Biology subjects

Fischer, D.

Publications and source records attributed to Fischer, D..

At least 19 recordsLinked to original sources

bioRxiv2026

ADSS1 is a suppressed metabolic control node in dystrophic skeletal muscle

Duchenne muscular dystrophy is initiated by dystrophin loss but is accompanied by profound metabolic remodelling. Here, we identify suppression of the muscle-enriched adenylosuccinate synthase, ADSS1, and the purine nucleotide cycle in mdx muscle. Integrated multi-omic profiling revealed a compensated purine-stress state in which nucleotide salvage and quality control were increased to preserve adenine nucleotide abundance and buffer consequential toxic/disruptive deoxy-/nucleotide production. Purine metabolism was the highest-impact joint pathway with metabolite and transcript hits in mdx muscle, and its maintenance program was directionally conserved in human ADSS1 myopathy. Interventions positioned around ADSS1 separated the outputs of this node. Ribose and dimethyl fumarate remodelled upstream or downstream stress programs, whereas only adenylosuccinic acid bypassed ADSS1 to expand the adenine nucleotide pool and remodel CoA/acetyl-CoA metabolism. All three interventions suppressed pro-adipogenic transcription without broadly correcting the lipidome. These findings identify ADSS1 as a regulated metabolic control node that couples purine retention to inflammatory and adipogenic remodelling in dystrophic muscle.

molecular biology↗

bioRxiv2025

Neuroanatomical Basis of Coma in Acute Ischemic Stroke

BackgroundAcute ischemic stroke (AIS) can lead to profound disturbances in consciousness, including coma, which is associated with poor prognosis and increased mortality. Clarifying the lesion patterns that precipitate loss of consciousness can refine pathophysiological models and guide prognosis. ObjectivesIn this study, we aim to identify the brain regions most commonly affected in comatose AIS and determine whether specific combinations of lesions are necessary and sufficient to produce coma. MethodsWe retrospectively analyzed 476 AIS patients (52 comatose) using diffusion-weighted imaging. Infarcts were automatically segmented, manually verified, and normalized to MNI space. Support vector regression lesion-symptom mapping (SVR-LSM) quantified voxel-wise associations with coma, controlling for lesion volume. To assess the necessity and sufficiency of lesion combinations, we employed permutation-based nested logistic regression models comparing all subsets of four anatomical predictors: brainstem, thalamus, cerebellum, and the rest of brain lesions. ResultsSVR-LSM revealed that coma was strongly associated with lesions involving the brainstem, thalamus, and cerebellum, whereas non-comatose patients exhibited predominantly cortical infarcts. Nested model comparisons showed that concurrent lesions to both the brainstem and thalamus were necessary and sufficient for coma. Additional involvement of the cerebellum or cerebral cortex did not improve predictive performance. ConclusionsComa after AIS results from a dual-node subcortical lesion pattern involving both the brainstem and thalamus. Cerebellar and cortical lesions, even when extensive, did not induce coma in the absence of the dual-brainstem and thalamic lesions. These observations emphasize the predominant role of lesion location over lesion volume in the pathogenesis of coma. They also support mechanistic models that position the brainstem and thalamic hubs as central to the neural circuitry underlying arousal. Furthermore, these findings delineate a specific anatomical substrate that may serve as a strategic target for circuit-based neuroprotective and neuromodulatory therapies.

neuroscience↗

bioRxiv2025

Reconstructing signaling histories of single cells via perturbation screens and transfer learning

