Biology subjects

Mayer, M.

Publications and source records attributed to Mayer, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Stuck in the weeds: Invasive grasses reduce tiger snake movement

Wetlands are particularly vulnerable to degradation in urban environments, partially due to the introduction of non-native plants. Invasive weeds in wetlands can replace native plants leading to alterations in habitat composition and vegetation, in turn, animal movements and ultimately population dynamics might be affected. Here we investigate how home range size and movements of western tiger snakes (Notechis scutatus occidentalis) differ in wetlands dominated by invasive kikuyu grass (Cenchrus clandestinus) compared to wetlands dominated by native vegetation to understand if and how the movement ecology of this top-order predator is altered by vegetation homogenization. To do so, we used Autocorrelated Kernel Density Estimators (AKDE) to estimate home range size, dynamic Brownian Bridge Movement Models to document movement trajectory confidence areas, and compared movement distances using a Bayesian regression model. Home range sizes by tiger snakes were 14.59 {+/-} 9.35 ha smaller in areas dominated by invasive versus native vegetation. Moreover, within-day movement distances tended to be smaller in areas dominated by invasive versus native vegetation (mean {+/-} SD: 9 {+/-} 3 m versus 18 {+/-} 6 m), but there was considerable overlap between the 95% credible intervals between these two groups. Smaller home ranges by tiger snakes in areas dominated by invasive kikuyu grass were likely driven by thermoregulation, with snakes moving vertically between basking locations on top of kikuyu and shelter sites at the base, rather than travelling horizontally along the ground to open basking areas in sites dominated by native vegetation. Additionally, fragmentation of sites dominated by invasive vegetation might have contributed to the comparatively smaller home ranges of snakes there. These findings add to our understanding how changes in habitat composition driven by invasive vegetation can affect animal space use and emphasise the need for further studies to understand how these changes affect population dynamics.

ecology↗

bioRxiv2023

Simultaneous Determination of Size and Shape of Single alpha-Synuclein Oligomers in Solution

Soluble oligomers of amyloid-forming proteins are implicated as toxic species in the context of several neurodegenerative diseases. Since the size and shape of these oligomers influences their toxicity, their biophysical characterization is essential for a better understanding of the structure-toxicity relationship. Amyloid oligomers are difficult to characterize by conventional approaches due to their heterogeneity in size and shape, their dynamic aggregation process, and their low abundance. This paper demonstrates that resistive-pulse measurements using polymer-coated solid-state nanopores enable single-particle level characterization of the size and shape of individual Syn oligomers in solution within minutes. A comparison of the resulting size distribution with single-particle analysis by transmission electron microscopy and mass photometry reveals that nanopore-based characterization agrees well with both methods, while providing better size resolution and elucidating that Syn samples are composed of stable oligomer sub-populations that contain multiples of approximately 12 monomers (i.e., 12-, 24-, 48-, 60-, 84-mers). Applying the unique capability of nanopores to approximate particle size and shape to picomolar concentrations of Syn oligomers in the putatively toxic size range, revealed shapes that agree well with previous estimates by cryo-EM with the added advantage that nanopore-based analysis occurs rapidly, in solution, and has the potential to become a widely accessible technique.

biophysics↗

bioRxiv2022

Cylicins are a structural component of the sperm calyx being indispensable for male fertility in mice and human

Cylicins are testis-specific proteins, which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2) genes have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cylicins have been localized in the acrosomal region of round spermatids, they resemble a major component of the calyx within the perinuclear theca at the posterior part of mature sperm nuclei. However, the role of Cylicins during spermiogenesis has not yet been investigated. Here, we applied CRISPR/Cas9-mediated gene-editing in zygotes to establish Cylc1- and Cylc2-deficient mouse lines as a model to study the function of these proteins. Cylc1 deficiency resulted in male subfertility, whereas Cylc2-/-, Cylc1-/y Cylc2+/-, and Cylc1-/y Cylc2-/- males were infertile. Phenotypical characterization revealed that loss of Cylicins prevents proper calyx assembly during spermiogenesis. This results in decreased epididymal sperm counts, impaired shedding of excess cytoplasm, and severe structural malformations, ultimately resulting in impaired sperm motility. Furthermore, exome sequencing identified an infertile man with a hemizygous variant in CYLC1 and a heterozygous variant in CYLC2, displaying morphological abnormalities of the sperm including the absence of the acrosome. Thus, our study highlights the relevance and importance of Cylicins for spermiogenic remodeling and male fertility in human and mouse, and provides the basis for further studies on unraveling the complex molecular interactions between perinuclear theca proteins required during spermiogenesis.

