules govern the physical chemistry of life, dictating their metabolic functions(1). However, how amino acid protonation alters protein hydration and solubility(2, 3) is an open question since Kuntz and Kauzmann proposed pH-driven protein desolvation in 1974(4). Here, in a series of high-resolution cryo-electron microscopy structures of a protein complex at different pH values (from pH 9.0 to 3.5) we examined thousands of observable hydration sites. Cryo-EM data, in agreement with constant-pH molecular dynamics simulations, show that nearly half of protein-bound waters exchanged with the bulk solvent upon acidification, with [~]100 waters lost per pH unit per molecule. The loss of waters was most significant around the side chains of glutamate and aspartate residues while specific polar residues, mostly asparagine, anchored persistent waters. A positionally conserved hydration layer was observed across all pH conditions, accounting for 40% of resolved waters. Those waters displayed denser packing than less persistent waters, forming a pH-independent solvation shell. Acid-induced water exchange also displaced bound iron, providing a mechanistic link between solvation and metal release. Our findings demonstrate the core principles of acid-driven protein desolvation, resolving a 50-year-old biochemical hypothesis(4).

biochemistry↗

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↗

Dung beetles do not profit from enhanced spatial heterogeneity in production forests: a large-scale forest manipulation experiment

O_LICentral European forest management strategies promoting structurally homogeneous closed-canopy forests have led to landscape-level declines in biodiversity and ecosystem multifunctionality. Conservation-targeted management programs aim at reintroducing structural heterogeneity into production forests, however, it is not well understood if species diversity and ecosystem functions generally profit from management promoting heterogeneity in forest structure. By removing and processing mammalian dung remains, dung beetles play an integral role in ecosystem functions in forests. C_LIO_LIIn one of the largest manipulative forest experiments in Central Europe to date, we analysed the effects of enhanced structural heterogeneity in production forests, climate, and mammalian defecation on dung beetle diversity and dung removal rates at the local and landscape level. We assessed communities of dung beetles and dung removal rates on 234 study patches (50 x 50 m) in eleven paired forest landscapes across a climatic gradient in Germany. Forest landscapes were either managed to conserve a homogeneous closed canopy or to create a heterogeneous forest structure with forest patches varying in canopy coverage and dead wood availability. C_LIO_LIWe did not find that more heterogeneously managed forests had higher dung beetle species diversity and dung removal rates. Canopy openings did not increase species turnover but decreased species diversity. C_LIO_LIAlong the climate gradient, dung beetle average biomass and dung removal decreased with increasing temperature. Canopy openings in combination with higher temperatures negatively impacted all abundant dung beetle species, but especially the large species Anoplotrupes stercorosus, comprising > 90% of the total dung beetle biomass. C_LIO_LISynthesis and application: Our results suggest that dung beetles do not profit from management increasing the structural heterogeneity of forests. Due to a restricted climate and habitat niche of the current Central European dung beetle fauna, future warming and openings in forest structure might have negative effects on dung beetles and consequently on the ecosystem services they provide in Central European production forests. C_LI

ecology↗

Distinct 2-phenyl-imidazo pyridine derivatives drive ER degradation and selectively impair proliferation of ER+ breast cancer cells via the aryl hydrocarbon receptor

X15695 is a 2-phenyl-imidazo[1, 2] pyridine derivative identified as an orally active, selective oestrogen receptor (ER) degrader that inhibits the proliferation of ER+ breast cancer cells. Here, we show that X15695 is an aryl hydrocarbon receptor (AHR) ligand that stabilises the AHR more efficiently than its classical ligand, indirubin. X15695 enables AHR to form a complex with the ER, promoting its proteasomal degradation. In the presence of oestradiol, X15695 outperforms the standard of care drug fulvestrant in suppressing the growth of ER+ breast cancer cells, either expressing the wild-type or clinically relevant ER mutant forms (Y537S and D538G), and of patient-derived xenograft organoids established from ER+ tumours. Using computational techniques, we discovered that a low pKa value resulting from electron-withdrawing substituents in the 2-phenyl-imidazo[1, 2] pyridine compounds is a key feature that identify them as potent AHR ligands, leading to the potential discovery of additional derivatives for future therapeutic development.

cancer biology↗

Neural crest cell biology shapes lizard skull evolution across evolutionary time scales

