Biology subjects

Fischer, A.

Publications and source records attributed to Fischer, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Productivity of the eelgrass biotope and the resilience of fisher-hunter-gatherers in prehistoric Denmark

In the shallow coastal waters of the Danish archipelago, eelgrass (Zostera marina) forms extensive and extremely productive stands, which support food webs that are isotopically distinct from those based on the primary productivity of marine phytoplankton. The isotopic signatures of eelgrass and phytoplankton food webs explain much of the variation in {delta}13C, {delta}15N and {delta}34S values in marine vertebrate remains recovered from prehistoric coastal sites in Denmark. Isotope data from human and dog remains reflect the overwhelming importance of the eelgrass biotope to the fisher-hunter-gatherer (FHG) subsistence during the Late Mesolithic Ertebolle epoch ([~]7400-5800 cal BP). By recognising eelgrass and pelagic resources as isotopically distinct, we obtain more accurate diet reconstructions and dietary 14C reservoir effect corrections for Ertebolle individuals. Longstanding research issues, including technology, palaeodemography, and the resilience and sustainability of the FHG economy need to be reassessed in view of the isotopic signature and productivity of the eelgrass biotope in Danish waters. Eelgrass productivity is also pertinent to comparisons between Ertebolle and Neolithic economies in Denmark, and between FHG adaptations in Denmark and neighbouring regions, and may be key to understanding the much-discussed delay in the transition to farming.

ecology↗

bioRxiv2024

A role for astrocytic miR-129-5p in Frontotemporal Dementia

Frontotemporal dementia is a debilitating neurodegenerative disorder characterized by frontal and temporal lobe degeneration, resulting in behavioral changes, language difficulties, and cognitive decline. In this study, smallRNA sequencing was conducted on postmortem brain tissues obtained from FTD patients with GRN, MAPT, or C9ORF72 mutations, focusing on the frontal and temporal lobes. Our analysis identified miR-129-5p as consistently deregulated across all mutation conditions and brain regions. Functional investigations revealed a novel role of miR-129-5p in astrocytes, where its loss led to neuroinflammation and impaired neuronal support functions, including reduced glutamate uptake. Depletion of miR-129-5p in astrocytes resulted in the loss of neuronal spines and altered neuronal network activity. These findings highlight miR-129-5p as a potential therapeutic target in neurodegenerative diseases and also sheds light on the role of astrocytes in Frontotemporal dementia pathogenesis.

neuroscience↗

bioRxiv2024

Steppe Ancestry in western Eurasia and the spread of the Germanic Languages

Today, Germanic languages, including German, English, Frisian, Dutch and the Nordic languages, are widely spoken in northwest Europe. However, key aspects of the assumed arrival and diversification of this linguistic group remain contentious1-3. By adding 712 new ancient human genomes we find an archaeologically elusive population entering Sweden from the Baltic region by around 4000 BP. This population became widespread throughout Scandinavia by 3500 BP, matching the contemporaneous distribution of Palaeo-Germanic, the Bronze Age predecessor of Proto-Germanic4-6. These Baltic immigrants thus offer a new potential vector for the first Germanic speakers to arrive in Scandinavia, some 800 years later than traditionally assumed7-12. Following the disintegration of Proto-Germanic13-16, we find by 1650 BP a southward push from Southern Scandinavia into presumed Celtic-speaking areas, including Germany, Poland and the Netherlands. During the Migration Period (1575-1375 BP), we see this ancestry representing West Germanic Anglo-Saxons in Britain, and Langobards in southern Europe. We find a related large-scale northward migration into Denmark and South Sweden corresponding with historically attested Danes and the expansion of Old Norse. These movements have direct implications for multiple linguistic hypotheses. Our findings show the power of combining genomics with historical linguistics and archaeology in creating a unified, integrated model for the emergence, spread and diversification of a linguistic group.

genetics↗

bioRxiv2024

The aging-induced long non-coding RNA MIRIAL controls endothelial cell and mitochondrial function