developmental biology↗

bioRxiv2022

Site-specific C-terminal fluorescent labeling of Tau protein

Formation of Tau protein aggregates in neurons is a pathological hallmark of several neurodegenerative diseases, including Alzheimers disease. Fluorescently-labeled Tau protein is therefore useful to study the aggregation of these pathological proteins and to identify potential therapeutic targets. Conventionally, cysteine residues are used for labeling Tau proteins, however, the full-length Tau isoform contains two cysteine residues in the microtubule-binding region, which are implicated in Tau aggregation by forming intermolecular disulfide bonds. In order to prevent the fluorescent label from disturbing the microtubule binding region, we developed a strategy to fluorescently label Tau at its C-terminus while leaving cysteine residues unperturbed. We took advantage of a Sortase A-mediated transpeptidation approach to bind a short peptide (GGGH6-Alexa647) with a His-tag and a covalently attached Alexa 647 fluorophore to the C-terminus of Tau. This reaction relies on the presence of a Sortase recognition motif (LPXTG), which we attached to the C-terminus of recombinantly expressed Tau. We determined the possible effects of the resulting C-terminal modification on the secondary structure of Tau protein, its aggregation kinetics, and fibril morphology compared to the unlabeled native Tau protein in vitro. The results showed no significant differences between the native and C-terminally labeled Tau monomer with regard to aggregation kinetics, secondary structure, and morphology.

biophysics↗

bioRxiv2022

Co-occurrence patterns and habitat selection of the mountain hare, European hare, and European rabbit in urban areas of Sweden

Assessing the underlying mechanisms of co-occurrence patterns can be challenging as biotic and abiotic causations are hard to disentangle. To date, few studies have investigated co-occurrence patterns within urban areas that constitute novel habitat to numerous wildlife species. Moreover, as urban areas expand and are increasingly used as habitat by wildlife, there is a need for a better understanding of urban ecology to facilitate human-wildlife coexistence. Here, we investigated co-occurrence patterns and habitat selection of the European hare (Lepus europaeus), mountain hare (L. timidus), and European rabbit (Oryctolagus cuniculus) inside urban areas of Sweden, using joint species distribution models and generalized linear mixed models based on citizen science observations. All three species were observed within urban areas, but European hares and rabbits appear to be more successful urban colonizers compared to mountain hares. Overall, our findings suggested that urban occurrence by all three lagomorphs was related to suitable conditions within the distribution of each species (e.g. climate and elevation), rather than by the presence of other lagomorph species or specific land cover types within urban areas. On a finer spatial scale, our findings suggested facilitation of European hares by rabbits, though the mechanism for this remains unclear. European hares and rabbits generally selected for green urban areas and mountain hares for residential gardens, which likely constitute suitable foraging sites. Our findings contribute to the understanding of urban ecology and provide valuable insight for management measures of the three lagomorphs in urban areas of Sweden.

ecology↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part I: 2D Space Perception by 2D Linear Translation

