Biology subjects

Huber, M.

Publications and source records attributed to Huber, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Thermodynamic Model and Experiments Indicate Kinetically Trapped States in Ionisable Lipid Nanoparticles

Lipid nanoparticles (LNPs) are the leading delivery vehicles for RNA-based therapies, with pH-dependent mesophase transitions of their ionizable lipids proposed to play a crucial role in LNP function and endosomal escape. However, a consistent quantitative framework linking molecular lipid properties to the thermodynamics of these transitions is still lacking. Here, we establish such a framework by combining X-ray scattering, fluorescence spectroscopy, all-atom molecular dynamics simulations, and continuum modeling. Using small-angle X-ray scattering (SAXS) and Laurdan fluorescence spectroscopy, we characterize the pH- and temperature-dependent phase behavior of both bulk lipid systems and LNPs containing the ionisable lipids MC3 or ALC-0315. Laurdan fluorescence measurements reveal the same pH- and temperature-dependent transitions in bulk and LNP systems, which closely follow the inverse micellar (LII) - inverse hexagonal (HII) transitions identified by SAXS, establishing Laurdan as a reporter of these mesophase transitions in LNPs. We combine experimental and simulation data to parameterize a continuum model of the LII - HII transition, providing a quantitative description of mesophase stability. The model reveals that geometric frustration arising from packing constraints is a key determinant of mesophase stability. By combining experimental and simulation data with theoretical analysis, we determine the relevant membrane parameters, including mean and Gaussian curvature bending rigidities, and identify the parameter ranges that govern phase stability. Together, these results establish a quantitative continuum theory for pH-dependent mesophase transitions of ionisable lipid and suggest metastable states in response to pH changes as an inherent feature of LNP core phase.

biophysics↗

bioRxiv2026

Influenza A virus NS1 sequesters RNA:DNA hybrids to evade RNase H1-dependent innate immunity

RNA:DNA hybrids, and their aberrant accumulation, are key regulators of human genome integrity and innate immunity. Given the functional parallels and extensive interplay between the human genome and viral genetic material, RNA:DNA hybrids also have established roles during infections with DNA viruses and retroviruses. Nevertheless, the presence and consequences of RNA:DNA hybrids in RNA virus infections, which lack a DNA phase, remain largely uncharacterized. Here, we show that infection of human cells with influenza A virus (IAV), but not several other respiratory negative-sense RNA viruses, induces the unexpected accumulation of RNA:DNA hybrids in perinuclear regions. Sequencing of infection-induced cytoplasmic RNA:DNA hybrids revealed that they derive predominantly from the human host genome, with apparent preference for intronic and intergenic sequences, although an intriguing fraction also originates from the IAV genome, with some enrichment for specific viral segments. Notably, we identify the IAV non-structural protein, NS1, as a key determinant of RNA:DNA hybrid localization and stability: NS1 is required for, and co-localizes with, perinuclear RNA:DNA hybrids, and its absence appears to sensitize RNA:DNA hybrids to metabolism by the cellular ribonuclease, RNase H1. Furthermore, experimental loss of RNase H1 attenuates IAV-induced antiviral responses, including type I interferon and inflammatory gene expression programs, indicating that RNA:DNA hybrid metabolism likely contributes to host defense. Overall, our findings uncover host- and viral-origin RNA:DNA hybrids as a previously unrecognized feature of a human pathogenic RNA virus infection, and suggest a mechanism by which a viral product antagonizes host responses mediated via these unusual nucleic acids by spatial sequestration.

immunology↗

bioRxiv2026

Comparable daughter radionuclide redistribution with superior tumor absorbed dose of the SSTR2 antagonist Ac-DOTA-TATE

