Biology subjects

Weiler, M.

Publications and source records attributed to Weiler, M..

8 recordsLinked to original sources

bioRxiv2026

Lipid nanoparticle shape and morphology determine the magnitude and duration of mRNA transfection

Lipid nanoparticles (LNP) are widely used for nucleic acid delivery, with current optimization efforts mainly focusing on refining formulation features, enabling extrahepatic targeting, and improving therapeutic efficacy. Particle shape and internal architecture are variables often overlooked in LNP design, although they critically influence particle stability, biodistribution, cellular uptake, and transfection. Here, we investigate how formulation and process parameters impact LNP shape, morphology, and internal structure, and how these structural features, in turn, influence mRNA loading, cell uptake, and expression. We demonstrate that modulation of lipid composition by increasing DSPC content drives a transition from compact spherical to vesicular non-spherical morphologies, with altered RNA loading at the single-particle level. While non-spherical LNP exhibited higher cellular uptake than spherical LNP, it was identified that this increase was relatively modest compared with the substantially higher and sustained protein expression for non-spherical structures. This suggests that increased uptake alone cannot explain the enhanced transfection performance. The trend was conserved across LNP formulations comprising clinically relevant ionizable lipids SM-102, ALC-0315 and DLin-MC3-DMA. Taken together, these findings establish LNP shape and internal morphology as functionally relevant design variables that should be considered in the design of next-generation LNP with improved mRNA delivery and expression.

pharmacology and toxicology↗

bioRxiv2026

Oncodevelopmental plasticity of the skeleton in myeloid neoplasms

Myelofibrosis in patients with myeloproliferative neoplasms (MPNs) is traditionally characterized by bone marrow fibrosis and osteosclerosis, with de novo bone formation commonly attributed to impaired osteoclast-mediated resorption. Here, we challenge this paradigm by demonstrating that a solitary clonal driver mutation simultaneously induces pathological bone formation and resorption, with osteosclerosis acting to conceal localized and active bone destruction rather than inhibiting it. Through population analysis; clinical imaging; patient-derived multi-tissue sequencing; murine models and organ-on-a-chip systems, we demonstrate that spatial and ontogeny-dependent remodeling in mesoderm- and neural crest-derived bones is mechanistically interconnected via a previously unidentified osteochondral stromal injury program. Neural crest-derived stromal cells suppress osteogenic programs and undergo injury-induced lineage plasticity with ectopic chondrogenesis, mirroring pathological remodeling in mesoderm-derived growth plate regions. This shared injury response promotes osteoclastogenesis and is mediated by a conserved Thrombospondin 1+ (THBS1+) stromal population that links fibrotic remodeling to bone loss. Combined pharmacological inhibition of THBS1 and JAK signaling reduces myeloproliferation, halts fibrosis progression, and restores two developmentally distinct bones, establishing THBS1 as a unifying therapeutic target in myelofibrosis.

cancer biology↗

bioRxiv2026

Seasonal dynamics and sun/shade heterogeneity of leaf gas exchange and VOC emissions inside a tall temperate forest canopy

Leaf gas exchange is the key driver of forest carbon uptake and directly determines forest carbon sink activity. Additionally, plants release a variety of biogenic volatile organic compounds (VOCs) acting as stress signals of trees. However, continuous hourly resolved measurements of leaf gas exchange and VOC emissions in tall tree canopies are challenging and remain scarce. To this end, we developed a sophisticated in-situ leaf gas exchange measurement system with 24 cuvettes deployed on mature Fagus sylvatica (n=3) and Pseudotsuga menziesii (n=3) individuals in a mixed temperate forest. We additionally measured sap flux density (Js), radial growth and tree water deficit (TWD) to gain a holistic picture of seasonal leaf and stem water and carbon flux dynamics during the summer of 2024. During midsummer, we found a gradual reduction of stomatal conductance (gs) and VOC emissions of sun, but not shade branchlets of P. menziesii in response to moderate atmospheric and edaphic drying. Decreased gs led to a downregulation of transpiration (E), Js, and carbon isotope discrimination accompanied by an increase in TWD and intrinsic water used efficiency. Leaf gas exchange of shade branchlets remained unaffected due to microclimatic buffering effects. Contrarily, sun leaves of F. sylvatica, profited from sunny midsummer conditions and increased leaf gas exchange, whereas shade leaves benefitted from more diffuse light during early summer exhibiting similar carbon assimilation, transpiration and VOC emissions as sun leaves. For both species we found a clear time lag of four to five hours between maximum leaf and stem water fluxes and a delay of up to 20 hours for the recovery of TWD, highlighting the role of stem water reserves. Pronounced seasonal and diurnal differences of leaf gas exchange, stem water fluxes and VOC emissions showed, that continuous data are essential to better understand variability of ecosystem flux dynamics.

