Biology subjects

Lehmann, S.

Publications and source records attributed to Lehmann, S..

18 recordsLinked to original sources

bioRxiv2026

Neurobiological alterations and autism-like phenotype in mice following regulatory-limit exposure to fungicides in drinking water

Neurodevelopmental conditions, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), have increased markedly over recent decades. This rise parallels the widespread use of agrochemicals, suggesting a contribution of environmental exposures. We hypothesize that pesticide residues may disrupt brain development and promote neurodevelopmental disorders. Here, we test whether concentrations permitted in drinking water affect brain development using a maternal exposure model in wild-type mice. Exposure to a fungicide mixture at 0.3 g/L, below the current European regulatory limit of 0.5 g/L, impairs corticogenesis and is associated with alterations in synaptic function and glutamatergic signaling. Offspring exhibit delays in sensory development, reduced social interactions, and increased stereotyped behaviors. We identify the adenosine A2A receptor as a molecular target of anilinopyrimidine fungicides. Together, these findings indicate that low-dose exposure to this fungicide mixture can induce an autism spectrum-like phenotype in the offspring.

neuroscience↗

bioRxiv2026

Symbiont effectors modulate plant signalling to increase host stress resilience

Plant colonizing mutualistic symbionts confer beneficial effects to their hosts, which often includes increased growth, and biotic and abiotic stress resilience. How these benefits are activated on a molecular level is mostly unknown. Here, we describe effector candidates of the fungal symbiont Serendipita indica (Si), which modulate plant stress signalling pathways. By analyzing the Si effector interactome, we reveal frequent targeting of stress related host proteins, which are linked to the identified effector signalling functions. Moreover, functional data indicate that Si effectors modulate abiotic stress response of Arabidopsis, as well as resistance to pathogen infection. Analysis of symbiont effectors might not only uncover previously unreported molecular mechanisms that increase plant fitness but might also be used to identify potential genetic traits for crop improvement under changing climates.

plant biology↗

bioRxiv2026

Personal network features are embodied in real-time social interaction dynamics

People navigate dozens of social interactions daily. Through these, they construct and maintain diverse social networks. While personal dispositions drive how people interact and connect others, the resulting networks feed back into daily social experiences by creating interaction opportunities and modulating cognitive processes. Here, we show that peoples moment-to-moment interaction behaviors are informative of the structure of their personal social network, even if the interaction occurs between strangers. We paired 104 strangers to perform an interactive motor task and investigated whether emergent leader-follower roles and spontaneous movement synchronization reflected similarities or differences in their personal networks. Participants with tighter networks (smaller, denser, more constrained, and with fewer communities) relative to the interaction partner adapted their movements to the partner more. Using multivariate temporal response functions (mTRF) to measure neural encoding of self and others movements, we found that, conversely, participants with less tight networks exhibited higher neural encoding of their partners movements. This suggests that the network effect on behavioral adaptation was unlikely to be driven by heightened monitoring of the partner. Higher spontaneous movement synchronization was associated with higher personality agreeableness and personality similarity between interacting partners. Our results demonstrate that signatures of personal social environment manifest dynamically in real-time behaviors and that these effects are independent of personality effects. Thus, social networks set an additional context for interpersonal interaction even for partners without a prior relationship.

neuroscience↗

bioRxiv2026

Transcriptionally defined AML cell states associate with treatment response and microenvironmental remodeling

