Biology subjects

Hahn, M.

Publications and source records attributed to Hahn, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Myopathy-causing variants of PYROXD1 converge on impaired RNA ligation

RNA ligation is critical for RNA processing pathways including pre-tRNA splicing. RTCB is the only essential RNA ligase in humans and the catalytic subunit of the tRNA ligase complex (tRNA-LC). Its active site is sensitive to oxidation and strictly depends on oxidoreductase PYROXD1, the only tRNA-LC subunit with multiple known pathogenic protein-coding variants. The role of RNA ligation in PYROXD1 myopathy remained contentious: loss of PYROXD1 primarily affects mitochondria, and ligation-linked readouts are inconsistent in existing assays. Here, we reveal that PYROXD1 is physically, genetically and functionally committed to the tRNA-LC. Selectively impairing RTCB activation reproduces hallmarks of PYROXD1 dysfunction, including mitochondrial deregulation. Using degron-based depletion of endogenous PYROXD1, we show that all six single amino acid variants reported in patients fail to sustain RNA ligation in proportion to their clinical severity. The variants segregate into three mechanistic classes: they lower protein stability, disrupt the NADPH-mediated conformational switch, or impair RTCB engagement by the C-terminal tail, a sequence unique to PYROXD1 and directly affected in the most severe variant D500N. Variant-level measurements in the degron model predict outcomes in homozygous and compound heterozygous patient fibroblasts. Together, these data establish impaired RNA ligation as the driver of PYROXD1 pathogenicity.

biochemistry↗

bioRxiv2026

Two homologous Alt a1-like fungal proteins possess dual activities in HIR-associated immune signaling and EDS1-dependent cell death

Necrotrophic fungi secrete numerous Cell Death-Inducing Proteins (CDIPs) that manipulate host immunity to promote disease, yet the signaling pathways underlying their phytotoxic activity remain poorly understood. Here, we identify the Botrytis cinerea Hypersensitive response-inducing protein 1 (Hip1) as a close homolog of the recently described Sclerotinia sclerotiorum effector Plant Early Immunosuppressive Effector 1 (PEIE1) and investigate the molecular basis of its activity. HIP1 and PEIE1 share high sequence similarity and a conserved AlphaFold-predicted Alt a1-like fold, they interact with the Arabidopsis plasma membrane protein HIR4, and they induce strong necrosis in Nicotiana benthamiana. Despite their high structural similarity, Hip1 and PEIE1 differ in their reported roles during fungal infection. Unexpectedly, Hip1-induced cell death requires the central immune regulator ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1) as well as the downstream helper NLR network comprising ADR1 and NRG1. Together, our findings establish Hip1 as a closely related homolog of PEIE1 and suggest that these closely related Alt a1-like proteins possess dual activities: modulation of HIR-associated immune signaling and activation of EDS1-dependent host cell death.

plant biology↗

bioRxiv2026

Deletion of 29 cell death-inducing proteins and phytotoxin biosynthetic genes does not completely abolish virulence of Botrytis cinerea

Botrytis cinerea is a necrotrophic plant pathogen with an extremely wide host range. During invasion, the fungus induces rapid host cell death and proliferates in the necrotic tissue. Host killing involves secretion of lytic enzymes, phytotoxic metabolites and cell death inducing proteins (CDIPs), but their relative contributions are poorly understood. We have previously shown that the sequential knockout of up to 12 CDIPs leads to a substantial reduction of virulence of B. cinerea mutants. In this study, we identified additional CDIPs and generated an unprecedented series of multi-gene deletion mutants in a filamentous fungus, culminating in a 29x mutant carrying deletions of 27 CDIP-encoding genes and two genes required for the biosynthesis of the phytotoxins botrydial and botcinic acid. These multi-k.o. mutants were strongly reduced in virulence and almost unable to infect apple fruit tissue, but still induced slowly expanding necrosis on leaves, demonstrating that additional determinants of host killing remain to be identified. Overexpression of the highly phytotoxic Nep1 in a 22-fold CDIP mutant failed to increase its virulence. Reevaluation of several CDIPs previously described as virulence factors revealed for most of them only small or no significant contributions to pathogenesis. Generation of a mutant lacking all six predicted endo-polygalacturonases confirmed only for PG1 and PG2 a major role for cell wall degradation and infection. Our work demonstrates that necrotrophic pathogenesis in B. cinerea does not depend on a few primary virulence determinants, but rather on a highly redundant network of host damaging factors.