Manipulating the signaling environment is an effective approach to alter cellular states for broad-ranging applications, from engineering tissues to treating diseases. Such manipulation requires knowing the signaling states and histories of the cells in situ, for which high-throughput discovery methods are lacking. Here, we present an integrated experimental-computational framework that learns signaling response signatures from a high-throughput in vitro perturbation atlas and infers combinatorial signaling activities in in vivo cell types with high accuracy and temporal resolution. Specifically, we generated signaling perturbation atlas across diverse cell types/states through multiplexed sequential combinatorial screens on human pluripotent stem cells. Using the atlas to train IRIS, a neural network-based model, and predicting on mouse embryo scRNAseq atlas, we discovered global features of combinatorial signaling code usage over time, identified biologically meaningful heterogeneity of signaling states within each cell type, and reconstructed signaling histories along diverse cell lineages. We further demonstrated that IRIS greatly accelerates the optimization of stem cell differentiation protocols by drastically reducing the combinatorial space that needs to be tested. This framework leads to the revelation that different cell types share robust signal response signatures, and provides a scalable solution for mapping complex signaling interactions in vivo to guide targeted interventions.

developmental biology↗

bioRxiv2025

A high-quality reference genome for the Ural Owl (Strix uralensis) enables investigations of cell cultures as a genomic resource for endangered species

BackgroundReference genomes have a wide range of applications. Yet, we are from a complete genomic picture for the tree of life. We here contribute another piece to the puzzle by providing a high-quality reference genome for the Ural Owl (Strix uralensis), a species of conservation concern and efforts affected by habitat destruction and climate change. ResultsWe generated a reference genome assembly for the Ural Owl based on high-fidelity (HiFi) long reads and chromosome conformation capture (Hi-C) data. It figures amongst the best avian genome assemblies currently available (BUSCO completeness of 99.94 %). The primary assembly had a size of 1.38 Gb with a scaffold N50 of 90.1 Mb, while the alternative assembly had a size of 1.3 Gb and a scaffold N50 of 17.0 Mb. We show an exceptionally high repeat content (21.07 %) that is different from those of other bird taxa with repeat extensions. We confirm a Strix characteristic chromosomal fusion and support the observation that bird microchromosomes have a higher density of genes, associated with a reduction in gene length due to shorter introns. An analysis of gene content provides evidence of changes in the keratin gene repertoire as well as modifications of metabolism genes of owls. This opens an avenue of research if this is related to flight adaptations. The population size history of the Ural Owl decreased over long periods of time with increases during the Eemian interglacial and stable size during the last glacial period. Ever since it is declining to its currently lowest effective population size. We also investigated cell culture of progressive passages as a tool for genetic resources. Karyotyping of passages confirmed no large variants, while a SNP analysis revealed a low presence of short variants across cell passages. ConclusionsThe established reference genome is a valuable resource for ongoing conservation efforts, but also for (avian) comparative genomics research. Further research is needed to determine whether cell culture passages can be safely used in genomic research.

genomics↗

bioRxiv2024

Circulation of West Nile Virus and Usutu Virus in Birds in Germany, 2021 and 2022.

BackgroundUsutu virus (USUV) and West Nile virus (WNV) are zoonotic arthropod-borne orthoflaviviruses. The enzootic transmission cycles of both include Culex mosquitoes as vectors and birds as amplifying hosts. For more than ten years, these viruses have been monitored in birds in Germany by a multidisciplinary network. While USUV is present nationwide, WNV used to be restricted to the central-east. MethodsIn 2021 and 2022, over 2300 live bird blood samples and organs from over 3000 deceased birds were subjected to molecular and serological analysis regarding presence of WNV and USUV. The samples were collected at sites all over Germany. ResultsCirculation of both viruses increased in 2022. For USUV, the nationwide presence of lineages Africa 3 and Europe 3 reported in previous years was confirmed. Lineage Europe 2, formerly restricted to the German east, was able to expand westward. Nonetheless, USUV neutralizing antibody (nAb) detection rates remained low (< 9%). 2021 and 2022 were characterized by stable enzootic circulation of WNV lineage 2, dominated by one previously identified subcluster (95% of generated sequences). In 2022, more than 20% of birds in the endemic region in eastern Germany carried nAb against WNV. Serological data also indicate expanding WNV circulation west and south of the known hotspots in Germany. ConclusionsUSUV circulates enzootically nationwide. Emergence of WNV at several new locations in Germany with a potential increase in human infections may be imminent. In this context, wild bird monitoring serves as a capable early-warning system in a One Health setting.