It has been hypothesized that effective cellular internalization is required for the retention of 225Ac daughter radionuclides. The complex decay chain of 225Ac and recoil-mediated release of daughters, particularly 213Bi (half-life (t1/2) = 46 min), raise concerns about redistribution that may reduce tumor absorbed dose (TAD) and increase off-target radiation exposure. Because somatostatin receptor subtype 2 (SSTR2) antagonists such as SSO110 are not internalized, it has been proposed that the daughter radionuclides are less effectively retained compared to internalizing agonists such as DOTA-TATE. We therefore performed a direct and quantitative comparison of daughter radionuclide redistribution following administration of [225Ac]Ac-SSO110 and [225Ac]Ac-DOTA-TATE. MethodsBiodistribution and 213Bi redistribution were evaluated in Balb/c nude mice bearing NCI-H69 small cell lung cancer xenografts. Repeated gamma counting combined with bi-exponential modeling was used to quantify 225Ac and 213Bi activity in tumor, blood, bone marrow, kidneys, liver, and intestines up to 96 h post-injection. TAD was calculated with and without accounting for experimentally-derived 213Bi redistribution. Real-time in vitro binding assays were conducted to characterize cellular retention of [225Ac]Ac-SSO110. Results[225Ac]Ac-SSO110 demonstrated higher tumor uptake and prolonged retention compared with [225Ac]Ac-DOTA-TATE, resulting in a 1.9-fold higher tumor-to-kidney ratio at 96 h and a 2.8-fold higher TAD. Redistribution of 213Bi from tumor was minimal and comparable between agonist and antagonist, with maximum tumor loss of 3.5% for [225Ac]Ac-SSO110 and 2% for [225Ac]Ac-DOTA-TATE. Accounting for daughter redistribution reduced TAD by less than 5% for both radioconjugates. No sustained 213Bi accumulation was observed in blood, kidneys, or liver, and only minimal activity was detected in bone marrow and intestines. Real-time binding studies demonstrated sustained cell-associated {beta}- signal following incubation with [225Ac]Ac-SSO110. ConclusionReceptor-mediated internalization is not required for effective retention of 225Ac daughter radionuclides. Despite negligible internalization, [225Ac]Ac-SSO110 achieved superior TAD and higher tumor-to-kidney ratio without increased daughter redistribution compared with the internalizing agonist [225Ac]Ac-DOTA-TATE. These findings question the necessity of internalization for daughter retention and support further evaluation of antagonist-based 225Ac radioligand therapy.

cancer biology↗

bioRxiv2026

Midbrain Tet1 dosage defines inter-individual binge-eating susceptibility

Binge-eating disorder (BED) is the most common eating disorder worldwide and carries life-altering comorbidities. While genetic and environmental risk factors have been identified, the mechanisms that determine inter-individual susceptibility to BED remain largely unknown. Here, we demonstrate that developmental dosage of the DNA hydroxymethylase Tet1 defines stable inter-individual differences in binge-eating susceptibility. In mice, midbrain dopaminergic neurons of the ventral tegmental area (VTADA) are essential for the induction of addictive binge-eating behavior, express high levels of Tet1, and undergo rapid and widespread DNA hydroxymethylation remodeling upon experimental binge eating. Strikingly, Tet1 haploinsufficiency creates pronounced inter-individual variation in binge-eating susceptibility even among genetically identical mice, which we trace to reduced connectivity between the prelimbic medial prefrontal cortex (mPFCPL) and the VTA. Chemogenetic inhibition of mPFCPL[->]VTA projections reduces binge-eating susceptibility, whereas EGR1-guided re-activation of TET1 in VTA dopaminergic neurons restores susceptibility, supporting a causal role for this axis. Importantly, TET1 promoter methylation in patients associates with binge-eating behavior and reward-circuit function, suggesting conservation of this regulatory network in humans. Collectively, these findings identify Tet1 dosage as a novel regulator of binge-eating susceptibility and provide a mechanistic basis for how inter-individual differences in behavior are established.