Visual perception plays a critical role in navigating space and extracting useful semantic information crucial to survival. To identify distant landmarks, we constantly shift gaze vectors through saccades, while still maintaining the visual perception of stable allocentric space. How can we sustain stable allocentric space so effortlessly? To solve this question, we have developed a new concept of NHT (Neural Holography Tomography). This model states that retinotopy is invisible (not available to consciousness) and must be converted to a time code by traveling alpha brainwaves to perceive objects consciously. According to this framework, if identical alpha phases are continually assigned to a landmark, we perceive its exact and consistent allocentric location. To test this hypothesis, we designed reaction time (RT) experiments to observe evidence of the predicted space-to-time conversion. Various visual stimuli were generated at a wide range of eccentricities either on a large TV (up to 40{degrees}) or by LED strips on a hemispherical dome (up to 60{degrees}). Participants were instructed to report the observed patterns promptly under either covert (no eye movement) or overt (with eye movement) conditions. As predicted, stimuli presented at the center of fixation always produced the fastest RTs. The additional RT delay was precisely proportional to the eccentricity of the peripheral stimulus presentation. Furthermore, both covert and overt attention protocols created the same RT delays, and trajectories of saccadic eye motions were in parallel to the overt RT vs. eccentricity. These findings strongly support our NHT model, in which the observed RT-eccentricity dependence is indicative of the spatiotemporal conversion required for maintaining a stable allocentric frame of reference. That is, we perceive space by time.

neuroscience↗

bioRxiv2022

Structural and functional impact by SARS-CoV-2 Omicron spike mutations

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), bearing an unusually high number of mutations, has become a dominant strain in many countries within several weeks. We report here structural, functional and antigenic properties of its full-length spike (S) protein with a native sequence in comparison with those of previously prevalent variants. Omicron S requires a substantially higher level of host receptor ACE2 for efficient membrane fusion than other variants, possibly explaining its unexpected cellular tropism. Mutations not only remodel the antigenic structure of the N-terminal domain of the S protein, but also alter the surface of the receptor-binding domain in a way not seen in other variants, consistent with its remarkable resistance to neutralizing antibodies. These results suggest that Omicron S has acquired an extraordinary ability to evade host immunity by excessive mutations, which also compromise its fusogenic capability.

biochemistry↗

bioRxiv2021

Biophysical and pharmacokinetic characterization of a small-molecule inhibitor of RUNX1/ETO tetramerization with anti-leukemic effects

Acute myeloid leukemia (AML) is a malignant disease of immature myeloid cells and the most prevalent acute leukemia among adults. The oncogenic homo-tetrameric fusion protein RUNX1/ETO results from the chromosomal translocation t(8;21) and is found in AML patients. The nervy homology region 2 (NHR2) domain of ETO mediates tetramerization; this oligomerization is essential for oncogenic activity. Previously, we identified the first-in-class small-molecule inhibitor of NHR2 tetramer formation, 7.44, which was shown to specifically interfere with NHR2, restore gene expression down-regulated by RUNX1/ETO, inhibit the proliferation of RUNX1/ETO-depending SKNO-1 cells, and reduce the RUNX1/ETO-related tumor growth in a mouse model. However, no biophysical and structural characterization of 7.44 binding to the NHR2 domain has been reported. Likewise, the compound has not been characterized as to physicochemical, pharmacokinetic, and toxicological properties. Here, we characterize the interaction between the NHR2 domain of RUNX1/ETO and 7.44 by biophysical assays and show that 7.44 interferes with NHR2 tetramer stability and leads to an increase in the dimer population of NHR2. The affinity of 7.44 with respect to binding to NHR2 is Klig = 3.95 {+/-} 1.28 M. By NMR spectroscopy combined with molecular dynamics simulations, we show that 7.44 binds with both heteroaromatic moieties to NHR2 and interacts with or leads to conformational changes in the N-termini of the NHR2 tetramer. Finally, we demonstrate that 7.44 has favorable physicochemical, pharmacokinetic, and toxicological properties. Together with biochemical, cellular, and in vivo assessments, the results reveal 7.44 as a lead for further optimization towards targeted therapy of t(8;21) AML.

biophysics↗

bioRxiv2021

Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth

To maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis, and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.

cell biology↗

bioRxiv2021

Inverse PI by NMR: Analysis of Ligand 1H-Chemical Shifts in the Protein-Bound State