microbiology↗

bioRxiv2024

Moderate-term dimethyl fumarate treatment reduces pathology of dystrophic skeletal and cardiac muscle in a mouse model

In Duchenne muscular dystrophy (DMD), corticosteroids significantly slow disease progression and have been used as a standard of care tool for more than 30 years. However, corticosteroids also impart side effects severe enough to preclude use in some patients. There remains an unmet need for new therapeutics that target the flow-on pathogenic mechanisms of DMD with a more favourable side-effect profile. We have previously demonstrated that short-term treatment with dual-purpose anti-inflammatory, anti-oxidative dimethyl fumarate (DMF), a drug with indication and established safety data in Multiple Sclerosis, more selectively modulates Duchenne (mdx) immunology than the frequently used corticosteroid, prednisone (PRED). Here, we assess the effect of moderate-term DMF treatment over 5 weeks in the typically mild mdx mouse model that we aggravated using exercise. We show that like PRED, DMF maintains anti-inflammatory action but with additional anti-fibrotic and anti-lipogenic effects on muscle with moderate-term use. This study supports our previous work highlighting DMF as a possible repurposing candidate for DMD, especially for patients who cannot tolerate chronic corticosteroid treatment.

pathology↗

bioRxiv2024

Evolutionary new centromeres in the snowy owl genome putatively seeded from a transposable element

Comparative genomic studies in birds have revealed that bird genomes are relatively repeat-poor and stable in terms of karyotype, size, and gene synteny/collinearity compared to other vertebrates. One notable exception is the owls, with cytogenetic studies demonstrating large variations in karyotypes and the evolution of unusual centromeric satellite repeats in some species. However, there has so far not been an investigation into genome architecture and repeat landscape of owls. Here, we present a chromosome-level genome assembly for the snowy owl (Bubo scandiacus). We find that the repeat DNA content in the relatively large snowy owl genome (1.6 Gb) is among the highest reported for any bird genome to date (28.34% compared to an average of [~]10% in other birds). The bulk of the snowy owl genomic repeat landscape consists of centromeric satellite DNA, which appears to have originated from an endogenous retrovirus (ERV1). Using gene collinearity analyses we show that the position of these evolutionary new centromeres (ECNs) are not homologous with chicken centromeres, and are located in regions with collinearity breaks to other bird genomes due to chromosomal rearrangements. Our results support rapid transposable element-driven evolution of lineage-specific centromeres, which could have played a role in reproductive isolation and speciation of the snowy owl.

genomics↗

bioRxiv2024

Empowering bioinformatics communities with Nextflow and nf-core

Standardised analysis pipelines are an important part of FAIR bioinformatics research. Over the last decade, there has been a notable shift from point-and-click pipeline solutions such as Galaxy towards command-line solutions such as Nextflow and Snakemake. We report on recent developments in the nf-core and Nextflow frameworks that have led to widespread adoption across many scientific communities. We describe how adopting nf-core standards enables faster development, improved interoperability, and collaboration with the >8,000 members of the nf-core community. The recent development of Nextflow Domain-Specific Language 2 (DSL2) allows pipeline components to be shared and combined across projects. The nf-core community has harnessed this with a library of modules and subworkflows that can be integrated into any Nextflow pipeline, enabling research communities to progressively transition to nf-core best practices. We present a case study of nf-core adoption by six European research consortia, grouped under the EuroFAANG umbrella and dedicated to farmed animal genomics. We believe that the process outlined in this report can inspire many large consortia to seek harmonisation of their data analysis procedures.