The vertebrate skull originates from two embryonic lineages, the mesoderm and the neural crest, offering a unique framework to study how developmental mechanisms connect phenotypic variation and evolutionary diversification. Using 3D geometric morphometrics, we analysed skull shape variation in lacertid lizards. Mesoderm- and neural crest-derived bones formed distinct, conserved modules at both micro- and macroevolutionary scales. In the common wall lizard (Podarcis muralis), rapid evolution of skull shape under sexual selection was primarily driven by neural crest-derived bones. While the primary axis of shape divergence in P. muralis aligned with a major axis of variation across lacertids, neural crest-derived bones exhibited slower evolutionary rates and lower morphological disparity than mesodermal-derived bones. We propose that this discrepancy between the role of the neural crest for skull evolution on micro- and macroevolution reflects constraints imposed by neural crest cell biology: although developmental plasticity enables rapid, correlated responses under sexual selection, pleiotropy may limit long-term evolvability of neural crest-derived skull regions. Teaser textThe bones of the vertebrate skull come from two developmental sources: the mesoderm and the neural crest. This dual origin allows to study how development influences evolution. Using 3D models of lizard skulls--including a species with exaggerated male traits linked to the neural crest--we examined patterns of skull variation. We found that neural crest-derived bones contribute to rapid changes driven by sexual selection. However, across different species, these same skull regions evolve more slowly and show less variation. This suggests that while neural crest cells may constrain long-term evolution because of their wide influence, they can also enable fast adaptations. The developmental biology of a trait therefore shapes its evolution.

evolutionary biology↗

Targeted degradation of USP7 in solid cancer cells reveals disparate effects of deubiquitinase inhibition vs. acute protein depletion

Proteolysis-targeting chimeras (PROTACs) co-op the ubiquitin system for targeted protein degradation, creating opportunities to interrogate cellular functions of proteins through "chemical knockdown". However, matched pairs of protein degraders and inhibitors, that possess high specificity and chemical complementarity, for individual components of the ubiquitin system have remained scarce. This includes reagents to modulate activity and abundance of deubiquitinases (DUBs), which critically regulate ubiquitin-mediated signaling. Here, using an integrated chemical biology approach, we explored the cellular function of the DUB USP7 as a case study comparing inhibition and degradation of this DUB in melanoma and pancreatic cancer cells. Through the synthesis of a degrader library, we identified potent USP7 PROTACs for each cancer type, established BRET-based ternary complex formation and quantified degradation efficiency. USP7 degraders and their cognate inhibitor were subsequently employed to characterize treatment-induced phenotypic alterations. Proteomic and cellular analyses revealed that highly specific degradation of USP7 modulated both shared and distinct protein sets across cancer cell types, without impacting cell growth. Notably, cellular responses to USP7 degradation differed markedly from those to USP7 inhibition. Moreover, our data uncovered broad proteomic and metabolic changes induced by prolonged USP7 inhibitor treatment. Collectively, our work provides a chemical toolbox of comprehensively characterized reagents to distinguish on-target phenotypes which will aid the understanding of the role of USP7 in malignant diseases. More broadly, our data emphasize the importance of increased specificity via PROTAC-mediated degradation and the potential of this modality to distinguish catalytic from non-catalytic as well as cell-line specific functions of DUBs.

biochemistry↗

Microevolutionary trends of tooth complexity in the Ibiza wall lizard, Podarcis pityusensis, mirror macroevolutionary trends in squamates

Tooth complexity has long been known as a powerful indicator of feeding in mammals and reptiles, often used to infer diets of long-extinct species. However, how these trends are established below the species level remains unclear. Here, we use Orientation Patch Count Rotated (OPCR) to quantify tooth complexity across eight populations of Podarcis pityusensis, an insular omnivorous lizard endemic to the Pityusic Islands of the Western Mediterranean. These populations vary widely in their extent of herbivory and specialisation, which we use to assess the link between complexity and diet. We find that increasing herbivory is matched with increasing dental complexity, with comparable effect sizes to those found on the macroevolutionary scale. We do not, however, find clear evidence of divergence of tooth complexity between sexes within populations (in a way that would be consistent with niche divergence), meaning that the extent to which this trait is plastic remains controversial. Our results suggest that dental complexity is a highly powerful metric to infer diet, and an informative candidate for linking micro- and macroevolutionary patterns.

evolutionary biology↗

Accounting for spatial interactions in the upscaling of ecosystem services

O_LIMaps of ecosystem service (ES) supply are frequently used to guide spatial planning, policy making, and ecosystem management. However, these are typically based upon coarse land-cover proxies. This approach lacks a strong mechanistic basis, and neglects spatial biodiversity dynamics and interactions among landscape properties that can modify ES provision. C_LIO_LIWe present an analytical framework for ES upscaling that incorporates spatial interactions between landscape properties to determine ES supply. The resulting models can be viewed as a spatially informed ES production function. The approach comprises seven steps that include several elements absent from most existing approaches, notably a procedure for identifying geodata variables that represent the true mechanistic drivers, the inclusion of spatial interactions in the upscaling model, and modification following expert feedback on the selected model. C_LIO_LIWe demonstrate the approach using two example ES from German grasslands: biodiversity conservation and water supply. We show that the inclusion of spatial interactions in the upscaling model improved model predictions from 15% to 33% depending on the ES evaluated. In addition, inclusion of spatial interactions led to reduced error associated with the upscaled estimates. C_LIO_LIBy overcoming several shortcomings of existing, upscaling approaches we generate resulting maps of ES supply that can more reliably inform spatial planning Further, the underlying models allow for simulation of changes in the drivers of ES supply and estimation of respective outcomes. These advantages have the potential to better link detailed local-scale ecological understanding and land management with large-scale ES supply mapping, and thus better inform decision making and spatial planning. C_LI