neuroscience↗

bioRxiv2026

Ac-DOTA-TATE in SSTR2-positive tumor models

Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors including small cell lung cancer (SCLC) and represents a validated target for peptide receptor radionuclide therapy. The SSTR2 agonist [177Lu]Lu-DOTA-TATE is clinically approved, however, treatment resistance and relapse occur. The SSTR2 antagonist SSO110 (DOTA-JR11, OPS201) demonstrates higher tumor uptake and longer retention than DOTA-TATE both pre-clinically and clinically. We performed a systemic head-to-head comparison of SSO110 labeled with various radionuclides of distinct emission characteristics to identify the optimal radionuclide for SSO110 and to compare antagonist with agonist performance. MethodsSSO110 was radiolabeled with 177Lu, 161Tb, 212Pb, and 225Ac. Biodistribution was assessed in AR42J and NCI-H69 xenograft models. Therapeutic efficacy of single and fractionated [212Pb]Pb-SSO110 was compared with [177Lu]Lu-SSO110 in NCI-H69 tumors. Single-dose efficacy of 225Ac-, 161Tb-, and 177Lu-labeled SSO110 was evaluated in both models. [{superscript 2}{superscript 2}Ac]Ac-DOTA-TATE served as agonist comparator. Tumor growth, survival, safety parameters, and tumor absorbed doses were analyzed. ResultsAll SSO110 radioconjugates demonstrated comparable biodistribution with high tumor uptake and favorable tumor-to-kidney ratios. In NCI-H69 tumors, [212Pb]Pb-SSO110 induced dose-dependent tumor growth delay but did not improve anti-tumor efficacy compared with [177Lu]u-SSO110 under single or fractionated regimens. [161Tb]Tb-SSO110 showed efficacy comparable to [177Lu]Lu-SSO110 in NCI-H69 model and significantly improved tumor growth delay in high-SSTR2-expressing AR42J tumors. Across both models, [225Ac]Ac-SSO110 demonstrated the highest therapeutic potency, inducing durable tumor regression and 100% survival at clinically relevant activities. [225Ac]Ac-SSO110 also outperformed the agonist comparator [225Ac]Ac-DOTA-TATE. Dosimetry analysis revealed a 63-fold higher tumor absorbed dose per injected administered activity for [225Ac]Ac-SSO110 compared with [212Pb]Pb-SSO110. All treatments were well tolerated without significant renal or hepatic toxicity. ConclusionTherapeutic efficacy of SSTR2-targeted peptide receptor radionuclide therapy appears to benefit from alignment between radionuclide physical half-life and ligand tumor residence time. Among the radionuclides evaluated, [225Ac]Ac-SSO110 demonstrated the most pronounced and durable anti-tumor efficacy, outperforming [161Tb]Tb-SSO110, [177Lu]Lu-SSO110, and the short-lived -emitter [212Pb]Pb-SSO110. These findings support clinical investigation of [225Ac]Ac-SSO110 in SSTR2-positive malignancies.

cancer biology↗

bioRxiv2025

PlantCV v4: Image analysis software for high-throughput plant phenotyping

PlantCV is an open-source Python project aimed at developing tools to address a range of image-based, plant phenotyping questions. PlantCV has been used for more than 10 years to automate trait collection from image data and the newest release, PlantCV version 4, continues to lower the barrier to entry for users without substantial coding experience through extensive example use-case tutorials and simplified installation. In addition to usability, we document added functionality since the release of PlantCV v2, including support for more image types such as fluorescence, thermal, and hyperspectral data. Finally, we describe the development of a new subpackage focused on morphological trait measurements like leaf angle, and demonstrate its utility as compared to more manual methods of data collection. CORE IDEASO_LIPlantCV is an open-source, open-development, Python-based software package that has a new release for improved functionality and usability to make image analysis flexible and easier for researchers without a coding background. C_LIO_LIPlantCV is now capable of handling new data types that are relevant to researchers, such as thermal and hyperspectral, and has built in functionality for extracting information from these image types. C_LIO_LIThe software project aims to lower the barrier to entry into image analysis for researchers by providing numerous, versioned, interactive tutorials that cover most common use cases, particularly in plant science. C_LI

