Biology subjects

Brunner, D.

Publications and source records attributed to Brunner, D..

7 recordsLinked to original sources

bioRxiv2024

Molecular Tracking and Cultivation Reveal Ammonia Oxidizing Archaea as Integral Members of the Human Skin Microbiome

BackgroundAmmonia-oxidizing archaea (AOA) have repeatedly been detected on human skin, yet their persistence, physiological traits, and adaptations remain poorly understood. Here, we identify Nitrosocosmicus species as integral members of the healthy skin microbiome using two complementary approaches. ResultsThrough cultivation, we enriched two autotrophic strains, Candidatus Nitrosocosmicus epidermidis and Ca. Nitrosocosmicus unguis, from human skin samples. Genomic analyses revealed specific adaptations for skin colonization, including genomic islands and expanded gene families linked to interactions with host proteins and signaling pathways, distinguishing these AOA from their soil-dwelling relatives. Parallel molecular profiling in cross-sectional and longitudinal cohorts (n=47) consistently detected Nitrosocosmicus particularly in sebaceous areas. Co-occurrence patterns with specific bacterial taxa reinforce their role as stable components of the skin microbiome. ConclusionsThese findings indicate that Nitrosocosmicus species are emerging commensals, evolutionarily capable of transitioning from soil to human skin, where they likely play a critical role in the skin ecosystem.

microbiology↗

bioRxiv2022

Benefits of global mutant huntingtin lowering diminish over time in a Huntington's disease mouse model

We have developed a novel inducible Huntingtons disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant Huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt ([~]50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow up revealed that the benefits, in all mHtt lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12- months of age and late mHtt lowering was unable to ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT-lowering therapeutics progress to the clinic, our findings suggest that moderate mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefit in humans.

neuroscience↗

bioRxiv2020

Essential role of non-vesicular lipid transport in microtubule-controlled cell polarisation

Cell polarisation is a fundamental biological process. Fission yeast is a key model system to study the molecular basis of microtubule-controlled cell polarisation. In this process, cells define prospective growth sites by generating distinct plasma membrane domains enriched in de novo synthesised sterols. Microtubules restrict the number and location of these domains by depositing factors at the cell poles. The mechanisms underlying such sterol-rich membrane domain formation and polarisation are largely unknown. We found that the oxysterol-binding proteins kes1p, osh2p and kes3p define three independent sterol delivery pathways to the plasma membrane. These mediate different phases of cell polarisation in a phosphoinositide-dependent fashion and differ in their requirement for vesicular trafficking steps. The redundant, kes1p- and osh2p-dependent pathways are vital and prime cell polarisation by mediating the formation of randomly distributed sterol-rich plasma membrane domains. Subsequent microtubule-controlled polarisation of these domains preferentially employs kes1p that directly delivers sterols to the plasma membrane independent of cdc42p. In cells lacking kes1p, polarisation becomes cdc42p-dependent, utilising mainly the kes3p-dependent pathway. Our study uncovers an essential biological function for non-vesicular lipid transport and establishes a molecular basis for different sterol-delivery pathways acting in cdc42p-independent and cdc42p-dependent cell polarisation.

cell biology↗

bioRxiv2020

Mechanochemical modelling of dorsal closure reveals emergent cell behaviour in tissue morphogenesis

Tissue morphogenesis integrates cell type-specific biochemistry and architecture, cellular force generation and mechanisms coordinating forces amongst neighbouring cells and tissues. We use finite element-based modelling to explore the interconnections at these multiple biological scales in embryonic dorsal closure, where pulsed actomyosin contractility in adjacent Amnioserosa (AS) cells powers the closure of an epidermis opening. Based on our in vivo observations, the model implements F-actin nucleation periodicity that is independent of MyoII activity. Our model reveals conditions, where depleting MyoII activity nevertheless indirectly affects oscillatory F-actin behaviour, without the need for biochemical feedback. In addition, it questions the previously proposed role of Dpp-mediated regulation of the patterned actomyosin dynamics in the AS tissue, suggesting them to be emergent. Tissue-specific Dpp interference supports the models prediction. The model further predicts that the mechanical properties of the surrounding epidermis tissue feed back on the shaping and patterning of the AS tissue. Finally, our models parameter space reproduces mutant phenotypes and provides predictions for their underlying cause. Our modelling approach thus reveals several unappreciated mechanistic properties of tissue morphogenesis.

systems biology↗

bioRxiv2020

Crowdsourcing digital health measures to predict Parkinson's disease severity: the Parkinson's Disease Digital Biomarker DREAM Challenge

Mobile health, the collection of data using wearables and sensors, is a rapidly growing field in health research with many applications. Deriving validated measures of disease and severity that can be used clinically or as outcome measures in clinical trials, referred to as digital biomarkers, has proven difficult. In part due to the complicated analytical approaches necessary to develop these metrics. Here we describe the use of crowdsourcing to specifically evaluate and benchmark features derived from accelerometer and gyroscope data in two different datasets to predict the presence of Parkinsons Disease (PD) and severity of three PD symptoms: tremor, dyskinesia and bradykinesia. Forty teams from around the world submitted features, and achieved drastically improved predictive performance for PD status (best AUROC=0.87), as well as tremor (best AUPR=0.75), dyskinesia (best AUPR=0.48) and bradykinesia (best AUPR=0.95) severity.

bioengineering↗

bioRxiv2019

Mouse Model Systems of Autism Spectrum Disorder: Replicability and Informatics Signature

3.BackgroundPhenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability and translatability, particularly in behavioral domains such as social and verbal function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies comprising five genetic mouse model systems of ASD. MethodsTo assess the robustness of our previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity, and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three-yearlong effort using informatics techniques to look for commonalities and differences. ResultsResults in the current study were very similar to our previously published results. The informatics signatures of the two model systems chosen for the replication showed that they were most distinguished by activity levels. Although the two model systems were opposite in this regard, those aspects of their social behavior not confounded by activity (vocalizations) were similar. ConclusionsOur results showed high intra-laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle differences in testing conditions, housing enrichment, or background strains and not so much on the variability of the behavioral phenotypes. The overall informatics analysis suggests two main classes of model systems that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.

animal behavior and cognition↗

bioRxiv2018

Reversible solidification of fission yeast cytoplasm after prolonged nutrient starvation

Cells depend on a highly ordered organization of their content and they must develop strategies to maintain the anisotropic distribution of organelles during periods of nutrient shortage. One of these strategies, observed in bacteria and in yeast cells with acutely interrupted energy production, is to solidify the cytoplasm. Here, we describe a different type of cytoplasm solidification that occurs in fission yeast cells having slowly run out of nutrients after multiple days of culturing. It provides the most profound reversible cytoplasmic solidification of yeast cells described to date. Our data suggest the involvement of a matrix with a certain mesh size that immobilizes cellular components in a size-dependent manner. We provide experimental evidence that cells need time, intrinsic nutrients and intrinsic energy sources to enter this state in the absence of external sources. Such cytoplasmic solidification may provide a robust means to protect cellular architecture in dormant cells.

cell biology↗