The study of protein-ligand interactions via protein-based NMR generally relies on the detection of chemical-shift changes induced by ligand binding. However, the chemical shift of the ligand when bound to the protein is rarely discussed, since it is not readily detectable. In this work we use protein deuteration in combination with [1H-1H]-NOESY NMR to extract 1H chemical shift values of the ligand in the bound state. The chemical shift perturbations (CSPs) experienced by the proton ligand resonances (free vs bound) are an extremely rich source of information on protein-ligand complexes. Besides allowing for the detection of intermolecular CH-{pi} interactions and elucidation of the protein-bound ligand conformation, the CSP information can be used to analyse (de)solvation effects in a site-specific manner. In conjunction with crystal structure information, it is possible to distinguish protons whose desolvation penalty is compensated for upon protein-binding, from those that are not. Combined with the previously reported PI by NMR technique for the protein-based detection of intermolecular CH-{pi} interactions, this method represents another important step towards the ultimate goal of Interaction-Based Drug Discovery.

biophysics↗

bioRxiv2021

Previously uncharacterized rectangular bacteria in the dolphin mouth

Much remains to be explored regarding the diversity of uncultured, host-associated microbes. Here, we report the discovery of unusual rectangular bacterial structures (RBSs) in the mouths of bottlenose dolphins. DNA staining revealed multiple paired bands within RBSs that suggested cells dividing along the longitudinal axis. Cryogenic transmission electron microscopy and tomography revealed parallel membrane-bound segments, suspected to be cells, encapsulated by an S-layer-like periodic surface covering. RBSs displayed novel pilus-like appendages with bundles of threads splayed at the tips. Multiple lines of evidence suggested that RBSs are bacterial and distinct from the Neisseriaceae genera Simonsiella and Conchiformibius, with which they share similar morphology and division patterning, including genomic DNA sequencing of micromanipulated RBSs, 16S rRNA gene sequencing, and fluorescence in situ hybridization. Our findings highlight the diversity of novel microbial forms and lifestyles that await discovery and characterization using tools complementary to genomics such as microscopy.

microbiology↗

bioRxiv2021

Light spectra trigger divergent gene expression in barley cultivars

Light spectra influence barley development, causing a diverse range of responses among cultivars that are poorly understood. Here, we exposed three barley genotypes with different light sensitivities to two light sources: fluorescent bulbs, over-representing green and red wavebands, and metal halide lamps, with a more balanced spectrum. We used RNA sequencing to identify the main genes and pathways involved in the different responses, and RT-qPCR to validate the expression values. Different grades of sensitivity to light spectra were associated with transcriptional reprogramming, plastid signals, and photosynthesis. The genotypes were especially divergent in the expression of genes regulated by transcription factors from MADS-box, WRKY, and NAC families, and in specific photoreceptors such as phytochromes and cryptochromes. Variations in light spectra also affected the expression of circadian clock, flowering time, and frost tolerance genes, among others, resembling plant responses to temperature. The relation between PPD-H1, HvVRN1, and HvFT1 expression might explain genotypic differences. Light-sensitive genotypes experienced a partial reversion of the vernalization process and senescence-related stress under the less favorable light quality conditions. The observed light-quality sensitivities reveal a complex mechanism of adaptation to regions with specific light quality features and/or possible regulation of light spectra in plant development during early spring. HighlightDevelopment genes were affected by light quality in the barley varieties tested. Different grades of sensitivity were related to the expression of transcription factors, senescence, light signaling and cold-regulated genes.

plant biology↗

bioRxiv2020

Bivariate genomic prediction of phenotypes by selecting epistatic interactions across years

