Biology subjects

Mayer, J.

Publications and source records attributed to Mayer, J..

18 recordsLinked to original sources

bioRxiv2026

Engineered endothelial cell grafts form functional anastomoses and enable recruitment of intravenously delivered human T cells in CAM tumor models

The development of cancer immunotherapies requires preclinical models that capture intravenous delivery, immune cell recruitment and intratumoral T cell activation. Conventional 3D in vitro systems lack perfused vascular networks, whereas mouse models are limited by throughput. The chick chorioallantoic membrane (CAM) assay enables rapid growth of vascularized tumors derived from human cancer cells in ovo, but its application to human T cell-based immunotherapy testing is constrained by CAM-derived vascularization and species-specific barriers between human immune cells and avian endothelium. Here, we establish an endothelial graft-enhanced CAM tumor model that incorporates an immortalized murine endothelial cell line capable of anastomosing with the chick vasculature. This generates a perfused and branched mammalian vascular interface within human tumor xenografts growing on the CAM. Human ICAM-1 expression on the grafted endothelial cells further enhances recruitment of intravenously delivered human T cells into CAM tumors. Using this platform, we demonstrate target-dependent intratumoral T cell activation by bispecific T cell engagers (TCEs) across tumor models, including evaluation of the clinically approved DLL3-targeting TCE tarlatamab in small cell lung cancer models.

bioengineering↗

bioRxiv2026

The prefrontal cortex outputs to the amygdala facilitate threat-discrimination learning

The medial prefrontal cortex (mPFC) plays a significant role in modulating the threat response, particularly in ambiguous circumstances. The mPFC performs this role through its connectivity with multiple brain regions, including the amygdala, long regarded as the central hub for threat responses. However, the roles of specific prefrontal projections to the amygdala in contextual threat discrimination are not yet fully understood, particularly regarding more complex learning tasks and when disentangling the functionally distinct prelimbic (PL) subunit of the mPFC. Here, we challenged mice with a contextual differential threat conditioning (DTC) learning task in which subjects were repeatedly exposed to one context predictive of a foot shock (CS+) and to a similar yet distinct context that was not (CS-). While control mice showed a similar threat response in both contexts immediately after threat conditioning, within a few days of contextual exposures, controls acquire threat discrimination and freeze less to CS- than to CS+ during late DTC. However, we found that inducing localized hypofunction of neuroplasticity in PL neurons projecting to the basolateral amygdala (BLA) impairs performance on DTC. This finding identifies the specific population of neurons in PL cortices as a critical site for learning to discriminate threat.

neuroscience↗

bioRxiv2025

MiniCARbids: Minimalistic human binding domains specifically tailored to CAR T applications

Traditionally, chimeric antigen receptor (CAR) T cells employ single-chain variable fragments (scFvs) as binding entities. While scFvs represent a convenient option due to their broad availability, they also come with drawbacks, in particular their tendency to cluster and their relatively large size. Moreover, most scFvs used in the CAR field are of non-human origin, potentially causing immunogenicity. Therefore, we established an engineering platform for minimalistic CAR binding domains (miniCARbids), which combine several critical advantages: (i) human origin, (ii) small size, (iii) efficient expression in T cells and (iv) single-domain architecture, among others. We demonstrate that miniCARbids can be engineered to recognize various antigens with antibody-like affinities, while being stable and aggregation-resistant. When miniCARbids are incorporated into CARs, they induce high anti-tumor potency in both adapter and conventional CAR formats. Remarkably, CD22-directed miniCARbid-based CARs showed similar or even more efficient tumor clearance in leukemia-bearing mice when compared with a CAR comprising the clinically tested m971-1xG4S scFv. Together, we introduce the miniCARbid engineering platform, enabling the generation of small, human antigen-binding domains with high potency in CAR T cells against virtually any target antigen.