plant biology↗

bioRxiv2025

Maladaptive aphid-induced transgenerational plasticity is overcome in nature

Inherited stress responses are widely assumed to be adaptive for plants by preparing offspring for renewed attack. To date, it remains unclear whether and under which conditions these responses may benefit the attacker rather than the host. Studying the interaction between the aphid Rhopalosiphum nymphaeae and its native host, the aquatic duckweed Spirodela polyrhiza, we show that aphids can either benefit or suffer from inherited stress responses, depending on metabolite identity and ecological context. In multigenerational clonal plant lineages maintained indoors, ancestral aphid herbivory increased aphid reproduction and reduced plant fitness under renewed attack, indicating that the net effect of inherited stress responses can favor the herbivore. However, not all inherited responses benefited the aphid: using genetic and chemical manipulations, we found that transgenerational priming of jasmonate enhanced aphid performance, whereas transgenerational priming of tyramine reduced it. Notably, tyramine--but not jasmonates--accumulated to higher levels across generations also in large mesocosms outdoors, albeit only within and not across growing seasons. Together, our results reveal that inherited responses of hosts can favor the attackers and highlight ecological context and life-cycle transitions as key determinants of the persistence, duration, and ecological consequences of inherited stress responses.

ecology↗

bioRxiv2025

Strain, procedures, and tools for reproducible genetic transformation and genome editing of Spirodela polyrhiza (L.) Schleid.

Duckweeds (Lemnaceae) have excellent potential for fundamental and applied research due to ease of cultivation, small size, and continuous fast clonal growth. However, their usage as model organisms and platforms for biotechnological applications is often limited by the lack of universal genetic manipulation methods necessary for transgene expression, gene editing, and other methods to modify gene expression. To identify suitable strains for genetic manipulation of the giant duckweed, Spirodela polyrhiza, we screened several genotypes for callus induction and regeneration and established genetic transformation. We have identified SP162 to be amenable to Agrobacterium-mediated transformation via tissue culture. The procedure is robust and reproducible across laboratories, allowing stable expression of different reporter genes and selectable markers, enabling CRISPR/Cas9-mediated genome editing. In addition, due to a weak small RNA-based silencing response, S. polyrhiza sustains prolonged periods of transgene activity in transient expression assays. To promote duckweed research and encourage the adoption of S. polyrhiza, we have made SP162 (ID#: 5676) and its genome publicly available and provide here detailed procedures for its cultivation and transformation. Furthermore, we created a web server to explore its genome, retrieve gene sequences, and implemented orthologous gene search and a gRNA design function for diverse CRISPR/Cas-based applications (https://agxu.uni-mainz.de/SP162/).

plant biology↗

bioRxiv2025

SMAD2 sets divergent thresholds for TGF-β-induced SMAD1/5 signaling and IgE-mediated pro-inflammatory activation of mast cells

ObjectiveTGF-{beta}/SMAD signaling controls mast cell (MC) development and exerts anti-inflammatory functions, while antigen (Ag)-triggered Fc{varepsilon}RI/MAPK activation commands pro-inflammatory processes. SMAD2 is a signaling hub integrating both, TGF-{beta}/ALK5-mediated SMAD2 C-terminal-and ERK-mediated SMAD2 linker-phosphorylation. Here, we analyzed the role of SMAD2 in TGF-{beta}-and Ag-stimulated signaling, and their cross-talk which regulate MC responses. MethodsThe CRISPR-Cas method was used to disable SMAD2 expression in the PMC-306 cell line. The transcriptome of the corresponding cells was analyzed by NGS in homeostatic and stimulated conditions. Activation of signaling intermediates, target gene responses and effector function were analyzed by qPCR, Western blot and ELISAs. The causal association of SMAD2 with the found effects was proven by re-introduction of a tagged SMAD2 in knock out cells. ResultsThe absence of SMAD2 led to increased proliferation and survival, and decreased transcription of target genes like Smad7 and Jun in steady state and upon TGF-{beta} treatment. Intriguingly, SMAD2 was found to regulate TGF-{beta}-mediated SMAD1/5 activation, resulting in augmented expression of Id3 in SMAD2-deficient MCs. Unexpectedly, we found that SMAD2 is indispensable for Ag-triggered production of pro-inflammatory cytokines, such as IL-6 and TNF. Re-introducing SMAD2 restores these events with varying sensitivity depending on the receptor system triggered. ConclusionsOur findings highlight a previously unrecognized role of SMAD2 as a decisive hub in TGF-{beta}-ALK5-SMAD1/5 and Ag-Fc{varepsilon}RI-MAPK signaling, suggesting that pharmacological modulation of SMAD2 activity could be leveraged as regulator of both suppressive and inflammatory MC functions.