plant biology↗

bioRxiv2025

Water stable isotopes reveal the ecohydrological importance of stemflow for mature and juvenile European beech

O_LIStemflow of forest trees can contribute a significant fraction of water to forests water fluxes; however, it is still unclear if and to what extent trees use stemflow for water supply and how much stemflow is lost by percolating below the root zone. C_LIO_LIWe applied deuterium-enriched stemflow equivalent to a throughfall depth of 23 mm to adult Fagus sylvatica trees to trace stemflow through the soil and trees. We continuously measured in-situ water stable isotope compositions in soil and xylem water and destructively sampled xylem water in the crowns of adult labelled (n=18), unlabelled F. sylvatica (n=15) and unlabeled Picea abies (n=9), complemented by destructive xylem water sampling of neighboring juvenile F. sylvatica (n=45). C_LIO_LIStemflow water supported 3.9 - 14.0% of daily sap flux of adult labelled F. sylvatica trees. In the soil, deuterium-enriched stemflow was detectable at a max. of 0 - 0.40 m to the labelled tree. However, unlabeled juvenile trees within a distance of [~]2 m showed label water uptake, indicating rooting into soil compartments affected by stemflow label. C_LIO_LIWe demonstrate the importance of stemflow as a water source for both adult and neighboring juvenile F. sylvatica, strongly profiting from stemflow infiltration. C_LI

plant biology↗

bioRxiv2025

Wnt-dependent spatiotemporal reprogramming ofbone marrow niches drives fibrosis

Bone marrow fibrosis is the most extensive matrix remodeling of the microenvironment and can include de novo formation of bone (osteosclerosis). Spatiotemporal information on the contribution of distinct bone marrow niche populations to this process is incomplete. We demonstrate that fibrosis-inducing hematopoietic cells cause profibrotic reprogramming of perivascular CXCL12 abundant reticular (CAR) progenitor cells resulting in loss of their hematopoiesis-support and upregulation of osteogenic and pro-apoptotic programs. In turn, peritrabecular osteolineage cells (OLCs) are activated in an injury-specific, Wnt-dependent manner, comparable to skeletal repair. OLCs fuel bone marrow fibrosis through their expansion and skewed differentiation, resulting in osteosclerosis and expansion of Ly6a+ fibroblasts. NCAM1 expression marks peritrabecular OLCs and their expansion into the central marrow is specific for fibrosis in mice and patients. Peritrabecular stromal b-catenin expression is linked to fibrosis in patients and inhibition of Wnt signaling reduces bone marrow fibrosis and osteosclerosis, possibly being a clinically relevant therapeutic target.

molecular biology↗

bioRxiv2024

Forest dieback in drinking water protection areas - a hidden threat to water quality

For centuries, forests have been considered a natural safeguard for drinking water quality. We challenge this view in light of the rising frequency of climate extremes, such as droughts coinciding with high temperatures, which have caused unprecedented pulses of forest dieback globally. Drought-induced forest diebacks may jeopardize the crucial role of forests in protecting water quality, potentially even turning forests into sources of contamination. To underscore the critical importance of the topic, here we provide the first comprehensive assessment of forest cover, type, and dieback (assessed as canopy cover loss) across drinking Water Protection Areas (WPAs) in Germany, one of the countries hit most severely by the unprecedented Central European drought of 2018-2020. Our findings reveal a high forest cover of 43% in WPAs, from which a substantial amount of 5% canopy cover got lost within only three years as a direct or indirect consequence of the drought. Spruce-dominated forests, constituting 28% of all forests in WPAs, were particularly susceptible, but other dominant tree species also experienced anomalously high mortality rates. Combining this assessment with exemplary records of nitrate concentrations in the groundwater of WPAs revealed that forest dieback can significantly impair drinking quality. On average, nitrate concentrations more than doubled in WPAs with severe forest dieback, whereas nitrate concentrations did not significantly change in undisturbed WPAs. However, we also found pronounced differences between WPAs affected by forest dieback, underlining the need for further data and research to derive a generalizable understanding of the underlying mechanisms and controls. Based on this assessment, we deduce critical data and knowledge gaps essential to developing well-informed prediction, adaptation, and mitigation strategies. We call for interdisciplinary research addressing the hidden threat forest dieback poses for our drinking water resources.