synthetic biology↗

bioRxiv2025

Multiplexing behavioral signals in sensory representations

Activity of sensory neurons is influenced not only by external stimuli but also by the animals behavioral state. It is well documented that behavior influences the general properties of neural activity, such as response gain. However, it is not known whether it could affect the sensory tuning of individual neurons in a more refined way and what the functional benefit of such nuanced modulation might be. Here, we investigate this in the mouse visual cortex using the data made available by the Allen Brain Observatory. Our analysis indicates that locomotion can modulate not only the gain of the entire neuronal response, but also more selectively control responses to specific stimuli. This modulation results in changes of neuronal tuning in different behavioral states. Using numerical simulations, we demonstrate that such patterns of gain modulation can multiplex behavioral information in sensory populations without compromising the accuracy of sensory coding. In that way, the visual cortex could instantiate an accurate, joint representation of sensory and movement-related signals and support computations that simultaneously require both types of information.

neuroscience↗

bioRxiv2024

Modulation of the ATP-adenosine signaling axis combined with radiotherapy facilitates anti-cancer immunity in brain metastasis

The immunosuppressive microenvironment in the brain poses a major limitation to successful therapy for brain metastases. Here we report that blockade of the ATP-to-adenosine-converting enzymes CD39 and CD73 and the adenosine receptor A2AR in combination with radiotherapy attenuates tumor progression in a breast-to-brain metastasis model by facilitating anti-cancer immunity. Immunophenotyping revealed loss of exhausted T cells and higher abundance of anti-cancer effector T cell populations. This effect was accompanied by a decrease of immunosuppressive lipid-laden macrophages and an expansion of CD14CD33high macrophages associated with antigen presentation. Analyses of human brain metastases samples supports a role of the ATP-adenosine signaling axis in modulating tumor inflammation and identified expression of CD39 and adenosine deaminase as predictive markers for patient survival and/or immune infiltration. Our findings demonstrate that the adenosine axis represents a druggable pathway to achieve local immunomodulation and treatment response, opening a new therapeutic avenue for brain metastases patients.

cancer biology↗

bioRxiv2024

On the specificity of manual triggers of autonomic nervous system responses using osteopathic cranial manipulative medicine

Significant autonomic nervous system responses to a specific osteopathic intervention, the cranial vault hold (CVH), have recently been demonstrated in forehead skin blood volume changes, heart rate, and respiration frequencies. The specificity of the CVH-intervention-related autonomic responses yet requires differentiation. Thus, we compared autonomic responses to CVH with responses to compression of the fourth ventricle (CV4) and to two corresponding SHAM conditions. Analysis of frequencies and amplitudes for changes in skin blood volume and respiration in low (LF; 0.05 - 0.12 Hz), intermediate (IM; 0.12 - 0.18 Hz), and high (HF; 0.18 - 0.4 Hz) frequency bands, and metrics of heartrate variability revealed significant decreases in LF range (from 0.12 to 0.10 Hz), increased LF and decreased IM durations, and increased skin blood volume amplitudes in response to CVH, but no significant skin blood volume responses to any of the control interventions. Ratio changes for respiration and skin blood volume frequencies approximately at 3:1 during CVH, remained unchanged in all other interventions. Heart rate decreased across conditions, indicating an increase in parasympathetic tone. This was also indicated by a significant increase in root mean of squared successive difference following CV4. We incurred that rhythmic response patterns in the LF and IM bands only appeared in CVH. This suggests specific physiological responses to CVH warranting further investigation by studying e.g., responses to CVH in physical or mental health disorders with autonomic involvement.

physiology↗

bioRxiv2024

Microbial resistance and resilience to drought under organic and conventional farming