immunology↗

bioRxiv2025

Identification, Purification and Characterization of Mast Cells in Murine Liver Fibrosis: Novel Methods, Expression Signatures and Correlation with Disease Severity

Mast cells (MCs) are myeloid cells of the innate immune system. As a first line of defense, they fulfill effector functions and immune modulatory properties. Upon activation, they release pro-inflammatory mediators such as cytokines and proteases. It has been suggested that MCs may contribute to the development of liver fibrosis. However, investigating hepatic MC biology in mice is challenging due to low MC numbers and a lack of suitable detection techniques relying on MC proteins and their modifications. Here, we evaluated whether the expression strength of MC markers correlates with the degree of liver fibrosis in mice and aimed to determine the frequency and localization of hepatic MCs. We applied both a toxic (DEN/CCl4 treatment) and a genetic (Mdr2-/- mice) liver fibrosis model in C57BL/6 mice and found significant correlations between fibrosis grade and the expression of several established MC markers. These correlations were further supported by data analyses from patients with fibrosis and hepatocellular carcinoma (HCC) using publicly available transcriptomics datasets. We used FACS to purify and isolate MCs from fibrotic mouse livers and verified MC signatures by qPCR analysis of MC-specific gene expression. Hepatic MCs were predominantly negative for Mast Cell Protease 5 (Mcpt5) and occurred at a low frequency (approximately 1-2% of leukocytes). Using Molecular CartographyTM of fibrotic liver sections, we determined the spatial localization, expression signature, abundance (approximately 2 cells/mm2) and cellular environment of murine hepatic MCs. In summary, we demonstrated the existence of MCs in murine fibrotic livers and defined MC expression signatures that correlate with the strength of liver fibrosis. These findings will help to study MC biology in murine models of liver disease more effectively in the future.

cell biology↗

bioRxiv2025

Copper resistance predicts heritable transgenerational fitness variation in the clonal duckweed Spirodela polyrhiza

Transgenerational plasticity in the absence of genetic change can alter organismal fitness, yet we know little about the genetic basis of transgenerational fitness effects. Here, we explored whether transgenerational fitness effects can be predicted by the rate of vegetative reproduction, plant resistance and defence. Thereto, we exposed monoclonal, singledescendant lineages from 56 globally distributed genotypes of the clonal duckweed Spirodela polyrhiza to five generations of copper excess, followed by five generations without stress, and then measured plant fitness and phenotypes in both environments. Previous copper excess reduced fitness variation within each genotype and elicited heritable and reproducible fitness effects that depended on both the genotype and environment: genotypes that benefited from previous stress under recurring conditions suffered when the stress was absent, and vice versa. These transgenerational fitness effects were predicted best by copper resistance, explaining 30% of the intraspecific variation: the more susceptible a genotype, the more its offspring suffered from ancestral stress in the absence of recurrent stress; however, these offspring became more resistant to copper excess, likely by protecting the photosystem II. Together, these findings show that transgenerational fitness effects are heritable and variable and likely controlled by genes that regulate plant reproduction and defence.

evolutionary biology↗

bioRxiv2025

In vitro approaches to study centriole and cilium function in early mouse embryogenesis

