Biology subjects

Wimmer, V.

Publications and source records attributed to Wimmer, V..

11 recordsLinked to original sources

bioRxiv2026

Microcystin-Driven Control of the Carbon-Concentrating Mechanism Shapes CO2 Fixation Dynamics in Microcystis aeruginosa PCC 7806

Bloom-forming cyanobacteria thrive in highly dynamic light environments, yet the mechanisms enabling rapid acclimation to fluctuating irradiance remain poorly understood. Here, we compared light acclimation in the bloom-forming cyanobacterium Microcystis aeruginosa PCC 7806 and the non-bloom-forming model cyanobacterium Synechocystis sp. PCC 6803 and investigated the role of the cyanobacterial toxin microcystin (MC) and its in vivo binding partner RubisCO in this process. Whereas Synechocystis grew faster under sustained high light, Microcystis performed better under low light and responded to transient high-light exposure with a remarkably rapid increase in photosynthetic activity and glycogen accumulation. These responses were markedly attenuated in an MC-deficient mutant. Although RubisCO from Microcystis exhibited pronounced light-dependent changes in activity, MC had only minor effects on RubisCO catalysis, arguing against a direct role in regulating enzyme function. Instead, extracellular MC elicited a transient transcriptional program characterized by induction of inorganic carbon acquisition systems, including the high-affinity bicarbonate transporter BCT1, consistent with activation of the carbon-concentrating mechanism (CCM) and enhanced carbon fixation in vivo. MC further stimulated the expression of photosynthesis-related genes, and altered carboxysome organization, and promoted extracarboxysomal localization of RubisCO. Together, our findings identify MC as a light-responsive signaling molecule that coordinates CCM activity, carbon acquisition, and photosynthetic acclimation, thereby enhancing adaptation of Microcystis to fluctuating irradiance and potentially contributing to its ecological success in cyanobacterial blooms.

microbiology↗

bioRxiv2025

Genetic barcoding uncovers the clonal makeup of solid and liquid biopsies

Intra-tumoral heterogeneity (ITH) is fueling tumor progression in breast cancer, as specific clones present within a tumor may have a selective advantage to colonize distant organs and escape therapy. Accurate sampling of ITH is therefore a pressing challenge in clinical oncology, to adequately predict recurrence and inform rational and personalized therapies. Here we used cellular barcoding to track the spatio-temporal composition of human breast cancer clones in six preclinical models - across two cell lines and four patient derived xenografts (PDXs). This allowed direct side-by-side quantitative comparison not only of intra-tumor clonal composition, but also of how that composition was reflected in needle biopsies and cell-free DNA (cfDNA). These analyses highlighted several clinically relevant findings. First, the use of orthogonal genetic and optical barcoding revealed that clonal diversity in the center of non-necrotic primary tumors was significantly higher compared to their periphery. Second, cfDNA barcode analysis suggested that DNA shedding in the vasculature varied largely, not only depending on necrosis and tumor burden, but also between models. Third, combining information captured in both solid and liquid biopsies can provide a more robust assessment of tumor clonal composition. Taken together, these results showcases the utility of these barcoded models to optimize the use of solid and liquid biopsies as surrogate markers of ITH.

cancer biology↗

bioRxiv2024

Transient inhibition of type I interferon enhances CD8+ T cell stemness and vaccine protection

