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See detailWhich demographic and socio-economic factors are associated with vaccination willingness and beliefs towards vaccination? Rapid report with first results
Leist, Anja UL; Klee, Matthias UL; Paccoud, Ivana UL et al

Report (2021)

In the framework of the CoVaLux project on vaccination and long COVID in Luxembourg, the project “Socio-economic determinants of long COVID and vaccination, and economic consequences with focus on labour ... [more ▼]

In the framework of the CoVaLux project on vaccination and long COVID in Luxembourg, the project “Socio-economic determinants of long COVID and vaccination, and economic consequences with focus on labour market and health care” aims to triangulate evidence from different data sources such as social security and general population data, the national cohort CON-VINCE as well as national health surveys. We seek to arrive at robust assessments of how socio-economic determinants shape vaccination willingness, occurrence, severity and persistence of long COVID, and economic consequences of long COVID in Luxembourg. [less ▲]

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See detailGenome Sequencing of SARS-CoV-2 Allows Monitoring of Variants of Concern through Wastewater
Herold, Malte; Fouquier d'herouël, Aymeric UL; May, Patrick UL et al

in Water (2021), 13(21 3018),

Monitoring SARS-CoV-2 in wastewater has shown to be an effective tool for epidemiological surveillance. More specifically, RNA levels determined with RT-qPCR have been shown to track with the infection ... [more ▼]

Monitoring SARS-CoV-2 in wastewater has shown to be an effective tool for epidemiological surveillance. More specifically, RNA levels determined with RT-qPCR have been shown to track with the infection dynamics within the population. However, the surveillance of individual lineages circulating in the population based on genomic sequencing of wastewater samples is challenging, as the genetic material constitutes a mixture of different viral haplotypes. Here, we identify specific signature mutations from individual SARS-CoV-2 lineages in wastewater samples to estimate lineages circulating in Luxembourg. We compare circulating lineages and mutations to those detected in clinical samples amongst infected individuals. We show that especially for dominant lineages, the allele frequencies of signature mutations correspond to the occurrence of particular lineages in the population. In addition, we provide evidence that regional clusters can also be discerned. We focused on the time period between November 2020 and March 2021 in which several variants of concern emerged and specifically traced the lineage B.1.1.7, which became dominant in Luxembourg during that time. During the subsequent time points, we were able to reconstruct short haplotypes, highlighting the co-occurrence of several signature mutations. Our results highlight the potential of genomic surveillance in wastewater samples based on amplicon short-read data. By extension, our work provides the basis for the early detection of novel SARS-CoV-2 variants. [less ▲]

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See detailFunctional meta-omics provide critical insights into long- and short-read assemblies
Galata, Valentina UL; Busi, Susheel Bhanu UL; Kunath, Benoît UL et al

in Briefings in Bioinformatics (2021)

Real-world evaluations of metagenomic reconstructions are challenged by distinguishing reconstruction artifacts from genes and proteins present in situ. Here, we evaluate short-read-only, long-read-only ... [more ▼]

Real-world evaluations of metagenomic reconstructions are challenged by distinguishing reconstruction artifacts from genes and proteins present in situ. Here, we evaluate short-read-only, long-read-only and hybrid assembly approaches on four different metagenomic samples of varying complexity. We demonstrate how different assembly approaches affect gene and protein inference, which is particularly relevant for downstream functional analyses. For a human gut microbiome sample, we use complementary metatranscriptomic and metaproteomic data to assess the metagenomic data-based protein predictions. Our findings pave the way for critical assessments of metagenomic reconstructions. We propose a reference-independent solution, which exploits the synergistic effects of multi-omic data integration for the in situ study of microbiomes using long-read sequencing data. [less ▲]

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See detailMantis: flexible and consensus-driven genome annotation
Queirós, Pedro; Delogu, Francesco UL; Hickl, Oskar UL et al

in GigaScience (2021), 10(6),

The rapid development of the (meta-)omics fields has produced an unprecedented amount of high-resolution and high-fidelity data. Through the use of these datasets we can infer the role of previously ... [more ▼]