The impacts of climate change, such as drought, can affect soil microbial communities. These communities are crucial for soil functioning and crop production. Organic and conventional cropping systems promote distinct soil microbiomes and soil organic carbon contents, which might maintain different capacities to mitigate drought effects on cropping systems. A field-scale drought simulation was performed in long-term organically and conventionally managed cropping systems differing in fertilization and pesticide application. The soil microbiome was assessed during and after drought in bulk soil, rhizosphere, and roots of wheat. We found that drought shifted microbial community structures, affecting fungi more strongly than prokaryotes. Microbial communities associated with crops (i.e. rhizosphere and root) were more strongly influenced by drought compared to bulk soil communities. A drought legacy effect was observed in the bulk soil after harvesting and rewetting. The resistance and resilience of the soil microbiome to severe drought did not significantly differ across the organic and conventional cropping systems, although few individual genera (e.g. Streptomyces, Rhizophagus, Actinomadura, and Aneurinibacillus) showed system-specific drought responses. All cropping systems showed relative increases in potential plant growth-promoting genera under drought. This agricultural field study indicated that fungal communities might be less resistant to drought than prokaryotic communities in cropping systems and these effects get more pronounced in closer association with plants. Organic fertilization or the reduction in pesticide application might not have the ability to buffer severe drought stress and additional farming practices might have to be incorporated to improve drought tolerance in cropping systems.

microbiology↗

bioRxiv2023

Orphan nuclear receptor NR2E3 and its small-molecule agonist induce cancer cell apoptosis through regulating p53, IFNα and MYC pathways

Orphan nuclear receptor NR2E3 activates p53 and induces cancer cell apoptosis. Further studies on p53-dependent and -independent functions of wild-type and mutated NR2E3 are needed. Herein, we showed that NR2E3 enhanced p53-DNA interactions in diverse cancer cells and up-regulated p53 and IFN pathways while down-regulating MYC pathway in cervical cancer cells. Studies of "All of Us" and TCGA databases showed NR2E3 nonsynonymous mutations associating with four cancers. We stratified NR2E3 SNVs for their cancer implications with the p53 reporter. A cancer-associated NR2E3R97Hmutation not only lost the wild-types tumor-suppressing functions but also prohibited the wild-type from enhancing p53 acetylation. These observations implicated the potential for pharmaceutically activating NR2E3 to suppress cancer. Indeed, NR2E3s small-molecule agonist 11a repressed 2-D and 3-D cultures of primary cells and cell lines of cervical cancer, in which screening FDA-approved anti-cancer drugs identified HDAC-1/2 inhibitor Romidepsin operating synergistically with 11a. The underlying molecular mechanisms included 11as down-regulating the transcription of Multidrug Resistance Protein ABCB1 that Romidepsin up-regulated. Transcriptomics studies revealed three synergy modes: (1) "sum-up" mode that the p53 pathway activated individually by 11a and Romidepsin got stronger by the combo; (2) "antagonism" mode that Romidepsin counteracted the activation of the Kras pathway by 11a; and (3) "de novo" mode that the combo instead of each individual drug repressed the MYC pathway. Conclusively, our experiments provide new data supporting tumor-suppressor like functions for wild-type NR2E3, reveal roles of mutated NR2E3 in cancer, and address values of NR2E3s agonist 11a in cancer therapy alone and combined.

cancer biology↗

bioRxiv2023

A YIPF5-GOT1A/B complex directs a transcription independent function of ATF6 in ER export

Exit from the endoplasmic reticulum is mediated by the Sar1/COPII machinery and a number of accessory factors. How the initial steps of cargo recruitment upstream of Sar1/COPII are mediated remains unclear, but the dihydropyridine FLI-06 inhibits cargo recruitment into ER exit sites. Here, we used chemical genetics screening approaches in conjunction with FLI-06 treatment and identified the ER membrane proteins YIPF5 and GOT1A/B as putative components of early export processes. Surprisingly, the two homologous proteins GOT1A and GOT1B, coded by GOLT1A and GOLT1B, respectively, exhibited opposite functions after treatment with FLI-06: increasing the expression of GOT1A or reducing the expression of GOT1B or YIPF5 prevented inhibition of ER-export by FLI-06. Inhibiting ER export with FLI-06 elicited a specific ER stress-related gene expression signature distinct from the ER-stress signature induced by Thapsigargin. The interactomes of GOT1A and GOT1B suggested a connection to ER-stress mediators. Moreover, RNA-Seq data showed that FLI-06-induced genes are strongly enriched for ATF6 target genes which are suppressed by GOLT1A overexpression or GOLT1B knock-down. This suggests that ATF6 signaling is involved in FLI-06-mediated toxicity, and we could demonstrate that siRNA-mediated knock-down or specific inhibitor of ATF6 rescued cells from FLI-06-mediated cell death. Knock-down or inhibition of ATF6 is sufficient to resume transport from the ER under FLI-06-treatment, suggesting that ATF6 is directly involved in the FLI-06-mediated ER-export block. Surprisingly, our data show that this ATF6 function is independent of de novo transcription, implying a novel, transcription-independent function of ATF6.