The importance of accurate genomic prediction of phenotypes in plant breeding is undeniable, as higher prediction accuracy can increase selection responses. In this study, we investigated the ability of three models to improve prediction accuracy by including phenotypic information from the last growing season. This was done by considering a single biological trait in two growing seasons (2017 and 2018) as separate traits in a multi-trait model. Thus, bivariate variants of the Genomic Best Linear Unbiased Prediction (GBLUP) as an additive model, Epistatic Random Regression BLUP (ERRBLUP) and selective Epistatic Random Regression BLUP (sERRBLUP) as epistasis models were compared with respect to their prediction accuracies for the second year. The results indicate that bivariate ERRBLUP is slightly superior to bivariate GBLUP in predication accuracy, while bivariate sERRBLUP has the highest prediction accuracy in most cases. The average relative increase in prediction accuracy from bivariate GBLUP to maximum bivariate sERRBLUP across eight phenotypic traits and studied dataset from 471/402 doubled haploid lines in the European maize landrace Kemater Landmais Gelb/Petkuser Ferdinand Rot, were 7.61 and 3.47 percent, respectively. We further investigated the genomic correlation, phenotypic correlation and trait heritability as the factors affecting the bivariate models predication accuracy, with genetic correlation between growing seasons being the most important one. For all three considered model architectures results were far worse when using a univariate version of the model, e.g. with an average reduction in prediction accuracy of 0.23/0.14 for Kemater/Petkuser when using univariate GBLUP. Key MassageBivariate models based on selected subsets of pairwise SNP interactions can increase the prediction accuracy by utilizing phenotypic data across years under the assumption of high genomic correlation across years.

genetics↗

bioRxiv2020

Accounting for epistasis improves genomic prediction of phenotypes with univariate and bivariate models across environments

We compared the predictive ability of various prediction models for a maize dataset derived from 910 doubled haploid lines from European landraces (Kemater Landmais Gelb and Petkuser Ferdinand Rot), which were tested in six locations in Germany and Spain. The compared models were Genomic Best Linear Unbiased Prediction (GBLUP) as an additive model, Epistatic Random Regression BLUP (ERRBLUP) accounting for all pairwise SNP interactions, and selective Epistatic Random Regression BLUP (sERRBLUP) accounting for a selected subset of pairwise SNP interactions. These models have been compared in both univariate and bivariate statistical settings within and across environments. Our results indicate that modeling all pairwise SNP interactions into the univariate/bivariate model (ERRBLUP) is not superior in predictive ability to the respective additive model (GBLUP). However, incorporating only a selected subset of interactions with the highest effect variances in univariate/bivariate sERRBLUP can increase predictive ability significantly compared to the univariate/bivariate GBLUP. Overall, bivariate models consistently outperform univariate models in predictive ability. Over all studied traits, locations, and landraces, the increase in prediction accuracy from univariate GBLUP to univariate sERRBLUP ranged from 5.9 to 112.4 percent, with an average increase of 47 percent. For bivariate models, the change ranged from -0.3 to +27.9 percent comparing the bivariate sERRBLUP to the bivariate GBLUP. The average increase across traits and locations was 11 percent. This considerable increase in predictive ability achieved by sERRBLUP may be of interest for "sparse testing" approaches in which only a subset of the lines/hybrids of interest is observed at each location. Key MessageThe prediction accuracy of genomic prediction of phenotypes can be increased by only including top ranked pairwise SNP interactions into the prediction models.

genetics↗

bioRxiv2020

Discovery of novel haplotypes for complex traits in landraces

Genetic variation is of crucial importance for selection and genetic improvement of crops. Landraces are valuable sources of diversity for germplasm improvement, but for quantitative traits efficient strategies for their targeted utilization are lacking. Here, we propose a genome-based strategy for making native diversity accessible for traits with limited genetic variation in elite germplasm. We generated ~ 1,000 doubled-haploid (DH) lines from three European maize landraces, pre-selected based on molecular and phenotypic information. Using GWAS, we mapped haplotype-trait associations for early development traits at high resolution in eleven environments. Molecular haplotype inventories of landrace derived DH libraries and a broad panel of 65 breeding lines based on 501,124 SNPs revealed novel variation for target traits in the landraces. DH lines carrying these novel haplotypes outperformed breeding lines not carrying the respective haplotypes. Most haplotypes associated with target traits showed stable effects across populations and environments and only limited correlated effects with undesired traits making them ideal for introgression into elite germplasm. Our strategy was successful in linking molecular variation to meaningful phenotypes and identifying novel variation for quantitative traits in plant genetic resources.