The rapid development of the (meta-)omics fields has produced an unprecedented amount of high-resolution and high-fidelity data. Through the use of these datasets we can infer the role of previously functionally unannotated proteins from single organisms and consortia. In this context, protein function annotation can be described as the identification of regions of interest (i.e., domains) in protein sequences and the assignment of biological functions. Despite the existence of numerous tools, challenges remain in terms of speed, flexibility, and reproducibility. In the big data era, it is also increasingly important to cease limiting our findings to a single reference, coalescing knowledge from different data sources, and thus overcoming some limitations in overly relying on computationally generated data from single sources.We implemented a protein annotation tool, Mantis, which uses database identifiers intersection and text mining to integrate knowledge from multiple reference data sources into a single consensus-driven output. Mantis is flexible, allowing for the customization of reference data and execution parameters, and is reproducible across different research goals and user environments. We implemented a depth-first search algorithm for domain-specific annotation, which significantly improved annotation performance compared to sequence-wide annotation. The parallelized implementation of Mantis results in short runtimes while also outputting high coverage and high-quality protein function annotations.Mantis is a protein function annotation tool that produces high-quality consensus-driven protein annotations. It is easy to set up, customize, and use, scaling from single genomes to large metagenomes. Mantis is available under the MIT license at https://github.com/PedroMTQ/mantis. [less ▲]

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See detailUnification of functional annotation descriptions using text mining
Queirós, Pedro; Novikova, Polina UL; Wilmes, Paul UL et al

in Biological Chemistry (2021)

A common approach to genome annotation involves the use of homology-based tools for the prediction of the functional role of proteins. The quality of functional annotations is dependent on the reference ... [more ▼]

A common approach to genome annotation involves the use of homology-based tools for the prediction of the functional role of proteins. The quality of functional annotations is dependent on the reference data used, as such, choosing the appropriate sources is crucial. Unfortunately, no single reference data source can be universally considered the gold standard, thus using multiple references could potentially increase annotation quality and coverage. However, this comes with challenges, particularly due to the introduction of redundant and exclusive annotations. Through text mining it is possible to identify highly similar functional descriptions, thus strengthening the confidence of the final protein functional annotation and providing a redundancy-free output. Here we present UniFunc, a text mining approach that is able to detect similar functional descriptions with high precision. UniFunc was built as a small module and can be independently used or integrated into protein function annotation pipelines. By removing the need to individually analyse and compare annotation results, UniFunc streamlines the complementary use of multiple reference datasets. [less ▲]

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See detailPersistence of birth mode-dependent effects on gut microbiome composition, immune system stimulation and antimicrobial resistance during the first year of life
Busi, Susheel Bhanu UL; de Nies, Laura UL; Habier, Janine UL et al

in ISME Communications (2021)

Caesarean section delivery (CSD) disrupts mother-to-neonate transmission of specific microbial strains and functional repertoires as well as linked immune system priming. Here we investigate whether ... [more ▼]

Caesarean section delivery (CSD) disrupts mother-to-neonate transmission of specific microbial strains and functional repertoires as well as linked immune system priming. Here we investigate whether differences in microbiome composition and impacts on host physiology persist at 1 year of age. We perform high-resolution, quantitative metagenomic analyses of the gut microbiomes of infants born by vaginal delivery (VD) or by CSD, from immediately after birth through to 1 year of life. Several microbial populations show distinct enrichments in CSD-born infants at 1 year of age including strains of Bacteroides caccae, Bifidobacterium bifidum and Ruminococcus gnavus, whereas others are present at higher levels in the VD group including Faecalibacterium prausnitizii, Bifidobacterium breve and Bifidobacterium kashiwanohense. The stimulation of healthy donor-derived primary human immune cells with LPS isolated from neonatal stool samples results in higher levels of tumour necrosis factor alpha (TNF-α) in the case of CSD extracts over time, compared to extracts from VD infants for which no such changes were observed during the first year of life. Functional analyses of the VD metagenomes at 1 year of age demonstrate a significant increase in the biosynthesis of the natural antibiotics, carbapenem and phenazine. Concurrently, we find antimicrobial resistance (AMR) genes against several classes of antibiotics in both VD and CSD. The abundance of AMR genes against synthetic (including semi-synthetic) agents such as phenicol, pleuromutilin and diaminopyrimidine are increased in CSD children at day 5 after birth. In addition, we find that mobile genetic elements, including phages, encode AMR genes such as glycopeptide, diaminopyrimidine and multidrug resistance genes. Our results demonstrate persistent effects at 1 year of life resulting from birth mode-dependent differences in earliest gut microbiome colonisation. [less ▲]