While therapy resistance in acute myeloid leukemia (AML) is often attributed to leukemic stem cells (LSCs), their functional properties are not fully captured by their well-established genetic landscape and cell lineage transcriptional programs. Here, we explore AML cell states and their associations to drug response and systemic immune context. We performed integrated single-cell transcriptomics and immunophenotyping on diagnostic AML samples (n=6) to define transcriptional cell state gene signatures. These were projected onto bulk RNA-seq data from 448 AML patients to assess associations with drug sensitivity, plasma proteomics, clinical features, and established prognostic scores. Longitudinal single-cell data from external cohorts and cell-cell communication analyses were used to examine treatment dynamics and microenvironmental signaling. We defined nine AML cell states, including progenitor-like, stromal-like, antigen-presenting, and monocytic programs. Stemness features were distributed across multiple states, with lymphoid-primed and stress-adapted progenitors showing the strongest alignment with established stemness scores. Distinct drug sensitivities emerged, including cell cycle checkpoint inhibitor sensitivity in stress-adapted progenitors and kinase inhibitor sensitivity in cycling progenitors, alongside shared resistance to BH3 mimetics in monocytic states. Stress-adapted progenitors were associated with adverse clinical features and expanded following venetoclax-based therapy. Monocytic states acted as immunosuppressive hubs via TIGIT signaling, while stromal-associated states received niche-derived survival signals. Overall, we define a framework that associates AML cell states with stemness, drug response, and microenvironmental interactions. These findings highlight distributed stemness, state-specific vulnerabilities, and niche-driven resistance mechanisms, informing more precise therapeutic strategies in AML.

cancer biology↗

bioRxiv2025

Discovery of an orally available potent ER aminopeptidase 1 (ERAP1) inhibitor that enhances anti-tumor responses and limits inflammatory autoimmunity in vivo.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that can regulate immune responses primarily by proteolytically processing peptides before loading and presentation on the cell surface by major histocompatibility class I molecules (MHC-I). ERAP1 activity can either reduce the immunogenicity of cancer cells by over-trimming cancer-associated antigenic peptides or contribute to autoimmunity by generating self-antigenic peptides. As a result, ERAP1 inhibition has emerged as a tractable approach for cancer immunotherapy and specific classes of autoimmunity. Here, we describe the discovery, after hit-to-lead optimization, of a potent and selective ERAP1 inhibitor based on the pyrrolidine 3-carboxylic acid scaffold that targets the regulatory allosteric site. The compound has favourable in vivo pharmacokinetics, including oral bioavailability, and can regulate the immunopeptidome of cancer cells and enhance cancer cell antigenicity in vivo in a dose-dependent manner, controlling tumor growth. In addition, when administered in the murine collagen-induced arthritis model, it does not induce any exacerbation of autoimmune responses but rather results in a dose-dependent therapeutic benefit. Our results demonstrate that ERAP1 inhibition can constitute a tractable approach to modulating immune responses for therapeutic applications, providing mechanistic insight and a valuable lead and in vivo tool for further drug development efforts and for interrogating ERAP1 biology.

immunology↗

bioRxiv2025

Activity-targeted metaproteomics enhances the ecophysiological characterization of cryptic syntrophic metabolisms

Syntrophic microbial consortia can contribute significantly to the activity and function of anoxic ecosystems, yet are often too rare to study their in situ physiologies using traditional molecular methods. Here, we combined bioorthogonal non-canonical amino acid tagging (BONCAT), stable isotope probing, and metaproteomics to improve the recovery of proteins from active members and track isotope incorporation in an anaerobic digestion community. Both click chemistry-enabled cell-sorting and direct protein pulldown coupled to metaproteomics improved recovery of isotopically labeled proteins during anaerobic acetate oxidation. Resulting labeled protein expression profiles revealed elevated activity of a rare and so-far uncharacterized syntrophic bacterium belonging to the family Natronincolaceae. BONCAT-based capture of newly translated proteins provided direct molecular evidence for the expression of a previously hypothesized oxidative glycine pathway for syntrophic acetate oxidation by this microorganism, showcasing the potential of targeted metaproteomics to characterize rare and active cells central to community metabolism in natural and engineered ecosystems.

microbiology↗

bioRxiv2025

The cellular state space of AML unveils novel NPM1 subtypes with distinct clinical outcomes and immune evasion properties