genetics↗

bioRxiv2020

Generalized gametic relationships for flexible analyses of parent-of-origin effects

Genomic imprinting causes alleles to influence the phenotype in a parent-of-origin-specific manner. In attempts to determine the effects of imprinted loci, gametic relationship matrices have widely been used in pedigree-based parent-of-origin analyses of population data. One drawback of this is the size of these matrices because they represent each individual by two gametic effects. Significantly fewer equations are needed if a previously published reduced imprinting model is used that relates observations from progeny without its own offspring to the transmitting abilities of their parents. This can be accomplished using a numerator relationship matrix, with only a single row and column per parent and ancestors. However, the reduced model is not applicable when the parents have records. To better handle the curse of dimensionality, we propose a combination of average gametic effects (transmitting abilities) for individuals without their own records and single gametic effects for others. The generalized gametic relationship matrix is the covariance of this mixture of genetic effects that allows for a significant reduction in the number of equations in gametic models depending on the trait, depth of pedigree, and population structure. It can also render the reduced model much more flexible by including observations from parents. Rules for setting-up its inverse from a pedigree are derived and implemented on an open-source program. The application of the same principles to phased marker data leads to a genomic version of the generalized gametic relationships. The implementation of generalized gametic models to the ASReml package is illustrated through worked examples.

genetics↗

bioRxiv2019

Caffeine-induced Plasticity of Grey Matter Volume in Healthy Brains: A placebo-controlled multimodal within-subject study

Disturbed sleep homeostatic states have been found to alter neuronal homeostasis and reduce grey matter (GM) volume. Caffeine intake that interferes with sleep homeostasis through antagonizing adenosine receptors can impair hippocampal synaptic strength, neurogenesis, as well as memory and learning in rats. In this study, reduced medial temporal GM volume was observed after daily caffeine intake in humans (3 x 150 mg x 10 days compared to 10-day placebo administration). The potential bias from reduced cerebral blood flow was controlled, and the GM reduction was independent of the change in sleep pressure. A decrease in working memory during daily caffeine intake was observed, albeit no association with the magnitude of GM changes. The findings indicate that daily caffeine intake might induce rapid cerebral plasticity and be detrimental for higher order cognitive performance in the long run. They may call into question whether the neuroprotective effects of caffeine found in acute or low dose administration in animals are generalizable onto the daily usage in humans.

neuroscience↗

bioRxiv2019

Improving imputation quality in BEAGLE for crop and livestock data

Imputation is one of the key steps in the preprocessing and quality control protocol of any genetic study. Most imputation algorithms were originally developed for the use in human genetics and thus are optimized for a high level of genetic diversity. Different versions of BEAGLE were evaluated on genetic datasets of doubled haploids of two European maize landraces, a commercial breeding line and a diversity panel in chicken, respectively, with different levels of genetic diversity and structure which can be taken into account in BEAGLE by parameter tuning. Especially for phasing BEAGLE 5.0 outperformed the newest version (5.1) which in turn also lead to improved imputation. Earlier versions were far more dependent on the adaption of parameters in all our tests. For all versions, the parameter ne (effective population size) had a major effect on the error rate for imputation of ungenotyped markers, reducing error rates by up to 98.5%. Further improvement was obtained by tuning of the parameters affecting the structure of the haplotype cluster that is used to initialize the underlying Hidden Markov Model of BEAGLE. The number of markers with extremely high error rates for the maize datasets were more than halved by the use of a flint reference genome (F7, PE0075 etc.) instead of the commonly used B73. On average, error rates for imputation of ungenotyped markers were reduced by 8.5% by excluding genetically distant individuals from the reference panel for the chicken diversity panel. To optimize imputation accuracy one has to find a balance between representing as much of the genetic diversity as possible while avoiding the introduction of noise by including genetically distant individuals.

genetics↗