Biology subjects

Simon, M.

Publications and source records attributed to Simon, M..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Behavioral Evidence for Enhanced Olfactory and Trigeminal Perception in Congenitally Deaf Individuals

Sensory deprivation, particularly hearing loss, is an excellent model to study neuroplasticity in the human brain and the adaptive behaviors that support the daily lives of deprived individuals. In adaptation to their hearing loss, deaf individuals rely on their other intact senses. Visual and tactile abilities are enhanced in deafness, but few studies have evaluated the olfactory function. This study aimed to compare the impact of congenital deafness on olfactory capacities using psychophysical tasks. Methodological issues raised in previous studies, such as homogeneous onset of deafness and cognitive function assessment, were considered. Eleven individuals with bilateral severe-to-profound deafness since birth were compared to 11 hearing non-signers similar in age (age range = 20-51 years old) and sex (7 women). The deaf subjects were assessed using various standardized neuropsychological tests to ascertain typical cognition. Olfactory functions were evaluated using the Sniffin Sticks battery test, which measures olfactory detection threshold, odor discrimination, and odor identification. Further, accuracy and response time were examined for the identification and localization of two odors to disentangle olfactory sensitivity from sensitivity in the trigeminal system. The Sniffin Sticks test demonstrated superior performances in the deaf participants to discriminate and identify odors. In line with this, they also showed higher sensitivity when both identifying and localizing odors. These findings suggest that congenital deafness is associated with superior performance in higher-level olfactory processing and increased sensitivity in the trigeminal system.

neuroscience↗

bioRxiv2022

Growth, organic matter release, aggregation and recycling during a diatom bloom: A model-based analysis of a mesocosm experiment

Mechanisms terminating phytoplankton blooms are often not well understood. Potentially involved processes such as consumption by grazers, flocculation, and viral lysis each have different post-bloom consequences on the processing of the organic material, therefore it is important to develop a better understanding of the relevance of these processes, and potential interactions between them. In this study, we present a model-based analysis of a spring bloom observed in a mesocosm experiment. The intermediate-complexity (27-state variable) numerical model we extended from an earlier version to this end can resolve C, N, P and Si cycles, and relevant processes like formation of various organic material size classes (low and high molecular weight (hereafter small and large) dissolved organic carbon (DOC), transparent exopolymer particles (TEP), and small/large detritus) and their degradation by two bacterial sub-communities (free-living and particle-attached) and planktonic protists (heterotrophic flagellates and ciliates). The model can explain > 90% of the variation of a rich set of observations consisting of 11 independent variables over the course of 13 days during which a bloom largely dominated by diatoms develops, and disappears almost entirely. Fluxes estimated by the model point to the importance of coagulation (TEP formation) as a sink term for DOC, and a source term for POC. Consequently, aggregation with TEPs constitute an important loss term for phytoplankton. The flocculated phytoplankton, and detrital material, in turn become rapidly degraded by the particle attached bacteria and other protist heterotrophs. Through a scenario analysis, the relevance of nutrient-stress enhanced lysis rates; alterations between small and large DOC in phytoplankton exudates; and coagulation of smaller DOC molecules were investigated. Our results suggest that the former two processes have negligible effects in isolation, but when combined with the latter, they can synergistically cause substantial deviations in TEP formation, hence, in flocculation rates; and consequently in the peak magnitude of the diatom bloom, and in timing of its termination. Our results point to a need for better understanding of processes governing the termination of phytoplankton blooms, their inter-dependencies, and consequences on the global biogeochemical cycles.

microbiology↗

bioRxiv2022

Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating T cells.

Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify tissue-specific and general gene-regulatory landscapes in the wide breadth of CD8+ TIL functional states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor entity-matching samples, and prioritize key elements by super-enhancer analysis. Our results reveal a human core chromatin trajectory to TIL dysfunction and identify involved key enhancers, transcriptional regulators, and deregulated target genes in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor infiltrating lymphocytes.

immunology↗

bioRxiv2022

New Microviridae isolated from Sulfitobacter reveals two cosmopolitan subfamilies of ssDNA phages infecting marine and terrestrial Alphaproteobacteria

The Microviridae family represents one of the major clades of ssDNA phages. Their cultivated members are lytic and infect Proteobacteria, Bacteroidetes, and Chlamydiae. Prophages have been predicted in genomes from Bacteroidales, Hyphomicrobiales, and Enterobacteraceae and cluster within the "Alpavirinae", "Amoyvirinae" and Gokushovirinae. We have isolated "Ascunsovirus oldenburgi" ICBM5, a novel phage distantly related to known Microviridae. It infects Sulfitobacter dubius SH24-1b and uses both a lytic and a carrier-state life strategy. Using ICBM5 proteins as a query, we uncovered in publicly available resources 65 new microviridae prophages and episomes in bacterial genomes and retrieved 47 environmental viral genomes (EVGs) from various viromes. Genome clustering based on protein content and phylogenetic analysis showed that ICBM5, together with Rhizobium phages, new prophages, episomes, and EVGs cluster within two new phylogenetic clades, here tentatively assigned the rank of subfamily and named "Tainavirinae" and "Occultatumvirinae". They both infect Rhodobacterales. Occultatumviruses also infect Hyphomicrobiales, including nitrogen-fixing endosymbionts from cosmopolitan legumes. A biogeographical assessment showed that tainaviruses and occultatumviruses are spread worldwide, in terrestrial and marine environments. The new phage isolated here shed light onto new and diverse branches of the Microviridae tree, suggesting that much of the ssDNA phage diversity remains in the dark.

microbiology↗

bioRxiv2022

Accurate proteome-wide measurement of methionine oxidation in aging mouse brains

The oxidation of methionine side chains has emerged as an important posttranslational modification of proteins. A diverse array of low-throughput and targeted studies have suggested that the oxidation of methionine residues in select proteins can have diverse impacts on cell physiology, ranging from detrimental effects on protein structure and stability to functional roles in cell signaling. Despite its importance, the large-scale investigation of methionine oxidation in a complex matrix, such as the cellular proteome, has been historically hampered by technical limitations. Herein we report a methodology, Methionine Oxidation by Blocking (MobB), that allows for accurate and precise quantification of low levels of methionine oxidation typically observed in vivo. To demonstrate the utility of this methodology, we applied MobB to the brain tissues of young (6 m.o.) and old (20 m.o.) mice and identified over 280 novel sites for in vivo methionine oxidation. We further demonstrated that oxidation stoichiometries for specific methionine residues are highly consistent between individual animals and methionine sulfoxides are enriched in clusters of functionally related gene products including membrane and extracellular proteins. However, we did not detect significant changes in methionine oxidation in brains of old mice. Our results suggest that under normal in vivo conditions methionine oxidation is a biologically regulated process rather than a result of stochastic chemical damage.

biochemistry↗

bioRxiv2021

A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A

Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in the regulation of aging and metabolism. Targeted sequencing identified a SIRT6 allele containing two linked substitutions (N308K/A313S) as enriched in Ashkenazi Jewish (AJ) centenarians as compared to AJ control individuals. Characterization of this SIRT6 (centSIRT6) allele demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double strand break repair, and more robust cancer cell killing compared to the wild type. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

molecular biology↗

bioRxiv2021

Origin, specification and differentiation of a rare supporting-like lineage in the developing mouse gonad

