Biology subjects

Neumann, M.

Publications and source records attributed to Neumann, M..

28 records · Page 2Linked to original sources

bioRxiv2021

Deprivation of dietary fiber in specific-pathogen-free mice promotes susceptibility to the intestinal mucosal pathogen Citrobacter rodentium

The change of dietary habits in Western societies, including reduced consumption of fiber, is linked to alterations in gut microbial ecology. Nevertheless, mechanistic connections between diet-induced microbiota changes that affect colonization resistance and enteric pathogen susceptibility are still emerging. We sought to investigate how a diet devoid of soluble plant fibers impacts the structure and function of a conventional gut microbiota in specific-pathogen-free (SPF) mice and how such changes alter susceptibility to a rodent enteric pathogen. We show that absence of dietary fiber intake leads to shifts in the abundances of specific taxa, microbiome-mediated erosion of the colonic mucus barrier, a reduction of intestinal barrier-promoting short-chain fatty acids, and increases in markers of mucosal barrier integrity disruption. Importantly, our results highlight that these low fiber diet-induced changes in the gut microbial ecology collectively contribute to a lethal colitis by the mucosal pathogen Citrobacter rodentium, which is used as a mouse model for enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively). Our study indicates that modern, low-fiber Western diets might make individuals more prone to infection by enteric pathogens via the disruption of mucosal barrier integrity by diet-driven changes in the gut microbiota, illustrating possible implications for EPEC and EHEC infections.

microbiology↗

bioRxiv2021

Deep time course proteomics of SARS-CoV and SARS-CoV-2-infected human lung epithelial cells (Calu-3) reveals strong induction of interferon-stimulated gene (ISG) expression by SARS-CoV-2 in contrast to SARS-CoV

SARS-CoV and SARS-CoV-2 infections are characterized by remarkable differences, including contagiosity and case fatality rate. The underlying mechanisms are not well understood, illustrating major knowledge gaps of coronavirus biology. In this study, protein expression of SARS-CoV- and SARS-CoV-2-infected human lung epithelial cell line Calu-3 was analysed using data-independent acquisition mass spectrometry (DIA-MS). This resulted in the so far most comprehensive map of infection-related proteome-wide expression changes in human cells covering the quantification of 7478 proteins across 4 time points. Most notably, the activation of interferon type-I response was observed, which surprisingly is absent in other recent proteome studies, but is known to occur in SARS-CoV-2-infected patients. The data reveal that SARS-CoV-2 triggers interferon-stimulated gene (ISG) expression much stronger than SARS-CoV, which reflects the already described differences in interferon sensitivity. Potentially, this may be caused by the enhanced expression of viral M protein of SARS-CoV in comparison to SARS-CoV-2, which is a known inhibitor of type I interferon expression. This study expands the knowledge on the host response to SARS-CoV-2 infections on a global scale using an infection model, which seems to be well suited to analyse innate immunity.

systems biology↗

bioRxiv2021

Investigating the Interplay Between Affective, Phonatory and Motoric Subsystems in Autism Spectrum Disorder Using a Multimodal Dialogue Agent

We explore the utility of an on-demand multimodal conversational platform in extracting speech and facial metrics in children with Autism Spectrum Disorder (ASD). We investigate the extent to which these metrics correlate with objective clinical measures, particularly as they pertain to the interplay be-tween the affective, phonatory and motoric subsystems. 22 participants diagnosed with ASD engaged with a virtual agent in conversational affect production tasks designed to elicit facial and vocal affect. We found significant correlations between vocal pitch and loudness extracted by our platform during these tasks and accuracy in recognition of facial and vocal affect, as-sessed via the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA-2) neuropsychological task. We also found significant correlations between jaw kinematic metrics extracted using our platform and motor speed of the dominant hand assessed via a standardised neuropsychological finger tapping task. These findings offer preliminary evidence for the usefulness of these audiovisual analytic metrics and could help us better model the interplay between different physiological subsystems in individuals with ASD.

neuroscience↗

bioRxiv2020

Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia

Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Systematic studies on human post-mortem brain tissue of patients with genetic subtypes of FTD are currently lacking. The Risk and Modyfing Factors of Frontotemporal Dementia (RiMod-FTD) consortium therefore has generated a multi-omics dataset for genetic subtypes of FTD to identify common and distinct molecular mechanisms disturbed in disease. Here, we present multi-omics datasets generated from the frontal lobe of post-mortem human brain tissue from patients with mutations in MAPT, GRN and C9orf72 and healthy controls. This data resource consists of four datasets generated with different technologies to capture the transcriptome by RNA-seq, and small RNA-seq, and supplemented this date with CAGE-seq, and methylation profiling. We show concrete examples on how to use the resulting data and confirm current knowledge about FTD and identify new processes for further investigation. This extensive multi-omics dataset holds great value to reveal new research avenues for this devastating disease.