bioinformatics↗

bioRxiv2024

Identifying the components of the Shewanella phage LambdaSo lysis system

Phage-induced lysis of Gram-negative bacterial hosts usually requires a set of phage lysis proteins, a holin, an endopeptidase and a spanin system, to disrupt each of the three cell envelope layers. Genome annotations and previous studies identified a gene region in the Shewanella oneidensis prophage LambdaSo, which comprises potential holin- and endolysin-encoding genes but lacks an obvious spanin system. By a combination of candidate approaches, mutant screening, characterization and microscopy we found that LambdaSo uses a pinholin/signal-anchor-release (SAR) endolysin system to induce proton-leakage and degradation of the cell wall. Between the corresponding genes we found that two extensively nested open reading frames encode a two-component spanin module Rz/Rz1. Unexpectedly, we identified another factor strictly required for LambdaSo-induced cell lysis, the phage protein Lcc6. Lcc6 is a transmembrane protein of 65 amino acid residues with hitherto unknown function, which acts at the level of holin in the cytoplasmic membrane to allow endolysin release. Thus, LambdaSo-mediated cell lysis requires at least four protein factors (pinholin, SAR-endolysin, spanin, Lcc6). The findings further extend the known repertoire of phage proteins involved in host lysis and phage egress. SignificanceFor the release of the assembled virions, phages have to breach the cell envelope. For Gram-negatives, this requires the disruption of three layers, the outer and inner membrane and the cell wall. In most cases, the lysis systems of phages infecting Gram-negatives comprises holins to disrupt or depolarize the membrane, thereby releasing or activating endolysins, which then degrade the cell wall. This, in turn, allows the spanins to become active and fuse outer and inner membrane, completing cell envelope disruption and allowing phage egress. Here we show that the presence of these three components may not be sufficient to allow cell lysis, implicating that also in known phages further factors may be required.

microbiology↗

bioRxiv2024

Human cytomegalovirus deploys molecular mimicry to recruit VPS4A to sites of virus assembly

The AAA-type ATPase VPS4 is recruited by proteins of the endosomal sorting complex required for transport III (ESCRT-III) to catalyse membrane constriction and membrane fission. VPS4A accumulates at the cytoplasmic viral assembly complex (cVAC) of cells infected with human cytomegalovirus (HCMV), the site where nascent virus particles obtain their membrane envelope. Here we show that VPS4A is recruited to the cVAC via interaction with pUL71. Sequence analysis, deep-learning structure prediction, molecular dynamics and mutagenic analysis identify a short peptide motif in the C-terminal region of pUL71 that is necessary and sufficient for the interaction with VPS4A. This motif is predicted to bind the same groove of the N-terminal VPS4A Microtubule-Interacting and Trafficking (MIT) domain as the Type 2 MIT-Interacting Motif (MIM2) of cellular ESCRT-III components, and this viral MIM2-like motif (vMIM2) is conserved across {beta}-herpesvirus pUL71 homologues. However, recruitment of VPS4A by pUL71 is dispensable for HCMV morphogenesis or replication and the function of the conserved vMIM2 during infection remains enigmatic. VPS4-recruitment via a vMIM2 represents a previously unknown mechanism of molecular mimicry in viruses, extending previous observations that herpesviruses encode proteins with structural and functional homology to cellular ESCRT-III components.

cell biology↗

bioRxiv2023

Fine-Tuning GBS Data with Comparison of Reference and Mock Genome Approaches for Advancing Genomic Selection in Less Studied Farmed Species

BackgroundDiversifying animal cultivation demands efficient genotyping for enabling genomic selection, but non-model species lack efficient genotyping solutions. The aim of this study was to optimize a genotyping-by-sequencing (GBS) double-digest RAD-sequencing (ddRAD) pipeline. Bovine data was used to automate the bioinformatic analysis. The application of the optimization was demonstrated on non-model European whitefish data. ResultsDdRAD data generation was designed for a reliable estimation of relatedness and is scalable to up to 384 samples. The GBS sequencing yielded approximately one million reads for each of the around 100 assessed samples. Optimizing various strategies to create a de-novo reference genome for variant calling (mock reference) showed that using three samples outperformed other building strategies with single or very large number of samples. Adjustments to most pipeline tuning parameters had limited impact on high-quality data, except for the identity criterion for merging mock reference genome clusters. For each species, over 15k GBS variants based on the mock reference were obtained and showed comparable results with the ones called using an existing reference genome. Repeatability analysis showed high concordance over replicates, particularly in bovine while in European whitefish data repeatability did not exceed earlier observations. ConclusionsThe proposed cost-effective ddRAD strategy, coupled with an efficient bioinformatics workflow, enables broad adoption of ddRAD GBS across diverse farmed species. While beneficial, a reference genome is not obligatory. The integration of Snakemake streamlines the pipeline usage on computer clusters and supports customization. This user-friendly solution facilitates genotyping for both model and non-model species.

