Biology subjects

Schmidt, C.

Publications and source records attributed to Schmidt, C..

At least 91 records · Page 5Linked to original sources

bioRxiv2021

Determinants of genetic diversity and species richness of North American amphibians

Ecological limits on the population sizes and number of species a region is capable of supporting are thought to simultaneously produce spatial patterns in genetic diversity and species richness. However, we do not know the extent to which resource-based environmental limits jointly determine these patterns of biodiversity in ectotherms because of their low energy requirements compared to endotherms. Here, we adapt a framework for the ways ecological limits may shape genetic diversity and species richness previously tested in mammals for amphibians to determine whether similar processes produce continental patterns of biodiversity across both taxa. Repurposing open, raw microsatellite data from 19 species sampled at 554 sites in North America we found that spatial patterns of genetic diversity run opposite to patterns of species richness and genetic differentiation. However, while measures of resource availability and niche heterogeneity predict 89% of the variation in species richness, these landscape metrics are poor predictors of genetic diversity. Although heterogeneity appears to be an important driver of genetic and species biodiversity patterns in both amphibians and mammals, our results suggest that variation in genetic diversity both within and across species makes it difficult to infer general processes producing spatial patterns of amphibian genetic diversity.

evolutionary biology↗

bioRxiv2020

pyActigraphy: open-source python package for actigraphy data visualisation and analysis

Over the past 40 years, actigraphy has been used to study rest-activity patterns in circadian rhythm and sleep research. Furthermore, considering its simplicity of use, there is a growing interest in the analysis of large population-based samples, using actigraphy. Here, we introduce pyActigraphy, a comprehensive toolbox for data visualization and analysis including multiple sleep detection algorithms and rest-activity rhythm variables. This open-source python package implements methods to read multiple data formats, quantify various properties of rest-activity rhythms, visualize sleep agendas, automatically detect rest periods and perform more advanced signal processing analyses. The development of this package aims to pave the way towards the establishment of a comprehensive open-source software suite, supported by a community of both developers and researchers, that would provide all the necessary tools for in-depth and large scale actigraphy data analyses. Required MetadataO_ST_ABSCurrent code versionC_ST_ABS

bioinformatics↗

bioRxiv2020

Lipid rafts interaction of the ARID3A transcription factor with EZRIN and G-Actin regulates B cell receptor signaling

Previously we demonstrated that the ARID3A transcription factor shuttles between the nucleus and the plasma membrane, where it localizes within lipid rafts. There it interacts with components of the B Cell Receptor (BCR) to reduce its ability to transmit downstream signaling. We demonstrate in this report that a direct component of ARID3A-regulated BCR signal strength is cortical Actin. ARID3A interacts with Actin exclusively within lipid rafts via the Actin binding protein EZRIN, which confines unstimulated BCRs within lipid rafts. BCR ligation discharges the ARID3A-EZRIN complex from lipid rafts allowing the BCR to initiate downstream signaling events. The ARID3A-EZRIN interaction occurs almost exclusively within unpolymerized G-Actin where EZRIN interacts with the multifunctional ARID3A REKLES domain. These observations provide a novel mechanism by which a transcription factor directly regulates BCR signaling.

immunology↗

bioRxiv2020

Elevation of Gut-Derived p-Cresol Molecular Networks in Astronauts During Spaceflight Informs Drug Metabolism and Performance

Metabolites produced by enteric microbes may have important effects on astronauts on long-duration missions. The NASA Twins Study provided the most comprehensive multi-scale omics data to date from which to extract molecular features of potential clinical significance to spaceflight. From the multivariate data, we identified an elevation of the uremic toxin p-cresol, which is produced by gut microbial fermentation of dietary tyrosine. p-Cresol has adverse metabolic effects via depletion of the hepatic sulfur pool, which impacts metabolism of drugs, endogenous metabolites, and xenobiotics. Moreover, p-cresol reshapes gut microbial community structure by facilitating survival of species such as clostridia and inhibition of butyrate producers. Spaceflight may also impact the genes responsible for the metabolism of p-cresol (e.g. SULT) and for the safe metabolism of common drugs used in space, such as acetaminophen (e.g. SULT, CYP4502E1, GST). Understanding p-cresol production and its related molecular networks in astronauts may lead to precision medicine advances that enhance astronaut safety and performance on long-duration missions.