cell biology↗

bioRxiv2023

Spike synchrony as a measure of Gestalt structure

The function of spike synchrony has long been debated in the neuroscience community. Some researchers view synchrony as a byproduct of brain activity, while others argue that it serves as a mechanism for binding perceptual features. We, however, argue for an alternative view on the computational role of synchrony: it can serve as a mechanism for estimating the prior probability of incoming stimuli. In V1, this probability can be estimated by comparing the input stimulus with previously acquired visual experience. Such experience is encoded in horizontal intracortical connections, as they are subject to change, learn, and adapt to incoming visual stimuli throughout the course of life. Thus, the V1 connectivity structure can encode the acquired visual experience in the form of its aggregate statistics. Since the aggregate statistics of natural images tend to follow the Gestalt principles, we can assume that V1 is more often exposed to Gestalt-like stimuli, and this is manifested in its connectivity structure. At the same time, the connectivity structure has an impact on the synchrony of neuronal firings in V1. In our work, we used a spiking model with V1-like connectivity to demonstrate that spike synchrony reflects the Gestalt structure of the stimulus. We conducted simulation experiments with three Gestalt laws: proximity, similarity, and continuity, and found significant differences in firing synchrony for stimuli with varying degrees of Gestalt-likeness. This allows us to conclude that spike synchrony indeed reflects the Gestalt structure of the stimulus, which can be interpreted as a mechanism for prior probability estimation. Author SummaryNeurons in the brain fire synchronously in different contexts, in response to different stimuli. However, the function of synchrony is very debatable in the neuroscience community. We suggest that synchrony plays an important role in brain computations: it can estimate how well a network is familiar with the incoming stimulus. We tested our hypothesis on the simulation of neuronal activity in a model of primary visual cortex - a brain region which is processing simple visual features, such as lines of different angle orientation. The connections between neurons in this brain area store the acquired visual experience in the form of its statistics, such as edge cooccurrences. We built the connectivity in our model in accordance with principles of connectivity in primary visual cortex, assuming that it reflects natural images statistics. We tested our model on artificial stimuli, which represented more and less experienced visual features. Our results showed that spike synchrony is a global phenomenon which emerges across the large parts of the network, and it reflects the familiarity of the network with the stimulus. Thus, it can serve as a form of recognition memory and has a potential for usage in various applications which require estimation of input familiarity.

neuroscience↗

bioRxiv2023

ProT-VAE: Protein Transformer Variational AutoEncoder for Functional Protein Design

The data-driven design of protein sequences with desired function is challenged by the absence of good theoretical models for the sequence-function mapping and the vast size of protein sequence space. Deep generative models have demonstrated success in learning the sequence to function relationship over natural training data and sampling from this distribution to design synthetic sequences with engineered functionality. We introduce a deep generative model termed the Protein Transformer Variational AutoEncoder (ProT-VAE) that furnishes an accurate, generative, fast, and transferable model of the sequence-function relationship for data-driven protein engineering by blending the merits of variational autoencoders to learn interpretable, low-dimensional latent embeddings and fully generative decoding for conditional sequence design with the expressive, alignment-free featurization offered by transformers. The model sandwiches a lightweight, task-specific variational autoencoder between generic, pre-trained transformer encoder and decoder stacks to admit alignment-free training in an unsupervised or semi-supervised fashion, and interpretable low-dimensional latent spaces that facilitate understanding, optimization, and generative design of functional synthetic sequences. We implement the model using NVIDIAs BioNeMo framework and validate its performance in retrospective functional prediction and prospective design of novel protein sequences subjected to experimental synthesis and testing. The ProT-VAE latent space exposes ancestral and functional relationships that enable conditional generation of novel sequences with high functionality and substantial sequence diversity. We anticipate that the model can offer an extensible and generic platform for machine learning-guided directed evolution campaigns for the data-driven design of novel synthetic proteins with "super-natural" function.