Developing vaccines that promote CD8+ T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1+ stem cell-like memory T (TSCM) cells are important determinants of long-lived memory. Yet, the developmental requirements for TSCM formation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive TSCM cell generation. TSCM cells were transcriptionally distinct and emerged from a transitional precursor of exhausted (TPEX) cellular state concomitant with viral clearance. TSCM differentiation correlated with T cell retention within the lymph node paracortex, due to increased CXCR3 chemokine abundance which disrupted gradient formation. These affects were due a counterintuitive increase in IFN{psi}, which controlled cell location. Combining IFNAR inhibition with mRNA-LNP vaccination promoted specific TSCM differentiation and enhanced protection against chronic infection. These finding propose a new approach to vaccine design whereby modulation of inflammation promotes memory formation and function. HIGHLIGHTSO_LIEarly, transient inhibition of the type I interferon (IFN) receptor (IFNAR) during acute viral infection promotes stem cell-like memory T (TSCM) cell differentiation without establishing chronic infection. C_LIO_LITSCM and precursor of exhausted (TPEX) cellular states are distinguished transcriptionally and by cell surface markers. C_LIO_LIDevelopmentally, TSCM cell differentiation occurs via a transition from a TPEX state coinciding with viral clearance. C_LIO_LITransient IFNAR blockade increases IFN{psi} production to modulate the ligands of CXCR3 and couple TSCM differentiation to cell retention within the T cell paracortex of the lymph node. C_LIO_LISpecific promotion of TSCM cell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge. C_LI

immunology↗

bioRxiv2023

Relative importance of MCL-1's Anti-Apoptotic versus Non-Apoptotic Functions in vivo

MCL-1 is an anti-apoptotic member of the BCL-2 protein family that ensures cell survival by blocking the intrinsic apoptotic cell death pathway1. MCL-1 is unique in being essential for early embryonic development and the survival of many cell types, including many cancer cells, which are not affected by the loss of the other anti-apoptotic BCL-2 family members1-4. Non-apoptotic functions of MCL-1 controlling mitochondrial ATP production and dynamics have been proposed to underlie this unique requirement for MCL-15-9. The relative contributions of the anti-apoptotic versus the non-apoptotic functions of MCL-1 in normal physiology have not been addressed. Here we replaced the coding sequence for MCL-1 with those for the anti-apoptotic proteins BCL-XL, BCL-2 or A1. We hypothesised that BCL-XL, BCL-2 and A1 may substitute for MCL-1 in the inhibition of apoptosis, but that they will not be able to replace MCL-1s non-apoptotic function. Strikingly, Mcl-1Bcl-xL/Bcl-xL and Mcl-1Bcl-2/Bcl-2 embryos survived to embryonic day 14.5, greatly surpassing the pre-implantation lethality of Mcl-1-/- embryos at E3.5. This demonstrates that the non-apoptotic functions of MCL-1 are dispensable for early development. However, at later stages of development and life after birth many cell types, particularly ones with high energy demand, were found to require both the anti-apoptotic and the non-apoptotic functions of MCL-1. These findings reveal the relative importance of these distinct functions of MCL-1 in physiology, providing important information for basic biology and the advancement of MCL-1 inhibitors in cancer therapy.

cell biology↗

bioRxiv2022

Assessing the response to genomic selection by simulation

The goal of any plant breeding program is to maximize genetic gain for traits of interest. In classical quantitative genetics, the genetic gain can be obtained from what is known as "Breeders equation". In the past, only phenotypic data was used to compute the genetic gain. The advent of genomic prediction has opened the door to the utilization of dense markers for estimating genomic breeding values or GBV. The salient feature of genomic prediction is the possibility to carry out genomic selection with the assistance of the kinship matrix, hence, improving the prediction accuracy and accelerating the breeding cycle. However, estimates of GBV as such do not provide the full information on the number of entries to be selected as in the classical response to selection. In this paper, we use simulation, based on a fitted mixed model for genomic prediction in a multi-environmental framework, to answer two typical questions of a plant breeder: (1) How many entries need to be selected to have a defined probability of selecting the truly best entry from the population; (2) What is the probability of obtaining the truly best entries when some top-ranked entries are selected.