molecular biology↗

bioRxiv2020

SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis

Epidemiological studies of the COVID-19 pandemic have revealed evidence of cardiac involvement and documented that myocardial injury and myocarditis are predictors of poor outcomes. Nonetheless, little is understood regarding SARS-CoV-2 tropism within the heart and whether cardiac complications result directly from myocardial infection. Here, we develop a human engineered heart tissue model and demonstrate that SARS-CoV-2 selectively infects cardiomyocytes. Viral infection is dependent on expression of angiotensin-I converting enzyme 2 (ACE2) and endosomal cysteine proteases, suggesting an endosomal mechanism of cell entry. After infection with SARS-CoV-2, engineered tissues display typical features of myocarditis, including cardiomyocyte cell death, impaired cardiac contractility, and innate immune cell activation. Consistent with these findings, autopsy tissue obtained from individuals with COVID-19 myocarditis demonstrated cardiomyocyte infection, cell death, and macrophage-predominate immune cell infiltrate. These findings establish human cardiomyocyte tropism for SARS-CoV-2 and provide an experimental platform for interrogating and mitigating cardiac complications of COVID-19.

immunology↗

bioRxiv2020

Hallmarks of Alpha- and Betacoronavirus non-structural protein 7+8 complexes

Coronaviruses infect many different species including humans. The last two decades have seen three zoonotic coronaviruses with SARS-CoV-2 causing a pandemic in 2020. Coronaviral non-structural proteins (nsp) built up the replication-transcription complex (RTC). Nsp7 and nsp8 interact with and regulate the RNA-dependent RNA-polymerase and other enzymes in the RTC. However, the structural plasticity of nsp7+8 complex has been under debate. Here, we present the framework of nsp7+8 complex stoichiometry and topology based on a native mass spectrometry and complementary biophysical techniques of nsp7+8 complexes from seven coronaviruses in the genera Alpha- and Betacoronavirus including SARS-CoV-2. Their complexes cluster into three groups, which systematically form either heterotrimers or heterotetramers or both, exhibiting distinct topologies. Moreover, even at high protein concentrations mainly heterotetramers are observed for SARS-CoV-2 nsp7+8. From these results, the different assembly paths can be pinpointed to specific residues and an assembly model is proposed.

biophysics↗

bioRxiv2020

No Evidence of Toxoplasma Gondii Infection in Urban and Rural Squirrels in Southern Manitoba, Canada

Wildlife in cities can act as reservoirs for parasites that can infect domestic pets and have implications for human health. For example, the Coccidian parasite Toxoplasma gondii can infect all mammalian species, with felids acting as the only definitive hosts. Rodents, such as squirrels, could play an important role in urban infection dynamics of T. gondii, as squirrels occur at higher densities in cities than in natural environments and regularly share their territories with cats. In urban and suburban areas squirrels can encounter infectious oocysts shed in cat feces in contaminated soil or in the food they eat. They are also preyed upon by cats making them a potentially important species for completing the T. gondii life cycle in cities. We hypothesized that due to increased exposure to cats, urban squirrels would be more susceptible to T. gondii infection relative to squirrels in more natural areas. We investigated this using molecular and serological methods on samples collected from American red squirrels (Tamiasciurus hudsonicus), eastern grey squirrels (Sciurus carolinensis), northern flying squirrels (Glaucomys sabrinus), and least chipmunks (Tamias minimus) in and around the city of Winnipeg, Manitoba, Canada. We tested a total of 230 tissue samples from 46 squirrels for T. gondii DNA using quantitative PCR and supplemented these data with analyses of 13 serum samples from grey squirrels (Sciurus carolinensis) testing for T. gondii antibodies by indirect ELISA. We found no evidence of T. gondii infection in any squirrel. This suggests that squirrels may not be important intermediate hosts of T. gondii in cities and do not need to be considered as sources of infection to cats.