neuroscience↗

bioRxiv2020

Highly efficient intercellular spreading of protein misfolding mediated by viral ligand - receptor interactions

Pathological protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble proteins of the same kind. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contributes to the prion-like spreading of protein misfolding is unclear. Exchange of cellular cargo by both direct cell-to-cell contact as well as via EV depends on receptor-ligand interactions and subsequent release of cargo into the cytosol. We hypothesized that enabling these interactions through viral ligands enhances the aggregate-inducing capacity of EV-associated proteopathic seeds. Using different cellular models propagating model prion-like protein aggregates, mouse-adapted prions or pathogenic Tau aggregates, we demonstrate that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase protein aggregate induction by direct cell-to-cell contact or via viral glycoprotein-decorated EV. Thus, receptor-ligand interactions are major determinants of intercellular aggregate dissemination. Further, our data raise the intriguing possibility that acute or latent viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer. HIGHLIGHTSO_LIDifferent types of proteopathic seeds are secreted in association with extracellular vesicles C_LIO_LIReceptor-ligand interactions are important drivers of direct cell-to-cell and extracellular vesicle-mediated spreading of protein misfolding C_LIO_LIViral glycoproteins mediating attachment and membrane fusion strongly enhance aggregate inducing capacity in recipient cells C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/173070v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1735b86org.highwire.dtl.DTLVardef@7ddaf5org.highwire.dtl.DTLVardef@b222aborg.highwire.dtl.DTLVardef@1022dd6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Lysine acetylation of TDP-43 drives phase separation and pathological aggregation

The trans-activation response DNA-binding protein TDP-43 regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Confirming the results from site-directed mutagenesis, we succeeded to introduce authentic acetyl-lysine at the identified sites via amber suppression. [AcK84]TDP-43 showed cytoplasmic mislocalization and the aggregation propensity of [acK136]TDP-43 was confirmed. With newly developed antibodies, we found that the nuclear sirtuin SIRT1 can potently deacetylate [acK136]TDP-43. Moreover, SIRT1 reduced the aggregation propensity of [acK136]TDP-43. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting novel regulatory mechanisms for TDP-43 pathogenesis.

cell biology↗

bioRxiv2019

The relationship between microbial biomass and disease in the Arabidopsis thaliana phyllosphere

A central goal in microbiome research is to learn what distinguishes a healthy from a dysbiotic microbial community. Shifts in diversity and taxonomic composition are important indicators of dysbiosis, but a full understanding also requires knowledge of absolute microbial population sizes. In addition to the number of microbial cells, information on taxonomic composition can provide important insight into microbiome function and disease state. Here we use shotgun metagenomics to simultaneously assess microbiome composition and microbial load in the phyllosphere of wild populations of the plant Arabidopsis thaliana. We find that wild plants vary substantially in the load of colonizing microbes, and that high loads are typically associated with the proliferation of single taxa, with only a few putatively pathogenic taxa achieving high abundances in the field. Our results suggest (i) that the inside of a plant leaf is on average sparsely colonized with an estimated two bacterial genomes per plant genome and an order of magnitude fewer eukaryotic microbial genomes, and (ii) that higher levels of microbial cells often indicate successful colonization by pathogens. Lastly, our results show that load is a significant explanatory variable for loss of estimated Shannon diversity in phyllosphere microbiomes, implying that reduced diversity may be a significant predictor of microbial dysbiosis in a plant leaf.

plant biology↗

bioRxiv2018

Effects of FLOWERING LOCUS T on FD during the transition to flowering at the shoot apical meristem of Arabidopsis thaliana