Gonadal sex determination represents a unique model for studying cell fate decisions. However, a complete understanding of the different cell lineages forming the developing testis and ovary remains elusive. Here, we investigated the origin, specification and subsequent sex-specific differentiation of a previously uncharacterized population of supporting-like cells (SLC) in the developing mouse gonads. The SLC lineage is closely related to the coelomic epithelium and specified as early as E10.5, making it the first somatic lineage to be specified in the bipotential gonad. SLC progenitors are localized within the genital ridge at the interface with the mesonephros and initially co-express Wnt4 and Sox9. SLCs become sexually dimorphic around E12.5, progressively acquire a Sertoli- or granulosa-like identity and contribute to the formation of the rete testis and rete ovarii. Finally, we found that WNT4 is a crucial regulator of the SLC lineage and is required for the formation of the rete testis. TeaserDescription of an uncharacterized multipotent gonadal cell lineage involved in testis and ovary development

developmental biology↗

bioRxiv2021

APOK3, a pollen killer antidote in Arabidopsis thaliana

According to the principles of heredity, each parental allele of hybrids equally participates in the progeny. At some loci, however, it happens that one allele is favored to the expense of the other. Gamete killers are genetic systems where one allele (the killer) triggers the death of the gametes carrying the other (killed) allele. They have been found in many organisms, and are of major interest to understand mechanisms of evolution and speciation. Gamete killers are particularly prevalent in plants, where they can compromise crop breeding. Here, we deciphered a pollen killer in Arabidopsis thaliana by exploiting natural variation, de novo genomic sequencing and mutants, and analyzing segregations in crosses. We found that the killer allele carries an antidote gene flanked by two elements mandatory for the killing activity. We identified the gene encoding the antidote, a chimeric protein addressed to mitochondria. This gene appeared in the species by association of domains recruited from other genes, and it recently underwent duplications within a highly variable locus, particularly in the killer genotypes. Exploring the species diversity, we identified sequence polymorphisms correlated with the antidote activity.

genetics↗

bioRxiv2021

Broad domains of histone marks in the highly compact Paramecium macronuclear genome

The unicellular ciliate Paramecium contains a large vegetative macronucleus with several unusual characteristics including an extremely high coding density and high polyploidy. As macronculear chromatin is devoid of heterochromatin our study characterizes the functional epigenomic organisation necessary for gene regulation and proper PolII activity. Histone marks (H3K4me3, H3K9ac, H3K27me3) revealed no narrow peaks but broad domains along gene bodies, whereas intergenic regions were devoid of nucleosomes. Our data implicates H3K4me3 levels inside ORFs to be the main factor to associate with gene expression and H3K27me3 appears to occur as a bistable domain with H3K4me3 in plastic genes. Surprisingly, silent and lowly expressed genes show low nucleosome occupancy suggesting that gene inactivation does not involve increased nucleosome occupancy and chromatin condensation. Due to a high occupancy of Pol II along highly expressed ORFs, transcriptional elongation appears to be quite different to other species. This is supported by missing heptameric repeats in the C-terminal domain of Pol II and a divergent elongation system. Our data implies that unoccupied DNA is the default state, whereas gene activation requires nucleosome recruitment together with broad domains of H3K4me3. This could represent a buffer for paused Pol II along ORFs in absence of elongation factors of higher eukaryotes.

genomics↗

bioRxiv2021

Generation, quality control, and analysis of the first genomically humanised knock-in mice for the ALS/FTD genes SOD1, TARDBP (TDP-43), and FUS