pathology↗

bioRxiv2020

Continued topographical learning- and relearning-dependent activity in the resting state after post-training sleep and wake

Continuation of experience-dependent neural activity during offline periods of sleep and wakefulness is a critical element of memory consolidation. Using functional magnetic resonance imaging (fMRI), offline consolidation effects have been evidenced probing behavioral and neurophysiological changes during memory retrieval, i.e. in the context of task practice. Resting state fMRI (rfMRI) further allows investigating the offline evolution of recently learned information, without confounding task-related effects. In the present study, we used rfMRI to investigate offline changes in functional connectivity (FC) and Amplitude of Low Frequency Fluctuation (ALFF) associated with learning and relearning in a spatial navigation task, following an episode of post-training wake or sleep, respectively. Resting state activity was measured immediately (i) before and (ii) after topographical learning in a virtual town, (iii) 4 days later after regular sleep (RS) vs. sleep deprivation (SD) on the first post-learning night, and (iv) after topographical re-learning in an extended town encompassing the initial map. Task (navigation)-based fMRI activity was also recorded on Day 1 and Day 4 during target retrieval. Our results highlight the continuation of navigation-related activity in the subsequent resting state, as evidenced by changes in FC and ALFF in task-related neural networks. Behavioural performance was not modulated by post-training SD vs RS. However, in line with prior reports, post-training SD was associated with increased FC between navigation-related brain structures when faced to the task of learning a novel but related environment in the extended version of the city at Day 4. These results suggest the use of compensatory resources to link novel information with SD-related less efficiently consolidated memory traces.

neuroscience↗

bioRxiv2020

Inconsistent effects of urbanization on amphibian genetic diversity

Habitat loss and fragmentation are leading causes of vertebrate population declines. These declines are thought to be partly due to decreased connectivity and habitat loss reducing population sizes in human transformed habitats. With time this can lead to reduced effective population size and genetic diversity which restricts the ability of wildlife to cope with environmental change through genetic adaptation. However, it is not well understood whether these effects are generally applicable across taxa. Here, we repurposed and synthesized raw microsatellite data from online repositories from 19 amphibian species sampled at 554 sites in North America. For each site, we estimated gene diversity, allelic richness, effective population size, and population differentiation. Using binary urban-rural census designations, and continuous measures of human population density and the Human Footprint Index, we tested for generalizable effects of human land use on amphibian genetic diversity. We found no consistent relationships for any of our genetic metrics. While we did not detect directional effects for most species, a few generalist species responded positively to urbanization. These results contrast with consistent negative effects of urbanization in mammals and species specific positive and negative effects in birds. In the context of widespread amphibian declines, our results suggest that habitat loss in human transformed habitats is a more immediate concern than declining genetic diversity in populations that persist.

evolutionary biology↗

bioRxiv2020

Assembly defects of the human tRNA splicing endonuclease contribute to impaired pre-tRNA processing in pontocerebellar hypoplasia

Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-[A] resolution X-ray crystal structure of a TSEN15-34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes.

biochemistry↗

bioRxiv2020

The developmental and genetic architecture of the sexually selected male ornament of swordtails

Sexual selection results in sex-specific characters like the conspicuously pigmented extension of the ventral tip of the caudal fin - the "sword" - in males of several species of Xiphophorus fishes. To uncover the genetic architecture underlying sword formation and to identify genes that are associated with its development, we characterized the sword transcriptional profile and combined it with genetic mapping approaches. Results showed that the male ornament of swordtails develops from a sexually non-dimorphic prepattern of transcription factors in the caudal fin. Among genes that constitute the exclusive sword transcriptome only two are located in the genomic region associated with this trait; the chaperone, fkbp9, and the potassium channel, kcnh8 that in addition to its neural function performs a role known to affect fin growth. This indicates that during evolution of swordtails a brain gene has been recruited for an additional function in establishing a male ornament.