The transition to flowering is a crucial step in the plant life cycle that is controlled by multiple endogenous and environmental cues, including hormones, sugars, temperature, and photoperiod. Permissive photoperiod induces FLOWERING LOCUS T (FT) in the phloem companion cells of leaves. The FT protein then acts as a florigen that is transported to the shoot apical meristem (SAM) where it physically interacts with the bZIP transcription factor FD and 14-3-3 proteins. However, despite the importance of FD for promoting flowering, its direct transcriptional targets are largely unknown. Here we combined ChIP-seq and RNA-seq to identify targets of FD at the genome-wide scale and assess the contribution of FT to binding DNA. We further investigated the ability of FD to form protein complexes with FT and TFL1 through the interaction with 14-3-3 proteins. Importantly, we observe direct binding of FD to targets involved in several aspects of the plant development not directly related to the regulation of flowering time. Our results confirm FD as central regulator of the floral transition at the shoot meristem and provides evidence for crosstalk between the regulation of flowering and other signaling pathways.\n\nMaterial DistributionThe author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.cell.com/molecular-plant/authors): Markus Schmid (markus.schmid@umu.se).\n\nContact InformationUme[a] Plant Science Centre (UPSC), Dept. of Plant Physiology Ume[a] University, SE-901 87 Ume[a], SWEDEN

plant biology↗

bioRxiv2018

Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia

Recent studies implicated that long non-coding RNAs (lncRNAs) may play a role in the progression and development of acute lymphoblastic leukemia, however, this role is not yet clear. In order to unravel the role of lncRNAs associated with B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) subtypes, we performed transcriptome sequencing and DNA methylation array across 82 BCP-ALL samples from three molecular subtypes (DUX4, Ph-like, and Near Haploid or High Hyperdiploidy). Unsupervised clustering of BCP-ALL samples on the basis of their lncRNAs on transcriptome and DNA methylation profiles revealed robust clusters separating three molecular subtypes. Using extensive computational analysis, we developed a comprehensive catalog of 1235 aberrantly dysregulated BCP-ALL subtype-specific lncRNAs with altered expression and methylation patterns from three subtypes of BCP-ALL. By analyzing the co-expression of subtype-specific lncRNAs and protein-coding genes, we inferred key molecular processes in BCP-ALL subtypes. A strong correlation was identified between the DUX4 specific lncRNAs and activation of TGF-{beta} and Hippo signaling pathways. Similarly, Ph-like specific lncRNAs were correlated with genes involved in activation of PI3K-AKT, mTOR, and JAK-STAT signaling pathways. Interestingly, the relapse-specific differentially expressed lncRNAs correlated with the activation of metabolic and signaling pathways. Finally, we showed a set of epigenetically altered lncRNAs facilitating the expression of tumor genes located at their cis location. Overall, our study provides a comprehensive set of novel subtype and relapse-specific lncRNAs in BCP-ALL. Our findings suggest a wide range of molecular pathways are associated with lncRNAs in BCP-ALL subtypes and provide a foundation for functional investigations that could lead to new therapeutic approaches.\n\nAuthor SummaryAcute lymphoblastic leukemia is a heterogeneous blood cancer, with multiple molecular subtypes, and with high relapse rate. We are far from the complete understanding of the rationale behind these subtypes and high relapse rate. Long non-coding (lncRNAs) has emerged as a novel class of RNA due to its diverse mechanism in cancer development and progression. LncRNAs does not code for proteins and represent around 70% of human transcripts. Recently, there are a number of studies used lncRNAs expression profile in the classification of various cancers subtypes and displayed their correlation with genomic, epigenetic, pathological and clinical features in diverse cancers. Therefore, lncRNAs can account for heterogeneity and has independent prognostic value in various cancer subtypes. However, lncRNAs defining the molecular subtypes of BCP-ALL are not portrayed yet. Here, we describe a set of relapse and subtype-specific lncRNAs from three major BCP-ALL subtypes and define their potential functions and epigenetic regulation. Our data uncover the diverse mechanism of action of lncRNAs in BCP-ALL subtypes defining how lncRNAs are involved in the pathogenesis of disease and the relevance in the stratification of BCP-ALL subtypes.

cancer biology↗

bioRxiv2018

Arabidopsis thaliana populations support long-term maintenance and parallel expansions of related Pseudomonas pathogens

Crop disease outbreaks are often associated with clonal expansions of single pathogenic lineages. To determine whether similar boom-and-bust scenarios hold for wild plant pathogens, we carried out a multi-year multi-site survey of Pseudomonas in the natural host Arabidopsis thaliana. The most common Pseudomonas lineage corresponded to a pathogenic clade present in all sites. Sequencing of 1,524 Pseudomonas genomes revealed this lineage to have diversified approximately 300,000 years ago, containing dozens of genetically distinct pathogenic sublineages. These sublineages have expanded in parallel within the same populations and are differentiated both at the level of gene content and disease phenotype. Such coexistence of diverse sublineages indicates that in contrast to crop systems, no single strain has been able to overtake these A. thaliana populations in the recent past. Our results suggest that the selective pressures acting on a plant pathogen in wild hosts may be more complex than those in agricultural systems.

microbiology↗