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See detailPathoFact: a pipeline for the prediction of virulence factors and antimicrobial resistance genes in metagenomic data
de Nies, Laura UL; Lopes, Sara; Busi, Susheel Bhanu UL et al

in Microbiome (2021)

Background Pathogenic microorganisms cause disease by invading, colonizing, and damaging their host. Virulence factors including bacterial toxins contribute to pathogenicity. Additionally, antimicrobial ... [more ▼]

Background Pathogenic microorganisms cause disease by invading, colonizing, and damaging their host. Virulence factors including bacterial toxins contribute to pathogenicity. Additionally, antimicrobial resistance genes allow pathogens to evade otherwise curative treatments. To understand causal relationships between microbiome compositions, functioning, and disease, it is essential to identify virulence factors and antimicrobial resistance genes in situ. At present, there is a clear lack of computational approaches to simultaneously identify these factors in metagenomic datasets. Results Here, we present PathoFact, a tool for the contextualized prediction of virulence factors, bacterial toxins, and antimicrobial resistance genes with high accuracy (0.921, 0.832 and 0.979, respectively) and specificity (0.957, 0.989 and 0.994). We evaluate the performance of PathoFact on simulated metagenomic datasets and perform a comparison to two other general workflows for the analysis of metagenomic data. PathoFact outperforms all existing workflows in predicting virulence factors and toxin genes. It performs comparably to one pipeline regarding the prediction of antimicrobial resistance while outperforming the others. We further demonstrate the performance of PathoFact on three publicly available case-control metagenomic datasets representing an actual infection as well as chronic diseases in which either pathogenic potential or bacterial toxins are hypothesized to play a role. In each case, we identify virulence factors and AMR genes which differentiated between the case and control groups, thereby revealing novel gene associations with the studied diseases. Conclusion PathoFact is an easy-to-use, modular, and reproducible pipeline for the identification of virulence factors, bacterial toxins, and antimicrobial resistance genes in metagenomic data. Additionally, our tool combines the prediction of these pathogenicity factors with the identification of mobile genetic elements. This provides further depth to the analysis by considering the genomic context of the pertinent genes. Furthermore, PathoFact’s modules for virulence factors, toxins, and antimicrobial resistance genes can be applied independently, thereby making it a flexible and versatile tool. PathoFact, its models, and databases are freely available at https://pathofact.lcsb.uni.lu. [less ▲]

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See detailHomogeneous selection promotes microdiversity in the glacier-fed stream microbiome
Fodelianakis, Styliianos; Busi, Susheel Bhanu UL; Wilmes, Paul UL et al

E-print/Working paper (2020)

Microdiversity, the organization of microorganisms into groups with closely related but ecologically different sub-types, is widespread and represents an important linchpin between microbial ecology and ... [more ▼]

Microdiversity, the organization of microorganisms into groups with closely related but ecologically different sub-types, is widespread and represents an important linchpin between microbial ecology and evolution. However, the drivers of microdiversification remain largely unknown. Here we show that selection promotes microdiversity in the microbiome associated with sediments in glacier-fed streams (GFS). Applying a novel phylogenetic framework, we identify several clades that are under homogeneous selection and that contain genera with higher levels of microdiversity than the rest of the genera. Overall these clades constituted ~44% and ~64% of community α-diversity and abundance, and both percentages increased further in GFS that were largely devoid of primary producers. Our findings show that strong homogeneous selection drives the microdiversification of specialized microbial groups putatively underlying their success in the extreme environment of GFS. This microdiversity could be threatened as glaciers shrink, with unknown consequences for microbial diversity and functionality in these ecosystems. [less ▲]