evolutionary biology↗

bioRxiv2020

Cardioids reveal self-organizing principles of human cardiogenesis

Organoids that self-organize into tissue-like structures have transformed our ability to model human development and disease. To date, all major organs can be mimicked using self-organizing organoids with the notable exception of the human heart. Here, we established self-organizing cardioids from human pluripotent stem cells that intrinsically specify, pattern and morph into chamber-like structures containing a cavity. Cardioid complexity can be controlled by signaling that instructs the separation of cardiomyocyte and endothelial layers, and by directing epicardial spreading, inward migration and differentiation. We find that cavity morphogenesis is governed by a mesodermal WNT-BMP signaling axis and requires its target HAND1, a transcription factor linked to human heart chamber cavity defects. In parallel, a WNT-VEGF axis coordinates myocardial self-organization with endothelial patterning and specification. Human cardioids represent a powerful platform to mechanistically dissect self-organization and congenital heart defects, serving as a foundation for future translational research. Highlights- Cardioids form cardiac-like chambers with inner endothelial lining and interact with epicardium - Cardioid self-organization and lineage complexity can be controlled by signaling - WNT-BMP signaling directs cavity formation in self-organized cardioids via HAND1 - WNT-VEGF coordinate endothelial patterning with myocardial cavity morphogenesis

developmental biology↗

bioRxiv2020

Common causes drive negative correlations between nuclear genetic and species level biodiversity

The processes that give rise to species richness gradients are not well understood, but may be linked to resource-based limits on the number of species a region can support. Ecological limits placed on regional species richness would also limit population sizes, suggesting that these processes could also generate genetic diversity gradients. If true, we might better understand how broad-scale biodiversity patterns are formed by identifying the common causes of genetic diversity and species richness. We develop a hypothetical framework based on the consequences of regional variation in ecological limits to simultaneously explain spatial patterns of species richness and neutral genetic diversity. Repurposing raw genotypic data spanning 38 mammal species sampled across 801 sites in North America, we show that estimates of genome-wide genetic diversity and species richness share spatial structure. Notably, species richness hotspots tend to harbor lower levels of within-species genetic variation. A structural equation model encompassing eco-evolutionary processes related to resource availability, habitat heterogeneity, and human disturbance explained 78% of variation in genetic diversity and 74% of the variation in species richness. These results suggest we can infer broad-scale patterns of species and genetic diversity using two simple environmental measures of resource availability and ecological opportunity.

evolutionary biology↗

bioRxiv2020

Socioeconomic variation across multiple cities predicts avian life-history strategies

Cities are the planets newest ecosystem and thus provide the opportunity to study community formation directly following major permanent environmental change. The human social and built components of environments can vary widely across different cities, yet it is largely unknown how these features of a city covary with the traits of colonizing species. We constructed a new dataset from open-source data with 44,670 observations of 160 Passerine species observed 1,908 urban areas across the United States. We found that as a citys housing density and median income increased it tended to support more migratory species and species with smaller body sizes and shorter lifespans. This suggests that differential survival and reproduction at the species-level can quickly generate geographical patterns of species trait variation across urban environments similar to those found in natural settings without the need for evolutionary change.

ecology↗

bioRxiv2019

Serum biochemistry suggests grey squirrels (Sciurus carolinensis) have poorer physiological condition in urban settings

Human food waste in cities presents urban wildlife with predictable, easily accessible high-calorie food sources, but this can be both beneficial and harmful for individual health. We analyzed body condition and serum chemistry (electrolyte levels, markers of kidney and liver function, protein, glucose, and cholesterol) in an urban and rural population of eastern grey squirrels (Sciurus carolinensis) to assess whether proximity to the human food waste that is associated with urban habitats had ill effects on health. We found no differences in body condition between habitats and no evidence of malnutrition at either site. However, urban squirrels had higher blood glucose, lower potassium, phosphorus, chloride, and albumin:globulin ratios. These results align with previous findings of increased dietary sugar in cities, and suggest that urban populations of grey squirrels are under greater environmental stress than rural populations.