Although centrioles and primary cilia play an essential role in early mammalian development, their specific function during the interval between their initial formation and the subsequent arrest of embryogenesis in embryos deficient in centrioles or cilia remains largely unexplored. Here, we demonstrate that different 3D in vitro model systems recapitulate early centriole and cilium formation in mouse development. Centrioles and cilia are dispensable in 3D in vitro mouse rosettes, a model system that mimics key events of implantation, including polarization and lumenogenesis. In gastruloids, a model system that recapitulates developmental processes up to 8.5 days after fertilization, centriole loss results in early disassembly. In contrast, cells devoid of cilia continue to form elongated, differentiated and polarized gastruloids, with minor differences at 96 h. Finally, we show that in a mutant affecting the centriolar distal appendages, cilia are absent from 2D cultures but are capable of forming in 3D rosettes and gastruloids, highlighting the importance of multifactorial 3D environment setups in developmental studies. SummaryThis study presents the first in vitro analysis of centriole and cilium formation during early mouse embryonic development, using 3D models to mimic implantation, tissue patterning, and axis elongation, offering a controlled platform for investigating their roles in embryogenesis.

developmental biology↗

bioRxiv2024

The XbnAb Cohort: 304 people with broadly neutralizing antibody activity to HIV-1

Broadly neutralizing antibodies (bnAbs) recognizing a diversity of HIV-1 strains are widely thought to be essential for an HIV-1 vaccine. Extensive knowledge on bnAbs has been gained from studying natural HIV infection by following bnAb evolution in individual people with HIV (PWH). However, it remains essential to increase knowledge of bnAb responses in large PWH cohorts to assess the feasibility of inducing bnAb activity by vaccination. To allow systematic analysis, we created the XbnAb cohort, a large bnAb-inducer cohort selected by screening plasma of PWH enrolled in the Swiss HIV Cohort Study (SHCS) and the Zurich Primary HIV Infection Study (ZPHI). The XbnAb cohort represents a retrospective, biobank-based cohort comprising data of 305 PWH who developed bnAb activity during HIV-1 infection. Here, we report on the characteristics of the XbnAb cohort and its potential for HIV vaccine research.

immunology↗

bioRxiv2024

Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development

The identification of HIV-1 Envelope glycoprotein (Env) traits associated with development of neutralization cross-reactivity in natural infection is critical for vaccine design. Here we describe the presence of additional Cysteine (Cys) residues in V1 that are enriched among people with elite neutralization breadth. Using >65,000 V1 sequences from the CATNAP database, the AMP trials and three large longitudinal HIV infection cohorts, the SHCS, ZPHI and CAPRISA studies, we show that Env variants with extra V1 Cys are present at low levels throughout infection and fluctuate in frequency over time within participants. We demonstrate an independent association of extra V1 Cys with elite plasma neutralization, and a strong preference for two versus one extra Cys, suggesting certain Envs introduce an additional disulfide bond for stabilization. We observed high levels of neutralization resistance among Envs from 34 bNAb donors, of which 17.6% had elongated V1 regions with extra Cys. We show that extra V1 Cys moderately increase neutralization resistance in an Env from a V2- Apex bNAb-inducer. Modulation of the accessibility of bNAb epitopes on this Env by extra V1 Cys enhanced epitope shielding of several regions, but increased V2 exposure. This suggests that escape from autologous neutralizing activity drove insertion of the extra V1 Cys, creating a modified antigen that may have favored V2 bNAb induction in this donor. Overall, we identify a rare motif of twin Cys in V1 that confers increased neutralization resistance and Env stabilization, is associated with bNAb induction, and may hold potential for incorporation into future HIV bNAb immunogens.

immunology↗

bioRxiv2024

Highly-sensitive reporter cell line for detection of interferon types I-III and their neutralization by antibodies