biochemistry↗

bioRxiv2023

Early alterations of thalamo- and hippocampo-cortical functional connectivity are biomarkers of epileptogenesis after traumatic brain injury

The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) study is a prospective multicenter clinical observational study to identify early biomarkers of epileptogenesis after moderate-to-severe traumatic brain injury (TBI). In this preliminary analysis of 37 patients, using a seed-based approach applied to acute (i.e., [≤] 14 days) functional magnetic resonance (MRI) imaging data, we directly test the hypothesis that the epileptogenic process following brain trauma is associated with functional changes within hippocampal and thalamo-cortical networks. Additionally, we hypothesize that the network connectivity involving thalamic and hippocampal circuits underlying early and late-onset epileptogenesis would differ. The three groups did not differ by sex distribution ({chi}2(2) = 1.8, p = .407), age (H(2) = 4.227, p = .121), admission Glasgow Coma Scale (H(2) = 3.850, p = .146) or postinjury day of the MRI session (H(2) = .695, p = .706). The primary finding is that patients with early seizures, a sign of early epileptogenesis, exhibited pattern 1, namely, an increased positive connectivity in thalamic and hippocampal networks, as compared to patients who had no epileptogenesis, or late epileptogenesis (p < .05, FWE-corrected at the cluster level). In contrast, this finding was absent in those patients who exhibited late seizures, with the latter group displayed pattern 2, namely, a lower positive and higher negative connectivity in the hippocampal network, as compared to patients who had no signs of epileptogenesis (p < .05, FWE-corrected at the cluster level). Patients with either pattern 1 or pattern 2 connectivity profiles in thalamic and hippocampal networks were significantly predictive of late (i.e., between 7 days and 2 years) epileptogenesis following brain trauma. A Receiver Operating Characteristic (ROC) Curve analysis model that included thalamic and hippocampal functional connectivity values presented an Area Under the Curve (AUC) 87.7, specificity 86.7, and sensitivity 84.6. Our results indicate that dysfunction in hippocampal and thalamo-cortical networks are potential biomarkers for early and late epileptogenesis following a TBI.

neuroscience↗

bioRxiv2021

Evaluating denoising strategies in resting-state fMRI in traumatic brain injury (EpiBioS4Rx)

ObjectiveResting-state functional MRI is increasingly used in the clinical setting and is now included in some diagnostic guidelines for severe brain injury patients. However, to ensure high-quality data, one should mitigate fMRI-related noise typical of this population. Therefore, we aimed to evaluate the ability of different preprocessing strategies to mitigate noise-related signal (i.e., in-scanner movement and physiological noise) in functional connectivity of traumatic brain injury patients. MethodsWe applied nine commonly used denoising strategies, combined into 17 pipelines, to 88 traumatic brain injury patients from the Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy clinical trial (EpiBioS4Rx). Pipelines were evaluated by three quality control metrics across three exclusion regimes based on the participants head movement profile. ResultsWhile no pipeline eliminated noise effects on functional connectivity, some pipelines exhibited relatively high effectiveness depending on the exclusion regime. Once high-motion participants were excluded, the choice of denoising pipeline becomes secondary - although this strategy leads to substantial data loss. Pipelines combining spike regression with physiological regressors were the best performers, whereas pipelines that used automated data driven methods performed comparatively worse. ConclusionIn this study, we report the first large-scale evaluation of denoising pipelines aimed at reducing noise-related functional connectivity in a clinical population known to be highly susceptible to in-scanner motion and significant anatomical abnormalities. If resting-state functional magnetic resonance is to be a successful clinical technique, it is crucial that procedures mitigating the effect of noise be systematically evaluated in the most challenging populations, such as traumatic brain injury datasets.

neuroscience↗