physiology↗

bioRxiv2019

Continent-wide effects of urbanization on bird and mammal genetic diversity

AbstractUrbanization and associated environmental changes are causing global declines in vertebrate populations. In general, population declines of the magnitudes now detected should lead to reduced effective population sizes for animals living in proximity to humans and disturbed lands. This is cause for concern because effective population sizes set the rate of genetic diversity loss due to genetic drift, the rate of increase in inbreeding, and the efficiency with which selection can act on beneficial alleles. We predicted that the effects of urbanization should decrease effective population size and genetic diversity, and increase population-level genetic differentiation. To test for such patterns, we repurposed and reanalyzed publicly archived genetic data sets for North American birds and mammals. After filtering, we had usable raw genotype data from 85 studies and 41,023 individuals, sampled from 1,008 locations spanning 41 mammal and 25 bird species. We used census-based urban-rural designations, human population density, and the Human Footprint Index as measures of urbanization and habitat disturbance. As predicted, mammals sampled in more disturbed environments had lower effective population sizes and genetic diversity, and were more genetically differentiated from those in more natural environments. There were no consistent relationships detectable for birds. This suggests that, in general, mammal populations living near humans may have less capacity to respond adaptively to further environmental changes, and be more likely to suffer from effects of inbreeding.

evolutionary biology↗

bioRxiv2019

Preserved wake-dependent cortical excitability dynamics predict cognitive fitness beyond age-related brain alterations

Age-related cognitive decline arises from alterations in brain integrity as well as in sleep-wake regulation. Here, we investigated whether preserved sleep-wake regulation of cortical function during wakefulness could represent a positive factor for cognitive fitness in aging, independently of early age-related changes in brain structure. We quantified cortical excitability dynamics during prolonged wakefulness as a sensitive marker of age-related alteration in sleep-wake regulation in 60 healthy older individuals (50-69y; 42 women). Brain structural integrity was assessed with amyloid-beta- and tau-PET, and with MRI. Participants cognition was extensively investigated. We show that individuals with preserved cortical excitability dynamics exhibit better cognitive performance, particularly in the executive domain, which is essential to successful cognitive aging. Critically, this association remained significant after accounting for brain integrity measures. Preserved dynamics of basic brain function during wakefulness could be essential to cognitive fitness in aging, independently from age-related brain structural modifications that can ultimately lead to dementia.

neuroscience↗

bioRxiv2019

Structural and functional characterisation of SiiA, an auxiliary protein from the SPI4-encoded type 1 secretion system from Salmonella enterica

Salmonella invasion is mediated by a concerted action of the Salmonella pathogenicity island 4 (SPI4)-encoded type one secretion system (T1SS) and the SPIl-encoded type three secretion system (T3SS-1). The SPI4-encoded T1SS establishes the first contact to the host membrane. It consists of five proteins (SiiABCDF) that secrete the giant adhesin SiiE. The exact mechanism by which the T1SS enables host cell recognition remains unclear. Here, we investigated structure-function relationships in SiiA, a non-canonical T1SS subunit located at the inner membrane (IM). We observe that SiiA consists of a membrane domain, an intrinsically disordered periplasmic linker region and a folded globular periplasmic domain (SiiA-PD). The crystal structure of SiiA-PD shows homology to that of MotB-PD and other peptidoglycan (PG)-binding domains. Indeed, SiiA-PD binds PG in vitro albeit at an acidic pH, only, whereas MotB-PD binds PG from pH 5.8 to 8. Mutation of Arg162 in SiiA impedes PG binding and reduces Salmonella invasion efficacy of polarized epithelial cells. SiiA forms a complex with SiiB at the IM, and the SiiA-MotB homology is likely paralleled by a SiiB-MotA homology. We show that, in addition to PG binding, the SiiAB complex translocates protons across the IM. Substituting Asp13 in SiiA impairs proton translocation. Overall, SiiA displays many properties previously observed in MotB. However, whereas the MotAB complex uses the proton motif force (PMF) to energize the bacterial flagellum, it remains to be shown how the use of the PMF by SiiAB assists T1SS function and ultimately Salmonella invasion.

microbiology↗