Project description:BackgroundPrevious studies reported varyingly positive, negative, or no relationships between caries and periodontitis. Therefore, the aim was to assess the potential co-occurrence of caries experience and periodontal inflammation on the same teeth.MethodsThis cross-sectional study used data from the Lithuanian National Oral Health Survey. The study included a stratified random sample of 1405 individuals aged 34-78, recruited from 5 Lithuanian cities and 10 peri-urban/rural areas (response rate 52%). Information about sociodemographic (age, sex, education, residence), behavioral (sugar-containing diet, tooth brushing frequency, use of interdental care products, last dental visit, smoking) and biological (systemic disease, use of medication and xerostomia) determinants was collected using the World Health Organization (WHO) Oral Health Questionnaire for Adults supplemented with additional questions. Clinical data were recorded using the WHO criteria and collected by one trained and calibrated examiner. Dental caries status was recorded as sound, decayed, missing, filled surfaces. Subsequently for the analyses, status was recorded at a tooth-level as decayed- and filled-teeth (DT and FT) including proximal, buccal, and oral surfaces. Two measures were used for periodontal status. The probing pocket depth (PPD) was measured at six sites and recorded at a tooth level into the absence of PPD or presence of PPD ≥ 4 mm. Bleeding on probing (BOP) was measured at the same six sites and was recorded as either present or absent at a tooth-level. Univariable and multivariable 2-level random intercept binary logistic regression analyses were utilized.ResultsPositive associations were found between DT and BOP (OR 1.42, 95% CI 1.20-1.67), FT and BOP (OR 2.07, 95% CI 1.82-2.23), DT and PPD (OR 1.38, 95% CI 1.15-1.67) and FT and PPD (OR 2.01, 95% CI 1.83-2.20).ConclusionsOur findings add evidence for the co-occurrence of periodontal inflammation and caries on the same teeth. This suggests the need for increased emphasis on a transdisciplinary approach in designing oral health interventions that target dental caries and periodontal disease simultaneously. In addition, longitudinal studies exploring the co-occurrence of caries and periodontal disease at the same sites, taking into consideration the levels of both conditions and genetic variation, are warranted.
Project description:Creativity is a complex, multi-faceted concept encompassing a variety of related aspects, abilities, properties and behaviours. If we wish to study creativity scientifically, then a tractable and well-articulated model of creativity is required. Such a model would be of great value to researchers investigating the nature of creativity and in particular, those concerned with the evaluation of creative practice. This paper describes a unique approach to developing a suitable model of how creative behaviour emerges that is based on the words people use to describe the concept. Using techniques from the field of statistical natural language processing, we identify a collection of fourteen key components of creativity through an analysis of a corpus of academic papers on the topic. Words are identified which appear significantly often in connection with discussions of the concept. Using a measure of lexical similarity to help cluster these words, a number of distinct themes emerge, which collectively contribute to a comprehensive and multi-perspective model of creativity. The components provide an ontology of creativity: a set of building blocks which can be used to model creative practice in a variety of domains. The components have been employed in two case studies to evaluate the creativity of computational systems and have proven useful in articulating achievements of this work and directions for further research.
Project description:The rates at which domains fold and codons are translated are important factors in determining whether a nascent protein will co-translationally fold and function or misfold and malfunction. In this study, we develop a chemical kinetic model that calculates a protein domain’s co-translational folding curve using only the domain’s bulk folding and unfolding rates and codon translation rates. We show that this model accurately predicts the course of co-translational folding measured in vivo for four different protein molecules. As part of our chemical kinetic model, we assume that there is steady-state translation kinetics through the time-course of the experiment. To prove that this assumption is valid, we performed Ribo-Seq experiments on two biological replicates of yeast cells to compare their ribosome profiles. For genes with sufficient coverage across the open reading frames in both the replicates, we compare the ribosome profiles from both replicates and see a strong correlation. This implies there is a steady-state and our assumption is valid.
Project description:Recent GWAS studies have made extensive use of large eQTL data sets to functionally
annotate index SNPs. With a large number of association signals located outside coding
regions there has been an intense search among sequence variants affecting gene
expression at the transcriptional level. However, little progress has been made in mapping
regulatory variants that affect protein levels at the translational or post-translational level. It is
now possible to undertake a protein QTL scan for focused sets of e.g. oxidized proteins by
mass spectrometry. We have established a collaboration with a longitudinal, family-based
study in France, the Stanislas cohort, which comprises circa 1000 nuclear families (4,295
individuals) and has follow up data for 10 years (three visits). We have undertaken a pilot
study in a focus set of 257 subjects from 79 families with the aim to integrate GWAS,
transcriptomic and DNA methylation data with proteomic data on a set of 100 proteins
measured in PBMCs. We have already generated GWAS data using Illumina's core-exome
chip as well as DNA methylation profiles with the 450K array. We propose to use RNA seq to
generate transcriptomic data of the corresponding PBMCs.