molecular biology↗

bioRxiv2026

Resolving the oak tree of life: comparing RADseq and whole genome resequencing methods for oak phylogenetics

Forest trees pose numerous potential challenges to phylogenomic inference. Their large effective population sizes and relatively long generation times lead to deep allele coalescence and consequently incomplete lineage sorting (ILS), which biases inferences of divergence times toward older ages and introduces gene tree discordance. Deep phylogenetic divergences, reaching back into the Paleocene, introduce reference-mapping biases. Introgression--the movement of genes between lineages--may result in different phylogenies being inferred depending on which individuals are included in analysis, even if the plurality of the genome favors the divergence history unaffected by introgression. These factors influence phylogenetic inference across the Tree of Life but are particularly prevalent in forest trees. Oaks (Quercus) are notable for all three influences. In addition, our knowledge of the oak phylogeny is currently based strongly on restriction site associated DNA sequencing (RADseq) datasets published over the past decade, which may introduce additional sources of uncertainty. In this chapter, we analyze a 322-species RADseq dataset and genome resequencing data from across the genus to address sources of uncertainty in our understanding of the global oak phylogeny, which we hope will serve as a model for other research groups working on comparable woody plant groups.

evolutionary biology↗

bioRxiv2026

Human T Cells From Resistant Hypertension Patients Promote Hypertension via TNF in humanized mice

ObjectivePreclinical studies suggest a pivotal role of adaptive immunity, particularly T cells, in hypertension. However, due to the multifactorial pathogenesis, there is still no definitive evidence for a causal role of T cells in the development of hypertension in humans. We sought to determine whether T cells from patients with treatment-resistant hypertension (TRH) directly modulate blood pressure and vascular function in vivo. MethodsPeripheral blood mononuclear cells (PBMCs) from TRH patients and healthy controls (HC) were adoptively transferred into immunodeficient NSG-(KbDb)^null mice. Hypertension was induced by angiotensin II infusion for 14 days and monitored continuously by radiotelemetry. ResultFollowing T cell engraftment, blood pressure was assessed at baseline and during AngII infusion in both groups of recipient mice. At baseline, systolic blood pressure did not differ between both groups. However, mice receiving TRH-PBMCs developed a significantly higher systolic blood pressure following AngII compared with HC-PBMC recipients. Endothelial dysfunction in isolated perfused kidneys was more pronounced in AngII-challenged TRH-PBMC recipients compared to HC-PBMC recipients. TRH-PBMC recipients displayed elevated effector memory CD4 T cells and Th17 frequencies in spleen and kidney, along with markedly increased renal expression of human T cell-derived TNF. Overnight incubation of mouse aortic rings with human TNF induced endothelial dysfunction, indicating a causal role of T cell-derived TNF. As a proof of concept, TNF inhibition attenuated AngII-induced hypertension in TRH-PBMC-engrafted mice. ConclusionT cells from patients with treatment-resistant hypertension promote an exaggerated hypertensive response and endothelial dysfunction in PBMC-engrafted humanized mice, promoted by TNF-mediated mechanisms. These findings provide evidence that T cell-derived TNF may contribute to the pathogenesis of human hypertension.

immunology↗

bioRxiv2025

Gas5A, a putative glucanosyltransferase from Botrytis, functions as cell death inducing protein in plants