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See detailDichloromethane Degradation Pathway from Unsequenced Hyphomicrobium sp. MC8b Rapidly Explored by Pan-Proteomics
Hayoun, Karim; Geersens, Emilie; Laczny, Cedric Christian UL et al

in Microorganisms (2020)

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See detailRoles of bacteriophages, plasmids and CRISPR immunity in microbial community dynamics revealed using time-series integrated meta-omics
Martinez Arbas, Susana UL; Narayanasamy, Shaman; Herold, Malte et al

in Nature Microbiology (2020)

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We ... [more ▼]

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We analysed generation-resolved iMGE–host dynamics spanning one and a half years in a microbial consortium from a biological wastewater treatment plant using integrated meta-omics. We identified 31 bacterial metagenome-assembled genomes encoding complete CRISPR–Cas systems and their corresponding iMGEs. CRISPR-targeted plasmids outnumbered their bacteriophage counterparts by at least fivefold, highlighting the importance of CRISPR-mediated defence against plasmids. Linear modelling of our time-series data revealed that the variation in plasmid abundance over time explained more of the observed community dynamics than phages. Community-scale CRISPR-based plasmid–host and phage–host interaction networks revealed an increase in CRISPR-mediated interactions coinciding with a decrease in the dominant ‘Candidatus Microthrix parvicella’ population. Protospacers were enriched in sequences targeting genes involved in the transmission of iMGEs. Understanding the factors shaping the fitness of specific populations is necessary to devise control strategies for undesirable species and to predict or explain community-wide phenotypes. [less ▲]

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See detailOptimised biomolecular extraction for metagenomic analysis of microbial biofilms from high-mountain streams
Busi, Susheel Bhanu UL; Pramateftaki, Paraskevi; Brandani, Jade et al

in PeerJ (2020)

Glacier-fed streams (GFS) are harsh ecosystems dominated by microbial life organized in benthic biofilms, yet the biodiversity and ecosystem functions provided by these communities remain under ... [more ▼]

Glacier-fed streams (GFS) are harsh ecosystems dominated by microbial life organized in benthic biofilms, yet the biodiversity and ecosystem functions provided by these communities remain under-appreciated. To better understand the microbial processes and communities contributing to GFS ecosystems, it is necessary to leverage high throughput sequencing. Low biomass and high inorganic particle load in GFS sediment samples may affect nucleic acid extraction efficiency using extraction methods tailored to other extreme environments such as deep-sea sediments. Here, we benchmarked the utility and efficacy of four extraction protocols, including an up-scaled phenol-chloroform protocol. We found that established protocols for comparable sample types consistently failed to yield sufficient high-quality DNA, delineating the extreme character of GFS. The methods differed in the success of downstream applications such as library preparation and sequencing. An adapted phenol-chloroform-based extraction method resulted in higher yields and better recovered the expected taxonomic profile and abundance of reconstructed genomes when compared to commercially-available methods. Affordable and straight-forward, this method consistently recapitulated the abundance and genomes of a mock community, including eukaryotes. Moreover, by increasing the amount of input sediment, the protocol is readily adjustable to the microbial load of the processed samples without compromising protocol efficiency. Our study provides a first systematic and extensive analysis of the different options for extraction of nucleic acids from glacier-fed streams for high-throughput sequencing applications, which may be applied to other extreme environments. [less ▲]

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See detailSARS-CoV-2 Transmission in Educational Settings During an Early Summer Epidemic Wave in Luxembourg
Mossong, Joël; Mombaerts, Laurent UL; Veiber, Lisa UL et al

E-print/Working paper (2020)

Background: The role of schools and children in the transmission of SARS-CoV-2 remains to be determined. Following a first wave in spring and gradual easing of lockdown, Luxembourg experienced an early ... [more ▼]