bioinformatics↗

bioRxiv2023

Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration

Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of PTEN or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and PTEN knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) enables axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries. Significance statementInjured axons in the CNS usually fail to regenerate, causing permanent disabilities. No clinically approved drugs are currently available to improve or accelerate axon regeneration. We demonstrate that pro-regenerative treatments induced tubulin detyrosination in axonal growth cones limits axon growth. Hence, cotreatment with parthenolide, a compound blocking detyrosination, synergistically accelerates neurite growth of primary murine and, demonstrated for the first time, human retinal ganglion cells. Furthermore, systemic application of the parthenolides prodrug DMAPT accelerates hIL-6-mediated optic nerve regeneration and locomotor recovery after severe spinal cord injury. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a potential (adjuvant) drug candidate for treating CNS injuries.

neuroscience↗

bioRxiv2022

VASH1/2 inhibition accelerates functional recovery of injured nerves

Treatments accelerating axon regeneration in the nervous system are still unavailable in the clinic. However, in culture, parthenolide markedly promotes adult sensory neurons axon growth by inhibiting microtubule detyrosination. Here, we show that overexpression of vasohibins increases microtubule detyrosination in growth cones and compromises growth in culture and in vivo. Moreover, overexpression of these proteins increases the required parthenolide concentrations to promote axon regeneration, while the knockdown of vasohibins or their enhancer SVBP abolishes parthenolides effects, verifying them as pharmacological targets for promoting axon growth. In vivo, repeated intravenous application of parthenolide or its prodrug di-methyl-amino-parthenolide (DMAPT) markedly facilitates regeneration of sensory, motor, and sympathetic axons in injured murine and rat nerves and accelerates functional re-covery. Moreover, orally applied DMAPT was similarly effective in promoting nerve regeneration. Thus, pharmacological inhibition of vasohibins facilitates axon regeneration in different species and nerves, making parthenolide and DMAPT promising drugs for curing nerve injury.

neuroscience↗

bioRxiv2022

Dimethyl fumarate modulates the Duchenne muscular dystrophy disease program following short-term treatment in mdx mice

New medicines are urgently required to treat the fatal neuromuscular disease, Duchenne muscular dystrophy (DMD). DMD involves progressive muscle damage and weakness, which are preceded by oxidative stress, inflammation, and mitochondrial dysfunction. Dimethyl fumarate (DMF) is a potent small molecule nuclear erythroid 2-related factor 2 (Nrf2) activator with current clinical utility in the treatment of multiple sclerosis and psoriasis. Pharmaceutical targeting of Nrf2 by DMF has strong translational potential for DMD, given it: (1) promotes antioxidant defence systems; (2) has a potent immuno-modulatory profile; and (3) can be rapidly re-purposed into clinical care strategies for DMD patients. Here, we tested two weeks of daily 100mg/kg DMF versus 5mg/kg standard care prednisone (PRED) treatment during the peak muscle degeneration period in juvenile mdx mice, the gold standard murine DMD model. Both drugs modulated seed genes driving the DMD disease program and improved muscle force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects that protected contracting muscles from fatigue, improved histopathology and augmented clinically compatible muscle function tests. In contrast, PRED treatment stunted mouse growth, worsened histopathology and modulated many normally expressed inflammatory and extracellular matrix (ECM) genes consistent with pan immunosuppression. These findings suggest DMF could be a more selective modulator of the DMD disease program with better efficacy and fewer side effects than standard care PRED therapy warranting follow-up studies to progress clinical translation.