The necrotrophic fungus Botrytis cinerea, releases numerous phytotoxic, cell death inducing proteins (CDIPs) during infection. The precise role of these proteins and their molecular function, however, is still unknown. Here, we report on the identification of a previously unknown CDIP, the glucanosyltransferase Gas5A. Functional characterization revealed that the C-terminal 60 aa of Gas5A are sufficient to induce cell death, independent from its putative enzymatic function. Gas5A localization and functional dependence on the receptor-associated kinase suppressor of BIR1-1 (SOBIR1) and the plant defense regulator ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1) indicate recognition as a pathogen-associated molecular pattern (PAMP) at the plant plasma membrane, but it is toxic also when delivered inside plant cells. Generation of a CRISPR/Cas9-assisted Botrytis knockout strain did not indicate any impact of Gas5A on virulence. Taken together, Gas5A represents a novel PAMP-like CDIP with additional intracellular phytotoxic activity.

plant biology↗

bioRxiv2025

Deep tissue optical 3D imaging reveals preferential preservation of extra-islet β-cells in late-onset Type 1 Diabetes

As residual {beta}-cell function may have positive effects on diabetes regulation in T1D, details on its spatial distribution and mass could provide important information for potential future therapeutic regimens. We implemented an optical 3D imaging pipeline to generate a first account of the 3D-spatial and volumetric distribution of the remaining {beta}-cells throughout the volume of an entire human late onset T1D pancreas at a microscopic resolution. As expected, {beta}-cell mass was dramatically lower than in the non-diabetic pancreas. However, the pancreatic head displayed a morphology and size resembling the non-diabetic pancreas and had a 3 times higher {beta}-cell density compared to the rest of the organ. Surprisingly, only a fraction of the residual {beta}-cells were located within islet structures. Instead, the absolute majority were present as extra-islet {beta}-cells, either as scattered individual cells or as clusters of {beta}-cells, spatially separated from all other endocrine cell-types. Jointly, these extra-islet {beta}-cells appeared roughly 60x less prone to succumb than islet associated {beta}-cells. In sharp contrast to {beta}-cell mass, -cell density appeared unaffected. This 3D whole organ depiction of an entire long standing, late onset, T1D pancreas shows that individual {beta}-cells may be preserved in a highly regionalized manner, potentially reflecting key aspects of disease dynamics.

pathology↗

bioRxiv2025

Identifiability of Bayesian Models of Cognition

Inferring the underlying computational processes from behavioral measurements is a fundamental approach in cognitive science and neuroscience. Although Bayesian decision theory has become a major normative framework for modeling cognition, it is unclear to what extent its modeling components (i.e., prior belief, likelihood function, and the loss function) can be recovered from behavioral data. Here, we systematically investigated the problem of inferring such Bayesian models from behavioral tasks. In contrast to a pessimistic picture often painted in previous research, our analytical results guarantee in-principle identifiability under broadly applicable conditions, without any a priori knowledge of prior or encoding. Simulations and applications on the basis of behavioral datasets validate that the predictions of this theory apply in realistic settings. Importantly, our results demonstrate that reliable recovery of the model often requires having data from multiple noise levels. This is a crucial insight that will guide future experimental design.

neuroscience↗

bioRxiv2025

Primary CD34+ cells of patients with VEXAS syndrome are highly sensitive to targeted treatment with TAK-243 and pevonedistat

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an autoinflammatory disease characterized by somatically acquired UBA1 mutations in hematopoietic stem cells. VEXAS patients present with significant therapeutic challenges such as severe treatment-resistant inflammation and predisposition to myeloid malignancies. In this study, we evaluated the efficacy of TAK-243, a UBA1 inhibitor, and pevonedistat, a NEDD8 inhibitor, in vitro on primary CD34+ hematopoietic stem and progenitor cells (HSPCs) from patients with VEXAS syndrome (n=5), myelodysplastic neoplasms (MDS) (n=10), as well as healthy controls (n=10). Our findings revealed that VEXAS patient-derived HSPCs exhibited significantly higher sensitivity to both TAK-243 (IC50: 22 nM) and pevonedistat (IC50: 553 nM) compared to MDS (IC50: 133 nM and 1048 nM, respectively) and healthy controls (IC50: 192 nM and 1107 nM, respectively) as demonstrated by reduced cell viability. Furthermore, VEXAS CD34+ cells exhibited significantly higher levels of apoptosis after treatment with both inhibitors. These results suggest that TAK-243 and pevonedistat selectively target UBA1-mutated progenitor cells, and indicate a broad therapeutic window in which malignant cells are eradicated but healthy hematopoiesis is not yet compromised. This study provides a strong rationale for further clinical investigation of TAK-243 and pevonedistat as targeted therapies for VEXAS patients, offering hope for improved management of this clinically challenging disorder and contributing to our understanding of its underlying molecular mechanisms.