Background: The role of schools and children in the transmission of SARS-CoV-2 remains to be determined. Following a first wave in spring and gradual easing of lockdown, Luxembourg experienced an early second epidemic wave before the start of summer school holidays on 15th July. This provided the opportunity to study the role of school-age children and school settings in SARS-CoV-2 transmission. More specifically, we compared the incidence in school-age children, teachers and the general working population, and estimated the number of secondary transmissions occurring at schools using contact tracing data. Findings: While SARS-CoV-2 incidence was much higher in adults aged 20 and above than in children aged 0 to 19 during the first wave in spring, no significant difference was found during the second wave in early summer. The incidence during the second wave was similar for pupils, teachers and the general working population. Based on a total of 424 reported confirmed COVID-19 cases in school-age children and teachers, we estimate that 179 index cases caused 49 secondary transmissions in schools. While some small clusters of mainly student-to-student transmission within the same class were identified, we did not observe any large outbreaks with multiple generations of infection. Interpretation: Transmission of SARS-CoV-2 within Luxembourg schools was limited during the early summer epidemic wave in 2020. Precautionary measures including physical distancing as well as easy access to testing, systematic contact tracing appears to have been successful in mitigating transmission within educational settings. Funding Statement: LV is supported by the Luxembourg National Research Fund grant COVID-19/2020- 1/14701707/REBORN, LM is supported by Luxembourg National Research Fund grant COVID19/14863306/PREVID, PW is supported by the European Research Council (ERC-CoG 863664). Declaration of Interests: No competing interests. Ethics Approval Statement: The Health Directorate has the legal permission to process patient confidential information for national surveillance of communicable diseases in general and contact tracing for the COVID-19 pandemic and individual patient consent is not required. [less ▲]

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See detailIntegration of time-series meta-omics data reveals how microbial ecosystems respond to disturbance
Herold, Malte; Martinez Arbas, Susana UL; Narayanasamy, Shaman et al

in Nature Communications (2020)

The development of reliable, mixed-culture biotechnological processes hinges on understanding how microbial ecosystems respond to disturbances. Here we reveal extensive phenotypic plasticity and niche ... [more ▼]

The development of reliable, mixed-culture biotechnological processes hinges on understanding how microbial ecosystems respond to disturbances. Here we reveal extensive phenotypic plasticity and niche complementarity in oleaginous microbial populations from a biological wastewater treatment plant. We perform meta-omics analyses (metagenomics, metatranscriptomics, metaproteomics and metabolomics) on in situ samples over 14 months at weekly intervals. Based on 1,364 de novo metagenome-assembled genomes, we uncover four distinct fundamental niche types. Throughout the time-series, we observe a major, transient shift in community structure, coinciding with substrate availability changes. Functional omics data reveals extensive variation in gene expression and substrate usage amongst community members. Ex situ bioreactor experiments confirm that responses occur within five hours of a pulse disturbance, demonstrating rapid adaptation by specific populations. Our results show that community resistance and resilience are a function of phenotypic plasticity and niche complementarity, and set the foundation for future ecological engineering efforts. [less ▲]

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See detailCompositional and functional characterisation of biomass-degrading microbial communities in guts of plant fibre- and soil-feeding higher termites.
Marynowska, Martyna; Goux, Xavier; Sillam-Dusses, David et al

in Microbiome (2020)

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See detailIntegrative omics analysis of the termite gut system adaptation to Miscanthus diet identifies lignocellulose degradation enzymes.
Calusinska, Magdalena; Marynowska, Martyna; Bertucci, Marie UL et al

in Communications Biology (2020)

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See detailGlutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function
Kurniawan, Henry; Franchina, Davide G.; Guerra, Luana UL et al

in Cell Metabolism (2020), 31(5), 920--9367

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for ... [more ▼]

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine’s functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase ( Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality. [less ▲]

