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Functional annotation of genes remains a challenge in fundamental biology and is a limiting factor for translational medicine. Computational approaches have been developed to process heterogeneous data into meaningful metrics, but often do not address how findings might be updated when new evidence comes to light. To address this challenge, we describe requirements for a framework for incremental data integration and propose an implementation based on phenotype ontologies and Bayesian probability updates. We apply the framework to quantify similarities between gene annotations and disease profiles. Within this scope, we categorize human diseases according to how well they can be recapitulated by animal models and quantify similarities between human diseases and mouse models produced by the International Mouse Phenotyping Consortium. The flexibility of the approach allows us to incorporate negative phenotypic data to better prioritize candidate genes, and to stratify disease mapping using sex-dependent phenotypes. All our association scores can be updated and we exploit this feature to showcase integration with curated annotations from high-precision assays. Incremental integration is thus a suitable framework for tracking functional annotations and linking to complex human pathology.

Periodontitis is inextricably linked to oxidative-reductive (redox) imbalance. However, little is still known about the resultant ability to scavenge oxygen free radicals in saliva and gingival crevicular fluid in patients with periodontitis. The multitude of enzymatic and non-enzymatic antioxidants and their synergistic effects cause an interest in the evaluation of the total antioxidative capacity. Thus, our study aimed to evaluate the total oxidative and antioxidative activity of gingival crevicular fluid and saliva in the periodontitis, as well as to relate these biomarkers to clinical indices of periodontopathy. Additionally, by calculating the oxidative stress index (OSI), the intensity of redox disturbances was also evaluated. Fifty-eight periodontitis patients were included in the study and divided into two subgroups depending on the severity of the disease. In the non-stimulated/stimulated saliva as well as a gingival crevicular fluid of the study group, we found significantly higher OSI and total oxidant status (TOS) as well as lower total antioxidant capacity (TAC). However, the ability to reduce iron ions (FRAP) was significantly lower only in stimulated and non-stimulated saliva of patients with periodontitis. The examined parameters correlated with the periodontium’s clinical condition, which indicates the exacerbation of the inflammatory process. However, TAC, TOS, OSI, and FRAP did not differentiate individual stages of periodontitis.

With the growing interest in new applications of metals in modern technologies, an increase in their concentration in the environment can be observed, which, in consequence, may constitute a hazard to human health. That is why it is of a great importance to establish “reference” levels of particular elements (essential or toxic) in human biological samples.The aim of this paper was to determine nickel in autopsy tissues of non-occupationally exposed subjects in Southern Poland (n = 60). Measurements were performed by means of electrothermal atomic absorption spectrometry after microwave-assisted acid digestion according to previously optimized and validated procedure. The results obtained indicate that data cover the wide range of concentrations and generally are consistent with other published findings. Nickel levels in the brain, stomach, liver, kidneys, lungs and heart (wet weight) were between 2.15–79.4 ng/g, 0.5–44.2 ng/g,7.85–519 ng/g, 12.8–725 ng/g, 8.47–333 ng/g and 2.3–97.7 ng/g, respectively. Females had generally lower levels of nickel in tissues than males (statistically significant relationships were found for the liver, kidneys and lungs), and median nickel concentrations in all studied material within all age groups had very similar values, with the exception of stomach.

Integrating reference datasets (e.g. from high-throughput experiments) with unstructured and manually-assembled information (e.g. notes or comments from individual researchers) has the potential to tailor bioinformatic analyses to specific needs and to lead to new insights. However, developing bespoke analysis pipelines from scratch is time-consuming, and general tools for exploring such heterogeneous data are not available. We argue that by treating all data as text, a knowledge-base can accommodate a range of bioinformatic data types and applications. We show that a database coupled to nearest-neighbor algorithms can address common tasks such as gene-set analysis as well as specific tasks such as ontology translation. We further show that a mathematical transformation motivated by diffusion can be effective for exploration across heterogeneous datasets. Diffusion enables the knowledge-base to begin with a sparse query, impute more features, and find matches that would otherwise remain hidden. This can be used, for example, to map multi-modal queries consisting of gene symbols and phenotypes to descriptions of diseases. Diffusion also enables user-driven learning: when the knowledge-base cannot provide satisfactory search results in the first instance, users can improve the results in real-time by adding domain-specific knowledge. User-driven learning has implications for data management, integration, and curation.