cancer biology↗

bioRxiv2025

Deep Learning-Enhanced Light Sheet Microscopy Unveils Semaglutide Impact on Cardiac Fibrosis

BackgroundExtensive preclinical research aims to develop novel therapeutics for myocardial fibrosis (MF), a condition marked by collagen accumulation that impairs cardiac function. MF is particularly relevant in heart failure with preserved ejection fraction (HFpEF), a growing clinical challenge with limited treatment options. However, current methods for quantifying MF in mouse models struggle to accurately capture its heterogeneous regional distribution, creating a significant barrier to reliably assessing the efficacy of therapeutics. PurposeTo develop a whole-heart fibrosis imaging and deep learning (DL)-based quantification method and validate the workflow by assessing the efficacy of a glucagon-like peptide-1 receptor (GLP-1R) agonist in mouse HFpEF model. Experimental ApproachBy utilizing a fluorescent collagen-labelling dye, tissue clearing and 3D light sheet microscopy, we developed a high-throughput imaging platform for MF. We established DL framework to quantify perivascular and replacement fibrosis, as well as hypertrophy, in 17 left ventricular (LV) segments. The antifibrotic effects of the GLP-1R agonist semaglutide were evaluated in the db/db UNx-ReninAAV mouse model, which exhibits diabetes, kidney failure, obesity, and hypertension. Key ResultsWhole-heart 3D light sheet microscopy, combined with artificial intelligence, enables micrometer-resolution analysis of MF distribution in rodents. This approach allows for detailed characterization of distinct regional fibrosis patterns. Chronic semaglutide treatment significantly reduced LV hypertrophy and perivascular fibrosis but had no significant effect on replacement fibrosis. Conclusions and ImplicationsThe established 3D imaging and quantification approach provides a powerful tool for evaluating the therapeutic efficacy of antifibrotic compounds and studying the cellular and pathological mechanisms underlying cardiovascular diseases.

pathology↗

bioRxiv2025

iPSC-Derived Cerebral Organoids Reveal Mitochondrial, Inflammatory and Neuronal Vulnerabilities in Bipolar Disorder

Bipolar disorder (BD) is increasingly recognized as a disorder with both mitochondrial dysfunction and heightened inflammatory reactivity, yet their contribution to neuronal activity remains unclear. To address these gaps, this study utilizes iPSC-derived cerebral organoids (COs) from BD patients and healthy controls to model disease-specific metabolic and inflammatory dysfunction in a physiologically relevant system. BD COs exhibited mitochondrial impairment, dysregulated metabolic function, and increased nod-leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome activation sensitivity. Treatment with MCC950, a selective NLRP3 inhibitor, effectively rescued mitochondrial function and reduced inflammatory activation in both BD and control COs. Additionally, a Bioactive Flavonoid Extract (BFE) was explored as a potential therapeutic, demonstrating partial rescue of inflammasome activation. These findings highlight a mitochondria-inflammasome axis in BD pathophysiology and establish a novel platform for studying BD-associated cellular mechanisms, ultimately bridging the gap between molecular dysfunction and therapeutic development.

neuroscience↗

bioRxiv2024

Combination of Imipridone ONC201 or ONC206 with Temozolomide and Radiotherapy in triple ITR therapy reduces intracranial tumor burden and prolongs survival in an orthotopic wild-type IDH GBM mouse model