synthetic biology↗

bioRxiv2022

Association Between Polygenic Risk Score And Gut Microbiome Of Multiple Sclerosis

BackgroundMultiple sclerosis (MS) is a complex autoimmune disease in which both the roles of genetic susceptibility and environmental/microbial factors have been investigated. More than 200 genetic susceptibility variants have been identified along with the dysbiosis of gut microbiota, both independently have been shown to be associated with MS. We hypothesize that MS patients harboring genetic susceptibility variants along with gut microbiome dysbiosis are at a greater risk of exhibiting the disease. We investigated the polygenic risk score for MS in conjunction with gut microbiota in the same cohort of 117 relapsing remitting MS (RRMS) and 26 healthy controls. DNA samples were genotyped using Illuminas Infinium Immuno array-24 v2 chip followed by calculating polygenic risk score and the microbiota was determined by sequencing the V4 hypervariable region of the 16S rRNA gene. ResultsWe identified two clusters of MS patients, Cluster A and B both having a higher polygenic risk score than the control group. The Cluster B with the higher polygenic risk score had a distinct gut microbiota, different than the Cluster A. MS group whose microbiome was similar to that of the control group despite a higher genetic risk score than the control group. This could be due to i) the non-active state of the disease in that group of MS patients at the time of fecal sample collection and/or ii) the restoration of the gut microbiome post disease modifying therapy to treat the MS. ConclusionOur study showed that there seems to be association between polygenic risk score and gut microbiome dysbiosis in triggering the disease in a small cohort of MS patients. The MS Cluster A who have a higher polygenic risk score but microbiome profile similar to that of healthy controls could be due to the remitting phase of the disease or due to the effect of disease modifying therapies.

genetics↗

bioRxiv2022

Estimating the distribution of livestock in space and time: a time-series contribution to livestock density mapping

More than one billion people rely on livestock for income, nutrition, and social cohesion, however livestock keeping can facilitate disease transmission and contribute to climate change. While data on the distribution of livestock thus have broad utility across a range of applications, efforts to map the distribution of livestock on a large scale are limited to the Gridded Livestock of the World (GLW) project. We present a complimentary effort to map the distribution of cattle and pigs in Malawi, Uganda, Democratic Republic of Congo (DRC), and South Sudan. In contrast to GLW, which uses dasymmetric modeling applied to census data to produce time-stratified estimates of livestock counts and spatial density, our work uses complex survey data and distinct modeling methods to generate a time-series of livestock distribution, defining livestock density as the ratio of animals to humans. In addition to favorable cross-validation results and general agreement with national density estimates derived from external data on national human and livestock populations, our results demonstrate extremely good agreement with GLW-3 estimates, supporting the validity of both efforts. Our results furthermore offer a high-resolution time series result and employ a definition of density which is particularly well-suited to the study of livestock-origin zoonoses.

ecology↗

bioRxiv2022

P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection

Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals converge on the activation of p38 kinases to initiate human NLRP1 inflammasome assembly: UV irradiation and microbial molecules that initiate the ribotoxic stress response critically relied on the MAP3 kinase ZAK to activate p38 and ultimately human NLRP1. Infection with insect-transmitted alphaviruses, including Semliki Forest, Ross River, and Chikungunya virus, also activated NLRP1 in a p38-dependent manner. In the absence on ZAK, inflammasome assembly was maintained, although at reduced levels, indicating contribution of other upstream kinases. NLRP1 activation by direct nanobody-mediated ubiquitination was independent of p38 activity. Stimulation of p38 by overexpression of MAP2 kinases MKK3 or MKK6 is sufficient for NLRP1 activation, and NLRP1 is directly phosphorylated by p38. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.

immunology↗

bioRxiv2019

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Although human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimers disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

neuroscience↗

bioRxiv2019

Elucidation of protein-protein interactions necessary for maintenance of the BCR-ABL signaling complex