This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
Project description:Microbial co-cultures have been used in several biotechnological applications. Within these co-cultures, the microorganisms tend to interact with each other and perform complex actions. Investigating metabolic interactions in microbial co-cultures is crucial in designing microbial consortia. Here, we present a pipeline integrating modelling and experimental approaches to understand metabolic interactions between organisms in a community. We define a new index named "Metabolic Support Index (MSI)", which quantifies the benefits derived by each organism in the presence of the other when grown as a co-culture. We computed MSI for several experimentally demonstrated co-cultures and showed that MSI, as a metric, accurately identifies the organism that derives the maximum benefit. We also computed MSI for a commonly used yeast co-culture consisting of Saccharomyces cerevisiae and Pichia stipitis and observed that the latter derives higher benefit from the interaction. Further, we designed two-stage experiments to study mutual interactions and showed that P. stipitis indeed derives the maximum benefit from the interaction, as shown from our computational predictions. Also, using our previously developed computational tool MetQuest, we identified all the metabolic exchanges happening between these organisms by analysing the pathways spanning the two organisms. By analysing the HPLC profiles and studying the isotope labelling, we show that P. stipitis consumes the ethanol produced by S. cerevisiae when grown on glucose-rich medium under aerobic conditions, as also indicated by our in silico pathway analyses. Our approach represents an important step in understanding metabolic interactions in microbial communities through an integrated computational and experimental workflow.
Project description:The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the enzyme may be targeted both covalently and non-covalently, minimal studies provide effective inhibitors against it. Recently, research has focused on covalent inhibitors based on their characteristic, highly-selective warheads and ability to prevent drug resistance. This prompted us to screen for new covalent inhibitors of Nedd4-1 using a combination of computational approaches. However, this task proved challenging due to the limited number of electrophilic moieties available in virtual libraries. Therefore, we opted to divide an existing covalent Nedd4-1 inhibitor into two parts: a non-covalent binding group and a pre-selected α, β-unsaturated ester that forms the covalent linkage with the protein. A non-covalent pharmacophore model was built based on molecular interactions at the binding site. The pharmacophore was then subjected to virtual screening to identify structurally similar hit compounds. Multiple filtrations were implemented prior to selecting four hits, which were validated with a covalent conjugation and later assessed by molecular dynamic simulations. The results showed that, of the four hit molecules, Zinc00937975 exhibited advantageous molecular groups, allowing for favourable interactions with one of the characteristic cysteine residues. Predictive pharmacokinetic analysis further justified the compound as a potential lead molecule, prompting its recommendation for confirmatory biological evaluation. Our inhouse, refined, pharmacophore model approach serves as a robust method that will encourage screening for novel covalent inhibitors in drug discovery.
Project description:Specific genetic variants in the mitochondrially encoded 12S ribosomal RNA gene (MT-RNR1) cause aminoglycoside-induced irreversible hearing loss. Mitochondrial DNA is usually not included in targeted sequencing experiments; however, off-target data may deliver this information. Here, we extract MT-RNR1 genetic variation, including the most relevant ototoxicity variant m.1555A>G, using the off-target reads of 473 research samples, sequenced through a capture-based, custom-targeted panel and whole exome sequencing (WES), and of 1245 diagnostic samples with clinical WES. Sanger sequencing and fluorescence-based genotyping were used for genotype validation. There was a correlation between off-target reads and mitochondrial coverage (rcustomPanel = 0.39, p = 2 × 10-13 and rWES = 0.67, p = 7 × 10-21). The median read depth of MT-RNR1 m.1555 was similar to the average mitochondrial genome coverage, with saliva and blood samples giving comparable results. The genotypes from 415 samples, including three m.1555G carriers, were concordant with fluorescence-based genotyping data. In clinical WES, median MT-RNR1 coverage was 56×, with 90% of samples having ≥20 reads at m.1555 position, and one m.1494T and three m.1555G carriers were identified with no evidence for heteroplasmy. Altogether, this study shows that obtaining MT-RNR1 genotypes through off-target reads is an efficient strategy that can impulse preemptive pharmacogenetic screening of this mitochondrial gene.
Project description:In this study we determined the target spectrum of the Vibrio cholerae dual RNA regulator VcdRP via pulse-expression of different variants followed by RNA-sequencing.
Project description:PURPOSE: A homozygous mutation in the H6 family homeobox 1 (HMX1) gene is responsible for a new oculoauricular defect leading to eye and auricular developmental abnormalities as well as early retinal degeneration (MIM 612109). However, the HMX1 pathway remains poorly understood, and in the first approach to better understand the pathway's function, we sought to identify the target genes. METHODS: We developed a predictive promoter model (PPM) approach using a comparative transcriptomic analysis in the retina at P15 of a mouse model lacking functional Hmx1 (dmbo mouse) and its respective wild-type. This PPM was based on the hypothesis that HMX1 binding site (HMX1-BS) clusters should be more represented in promoters of HMX1 target genes. The most differentially expressed genes in the microarray experiment that contained HMX1-BS clusters were used to generate the PPM, which was then statistically validated. Finally, we developed two genome-wide target prediction methods: one that focused on conserving PPM features in human and mouse and one that was based on the co-occurrence of HMX1-BS pairs fitting the PPM, in human or in mouse, independently. RESULTS: The PPM construction revealed that sarcoglycan, gamma (35kDa dystrophin-associated glycoprotein) (Sgcg), teashirt zinc finger homeobox 2 (Tshz2), and solute carrier family 6 (neurotransmitter transporter, glycine) (Slc6a9) genes represented Hmx1 targets in the mouse retina at P15. Moreover, the genome-wide target prediction revealed that mouse genes belonging to the retinal axon guidance pathway were targeted by Hmx1. Expression of these three genes was experimentally validated using a quantitative reverse transcription PCR approach. The inhibitory activity of Hmx1 on Sgcg, as well as protein tyrosine phosphatase, receptor type, O (Ptpro) and Sema3f, two targets identified by the PPM, were validated with luciferase assay. CONCLUSIONS: Gene expression analysis between wild-type and dmbo mice allowed us to develop a PPM that identified the first target genes of Hmx1.