Acute myeloid leukemia (AML) is a genetically and cellularly heterogeneous disease. We characterized 120 AMLs using genomic and transcriptomic analyses, including single-cell RNA sequencing. Our results reveal an extensive cellular heterogeneity that distorts the bulk transcriptomic profiles. Selective examination of the transcriptional signatures of >90,000 immature AML cells identified four main clusters, thereby extending current genomic classification of AML. Notably, NPM1 mutated AML could be stratified into two novel, clinically relevant classes, with NPM1class I associated with downregulation of MHC class II and excellent survival following hematopoietic stem cell transplantation (HSCT). NPM1class II was instead associated with resistance to allogeneic T cells in an ex vivo co culture assay, and importantly, dismal survival following HSCT. These findings provide new insights into the cellular state space of AML, define new diagnostic entities, and highlight potential therapeutic intervention points. Key PointsO_LIThe bulk transcriptional profiles of AML are mainly driven by a diverse set of cellular signatures. C_LIO_LISingle cell RNA-sequencing of the most common AML subtypes reveals marked heterogeneity extending beyond current genomic classification schemes. C_LIO_LINPM1-mutated AML can be divided into two new classes, with distinct immune evasion mechanisms and survival after transplantation. C_LI

cancer biology↗

bioRxiv2025

Genome-wide identification of genes involved in beetle odoriferous defensive stink gland function recognizes Laccase2 as the phenoloxidase responsible for toxic para-benzoquinone synthesis

Exocrine glands have evolved several times independently in Coleoptera to produce defensive chemical compounds with repellent, antimicrobial, or toxic effects. Research on such glands had focused on morphological or chemical ecology methods. However, modern genetic approaches were missing to better understand this biological process. With the rise of the red flour beetle, Tribolium castaneum, as a model for studies of development and pest biology, molecular genetic tools are now available to also study the safe generation of toxic compounds in defensive stink glands. Using the RNA-interference-based, genome-wide, phenotypic screen "iBeetle" and the re-analysis of gland-specific transcriptomics based on a significantly improved genome annotation, we could identify 490 genes being involved in odoriferous stink gland function. In the iBeetle screen, 247 genes were identified, of which we present here 178 genes identified during iBeetles 3rd phase, while the transcriptomics analyses identified 249 genes, with six genes being identified in both functional genomics approaches. Of these 490 genes, only about 40% of these genes have molecularly characterized homologs in the vinegar fly, while for 213 genes no fly homologs were recognized and for 13 genes no gene ontology at all was identified. This highlights the importance of genome-wide gene identification in tissues that have not been previously analyzed to recognize potentially new gene functions. Gene ontology analysis revealed "SNARE interactions in vesicular transport", "Lysosome", "Pancreatic secretion", and "MAPK signaling pathway - fly" as key pathways. Additionally, many of the genes are encoding enzymes, transcription factors, transporters, or are involved in membrane trafficking. As the phenoloxidase responsible for generating the toxic para-benzoquinones in the stink glands of the beetle, we could identify laccase2, which is expressed in the last secretory cell in contact with the cuticule-lined organelle, where the toxic compounds are safely produced before being released into the gland reservoir. Author summaryCertain beetles produce toxic substances to defend themselves against microorganisms or predators. For the generation of such chemicals, the beetles have specialized glands, which are organized in a way that they can produce and store the toxic compounds without harming themselves. The morphology and biochemistry of such glands had been intensively studied. However, the genes that are involved in this process had not been recognized. Here we present the identification of about 500 genes that are involved in the function of beetle defensive glands, which presents a starting point for a detailed molecular understanding of the process of safe production of toxic substances. A key feature for the production is the use of non-harmful precursors that are only finally processed by a specifically secreted enzyme called Laccase2 to become toxic in a cuticle-shielded organelle.