AimsVascular aging is characterized by the progressive deterioration of endothelial function. Long non-coding RNAs (lncRNAs) are critical regulators of gene expression and protein function. However, their involvement in aging-related dysregulation of endothelial cell function remains largely unknown. Here, we aim to characterize the aging-regulated lncRNA MIRIAL in endothelial cells. Methods + ResultsWe identified Mirial as an aging-induced lncRNA in RNA-sequencing data of mouse cardiac endothelial cells. In human umbilical vein endothelial cells (HUVECs), gapmer-mediated knockdown of MIRIAL led to decreases in proliferation, migration and basal angiogenic sprouting. Additionally, MIRIAL knockdown led to increased mitochondrial mass, spare respiratory capacity, and vascular endothelial growth factor (VEGF)-stimulated sprouting. Mechanistically, we demonstrate that MIRIAL forms an RNA{middle dot}DNA:DNA triple helix (triplex) with a regulatory region of the quiescence-promoting Forkhead Box O1 (FOXO1) gene, thus inducing its expression. The formation of this triplex involves an Alu element within the MIRIAL transcript, representing a previously undescribed mechanism of action for a lncRNA. Further, we generated a global Mirial knockout mouse line of. Angiogenic sprouting of aortic rings from Mirial knockout mice was reduced under basal conditions, but increased after VEGF administration, validating the in vitro angiogenic phenotype. Importantly, cardiac contractile function after acute myocardial infarction is severely reduced in Mirial knockout mice, as compared to wild-type littermates. ConclusionsThe lncRNA MIRIAL is an aging-induced regulator of endothelial quiescence and metabolism. Translational PerspectiveLncRNAs often exhibit cell-type or tissue-specific expression and regulation, rendering them potentially druggable targets requiring lower doses and having fewer side effects compared to protein targets. Our current research highlights, that loss of Mirial correlates with adverse outcomes post-acute myocardial infarction in a murine model. Dysregulation of MIRIAL in various human pathological conditions, such as ischemic heart disease, abdominal aortic aneurysm, cancer, and aging, indicates its potential as a diagnostic marker. Mechanistically, MIRIAL regulates endothelial quiescence by modulating FOXO1 expression, suggesting it as a promising therapeutic target to counteract the age-related decline in endothelial cell function.

cell biology↗

bioRxiv2023

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

BackgroundPericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although ageing is one of the main risk factors for cardiovascular disease, the consequences of ageing on cardiac pericytes are unknown. MethodsIn this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of Regulator of G protein signalling 5 (RGS5) loss of function and finally have performed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 deletion in pericytes on the neighbouring fibroblasts. ResultsAgeing reduced the pericyte area and capillary coverage in the murine heart. Single nucleus RNA sequencing analysis further revealed that the expression of Rgs5 was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, fibrosis, and induced morphological changes and a pro-fibrotic gene expression signature in pericytes characterized by the expression of different extracellular matrix components and growth factors e.g. TGFB2 and PDGFB. Indeed, culturing fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation as evidenced by the increased expression of smooth muscle actin in a TGF{beta}2-dependent mechanism. ConclusionsOur results have identified RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.

physiology↗

bioRxiv2023

Guidelines for performing ribosome profiling in plants including structural analysis of rRNA fragments

Ribosome profiling (or Ribo-seq) is a technique that provides genome-wide information on the translational landscape (translatome). Across different plant studies, variable methodological setups have been described which raises questions about the general comparability of data that were generated from diverging methodologies. Furthermore, a common problem when performing Ribo-seq are abundant rRNA fragments that are wastefully incorporated into the libraries and dramatically reduce sequencing depth. To remove these rRNA contaminants, it is common to perform preliminary trials to identify these fragments because they are thought to vary depending on nuclease treatment, tissue source, and plant species. Here, we compile valuable insights gathered over years of generating Ribo-seq datasets from different species and experimental setups. We highlight which technical steps are important for maintaining cross experiment comparability and describe a highly efficient approach for rRNA removal. Furthermore, we provide evidence that many rRNA fragments are structurally preserved over diverse nuclease regimes, as well as across plant species. Using a recently published cryo-electron microscopy (cryo-EM) structure of the tobacco 80S ribosome, we show that the most abundant rRNA fragments are spatially derived from the solvent-exposed surface of the ribosome. The guidelines presented here shall aid newcomers in establishing ribosome profiling in new plant species and provide insights that will help in customizing the methodology for individual research goals.

plant biology↗

bioRxiv2023

The Effect of Arm Restriction on Dynamic Stability and Upper Body Responses to Lateral Loss of Balance During Walking: An Observational Study