pathology↗

bioRxiv2021

Jetlag Expectations, not Circadian Parameters, Predict Jetlag Symptom Severity in Travelers

After a flight across multiple time zones, most people show a transient state of circadian misalignment causing temporary malaise known as jetlag disorder. The severity of the elicited symptoms is postulated to depend mostly on circadian factors such as the number of time zones crossed and the direction of travel. Here, we examined the influence of prior expectation on symptom severity, compared to said "classic" determinants, in order to gauge potential psychosocial effects in jetlag disorder. To this end, we monitored jetlag symptoms in travel-inexperienced individuals (n=90, 18-37y) via detailed questionnaires twice daily for one week before and after flights crossing >3 time zones. We found pronounced differences in individual symptom load that could be grouped into 4 basic symptom trajectories. Both traditional and newly devised metrics of jetlag symptom intensity and duration (accounting for individual symptom trajectories) recapitulated previous results of jetlag prevalence at about 50-60% as well as general symptom dynamics. Surprisingly, however, regression models showed very low predictive power for any of the jetlag outcomes. The classic circadian determinants, including number of time zones crossed and direction of travel, exhibited little to no link with jetlag symptom intensity and duration. Only expectation emerged as a parameter with systematic, albeit small, predictive value. These results suggest expectation as a relevant factor in jetlag experience - hinting at potential placebo effects and new treatment options. Our findings also caution against jetlag recommendations based on circadian principles but insufficient evidence linking circadian re-synchronization dynamics with ensuing symptom intensity and duration. Significance StatementJetlag disorder afflicts millions of travelers each year - a nuisance on holiday trips but also a danger in safety and performance-critical operations. For effective prevention and treatment, it is critical to understand what influences jetlag severity, i.e. jetlag symptom intensity and duration. In contrast to what guidelines state, in our study, we did not find that symptom severity could be explained by the number of time zones crossed or travel direction. Rather, travelers expectations about how long and strongly they will suffer from jetlag symptoms was the only factor systematically predicting jetlag severity. If this holds true not only for subjective but also objective symptoms, we need to revisit assumptions about how circadian desynchronization relates to experienced jetlag symptoms.

neuroscience↗

bioRxiv2020

Bacterial-like nonribosomal peptide synthetases produce cyclopeptides in the zygomycetous fungus Mortierella alpina

Fungi are traditionally considered as reservoir of biologically active natural products. However, an active secondary metabolism has long not been attributed to early diverging fungi such as Mortierella spec. Here, we report on the biosynthesis of two series of cyclic pentapeptides, the malpicyclins and malpibaldins, as products of Mortierella alpina ATCC32222. The molecular structures of malpicyclins were elucidated by HR-MS/MS, Marfeys method, and 1D and 2D NMR spectroscopy. In addition, malpibaldin biosynthesis was confirmed by HR-MS. Genome mining and comparative qRT-PCR expression analysis pointed at two pentamodular nonribosomal peptide synthetases (NRPS), malpicyclin synthetase MpcA and malpibaldin synthetase MpbA, as candidate biosynthetic enzymes. Heterologous production of the respective adenylation domains and substrate specificity assays proved promiscuous substrate selection and confirmed their respective biosynthetic roles. In stark contrast to known fungal NRPSs, MpbA and MpcA contain bacterial-like dual epimerase/condensation domains allowing the racemization of enzyme-tethered O_SCPLOWLC_SCPLOW-amino acids and the subsequent incorporation of O_SCPLOWDC_SCPLOW-amino acids into the metabolites. Phylogenetic analyses of both NRPS genes indicate a bacterial origin and a horizontal gene transfer into the fungal genome. This is the first report of nonribosomal peptide biosynthesis in basal fungi which highlights this paraphylum as novel and underrated resource of natural products. IMPORTANCEFungal natural compounds are industrially produced with application in antibiotic treatment, cancer medications and crop plant protection. Traditionally, higher fungi have been intensively investigated concerning their metabolic potential, but re-identification of already known compounds is frequently observed. Hence, alternative strategies to acquire novel bioactive molecules are required. We present the genus Mortierella as representative of the early diverging fungi as an underestimated resource of natural products. Mortierella alpina produces two families of cyclopeptides, denoted malpicyclins and malpibaldins, respectively, via two pentamodular nonribosomal peptide synthetases (NRPSs). These enzymes are much closer related to bacterial than to other fungal NRPSs, suggesting a bacterial origin of these NRPS genes in Mortierella. Both enzymes are the first biochemically characterized natural product biosynthesis enzymes of basal fungi. Hence, this report establishes early diverging fungi as prolific natural compound producers and sheds light on the origin of their biosynthetic capacity.