genetics↗

bioRxiv2024

Pathway activation model for personalized prediction of drug synergy

Targeted monotherapies for cancer often fail due to inherent or acquired drug resistance. By aiming at multiple targets simultaneously, drug combinations can produce synergistic interactions that increase drug effectiveness and reduce resistance. Computational models based on the integration of omics data have been used to identify synergistic combinations, but predicting drug synergy remains a challenge. Here, we introduce DIPx, an algorithm for personalized prediction of drug synergy based on biologically motivated tumor- and drug-specific pathway activation scores (PASs). We trained and validated DIPx in the AstraZeneca-Sanger (AZS) DREAM Challenge dataset using two separate test sets: Test Set 1 comprised the combinations already present in the training set, while Test Set 2 contained combinations absent from the training set, thus indicating the models ability to handle novel combinations. The Spearman correlation coefficients between predicted and observed drug synergy were 0.50 (95% CI: 0.47-0.53) in Test Set 1 and 0.26 (95% CI: 0.22-0.30) in Test Set 2, compared to 0.38 (95% CI: 0.34-0.42) and 0.18 (95% CI: 0.16-0.20), respectively, for the best performing method in the Challenge. We show evidence that higher synergy is associated with higher functional interaction between the drug targets, and this functional interaction information is captured by PAS. We illustrate the use of PAS to provide a potential biological explanation in terms of activated pathways that mediate the synergistic effects of combined drugs. In summary, DIPx can be a useful tool for personalized prediction of drug synergy and exploration of activated pathways related to the effects of combined drugs.

bioinformatics↗

bioRxiv2024

A candidate reference method for the quantification of α-synuclein in cerebrospinal fluid using an SI traceable primary calibrator and multiple reaction monitoring

Objectives-synuclein aggregation is an indicator of neurodegenerative diseases such as Parkinsons disease (PD) and recent advances have suggested that this protein could serve as a potential biomarker. It has been indicated that soluble and oligomeric -synuclein in biological fluids could have diagnostic applications for PD. Clinical laboratories currently rely on antibody-based assays to detect -synuclein. These assays have limited specificity, low sensitivity and poor inter-lab reproducibility, which prevents the validation of -synuclein as a biomarkers. This study aims to fill the unmet need for the standardisation of clinical measurements for -synuclein. MethodsWe report the first candidate reference method for -synuclein, using an SI traceable primary calibrator for -synuclein and isotope dilution mass spectrometry. The primary calibrator was traceably quantified utilising a combination of amino acid analysis and nuclear magnetic resonance. A targeted sample clean-up procedure involving a non-denaturing Lys-C digestion and solid-phase extraction allowed for the sensitive detection of multiple proteotypic -synuclein peptides in cerebrospinal fluid (CSF) samples. ResultsThe candidate reference method procedure showed linearity across three orders of magnitude, covering the physiological levels of -synuclein in CSF (LOQ = 0.1 ng/g). The method was used to quantify a cohort of CSF samples and the measurements were correlated with immunoassay-based quantifications. ConclusionsThe SI traceable quantification of -synuclein in complex biological matrices means that the role of this protein can be further elucidated in synucleinopathies. This candidate reference method would lead to the harmonisation of -synuclein measurements, which may allow for development of high throughput clinical tests.

biochemistry↗

bioRxiv2023

Modeling the simultaneous dynamics of proteins in blood plasma and the cerebrospinal fluid in human in vivo

The analysis of protein dynamics or turnover in patients has the potential to reveal altered protein recycling such as in Alzheimer disease, and to provide informative data regarding drug efficacy, or certain biological processes. The observed protein dynamics in a solid tissue or a fluid is the net result of protein synthesis and degradation, but also transport across biological compartments. We report an accurate 3-biological compartment model able simultaneously account for the protein dynamics observed in blood plasma and the cerebrospinal fluid (CSF) including a hidden central nervous system (CNS) compartment. We successfully applied this model to 69 proteins of a single individual displaying similar or very different dynamics in plasma and CSF. This study put a strong emphasis on the methods and tools needed develop this type of model. We believe it will be useful to any researcher dealing with protein dynamics data modeling.