When losing balance, upper-body movements serve as mechanical aids to regain stability. However, it remains unclear how these movements contribute to dynamic stability during recovery from a lateral loss of balance while walking with arm restriction. We aimed to 1) quantify the effect of arm restriction on gait stability and upper-body velocities, and 2) characterize upper-body kinematic strategies in response to lateral surface translations under different arm restriction conditions. Healthy adults were exposed to lateral surface translations while walking on a computerized treadmill under three conditions: free arms, 1-arm restricted and, 2-arms restricted. Dynamic stability and upper-body velocities for the first step after perturbation onset were extracted. We found decreased dynamic stability in the sagittal plane and increased trunk velocity in the 2-arm restricted condition compared to the free arms condition. Head and trunk movements in the mediolateral plane were in opposite directions in 44.31% of responses. Additionally, significant trunk velocities were observed in the opposite direction to the perturbation-induced loss of balance. Our results support the contribution of increased upper-body velocities to balance responses following arm-restricted walking perturbations and suggest that the 2-arm restricted condition may be utilized as a perturbation-based balance training, focusing on head and trunk responses.

neuroscience↗

bioRxiv2023

Bioengineering of a human innervated cardiac muscle model

Cardiac autonomic neurons control cardiac contractility. Dysregulation of the autonomic nervous system can lead to sympathetic overdrive resulting in heart failure and an increased incidence of fatal arrhythmias. Here, we introduce innervated engineered human myocardium (iEHM), a novel model of neuro-cardiac junctions, constructed by fusion of a bioengineered neural organoid (BENO) patterned to autonomic nervous system and engineered human myocardium (EHM). Projections of sympathetic neurons into engineered human myocardium formed presynaptic terminals in close proximity to cardiomyocytes and an extensive vascular network co-developing in the tissues. Contractile responses to optogenetic stimulation of the accordingly engineered neuronal component demonstrated functionality of neuro-cardiac junctions in iEHM. This model will serve as a human surrogate system to delineate neuron and cardiac cell contribution to brain and heart diseases and is an important step towards engineering a human brain to heart axis in a dish.

bioengineering↗

bioRxiv2023

A single-cell transcriptomic analysis of the mouse hippocampus after voluntary exercise

Exercise has been recognized as a beneficial factor for cognitive health, particularly in relation to the hippocampus, a vital brain region responsible for learning and memory. Previous research has demonstrated that exercise-mediated improvement of learning and memory in humans and rodents correlates with increased adult neurogenesis and processes related to enhanced synaptic plasticity. Nevertheless, the underlying molecular mechanisms are not fully understood. With the aim to further elucidate these mechanisms we provide a comprehensive dataset of the mouse hippocampal transcriptome at the single-cell level after four weeks of voluntary wheel-running. Our analysis provides a number of interesting observations. For example, the results suggest that exercise affects adult neurogenesis by accelerating the maturation of a subpopulation of Prdm16-expressing neurons. Moreover, we uncover the existence of an intricate crosstalk among multiple vital signaling pathways such as NF-{kappa}B, Wnt/{beta}-catenin, Notch, retinoic acid (RA) pathways altered upon exercise in a specific cluster of excitatory neurons within the Cornu Ammonis (CA) region of the hippocampus. In conclusion, our study provides an important resource dataset and sheds further light on the molecular changes induced by exercise in the hippocampus. These findings have implications for developing targeted interventions aimed at optimizing cognitive health and preventing age-related cognitive decline.

neuroscience↗

bioRxiv2023

Differential roles of CTP synthetases CTPS1 and CTPS2 in cell proliferation

The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo CTP production relies on CTP synthetases 1 and 2 (CTPS1 and 2) that catalyze the conversion of UTP into CTP. CTP synthetase activity is high in proliferating cells including cancer cells, however, the respective roles of CTPS1 and CTPS2 in cell proliferation are not known. By inactivation of CTPS1 and/or CTPS2 and complementation experiments, we showed that both CTPS1 and CTPS2 are differentially required for cell proliferation. CTPS1 was more efficient in promoting proliferation than CTPS2, in association with a higher intrinsic enzymatic activity that was more resistant to inhibition by 3-Deaza-uridine, an UTP analog. The contribution of CTPS2 to cell proliferation was modest when CTPS1 was expressed, but essential in absence of CTPS1. Public databases analysis of more than 1,000 inactivated cancer cell lines for CTPS1 or CTPS2 confirmed that cell growth is highly dependent of CTPS1 but less of CTPS2. Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation.