Glioblastoma remains the most lethal common primary brain tumor in adults with limited therapeutic options. TIC10/ONC201, a first-in-class imipridone we discovered, achieved meaningful therapeutic effects in phase I/II trials in patients with diffuse gliomas harboring H3K27M mutations, and currently the drug is in randomized phase III testing (ACTION trial; NCT05580562). ONC201 targets mitochondrial protease ClpP to disrupt oxidative phosphorylation and trigger the integrated stress response (ISR), TRAIL/DR5, and tumor cell death. We hypothesized that ONC201 and its analogue ONC206 synergize with temozolomide (TMZ) and ionizing radiation (IR), standard-of-care glioblastoma therapies. ONC201 enhances TMZ or IR-induced apoptosis, and cytotoxicity. ClpP-silencing suppresses ONC201-induced cytotoxicity but not TMZ or RT. Both ONC201 and ONC206 reduce expression of TMZ-resistance mediator MGMT. Suppression of MGMT protein was observed in H3K27M-mutated DIPG cell lines following treatment with ONC201 or ONC206 with or without TMZ. Cytokine profiling indicates distinct ONC201 alterations relative to TMZ suggesting distinct anti-tumor immune mechanisms. Triple IR+TMZ+ONC201 (ITR) therapy prolongs median survival to 123 days with a tail on survival curve (3-of-7 mice alive beyond 200-days) in an orthotopic U251 GBM model versus ONC201 (44-days; p=0.000197), IR (63-days; p=0.0012), TMZ (78-days; p=0.0354), ONC201+IR (55-days; p=0.0004), ONC201+TMZ (80-days; p=0.0041) and IR+TMZ (103-days; p>0.05). By 231-days, the only surviving mice were in IRT group. Our results support investigation of ONC201/ONC206 in combination with TMZ and IR (ITR) in GBM or H3K27M mutated diffuse glioma therapy.

cancer biology↗

bioRxiv2023

Plant infection by the necrotrophic fungus Botrytis requires actin-dependent generation of high invasive turgor pressure

The devastating pathogen Botrytis cinerea infects a broad spectrum of host plants, causing great socio-economic losses. The necrotrophic fungus rapidly kills plant cells, nourishing their walls and cellular contents. To this end, necrotrophs secretes a cocktail of cell wall degrading enzymes, phytotoxic proteins and metabolites. Additionally, many fungi produce specialized invasion organs that generate high invasive pressures to force their way into the plant cell. However, for most necrotrophs, including Botrytis, the biomechanics of penetration and its contribution to virulence are poorly understood. Here we use a combination of quantitative micromechanical imaging and CRISPR-Cas guided mutagenesis to show that Botrytis uses substantial invasive pressure, in combination with strong surface adherence, for penetration. We found that the fungus establishes a unique mechanical geometry of penetration that develops over time during penetration events, and which is actin cytoskeleton dependent. Furthermore, interference of force generation by blocking actin polymerization was found to decrease Botrytis virulence, indicating that also for necrotrophs, mechanical pressure is important in host colonization. Our results demonstrate for the first time mechanistically how a necrotrophic fungus such as Botrytis employs this "brute force" approach, in addition to the secretion of lytic proteins and phytotoxic metabolites, to overcome plant host resistance.

biophysics↗

bioRxiv2023

Illuminating the complete β-cell mass of the human pancreas - signifying a new view on the islets of Langerhans

Pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis, but critical information regarding their mass, distribution and composition is lacking within a whole organ context. Here, a new 3D imaging pipeline was applied to generate a first complete account of the insulin-producing islets throughout the human pancreas at a microscopic resolution and within a maintained spatial 3D context. These data show that human islets are far more heterogenous than previously accounted for with regards to their size distribution and cellular make up. By deep tissue 3D imaging, this in-depth study demonstrates that 50% of the human insulin-expressing islets are virtually devoid of glucagon-producing a-cells, an observation with significant implications for both experimental and clinical research. One Sentence Summary: New islet heterogeneity identified in the human pancreas