A substantial fraction of the human genome displays high sequence similarity with at least one other genomic sequence, posing a challenge for the identification of somatic mutations from short-read sequencing data. Here we annotate genomic variants in 2,658 cancers from the Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort with links to similar sites across the human genome. We train a machine learning model to use signals distributed over multiple genomic sites to call somatic events in non-unique regions and validate the data against linked-read sequencing in an independent dataset. Using this approach, we uncover previously hidden mutations in ~1,700 coding sequences and in thousands of regulatory elements, including in known cancer genes, immunoglobulins and highly mutated gene families. Mutations in non-unique regions are consistent with mutations in unique regions in terms of mutation burden and substitution profiles. The analysis provides a systematic summary of the mutation events in non-unique regions at a genome-wide scale across multiple human cancers. Cancer mutations in non-unique sequences are identified by machine learning on short-read data.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Fu ll S pectrum of I ntolerance to L oss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Diagnosis of periodontopathy is complex and includes defining the cause, type, stage, and grade of periodontitis. Therefore, alternative diagnostic methods are sought to indicate the progression of inflammation or to determine the effectiveness of therapy. Gingival crevicular fluid (GCF) biomarkers can be particularly useful because they most likely reflect the disease process of the periodontal tissues. However, the difficulty of collecting GCF for testing is the reason for the limited use in diagnostics. Because periodontitis is the primary source of nitrogen free radicals in the oral cavity, the aim of the study was to evaluate the biomarkers of nitrosative stress (nitric oxide, peroxynitrite, and S-nitrosothiols) in GCF, non-stimulated and stimulated saliva of 90 patients with periodontitis. The study group was divided into two subgroups, depending on the stage of the disease severity. We showed a significantly higher concentration of all assessed biomarkers in the non-stimulated and stimulated saliva of patients with periodontitis. However, significant changes in GCF has been shown only for peroxynitrite. The studied biomarkers did not correlate with clinical periodontal status, which probably results from their short-duration activity and the impact on a few factors in the oral cavity. Saliva and gingival fluid are not very useful in the differential diagnosis of periodontitis.

Patterns of somatic mutations in cancer genes provide information about their functional role in tumourigenesis, and thus indicate their potential for therapeutic exploitation. Yet, the classical distinction between oncogene and tumour suppressor may not always apply. For instance, TP53 has been simultaneously associated with tumour suppressing and promoting activities. Here, we uncover a similar phenomenon for GATA3, a frequently mutated, yet poorly understood, breast cancer gene. We identify two functional classes of frameshift mutations that are associated with distinct expression profiles in tumours, differential disease-free patient survival and gain- and loss-of-function activities in a cell line model. Furthermore, we find an estrogen receptor-independent synthetic lethal interaction between a GATA3 frameshift mutant with an extended C-terminus and the histone methyltransferases G9A and GLP, indicating perturbed epigenetic regulation. Our findings reveal important insights into mutant GATA3 function and breast cancer, provide the first potential therapeutic strategy and suggest that dual tumour suppressive and oncogenic activities are more widespread than previously appreciated.

The development of polymer matrices as dental drug carriers takes into account the following technological aspects of the developed formulations: the composition and the technology used to manufacture them, which affect the properties of the carriers, as well as the testing methods for assessing their behavior at application sites. The first part of this paper characterizes the methods for fabricating dental drug carriers, i.e., the solvent-casting method (SCM), lyophilization method (LM), electrospinning (ES) and 3D printing (3DP), describing the selection of technological parameters and pointing out both the advantages of using the mentioned methods and their limitations. The second part of this paper describes testing methods to study the formulation properties, including their physical and chemical, pharmaceutical, biological and in vivo evaluation. Comprehensive in vitro evaluation of carrier properties permits optimization of formulation parameters to achieve prolonged retention time in the dynamic oral environment and is essential for explaining carrier behavior during clinical evaluation, consequently enabling the selection of the optimal formulation for oral application.

Background: Oral Lichen planus (OLP) is a chronic inflammatory disease. Topical steroids are used as the treatment of choice. The alternative is photodynamic therapy (PDT). The study aimed to fabricate optimal biodegradable matrices for methylene blue or triamcinolone acetonide because of a lack of currently commercially available carriers that could adhere to the mucous. Methods: The study was designed as a 12-week single-blind prospective randomized clinical trial with 30 patients, full contralateral split-mouth design. Matrices for steroid and photosensitizer and laser device were fabricated. Fractal and texture analysis of photographs, taken in 405, 450, 405 + 450 nm wavelength, of lesions was performed to increase the objectivity of the assessment of treatment. Results: We achieved two total responses for treatment in case of steroid therapy and one in the case of PDT. Partial response was noted in 17 lesions treated using local steroid therapy and 21 in the case of PDT. No statistically significant differences were found between the effectiveness of both used methods. Statistically significant differences in fractal dimension before and after treatment were observed only in the analysis of photographs taken in 405 + 450 nm wavelength. Conclusions: Photodynamic therapy and topical steroid therapy are effective methods for treating OLP. Using a carrier offers the possibility of a more predictable and effective method of drug delivery into the mucous membrane. Autofluorescence enables the detection of lesions especially at the early stage of their development.