biochemistry↗

bioRxiv2019

Transneuronal delivery of designer-cytokine enables functional recovery after complete spinal cord injury

Spinal cord injury (SCI) often causes severe and permanent disabilities. The current study uses a transneuronal approach to stimulate spinal cord regeneration by AAV-hyper-IL-6 (hIL-6) application after injury. While preinjury PTEN knockout in cortical motoneurons fails to improve functional recovery after complete spinal cord crush, a single, postinjury injection of hIL-6 into the sensorimotor cortex markedly promotes axon regeneration in the corticospinal and, remarkably, raphespinal tracts enabling significant locomotion recovery of both hindlimbs. Moreover, transduced cortical motoneurons directly innervate serotonergic neurons in both sides of the raphe nuclei equally, enabling the synaptic release of hIL-6 and the transneuronal stimulation of raphe neurons in the brain stem. Functional recovery depends on the regeneration of serotonergic neurons as their degeneration induced by a toxin abolishes the hIL-6-mediated recovery. Thus, the transneuronal application of highly potent cytokines enables functional regeneration by stimulating neurons in the deep brain stem that are otherwise challenging to access, yet highly relevant for functional recovery after SCI. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/831271v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@55b30corg.highwire.dtl.DTLVardef@5e0729org.highwire.dtl.DTLVardef@1282d8dorg.highwire.dtl.DTLVardef@c6bbf7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

How cognitive and environmental constraints influencethe reliability of simulated animats in groups

Evolving in groups can either enhance or reduce an individuals task performance. Still, we know little about the factors underlying group performance, which may be reduced to three major dimensions: (a) the individuals ability to perform a task, (b) the dependency on environmental conditions, and (c) the perception of, and the reaction to, other group members. In our research, we investigated how these dimensions interrelate in simulated evolution experiments using adaptive agents equipped with Markov brains (\"animats\"). We evolved the animats to perform a spatial-navigation task under various evolutionary setups. The last generation of each evolution simulation was tested across modified conditions to evaluate and compare the animats reliability when faced with change. Moreover, the complexity of the evolved Markov brains was assessed based on measures of information integration. We found that, under the right conditions, specialized animats were as reliable as animats already evolved for the modified tasks, that interaction between animats was dependent on the environment and on the design of the animats, and that the task difficulty influenced the correlation between the performance of the animat and its brain complexity. Generally, our results suggest that the interrelation between the aforementioned dimensions is complex and their contribution to the groups task performance, reliability, and brain complexity varies, which points to further dependencies. Still, our study reveals that balancing the group size and individual cognitive abilities prevents over-specialization and can help to evolve better reliability under unknown environmental situations.\n\nAuthor SummaryThe ability to adapt to environmental changes is an essential attribute of organisms which have had evolutionary success. We designed a simulated evolution experiment to better understand the relevant features of such organisms and the conditions under which they evolve: First, we created diverse groups of cognitive systems by evolving simulated organisms (\"animats\") acting in groups on a spatial-navigation task. Second, we post-evolutionary tested the final evolved animats in new environments-not encountered before- in order to test their reliability when faced with change. Our results imply that the ability to generalize to environments with changing task demands can have complex dependencies on the cognitive design and sensor configuration of the organism itself, as well as its social or environmental conditions.

animal behavior and cognition↗