Interferons (IFNs) are a critical component of innate immune defenses and limit viral disease severity. To advance studies on IFNs and their neutralization by pathogenic autoantibodies, we generated a Renilla luciferase-based reporter cell line capable of detecting the activities of IFN-Is, IFN-II, and IFN-IIIs. The reporter cell line exhibits a 125-to 2000-fold higher sensitivity to IFNs than a commonly-used alternative biological reporter system, and allows for a rapid and simple live-cell workflow for detecting low titer amounts of neutralizing anti-IFN antibodies.

immunology↗

bioRxiv2024

CODI: Enhancing machine learning-based molecular profiling through contextual out-of-distribution integration

Molecular analytics increasingly utilize machine learning (ML) for predictive modeling based on data acquired through molecular profiling technologies. However, developing robust models that accurately capture physiological phenotypes is challenged by a multitude of factors. These include the dynamics inherent to biological systems, variability stemming from analytical procedures, and the resource-intensive nature of obtaining sufficiently representative datasets. Here, we propose and evaluate a new method: Contextual Out-of-Distribution Integration (CODI). Based on experimental observations, CODI generates synthetic data that integrate unrepresented sources of variation encountered in real-world applications into a given molecular fingerprint dataset. By augmenting a dataset with out-of-distribution variance, CODI enables an ML model to better generalize to samples beyond the initial training data. Using three independent longitudinal clinical studies and a case-control study, we demonstrate CODIs application to several classification scenarios involving vibrational spectroscopy of human blood. We showcase our approachs ability to enable personalized fingerprinting for multi-year longitudinal molecular monitoring and enhance the robustness of trained ML models for improved disease detection. Our comparative analyses revealed that incorporating CODI into the classification workflow consistently led to significantly improved classification accuracy while minimizing the requirement of collecting extensive experimental observations. SIGNIFICANCE STATEMENTAnalyzing molecular fingerprint data is challenging due to multiple sources of biological and analytical variability. This variability hinders the capacity to collect sufficiently large and representative datasets that encompass realistic data distributions. Consequently, the development of machine learning models that generalize to unseen, independently collected samples is often compromised. Here, we introduce CODI, a versatile framework that enhances traditional classifier training methodologies. CODI is a general framework that incorporates information about possible out-of-distribution variations into a given training dataset, augmenting it with simulated samples that better capture the true distribution of the data. This allows the classification to achieve improved predictive performance on samples beyond the original distribution of the training data.

bioinformatics↗

bioRxiv2024

Limiting mitochondrial-derived ATP transfer to the cytosol enhances T-cell activation

T-cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generated T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, impeding NAD+ regeneration. Interestingly, Ant2-/- naive T cells exhibited enhanced activation, proliferation, and effector functions compared to wild-type controls. Metabolic profiling revealed that these cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Pharmacological inhibition of ANT in wild-type T cells recapitulated the Ant2-/- phenotype, and improved adoptive cell therapy of cancer. Our findings suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T-cell function. These results highlight the critical role of mitochondrial metabolism in regulating T-cell fate and underscore the therapeutic potential of targeting ANT for immune modulation.

immunology↗

bioRxiv2024

Herbivory can increase plant fitness via reduced interspecific competition. Evidence from models and mesocosms

Herbivores are generally considered to reduce plant fitness. However, as in natural communities herbivores often feed on several competing plant species, herbivores can also increase plant fitness by reducing interspecific competition among plants. In this study, we developed a testable model to predict plant fitness in the presence of an interspecific competitor and an herbivore that feeds on both plant species. Our model allows to predict at which herbivore and competitor densities the focal species will benefit from herbivory. This can be estimated by quantifying the effects of the herbivore on the fitness of the focal plant and on its competitor, and by estimating the levels of intra- and interspecific competition in a pair-wise fashion, respectively. We subsequently validated the model in indoor microcosms using three interacting species: an aquatic macrophyte (the giant duckweed Spirodela polyrhiza), its native competitors (green algae), and its native herbivore (the pond snail Lymnaea stagnalis). Additional outdoor mesocosm experiments supported our model under natural conditions. Together, this study provides a conceptual framework to understand how herbivores shape plant fitness in a community context.

ecology↗