cell biology↗

bioRxiv2023

A novel miR-99b-5p-Zbp1 pathway in microglia contributes to the pathogenesis of schizophrenia

Schizophrenia is a psychiatric disorder that is still not readily treatable. Pharmaceutical advances in the treatment of schizophrenia have mainly focused on the protein coding part of the human genome. However, the vast majority of the human transcriptome consists of non-coding RNAs. MicroRNAs are small non-coding RNAs that control the transcriptome at the systems level. In the present study we analyzed the microRNAome in blood and postmortem brains of controls and schizophrenia patients and found that miR-99b-5p was downregulated in both the prefrontal cortex and blood of patients. At the mechanistic level we show that inhibition of miR-99b-5p leads to schizophrenia-like phenotypes in mice and induced inflammatory processes in microglia linked to synaptic pruning. The miR-99b-5p-mediated inflammatory response in microglia depended on Z-DNA binding protein 1 (Zbp1) which we identified as a novel miR-99b-5p target. Antisense oligos (ASOs) against Zbp1 ameliorated the pathological phenotypes caused by miR-99b-5p inhibition. In conclusion, we report a novel miR-99b-5p-Zbp1 pathway in microglia that contributes to the pathogenesis of schizophrenia. Our data suggest that strategies to increase the levels of miR-99b-5p or inhibit Zbp1 could become a novel therapeutic strategy.

neuroscience↗

bioRxiv2023

Enhanced inflammatory signaling driven by metabolic switch in Aicardi-Goutieres syndrome

Aicardi-Goutieres syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterised by neurological involvement with onset in childhood. Chronic inflammation in response to uncontrolled type I IFN production is, among other things, associated with IP-10 secretion. We analysed, at the single-cell transcriptomic levels, peripheral blood samples from patients bearing AGS-causing mutations in SAMHD1, RNASEH2B or ADAR1 genes. Using machine-learning approaches and differential gene expression we identified a drastic loss of transcription factor hypoxia induced factor 1 (HIF-1) expression and activity associated with features of a metabolic switch and mitochondrial stress in monocytes/dendritic cells. Chemical stabilization of HIF-1, with a synthetic drug in an in vitro model of AGS, allowed us to reverse the energy metabolic switch, attenuate mitochondrial stress and markedly reduce IP-10 production. We therefore propose that energy metabolic switch contributes to exacerbated chronic inflammation in AGS, and that targeting this pathway might represent a promising therapeutic approach.

immunology↗

bioRxiv2022

The Selection Landscape and Genetic Legacy of Ancient Eurasians

The Holocene (beginning [~]12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical, and mental health of present-day populations. Using a dataset of >1600 imputed ancient genomes 1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify major selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported, and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in >400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic, and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, while risk alleles for diabetes and Alzheimers disease are enriched for Western Hunter-gatherer ancestry. Our results suggest that ancient selection and migration were major contributors to the distribution of phenotypic diversity in present-day Europeans.

evolutionary biology↗

bioRxiv2022

Ageing impairs the neuro-vascular interface in the heart

Aging is a major risk factor for impaired cardiovascular health. The aging myocardium is characterized by electrophysiological dysfunctions such as a reduced heart rate variability. These alterations can be intrinsic within cardiomyocytes, but might be modulated by the cardiac autonomic nervous system, as well1. It is known that nerves align with vessels during development2, but the impact of aging on the cardiac neuro-vascular interface is unknown. Here, we report that aging reduces nerve density specifically in the left ventricle and dysregulates vascular-derived neuro-regulatory genes. Aging leads further to a down-regulation of miR-145 and de-repression of the neuro-repulsive factor Semaphorin-3A. miR-145 deletion increased Sema3a expression and reduced axon density, thus mimicking the observed aged heart phenotype. Removal of senescent cells, which accumulated with chronological age while nerve density declined, rescued from age-induced dennervation, reduced Sema3a expression and preserved heart rate variability. These data suggest that senescence-associated regulation of neuro-regulatory genes contributes to a declined nerve density of the aging heart and thereby to a reduced heart rate variability.