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See detailUnderstanding the role of Fusobacterium nucleatum metabolism in colon cancer initiation and progression
Ternes, Dominik UL; Karta, Jessica UL; Tsenkova, Mina UL et al

Poster (2020, February 22)

Accumulating evidence suggests that dysbiosis, a state of pathological imbalance in the human gut microbiome, is present in patients suffering from colorectal cancer (CRC). 16S rRNA gene sequencing, as ... [more ▼]

Accumulating evidence suggests that dysbiosis, a state of pathological imbalance in the human gut microbiome, is present in patients suffering from colorectal cancer (CRC). 16S rRNA gene sequencing, as well as metagenomic and metatranscriptomic analyses, identified specific bacteria being associated with CRC. Among others, Fusobacterium ssp. have been found to directly interact with cancer or immune cells of their host. However, only a limited number of CRC-associated microbes have been examined for host-microbial interactions and, as such, the role of bacteria in the etiology of the disease remains largely elusive. Our aim is the development of predictive and experimental models that allow to not only study the host-microbiota interactions but are also amenable to high-throughput experimentation and large-scale omics-data integration. Ultimately, such models should help to get from meta-omics to cellular mechanism and, moreover, serve as tools for reproducible analyses of host-microbial interaction mechanisms of on a transcriptomic, proteomic, and metabolomic level. Our research proposes an integrative study approach allowing us to bridge meta-omics with functional mechanisms by focusing on the interaction taking place between F. nucleatum and patient-derived CRC cells. [less ▲]

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See detailMicrobiome in Colorectal Cancer: How to Getfrom Meta-omics to Mechanism?
Ternes, Dominik UL; Karta, Jessica UL; Tsenkova, Mina UL et al

in Trends in Microbiology (2020)

Mounting evidence from metagenomic analyses suggests that a state of pathological microbial imbalance or dysbiosis is prevalent in the gut of patients with colorectal cancer. Several bacterial taxa have ... [more ▼]

Mounting evidence from metagenomic analyses suggests that a state of pathological microbial imbalance or dysbiosis is prevalent in the gut of patients with colorectal cancer. Several bacterial taxa have been identified of which representative isolate cultures interact with human cancer cells in vitro and trigger disease path-ways in animal models. However, how the complex interrelationships in dysbiotic communities may be involved in cancer pathogenesis remains a crucial question.Here, we provide a survey of current knowledge of the gut microbiome in colorectal cancer. Moving beyond observational studies, we outline new experimental approaches for gaining ecosystem-level mechanistic understanding of the gut microbiome’s role in cancer pathogenesis [less ▲]

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See detailConnecting environmental exposure and neurodegeneration using cheminformatics and high resolution mass spectrometry: potential and challenges
Schymanski, Emma UL; Baker, Nancy C.; Williams, Antony J et al

in Environmental Science. Processes and Impacts (2019)

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary ... [more ▼]

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary approach. Rapid developments in analytical and data technologies, such as non-target high resolution mass spectrometry (NT-HR-MS), have opened up new possibilities to accomplish this, inconceivable 20 years ago. While NT-HR-MS is being applied to increasingly complex research questions, there are still many unidentified chemicals and uncertainties in linking exposures to human health outcomes and environmental impacts. In this perspective, we explore the possibilities and challenges involved in using cheminformatics and NT-HR-MS to answer complex questions that cross many scientific disciplines, taking the identification of potential (small molecule) neurotoxicants in environmental or biological matrices as a case study. We explore capturing literature knowledge and patient exposure information in a form amenable to high-throughput data mining, and the related cheminformatic challenges. We then briefly cover which sample matrices are available, which method(s) could potentially be used to detect these chemicals in various matrices and what remains beyond the reach of NT-HR-MS. We touch on the potential for biological validation systems to contribute to mechanistic understanding of observations and explore which sampling and data archiving strategies may be required to form an accurate, sustained picture of small molecule signatures on extensive cohorts of patients with chronic neurodegenerative disorders. Finally, we reflect on how NT-HR-MS can support unravelling the contribution of the environment to complex diseases. [less ▲]

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