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Rare diseases may affect the quality of life of patients and be life-threatening. Therapeutic opportunities are often limited, in part because of the lack of understanding of the molecular mechanisms underlying these diseases. This can be ascribed to the low prevalence of rare diseases and therefore the lower sample sizes available for research. A way to overcome this is to integrate experimental rare disease data with prior knowledge using network-based methods. Taking this one step further, we hypothesized that combining and analyzing the results from multiple network-based methods could provide data-driven hypotheses of pathogenic mechanisms from multiple perspectives.We analyzed a Huntington's disease transcriptomics dataset using six network-based methods in a collaborative way. These methods either inherently reported enriched annotation terms or their results were fed into enrichment analyses. The resulting significantly enriched Reactome pathways were then summarized using the ontological hierarchy which allowed the integration and interpretation of outputs from multiple methods. Among the resulting enriched pathways, there are pathways that have been shown previously to be involved in Huntington's disease and pathways whose direct contribution to disease pathogenesis remains unclear and requires further investigation.In summary, our study shows that collaborative network analysis approaches are well-suited to study rare diseases, as they provide hypotheses for pathogenic mechanisms from multiple perspectives. Applying different methods to the same case study can uncover different disease mechanisms that would not be apparent with the application of a single method.
BACKGROUND: The mammalian Natural Killer Complex (NKC) harbors genes and gene families encoding a variety of C-type lectin-like proteins expressed on various immune cells. The NKC is a complex genomic region well-characterized in mice, humans and domestic animals. The major limitations of automatic annotation of the NKC in non-model animals include short-read based sequencing, methods of assembling highly homologous and repetitive sequences, orthologues missing from reference databases and weak expression. In this situation, manual annotations of complex genomic regions are necessary. METHODS: This study presents a manual annotation of the genomic structure of the NKC region in a high-quality reference genome of the domestic cat and compares it with other felid species and with representatives of other carnivore families. Reference genomes of Carnivora, irrespective of sequencing and assembly methods, were screened by BLAST to retrieve information on their killer cell lectin-like receptor (KLR) gene content. Phylogenetic analysis of in silico translated proteins of expanded subfamilies was carried out. RESULTS: The overall genomic structure of the NKC in Carnivora is rather conservative in terms of its C-type lectin receptor gene content. A novel KLRH-like gene subfamily (KLRL) was identified in all Carnivora and a novel KLRJ-like gene was annotated in the Mustelidae. In all six families studied, one subfamily (KLRC) expanded and experienced pseudogenization. The KLRH gene subfamily expanded in all carnivore families except the Canidae. The KLRL gene subfamily expanded in carnivore families except the Felidae and Canidae, and in the Canidae it eroded to fragments. CONCLUSIONS: Knowledge of the genomic structure and gene content of the NKC region is a prerequisite for accurate annotations of newly sequenced genomes, especially of endangered wildlife species. Identification of expressed genes, pseudogenes and gene fragments in the context of expanded gene families would allow the assessment of functionally important variability in particular species.
- MeSH
- anotace sekvence MeSH
- buňky NK * imunologie metabolismus MeSH
- Carnivora * genetika MeSH
- fylogeneze * MeSH
- genom MeSH
- genomika * metody MeSH
- kočky genetika MeSH
- lektiny typu C genetika MeSH
- zvířata MeSH
- Check Tag
- kočky genetika MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
BACKGROUND: The advancement of sequencing technologies results in the rapid release of hundreds of new genome assemblies a year providing unprecedented resources for the study of genome evolution. Within this context, the significance of in-depth analyses of repetitive elements, transposable elements (TEs) in particular, is increasingly recognized in understanding genome evolution. Despite the plethora of available bioinformatic tools for identifying and annotating TEs, the phylogenetic distance of the target species from a curated and classified database of repetitive element sequences constrains any automated annotation effort. Moreover, manual curation of raw repeat libraries is deemed essential due to the frequent incompleteness of automatically generated consensus sequences. RESULTS: Here, we present an example of a crowd-sourcing effort aimed at curating and annotating TE libraries of two non-model species built around a collaborative, peer-reviewed teaching process. Manual curation and classification are time-consuming processes that offer limited short-term academic rewards and are typically confined to a few research groups where methods are taught through hands-on experience. Crowd-sourcing efforts could therefore offer a significant opportunity to bridge the gap between learning the methods of curation effectively and empowering the scientific community with high-quality, reusable repeat libraries. CONCLUSIONS: The collaborative manual curation of TEs from two tardigrade species, for which there were no TE libraries available, resulted in the successful characterization of hundreds of new and diverse TEs in a reasonable time frame. Our crowd-sourcing setting can be used as a teaching reference guide for similar projects: A hidden treasure awaits discovery within non-model organisms.