physiology↗

bioRxiv2022

Conserved reduction of m6A marks during aging and neurodegeneration is linked to altered translation of synaptic transcripts

N6-methyladenosine (m6A) plays diverse roles in the regulation of mRNA metabolism. In the mammalian brain it has been linked to developmental processes and memory function. However, the precise role of m6A in the context synaptic plasticity and especially during impaired cognition are not fully understood. Here, we describe the mouse and human brain m6A epi-transcriptome in a tissue-specific manner. We furthermore show that m6A levels undergo a massive decrease across mouse brain regions as a consequence of aging. In addition, Alzheimer's disease in humans correlates with decreased N6-methylation in a similar population of transcripts that are linked to synaptic function and localized to synapses, such as the calcium/calmodulin-dependent kinase II (CaMKII). We furthermore show that reduced m6A levels impair synaptic protein-synthesis of CAMKII. Our results suggest that m6A-RNA-methylation is an important mechanism to control synaptic protein synthesis which is affected early in cognitive diseases. Significance statementThe addition of N6-methyladenosine (m6A) to RNA plays a role in various cellular processes and its de-regulation has been linked to several devastating diseases. The precise role of m6A RNA-methylation in the adult brain is, however, not well understood. In our study, we describe the genome-wide m6A epi-transcriptome in the healthy and diseased brains of mice and humans. Our data demonstrate that a substantial amount of m6A transcripts are conserved. These transcripts are linked to the regulation of synaptic processes and are localized to synapses. In the diseases brain we detect RNA hypomethylation across multiple transcripts in all investigated brain regions and across species. At the mechanistic level we find that reduced m6A levels specifically impairs synaptic protein-synthesis.

neuroscience↗

bioRxiv2022

HAPLN1 is a driver for peritoneal carcinomatosis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favored a more permissive microenvironment, which accelerated the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via hyaluronic acid synthesis and signaling, promoted adoption of a highly plastic cancer cell state, facilitating EMT, stemness, invasion and immunomodulation in a paracrine manner. Extracellular HAPLN1 modifies cancer cells as well as fibroblasts, rendering them immunomodulatory. We identify HAPLN1 as a prognostic marker and a driver for peritoneal metastasis in PDAC.

cancer biology↗

bioRxiv2022

Population Genomics of Stone Age Eurasia

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. To investigate the cross-continental impacts we shotgun-sequenced 317 primarily Mesolithic and Neolithic genomes from across Northern and Western Eurasia. These were imputed alongside published data to obtain diploid genotypes from >1,600 ancient humans. Our analyses revealed a Great Divide genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers (HGs) were highly genetically differentiated east and west of this zone, and the impact of the neolithisation was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacements of HGs in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, while east of the Urals relatedness remained high until [~]4,000 BP, consistent with persistence of localised HG groups. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive but we demonstrate that HGs from the Middle Don region contributed ancestry to them. Yamnaya-groups later admixed with individuals associated with the Globular Amphora Culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a Neolithic steppe cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

evolutionary biology↗

bioRxiv2022

Remorin proteins serve as membrane topology scaffolds in plants

Organization of membrane topologies in plants has so far been mainly attributed to the cell wall and the cytoskeleton. Taking rhizobial infections of legume root cells, where plasma membranes undergo dynamic and large-scale topology changes, as an initial model, we challenged this paradigm and tested whether additional scaffolds such as plant-specific remorins that accumulate on highly curved and often wall-less plasma membrane domains, control local membrane dynamics. Indeed, loss-of-function mutants of the remorin protein SYMREM1 failed to develop stabilized membrane tubes as found in colonized cells in wild-type plants, but released empty membrane spheres instead. Expression of this and other remorins in wall-less protoplasts allowed engineering different membrane topologies ranging from membrane blebs to long membrane tubes. Reciprocally, mechanically induced membrane indentations were equally stabilized by SYMREM1. This function is likely supported by remorin oligomerization into antiparallel dimers and the formation of higher order membrane scaffolding structures. Taken together we describe an evolutionary confined mechanism that allows the stabilization of large-scale membrane conformations and curvatures in plants. One-sentence summaryThe remorin SYMREM1 evolved as structural membrane scaffold that stabilizes membrane tubulation and curvature during symbiotic intracellular infections.

plant biology↗