Amyotrophic lateral sclerosis - frontotemporal dementia spectrum disorder (ALS/FTD) is a complex neurodegenerative disease; up to 10% of cases are familial, usually arising from single dominant mutations in >30 causative genes. Transgenic mouse models that overexpress human ALS/FTD causative genes have been the preferred organism for in vivo modelling. However, while conferring human protein biochemistry, these overexpression models are not ideal for dosage-sensitive proteins such as TDP-43 or FUS. We have created three next-generation genomically humanised knock-in mouse models for ALS/FTD research, by replacing the entire mouse coding region of Sod1, Tardbp (TDP-43) and Fus, with their human orthologues to preserve human protein biochemistry, with exons and introns intact to enable future modelling of coding or non-coding mutations and variants and to preserve human splice variants. In generating these mice, we have established a new-standard of quality control: we demonstrate the utility of indirect capture for enrichment of a region of interest followed by Oxford Nanopore sequencing for robustly characterising large knock-in alleles. This approach confirmed that targeting occurred at the correct locus and to map homologous recombination events. Furthermore, extensive expression data from the three lines shows that homozygous humanised animals only express human protein, at endogenous levels. Characterisation of humanised FUS animals showed that they are phenotypically normal compared to wildtype littermates throughout their lifespan. These humanised mouse strains are critically needed for preclinical assessment of interventions, such as antisense oligonucleotides (ASOs), to modulate expression levels in patients, and will serve as templates for the addition of human ALS/FTD mutations to dissect disease pathomechanisms.

neuroscience↗

bioRxiv2021

Mechanisms of DNA repair have evolved to minimise the probability of nonsense mutations.

Variation in sequence mutability has important implications for evolutionary models and predicting disease occurrence, and is driven in part by evolutionary divergence in mechanisms of DNA repair. The aim of this study was twofold: first, to assess the effect of local sequence context on substitution rates in the mouse lineage; second, to investigate the relationship between sequence mutability and selection. We show that the 7-mer context (i.e three bases either side of the base of interest) explains more variation in substitution rates between chromosomes in the mouse lineage than either the 3-mer, 5-mer, or 9-mer contexts. Furthermore, we also show that 7-mer substitutions with the potential to cause nonsense mutations when they occur in translated sequences occur at a lower rate across the genome than 7-mer substitutions with the potential to cause synonymous mutations. We propose that mechanisms of DNA repair have evolved to prioritise substitutions that are more likely to be deleterious to fitness.

genomics↗

bioRxiv2021

Vesicle-bound regulatory RNAs are associated with tissue aging

Previous work on murine models and human demonstrated global as well as tissue-specific molecular aging trajectories in solid tissues and body fluids1-8. Extracellular vesicles like exosomes play a crucial role in communication and information exchange in between such systemic factors and solid tissues9,10. We sequenced freely circulating and vesicle-bound small regulatory RNAs in mice at five time points across the average life span from 2 to 18 months. Intriguingly, each small RNA class exhibits unique aging patterns, which showed differential signatures between vesicle-bound and freely circulating molecules. In particular, tRNA fragments showed overall highest correlation with aging which also matched well between sample types, facilitating age prediction with non-negative matrix factorization (86% accuracy). Interestingly, rRNAs exhibited inverse correlation trajectories between vesicles and plasma while vesicle-bound microRNAs (miRNAs) were exceptionally strong associated with aging. Affected miRNAs regulate the inflammatory response and transcriptional processes, and adipose tissues show considerable effects in associated gene regulatory modules. Finally, nanoparticle tracking and electron microscopy suggest a shift from overall many small to fewer but larger vesicles in aged plasma, potentially contributing to systemic aging trajectories and affecting the molecular aging of organs.

molecular biology↗

bioRxiv2021

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down Syndrome-related phenotypes

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, causative genes remain mostly unknown. Animal models enable identification of these genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. Here, we comprehensively phenotype Dp1Tyb mice and find wide-ranging DS-like phenotypes including aberrant megakaryopoiesis, reduced bone density, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for studies of many complex DS phenotypes.

genetics↗

bioRxiv2021

Nitrogen availability drives gene length of dominant prokaryotes and diversity of genes acquiring Nitrogen-species in oceanic systems