Approximately 50% of chronic myeloid leukemia (CML) patients in deep remission experience a return of clinical CML after withdrawal of tyrosine kinase inhibitors (TKIs). This suggests signaling of inactive BCR-ABL, which allows for survival of cancer cells, leading to relapse. Understanding the dynamics of BCR-ABL signaling complex holds a key to the mechanism of BCR-ABL signaling. Here, we demonstrate that TKIs inhibit catalytic activity of BCR-ABL, but do not dissolve the BCR-ABL core signaling complex consisting of CrkL, SHC1, Grb2, SOS1, cCbl, and SHIP2. We show that CrkL binds to proline-rich regions located in C-terminal, intrinsically disordered region of BCR-ABL, that deletion of pleckstrin homology domain of BCR-ABL diminishes interaction with SHC1, and that BCR-ABL sequence motif located in disordered region around phosphorylated tyrosine 177 mediates binding of at least three core complex members, the Grb2, SOS1 and cCbl. Introduction of Y177F substitution blocks association with Grb2, SOS1 and cCbl. Further, we identified SHIP2 binding sites within the src-homology and tyrosine kinase domains of BCR-ABL. We found that BCR-ABL is unable to phosphorylate SHC1 in cells lacking SHIP2. Reintroducing SHIP2 into Ship2 knock-out cells restored SHC1 phosphorylation, which depended on inositol phosphatase activity of SHIP2. Our findings provide characterization of protein-protein interactions in the BCR-ABL signaling complex, and support the concept of targeting BCR-ABL signaling in CML by inhibition of its interactions with the members of the core complex.

molecular biology↗

bioRxiv2018

Association of HLA class I type with prevalence and outcome of patients with acute myeloid leukemia and mutated nucleophosmin

Acute myeloid leukemia with mutated nucleophosmin (NPMc+ AML) forms a distinct AML subgroup with better prognosis which can potentially be associated with immune response against the mutated nucleophosmin (NPM). As the T-cell-mediated immunity involves antigen presentation on HLA class I molecules, we hypothesized that individuals with suitable HLA type could be less prone to develop NPMc+ AML. We compared HLA class I distribution in NPMc+ AML patient cohort (398 patients from 5 centers) with the HLA allele frequencies of the caucasian population and found HLA-A*02, B*07, B*40 and C*07 underrepresented in the NPMc+ AML group. Presence of B*07 or C*07:01 antigen was associated with better survival in patients without concomitant FLT3 internal tandem duplication. Candidate NPM-derived immunopeptides were found for B*40 and B*07 using prediction software tools. Our findings suggest that a T-cell-mediated immune response could actually explain better prognosis of NPMc+ patients and provide a rationale for attempts to explore the importance of immunosuppressive mechanisms in this AML subgroup.

cancer biology↗

bioRxiv2017

Combination of mitochondrial tRNA and OXPHOS mutation reduces lifespan and physical condition in aged mice

Mutations in the mitochondrial DNA (mtDNA) are widely known to impact on lifespan and tissue integrity. For example, more than 250 pathogenic mtDNA mutations are known, many of which lead to neurological symptoms. In addition, major neurodegenerative diseases share key components of their etiopathogenesis with regard to mtDNA mutations, mitochondrial dysfunction and oxidative stress. In our study we used a set of conplastic mouse models carrying stable point mutations in mitochondrial genes of transfer RNA (tRNA) and oxidative phosphorylation (OXPHOS)-proteins. We analyzed the impact of these mutations on complex traits like lifespan, learning and memory in the ageing process. The combination of both point mutations in the OXPHOS complex IV gene and adenine insertions in the mitochondrially encoded tRNA arginine (tRNA-Arg) gene (mt-Tr) leads to an age-dependent phenotype with elevated mitochondrial superoxide production in the neocortex. Mice with this combination of tRNA and OXPHOS mutations show significantly reduced lifespan and poor physical constitution at the age of 24 months, whereas single point mutations in OXPHOS or mt-tRNA(Arg) do not have this impact. Therefore, we suggest a synergistic effect of these mutations.

developmental biology↗