genetics↗

bioRxiv2021

Performance of genetic imputation across commercial crop species

We show that accurate imputation can be carried out in three commercial plant species (maize, sugar beet and wheat) and that accurate imputation does not require a pedigree, although pedigree information can improve accuracy and speed. Our approach uses a hidden Markov model to build a haplotype library from individuals genotyped at high-density and then uses this library to impute low-density genotyped individuals to high-density. To build the library, we use founders when the pedigree is known, or a sample of progeny when the pedigree is unknown. Without a pedigree, and with 50 individuals genotyped at high-density and 100 low-density markers per chromosome, the median accuracies were 0.97 (maize), 0.96 (sugar beet), and 0.94 (wheat). We obtained similar accuracies with a pedigree. For biparental crosses with 100 markers per chromosome, median accuracies were 0.96 (maize), 0.96 (sugar beet) and 0.94 (wheat). For the imputation scenarios without a pedigree, we compared accuracies with those obtained by running Beagle 5.1. In all but one scenario, our method outperformed Beagle. We believe that plant breeders can effectively apply imputation in many crop species.

genetics↗

bioRxiv2020

Severe dysregulation of TNF expression leads to multiple inflammatory diseases and embryonic death

Post-transcriptional regulation mechanisms regulate mRNA stability or translational efficiency via ribosomes and recent evidence indicates that it is a major determinant of the accurate levels of cytokine mRNAs. While transcriptional regulation of Tnf has been well studied and found to be important for the rapid induction of Tnf mRNA and regulation of the acute phase of inflammation, study of its post-transcriptional regulation has been largely limited to the role of the AU-rich element (ARE), and to a lesser extent, that of the constitutive decay element (CDE). We have identified a new regulatory element (NRE) in the 3 untranslated region (3UTR) of Tnf, and demonstrate that ARE, CDE and NRE cooperate to efficiently down regulate Tnf expression and prevent autoimmune inflammatory diseases. We also show for the first time that excessive TNF may lead to embryonic death.

immunology↗

bioRxiv2020

BCL-XL is essential for the protection from secondary anemia caused by radiation-induced fatal kidney damage

Studies of gene-targeted mice identified the roles of the different pro-survival BCL-2 proteins during embryogenesis, but less is known about the roles of these proteins in adults, including in the response to cytotoxic stresses, such as treatment with anti-cancer agents. We investigated the role of BCL-XL in adult mice using a strategy where prior bone marrow transplantation allowed for loss of BCL-XL exclusively in non-hematopoietic tissues to prevent anemia caused by BCL-XL-deficiency in erythroid cells. Unexpectedly, the combination of total-body {gamma}-irradiation (TBI) and genetic loss of Bcl-x caused secondary anemia resulting from chronic renal failure due to apoptosis of renal tubular epithelium with secondary obstructive nephropathy. These findings identify a critical protective role of BCL-XL in the adult kidney and inform on the use of BCL-XL inhibitors in combinations with DNA damage-inducing drugs for cancer therapy. SummaryThe inducible loss of BCL-XL in all cells of adult mice causes primary anemia due to apoptosis of erythroid and megakaryocytic cell populations. In contrast {gamma}-radiation plus loss of BCL-XL in all cells except hematopoietic cells causes secondary anemia resulting from kidney damage.

pharmacology and toxicology↗

bioRxiv2020

Phasing and imputation of single nucleotide polymorphism data of missing parents of bi-parental plant populations