systems biology↗

bioRxiv2023

Enabling population protein dynamics through Bayesian modeling

The knowledge of protein dynamics or turnover in patients provides invaluable information related to certain diseases, drug efficacy, or biological processes. A great corpus of experimental and computational methods has been developed, including by us, in the case of human patients followed in vivo. Moving one step further, we propose here a new modeling approach to capture the highly relevant notion of population protein dynamics. Using two data sets, we show that models inspired by population pharmacokinetics can accurately capture protein turnover within a cohort of individuals, even in presence of substantial inter-individual variability. Such models pave the way for comparative studies searching for altered dynamics or biomarkers in diseases.

systems biology↗

bioRxiv2023

Transporter-mediated depletion of extracellular proline directly contributes to plant pattern-triggered immunity against a bacterial pathogen

Plants possess cell surface-localized immune receptors that detect pathogen-associated molecular patterns (PAMPs) and initiate defenses that provide effective resistance against microbial pathogens. Many PAMP-induced signaling pathways and cellular responses are known, yet how pattern-triggered immunity (PTI) limits pathogen growth in plants is poorly understood. Through a combined metabolomics and genetics approach, we discovered that plant-exuded proline is a virulence-inducing signal and nutrient for the bacterial pathogen Pseudomonas syringae, and that PAMP-induced depletion of proline from the extracellular spaces of Arabidopsis leaves directly contributes to PTI against P. syringae. We further show that PAMP-induced depletion of extracellular proline requires the amino acid transporter Lysine Histidine Transporter 1 (LHT1). This study demonstrates that depletion of a single extracellular metabolite is an effective component of plant innate immunity. Given the important role for amino acids as nutrients for microbial growth, their depletion at sites of infection may be a broadly effective means for defense against many pathogens.

plant biology↗

bioRxiv2023

Syndecan-1 as specific cerebrospinal fluid biomarker of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease often characterized by remission and relapse periods occurring at irregular intervals after an initial attack (clinically isolated syndrome) and followed by a gradual progression of disability. Clinical symptoms, magnetic resonance imaging and abnormalities in cerebrospinal fluid (CSF) immunoglobulin profile allow diagnosis with a good sensitivity. However, current biomarkers lack specificity or have poor individual prognostic value. To identify novel candidate biomarkers of MS, we analysed 1) the CSF proteome from symptomatic controls and patients with clinically isolated syndrome or remitting-relapsing multiple sclerosis (n=40), and 2) changes in oligodendrocyte secretome upon proinflammatory or pro-apoptotic treatment. Proteins exhibiting differences in abundance in both studies were combined with previously described MS biomarkers to build a list of 87 proteins that were quantified by parallel reaction monitoring (PRM) in CSF samples from a new cohort comprising symptomatic controls and MS patients at different disease stages (n=60). The eleven proteins that passed this qualification step were subjected to a new PRM assay from a larger cohort (n=158) comprising patients with MS at different disease stages or with other inflammatory or non-inflammatory neurological disorders. Collectively, these studies identified a biomarker signature of MS that might improve MS diagnosis and prognosis. These include the oligodendrocyte precursor cell proteoglycan Syndecan-1, which was more efficient than previously described biomarkers to discriminate MS from other inflammatory and non-inflammatory neurological disorders.

neuroscience↗

bioRxiv2020

Structural and functional insights into the mechanism of action of plant boron transporters