cell biology↗

bioRxiv2023

TRAIL agonists rescue mice from radiation-induced lung injury

Cancer therapy is often limited by toxicity from pneumonitis. This often-lethal side effect is known to be impacted by innate immunity, and in particular the pathways regulated by the TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from the lethal effects of radiation. We found that two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound #10 (TIC10/ONC201), could achieve this goal. Both compounds could completely protect mice from lethality by reducing pneumonitis, alveolar-wall thickness, and oxygen desaturation. At the molecular level, this protection appeared to be due to the inhibition of CCl22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from high doses of radiation exposure has important translational implications. One Sentence SummaryPrevention of lethality, pneumonitis, lung fibrosis and skin dermatitis post-{psi}-irradiation by short- term treatment with innate immune TRAIL pathway agonists

pathology↗

bioRxiv2023

Serine peptidases and increased amounts of soluble proteins contribute to heat priming of the plant pathogenic fungus Botrytis cinerea

Botrytis cinerea causes grey mold disease in leading crop plants. The disease develops only at cool temperatures, but the fungus remains viable in warm climates and can survive periods of extreme heat. We discovered a strong heat priming effect in which the exposure of B. cinerea to moderately high temperatures greatly improves its ability to cope with subsequent, potentially lethal temperature conditions. We showed that priming promotes protein solubility during heat stress and discovered a group of priming-induced serine-type peptidases. Several lines of evidence, including transcriptomics, proteomics, pharmacology, and mutagenesis data, link these peptidases to the B. cinerea priming response, highlighting their important roles in regulating priming-mediated heat adaptation. By imposing a series of sub-lethal temperature pulses that subverted the priming effect, we managed to eliminate the fungus and prevent disease development, demonstrating the potential for developing temperature-based plant protection methods by targeting the fungal heat priming response. ImportancePriming is a general and important stress adaptation mechanism. Our work highlights the importance of priming in fungal heat adaptation, reveals novel regulators and aspects of heat adaptation mechanisms, and demonstrates the potential of affecting microorganisms, including pathogens through manipulations of the heat adaptation response.

microbiology↗

bioRxiv2022

A unifying theory explains seemingly contradicting biases in perceptual estimation

Perceptual biases are widely regarded as a window into the computational principles underlying human perception. To understand these biases, previous work has proposed a number of conceptually different and even seemingly contradicting ingredients, including attraction to a Bayesian prior, repulsion from the prior due to efficient coding, and central tendency effects on a bounded range. We present a unifying Bayesian theory of biases in perceptual estimation. We theoretically demonstrate an additive decomposition of perceptual biases into attraction to a prior, repulsion away from regions with high encoding precision, and regression away from the boundary. The results reveal a simple and universal rule for predicting the direction of perceptual biases. Our theory accounts for, and leads to new understandings of biases in the perception of a variety of stimulus attributes, including orientation, color, and magnitude.

neuroscience↗

bioRxiv2022

An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy

Optical projection tomography (OPT) and light sheet fluorescence microscopy (LSFM) are high-resolution optical imaging techniques operating in the mm-cm range, ideally suited for ex vivo 3D whole mouse brain imaging. Although these techniques exhibit high sensitivity and specificity for antibody-labeled targets, the provided anatomical information remains limited. To allow anatomical mapping of fluorescent signal in whole brain, we developed a novel magnetic resonance (MR) - based template with its associated tissue priors and atlas labels, specifically designed for brains subjected to tissue processing protocols required for 3D optical imaging. We investigated the effect of tissue pre-processing and clearing on brain size and morphology and developed optimized templates for BABB/Murrays clear (OCUM) and DBE/iDISCO (iOCUM) cleared brains. By creating optical-(i)OCUM fusion images using our mapping procedure, we localized dopamine transporter and translocator protein expression and tracer innervation from the eye to the lateral geniculate nucleus of thalamus and superior colliculus. These fusion images allowed for precise anatomical identification of fluorescent signal in discrete brain areas. As such, these templates enable applications in a broad range of research areas integrating optical 3D brain imaging by providing an MR template for cleared brains.

neuroscience↗