ecology↗

Bacterial membrane vesicles of Pseudomonas aeruginosa activate AMPK signaling through inhibition of mitochondrial complex III

Bacterial membrane vesicles (BMVs) are secreted by many pathogenic bacteria and known to stimulate various host responses upon infection, thereby contributing to the pathogenicity of bacterial pathogens like Pseudomonas aeruginosa. While the effects of BMVs on host immune responses are well studied, little is known about their impact on cell metabolism and mitochondrial respiration. Here, we show that P. aeruginosa BMVs (1) reprogram cell metabolism of human lung cells, (2) negatively affect mitochondrial respiration by (3) specifically inhibiting complex III of the electron transport chain leading to (4) the activation of AMP-activated protein kinase (AMPK) signaling which in turn results in (5) AMPK-dependent inhibition of global protein synthesis.

cell biology↗

Extreme diversity of phage amplification rates and phage-antibiotic interactions revealed by PHORCE

Growth rate plays a fundamental role in microbiology and serves as an important proxy for fitness in evolution. While high-throughput measurements of bacterial growth rates are easily performed in any microbiology lab, similar methods are lacking for bacteriophages. This gap hinders systematic comparisons of important phage phenotypes, such as their amplification rate in bacterial populations and their bactericidal effect, across different phages and environmental conditions. Here, we show that the amplification rate of lytic phages can be quantified by analyzing bacterial population growth and collapse dynamics under phage predation using a parsimonious mathematical model - an approach termed PHORCE (Phage-Host Observation for Rate estimation from Collapse Events). We found that the resulting phage amplification rate captures the bactericidal effect independent of initial phage and bacterial population sizes and across different growth conditions. Using high-throughput PHORCE, we found that the amplification rates of Escherichia coli phages vary widely by more than three orders of magnitude. Furthermore, our approach suggests that phage-antibiotic interactions are predominantly determined by the antibiotic, and not by the phage. In particular, the ribosome-inhibiting antibiotic doxycycline generally showed antagonism with phage amplification, whereas the DNA-damaging antibiotic nitrofurantoin was synergistic. This framework provides a means to quantitatively characterize phage phenotypes and may facilitate future high-throughput phage screens for antibacterial applications.

microbiology↗

Layer-specific control of inhibition by NDNF interneurons

Neuronal processing of external sensory input is shaped by internally-generated top-down information. In the neocortex, top-down projections predominantly target layer 1, which contains NDNF-expressing interneurons, nestled between the dendrites of pyramidal cells (PCs). Here, we propose that NDNF interneurons shape cortical computations by presynap-tically inhibiting the outputs of somatostatin-expressing (SOM) interneurons via GABAergic volume transmission in layer 1. Whole-cell patch clamp recordings from genetically identified NDNF INs in layer 1 of the auditory cortex show that SOM-to-NDNF synapses are indeed modulated by ambient GABA. In a cortical microcircuit model, we then demonstrate that this mechanism can control inhibition in a layer-specific way and introduces a competition for dendritic inhibition between NDNF and SOM interneurons. This competition is mediated by a unique mutual inhibition motif between NDNF interneurons and the synaptic outputs of SOM interneurons, which can dynamically prioritise different inhibitory signals to the PC dendrite. NDNF interneurons can thereby control information flow in pyramidal cells by redistributing dendritic inhibition from fast to slow timescales and by gating different sources of dendritic inhibition, as exemplified in a predictive coding application. This work corroborates that NDNF interneurons are ideally suited to control information flow within cortical layer 1.

neuroscience↗

Reassembly of a tropical rainforest ecosystem: A new chronosequence in the Ecuadorian Choco tested with the recovery of tree attributes