Boron has essential roles in plant growth and development. BOR proteins are key in the active uptake and distribution of boron, and regulation of intracellular boron concentrations. However, their mechanism of action remains poorly studied. BOR proteins are members of the SLC4 family of transporters and thus homologues of well studied mammalian transporters including the human Anion Exchanger 1 (hAE1). Here we generated Arabidopsis thaliana BOR1 (AtBOR1) variants based i) on known disease causing mutations of hAE1 (S466R, A500R) and ii) a loss of function mutation (D311A) identified in the yeast BOR protein, ScBOR1p. The AtBOR1 variants express in yeast and localise to the plasma membrane, although both S466R and A500R exhibit lower expression than the WT AtBOR1 and D311A. The D311A, S466R and A500R mutations result in a loss of boron efflux activity in a yeast bor1p knockout strain. A. thaliana plants containing these three individual mutations exhibit substantially decreased growth phenotypes in soil under conditions of low boron. These data confirm an important role for D311 in the function of the protein and show that mutations equivalent to disease causing mutations in hAE1 have major effects in AtBOR1. We also obtained a low resolution cryo-EM structure of a BOR protein from Oryza sativa, OsBOR3 lacking the 30 C-terminal amino acids. This structure confirms the gate and core domain organisation previously observed for related proteins, and is strongly suggestive of an inward facing conformation.

plant biology↗

bioRxiv2020

RNA splicing alterations induce a cellular stress response associated with poor prognosis in AML

RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are relatively uncommon in Acute Myeloid Leukemia (AML, < 20%). We examined whether RNA splicing differences exist in AML even in the absence of splicing factor mutations. Analyzing RNA-seq data from two independent cohorts of AML patients, we identified recurrent differential alternative splicing between patients with poor and good prognosis. These alternative splicing events occurred even in patients without any discernible splicing factor mutations. The alternative splicing events recurrently occurred in genes involved in specific molecular functions, primarily related to protein translation. Developing informatics tools to predict the functional impact of alternative splicing on the translated protein, we discovered that ~45% of the splicing events directly affected highly conserved protein domains. Several splicing factors were themselves misspliced in patients, and the splicing of their target transcripts were also altered. By studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELNAdv patients resulted in the induction of an integrated stress response and up- regulation of inflammation-related genes. Lastly, using machine learning techniques, we identified a set of four genes whose alternative splicing can refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort. Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance.

cancer biology↗

bioRxiv2019

In Vivo Large Scale Mapping Of Protein Turnover In The Human Cerebrospinal Fluid

The extraction of accurate physiological parameters from clinical samples provides a unique perspective to understand disease etiology and evolution, including under therapy. We introduce a new proteomics framework to map patient proteome dynamics in vivo, either proteome wide or in large targeted panels. We applied it to ventricular cerebrospinal fluid (CSF) and could determine the turnover parameters of almost 200 proteins, whereas a handful were known previously. We covered a large number of neuron biology- and immune system-related proteins including many biomarkers and drug targets. This first large data set unraveled a significant relationship between turnover and protein origin that relates to our ability to investigate the central nervous system physiology precisely in future studies. Our data constitute a reference in CSF biology as well as a repertoire of peptides for the community to design new proteome dynamics analyses. The disclosed methods apply to other fluids or tissues provided sequential sample collection can be performed.

systems biology↗

bioRxiv2017

Tau hyperphosphorylation on T217 in cerebrospinal fluid is specifically associated to amyloid-β pathology

IntroductionModification of CSF tau phosphorylation in AD remains controversial since total-tau and phospho-tau levels measured by immunoassays are highly correlated.\n\nMethodsStoichiometry of phosphorylation of CSF tau was monitored on five sites by mass spectrometry. We compared 50 participants with AD at mild to moderate stages, others tauopathies and controls then confirmed our results in a cohort of 86 participants cognitively normal or with mild cognitive impairment and stratified according to amyloid-{beta} status.\n\nResultsChanges in tau phosphorylation rates were observed in AD participants but not in other tauopathies. T181 appeared slightly hyperphosphorylated in AD. In comparison, T217 phosphorylation, was considerably modified. We demonstrated T217 hyperphosphorylation occurred systematically in amyloid positive participants even at preclinical stage (AUC 0.999). T217 phosphorylation change specificity overpasses other phosphorylated tau sites investigated in this study, but also CSF total-tau and p-tau levels.\n\nDiscussionCSF T217 hyperphosphorylation defines a specific tauopathy status concomitant with {beta}-amyloidosis.

neuroscience↗