Nitrogen (N) is a key element for prokaryotes in the oceans and often limits phytoplankton primary production. An untested option to reduce prokaryotic N-demand under N-limitation is to reduce gene length. Here we show that in the sunlit Atlantic Ocean genes of the prokaryotic microbial communities in the permanently stratified N-limited (sub)tropics are up to 20% shorter than in N-replete regions further south and north. Average gene length (AGL) of major pelagic prokaryotic genera and two virus families correlated positively with nitrate concentrations. Further, the genomic G+C content of 60% of the taxa was lower and the gene repertoire to acquire inorganic and organic N-species higher in N-limited than in N-replete regions. A comparison of the N-demand by reducing gene length or G+C content showed that the former is much more efficient to save N. Our findings introduce a novel and most effective mode of evolutionary adaptation of prokaryotes to save resources including N and energy. They further show an enhanced diversification of genes acquiring N-species and -compounds in N-deplete relative to N-replete regions and thus add important information for a better understanding of the evolutionary adaptation of prokaryotes to N-availability in oceanic systems.

microbiology↗

bioRxiv2020

CAZymes in Maribacter dokdonensis 62-1 from the Patagonian shelf: Genomics and physiology compared to related flavobacteria and a co-occurring Alteromonas strain

Carbohydrate-active enzymes (CAZymes) are an important feature of bacteria in productive marine systems such as continental shelves, where phytoplankton and macroalgae produce diverse polysaccharides. We herein describe Maribacter dokdonensis 62-1, a novel strain of this flavobacterial species, isolated from alginate-supplemented seawater collected at the Patagonian continental shelf. M. dokdonensis 62-1 harbors a diverse array of CAZymes in multiple polysaccharide utilization loci (PUL). Two PUL encoding polysaccharide lyases from families 6, 7, 12 and 17 allow substantial growth with alginate as sole carbon source, with simultaneous utilization of mannuronate and guluronate as demonstrated by HPLC. Furthermore, strain 62-1 harbors a mixed-feature PUL encoding both ulvan- and fucoidan-targeting CAZymes. Core-genome phylogeny and pangenome analysis revealed variable occurrence of these PUL in related Maribacter and Zobellia strains, indicating specialization to certain "polysaccharide niches". Furthermore, lineage- and strain-specific genomic signatures for exopolysaccharide synthesis possibly mediate distinct strategies for surface attachment and host interaction. The wide detection of CAZyme homologs in algae-derived metagenomes suggests global occurrence in algal holobionts, supported by sharing multiple adaptive features with the hydrolytic model flavobacterium Zobellia galactanivorans. Comparison with Alteromonas sp. 76-1 isolated from the same seawater sample revealed that these co-occurring strains target similar polysaccharides but with different genomic repertoires, coincident with differing growth behavior on alginate that might mediate ecological specialization. Altogether, our study contributes to the perception of Maribacter as versatile flavobacterial polysaccharide degrader, with implications for biogeochemical cycles, niche specialization and bacteria-algae interactions in the oceans.

microbiology↗

bioRxiv2020

Sweet and magnetic: Succession and CAZyme expression of marine bacterial communities encountering a mix of alginate and pectin particles

Polysaccharide particles are an important nutrient source and microhabitat for marine bacteria. However, substrate-specific bacterial dynamics in a mixture of particle types with different polysaccharide composition, as likely occurring in natural habitats, are undescribed. Here, we studied the composition, functional diversity and gene expression of marine bacterial communities encountering a mix of alginate and pectin particles. Communities were collected above macroalgal forests near Helgoland Island - where polysaccharide-rich particles might regularly occur - and exposed to a mix of magnetic particles of each polysaccharide, allowing the targeted evaluation by particle type. Amplicon, metagenome and metatranscriptome sequencing revealed that particle-associated (PA) and free-living (FL) communities significantly differed in composition and metabolism, whereas dynamics on alginate and pectin particles were unexpectedly similar. Amplicon sequence variants (ASVs) from Tenacibaculum, Colwellia, Psychrobium and Psychromonas dominated the community on both particle types. Corresponding metagenome-assembled genomes (MAGs) expressed diverse alginate lyases, several co-localized in polysaccharide utilization loci. One low-abundance MAG related to Catenovulum showed pectin specialization through upregulated GH53 and GH105 genes. A single Glaciecola ASV dominated the FL fraction, likely persisting on particle-derived oligomers through different glycoside hydrolases. The bacterial preference for alginate, whereas pectin mainly served as colonization scaffold, illuminates substrate-driven microbial dynamics within mixed polysaccharide resources. Moreover, elevated ammonium metabolism signifies nitrogen availability as important factor on particles, whereas elevated methylcitrate and glyoxylate cycles illustrate nutrient-limited conditions in the surrounding water. These insights expand our understanding of bacterial microscale ecology, niche specialization and the biological carbon pump in macroalgae-rich habitats.