From hunting and foraging to clearing land for agriculture, humans modify forest biodiversity, landscapes, and climate. Forests constantly undergo disturbance-recovery dynamics and understanding them is a major objective of ecologists and conservationists. Chronosequences are a useful tool for understanding global restoration efforts. They represent a space-for-time substitution approach suited for the quantification of the resistance of ecosystem properties to withstand disturbance and the resilience of these properties until reaching pre-disturbance levels. Here we introduce a newly established chronosequence with 62 plots (50 50 m) in active cacao plantations and pastures, early and late regeneration, and mature old-growth forests, across a 200 km2 area in the extremely wet Choco rainforest. Our chronosequence covers by far the largest total area of plots compared to others in the Neotropics. Plots ranged from 159-615 masl in a forested landscape with 74 {+/-} 2.8 % forest cover within a 1-km radius including substantial old-growth forest cover. Land-use legacy and regeneration time were not confounded by elevation. We tested how six forest structure variables (maximum tree height and DBH, basal area, number of stems, vertical vegetation heterogeneity, and light availability), aboveground biomass (AGB), and rarefied tree species richness change along our chronosequence. Forest structure variables, AGB, and tree species richness increased with regeneration time and are predicted to reach similar levels to those in old-growth forests after ca. 30-116, 202, and 108 yrs, respectively. Compared to previous work in the Neotropics, old-growth forests in Canande accumulate high AGB that takes one of the largest time spans reported until total recovery. Our chronosequence comprises one of the largest tree species pools, covers the largest total area of regenerating and old-growth forests, and has higher forest cover than other Neotropical chronosequences. Hence, our chronosequence can be used to determine the time for recovery and stability (resistance and resilience) of different taxa and ecosystem functions, including species interaction networks. This integrative effort will ultimately help to understand how one of the most diverse forests on the planet recovers from large-scale disturbances.

ecology↗

A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding

Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood. To correlate systematically genetic, transcriptional and proteomic phenotypes, our study involved an integrative analysis of fibroid, myometrium and endometrium tissues from 137 patients, utilising genome-wide SNP arrays, targeted sequencing, RNA sequencing and proteomics. Our findings reveal 39.7% of UFs possess MED12 mutations, alongside novel variants in genes such as COL4A5 and COL4A6. Multi-omics factor analysis of integrated protein and mRNA highlighted differential regulation related to extracellular matrix remodelling, proteolysis and homeostasis in fibroid versus myometrium tissues, and distinct gene sets associated with RNA splicing in the endometrium of patients with HMB, particularly in MED12-mutated fibroids. Our study proposes a model, which is supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding. This integrative approach unravels complex molecular pathways in UF pathogenesis and HMB, offering novel insights for targeted therapeutic development.

systems biology↗

Coagulation activation-induced fibrinolysis biomarker changes depend on thrombophilic risk factors and their clinical phenotype: an interventional in vivo study

BackgroundRecently we have shown alterations in the anticoagulant response to recombinant activated factor VII (rFVIIa)-induced coagulation activation in patients with thrombophilia. ObjectivesHere we extended this in vivo model to study fibrinolysis biomarkers. MethodsThe study population included 56 patients with thrombophilia and a history of venous thromboembolism (VTE+), 38 asymptomatic patients with thrombophilia (VTE-) and 35 healthy controls. Plasma levels of D-dimer, plasmin-2-antiplasmin complex (PAP), and plasminogen activator inhibitor-1 (PAI-1) were monitored over 8 hours after rFVIIa infusion (15 {micro}g/kg) along with thrombin activation markers and activated protein C (APC). ResultsIn all cohorts, PAP increased (P<3.9{middle dot}10-10) and PAI-1 decreased (P<3.5{middle dot}10-8). In contrast to thrombin-antithrombin complex (TAT), which also increased temporarily in all cohorts (P<3.6{middle dot}10-6), changes of PAP and PAI-1 did not reverse during the observation period. The area under the curve (AUC) of PAP (respectively TAT), as measure of plasmin (respectively thrombin) formation, was greater in the VTE+ cohort than in healthy controls (PAP AUC P=0.003, TAT AUC P=2.5{middle dot}10-4) and showed correlation (r=0.554). As evidenced by the respective AUCs, asymptomatic factor V Leiden (FVL) carriers in the VTE-cohort showed less PAP formation (P=9{middle dot}10-4), more pronounced PAI-1 decline (P=0.010), and increased APC formation (P=0.020) than those within the VTE+ group (n=19 each). This was not observed in prothrombin 20210G>A carriers or patients with unexplained familial thrombophilia. ConclusionrFVIIa-induced thrombin formation is associated with fibrinolysis parameter changes outlasting the concomitant anticoagulant response. Both correlate with thrombosis history in FVL and might help to explain its variable clinical expressivity. EssentialsO_LIImpairment of fibrinolysis might result in increased risk of thrombosis. C_LIO_LIWe studied fibrinolytic biomarkers after coagulation activation by recombinant factor VIIa. C_LIO_LIHereby induced alterations in fibrinolytic biomarkers outlast concomitant anticoagulant changes. C_LIO_LIFactor V Leiden carriers with or without thrombosis showed distinct fibrinolytic changes. C_LI

pathology↗