This paper presents an extension to a heuristic method for phasing and imputation of genotypes of descendants in bi-parental populations so that it can phase and impute genotypes of parents of bi-parental populations that are fully ungenotyped or partially genotyped. The imputed genotypes of the parent are then used to impute low-density genotyped descendants of the bi-parental population to high-density. The extension works in three steps. First, it identifies whether a parent has no or low-density genotypes available and it identifies all of its relatives that have high-density genotypes. Second, using the high-density information of relatives, it determines whether the parent is homozygous or heterozygous for a given locus. Third, it phases heterozygous positions of the parent by matching haplotypes to its relatives. We implemented the new algorithm in an extension of the AlphaPlantImptue software and tested its accuracy of imputing missing parent genotypes in simulated bi-parental populations from different scenarios. We also tested the accuracy of imputation of the missing parents descendants using the true genotype of the parent and compared this to using the imputed genotypes of the parent. Our results show that across all scenarios, the accuracy of imputation of a parent, measured as the correlation between true and imputed genotypes, was > 0.98 and did not drop below [~] 0.96. The imputation accuracy of a parent was always higher when it was inbred than when it was outbred and when it had low-density genotypes. Including ancestors of the parent at HD, increasing the number of crosses and the number of high-density descendants all increased the accuracy of imputation. The high imputation accuracy achieved for the parent across all scenarios translated to little or no impact on the accuracy of imputation of its descendants at low-density. Key MessageNew fast and accurate method for phasing and imputation of SNP chip genotypes within diploid bi-parental plant populations.

genetics↗

bioRxiv2020

The influence of QTL allelic diversity on QTL detection in multi-parent populations: a simulation study in sugar beet

Multi-parent populations (MPPs) are important resources for studying plant genetic architecture and detecting quantitative trait loci (QTLs). In MPPs, the QTL effects can show various levels of allelic diversity, which is an important factor influencing the detection of QTLs. In MPPs, the allelic effects can be more or less specific. They can depend on an ancestor, a parent or the combination of parents in a cross. In this paper, we evaluated the effect of QTL allelic diversity on the QTL detection power in MPPs. We simulated: a) cross-specific QTLs; b) parental and ancestral QTLs; and c) bi-allelic QTLs. Inspired by a real application, we tested different MPP designs (diallel, chessboard, factorial, and NAM) derived from five or nine parents to explore the ability to sample genetic diversity and detect QTLs. Using a fixed total population size, the QTL detection power was larger in MPPs with fewer but larger crosses derived from a reduced number of parents. The use of a larger set of parents was useful to detect rare alleles with a large phenotypic effect. The benefit of using a larger set of parents was however conditioned on an increase of the total population size. We also determined empirical confidence intervals for QTL location to compare the resolution of different designs. For QTLs representing 6% of the phenotypic variation, using 1600 offspring individuals, we found 95% empirical confidence intervals of 50 and 26 cM for cross-specific and bi-allelic QTLs, respectively. MPPs derived from less parents with few but large crosses generally increased the QTL detection power. Using a larger set of parents to cover a wider genetic diversity can be useful to detect QTLs with a reduced minor allele frequency when the QTL effect is large and when the total population size is increased.

genetics↗

bioRxiv2018

A heuristic method for fast and accurate phasing and imputation of single nucleotide polymorphism data in bi-parental plant populations

This paper presents a new heuristic method for phasing and imputation of genomic data in diploid plant species. Our method, called AlphaPlantImpute, explicitly leverages features of plant breeding programs to maximise the accuracy of imputation. The features are a small number of parents, which can be inbred and usually have high-density genomic data, and few recombinations separating parents and focal individuals genotyped at low-density (i.e. descendants that are the imputation targets). AlphaPlantImpute works roughly in three steps. First, it identifies informative low-density genotype markers in parents. Second, it tracks the inheritance of parental alleles and haplotypes to focal individuals at informative markers. Finally, it uses this low-density information as anchor points to impute focal individuals to high-density.\n\nWe tested the imputation accuracy of AlphaPlantImpute in simulated bi-parental populations across different scenarios. We also compared its accuracy to existing software called PlantImpute. In general, AlphaPlantImpute had better or equal imputation accuracy as PlantImpute. The computational time and memory requirements of AlphaPlantImpute were tiny compared to PlantImpute. For example, accuracy of imputation was 0.96 for a scenario where both parents were inbred and genotyped at 25,000 markers per chromosome and a focal F2 individual was genotyped with 50 markers per chromosome. The maximum memory requirement for this scenario was 0.08 GB and took 37 seconds to complete.

genomics↗