microbiology↗

bioRxiv2020

Lipidomic analysis of roseobacters of the pelagic RCA cluster and their response to phosphorus limitation

The marine roseobacter-clade Affiliated cluster (RCA) represents one of the most abundant groups of bacterioplankton in the global oceans, particularly in temperate and sub-polar regions. They play a key role in the biogeochemical cycling of various elements and are important players in oceanic climate-active trace gas metabolism. In contrast to copiotrophic roseobacter counterparts such as Ruegeria pomeroyi DSS-3 and Phaeobacter sp. MED193, RCA bacteria are truly pelagic and have smaller genomes. We have previously shown that RCA bacteria do not appear to encode the PlcP-mediated lipid remodelling pathway, whereby marine heterotrophic bacteria remodel their membrane lipid composition in response to phosphorus (P) stress by substituting membrane glycerophospholipids with alternative glycolipids or betaine lipids. In this study, we report lipidomic analysis of six RCA isolates. In addition to the commonly found glycerophospholipids such as phosphatidylglycerol and phosphatidylethanolamine, RCA bacteria synthesise a relatively uncommon phospholipid, acylphosphatidylglycerol, which is not found in copiotrophic roseobacters. Instead, like the abundant SAR11 clade, RCA bacteria upregulate ornithine lipid biosynthesis in response to P stress, suggesting a key role of this aminolipid in the adaptation of marine heterotrophs to oceanic nutrient limitation.

microbiology↗

bioRxiv2020

A Sea Change in Microbial Enzymes: Heterogeneous latitudinal and depth-related gradients in bulk water and particle-associated enzymatic activities from 30°S to 59°N in the Pacific Ocean

Heterotrophic microbes initiate organic matter degradation using extracellular enzymes. Our understanding of differences in microbial enzymatic capabilities, especially among particle-associated taxa and in the deep ocean, is limited by a paucity of hydrolytic enzyme activity measurements. Here, we measured the activities of a broad range of hydrolytic enzymes (glucosidases, peptidases, polysaccharide hydrolases) in epipelagic to bathypelagic bulk water (non-size fractionated), and on particles ([≥] 3 m) along a 9,800 km latitudinal transect from 30{degrees}S in the South Pacific to 59{degrees}N in the Bering Sea. Individual enzyme activities showed heterogeneous latitudinal and depth-related patterns, with varying biotic and abiotic correlates. With increasing latitude and decreasing temperature, lower laminarinase activities sharply contrasted with higher leucine aminopeptidase (leu-AMP) and chondroitin sulfate hydrolase activities in bulk water. Endopeptidases (chymotrypsins, trypsins) exhibited patchy spatial patterns, and their activities can exceed rates of the widely-measured exopeptidase, leu-AMP. Compared to bulk water, particle-associated enzymatic profiles featured a greater relative importance of endopeptidases, a broader spectrum of polysaccharide hydrolases, and latitudinal and depth-related trends that paralleled variations in particle fluxes. As water depth increased, enzymatic spectra on particles and in bulk water became narrower, and diverged more from one another. These distinct latitudinal and depth-related gradients of enzymatic activities underscore the biogeochemical consequences of emerging global patterns of microbial community structure and function, from surface to deep waters, and among particle-associated taxa.

microbiology↗