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: The objective of this study was to compare the detection of caries in bitewing radiographs by multiple dentists with an automatic method and to evaluate the detection performance in the absence of a reliable ground truth. MATERIALS AND METHODS: Four experts and three novices marked caries using bounding boxes in 100 bitewing radiographs. The same dataset was processed by an automatic object detection deep learning method. All annotators were compared in terms of the number of errors and intersection over union (IoU) using pairwise comparisons, with respect to the consensus standard, and with respect to the annotator of the training dataset of the automatic method. RESULTS: The number of lesions marked by experts in 100 images varied between 241 and 425. Pairwise comparisons showed that the automatic method outperformed all dentists except the original annotator in the mean number of errors, while being among the best in terms of IoU. With respect to a consensus standard, the performance of the automatic method was best in terms of the number of errors and slightly below average in terms of IoU. Compared with the original annotator, the automatic method had the highest IoU and only one expert made fewer errors. CONCLUSIONS: The automatic method consistently outperformed novices and performed as well as highly experienced dentists. CLINICAL SIGNIFICANCE: The consensus in caries detection between experts is low. An automatic method based on deep learning can improve both the accuracy and repeatability of caries detection, providing a useful second opinion even for very experienced dentists.
- MeSH
- interproximální technika MeSH
- lidé MeSH
- náchylnost k zubnímu kazu * MeSH
- zubní kaz * diagnostické zobrazování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: The aim of this work was to assemble a large annotated dataset of bitewing radiographs and to use convolutional neural networks to automate the detection of dental caries in bitewing radiographs with human-level performance. MATERIALS AND METHODS: A dataset of 3989 bitewing radiographs was created, and 7257 carious lesions were annotated using minimal bounding boxes. The dataset was then divided into 3 parts for the training (70%), validation (15%), and testing (15%) of multiple object detection convolutional neural networks (CNN). The tested CNN architectures included YOLOv5, Faster R-CNN, RetinaNet, and EfficientDet. To further improve the detection performance, model ensembling was used, and nested predictions were removed during post-processing. The models were compared in terms of the [Formula: see text] score and average precision (AP) with various thresholds of the intersection over union (IoU). RESULTS: The twelve tested architectures had [Formula: see text] scores of 0.72-0.76. Their performance was improved by ensembling which increased the [Formula: see text] score to 0.79-0.80. The best-performing ensemble detected caries with the precision of 0.83, recall of 0.77, [Formula: see text], and AP of 0.86 at IoU=0.5. Small carious lesions were predicted with slightly lower accuracy (AP 0.82) than medium or large lesions (AP 0.88). CONCLUSIONS: The trained ensemble of object detection CNNs detected caries with satisfactory accuracy and performed at least as well as experienced dentists (see companion paper, Part II). The performance on small lesions was likely limited by inconsistencies in the training dataset. CLINICAL SIGNIFICANCE: Caries can be automatically detected using convolutional neural networks. However, detecting incipient carious lesions remains challenging.
- MeSH
- deep learning * MeSH
- lidé MeSH
- náchylnost k zubnímu kazu MeSH
- neuronové sítě MeSH
- zubní kaz * diagnostické zobrazování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Currently, there is very little research aimed at developing medical knowledge extraction tools for major West Slavic languages (Czech, Polish, and Slovak). This project lays the groundwork for a general medical knowledge extraction pipeline, introducing the resource vocabularies available for the respective languages (UMLS resources, ICD-10 translations and national drug databases). It demonstrates the utility of this approach on a case study using a large proprietary corpus of Czech oncology records consisting of more than 40 million words written about more than 4,000 patients. After correlating MedDRA terms found in patients' records with drugs prescribed to them, significant non-obvious associations were found between selected medical conditions being mentioned and the probability of certain drugs being prescribed over the course of the patient's treatment, in some cases increasing the probability of prescriptions by over 250%. This direction of research, producing large amounts of annotated data, is a prerequisite for training deep learning models and predictive systems.
- MeSH
- farmaceutické databáze * MeSH
- jazyk (prostředek komunikace) * MeSH
- lékařská onkologie MeSH
- lidé MeSH
- mezinárodní klasifikace nemocí MeSH
- znalosti MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Thermal reactions can significantly alter the metabolomic and lipidomic content of biofluids and tissues during storage. In this study, we investigated the stability of polar metabolites and complex lipids in dry human serum and mouse liver extracts over a three-day period under various temperature conditions. Specifically, we tested temperatures of -80 °C (freezer), -24 °C (freezer), -0.5 °C (polystyrene box with gel-based ice packs), +5 °C (refrigerator), +23 °C (laboratory, room temperature), and +30 °C (thermostat) to simulate the time between sample extraction and analysis, shipping dry extracts to different labs as an alternative to dry ice, and document the impact of higher temperatures on sample integrity. The extracts were analyzed using five fast liquid chromatography-mass spectrometry (LC-MS) methods to screen polar metabolites and complex lipids, and over 600 metabolites were annotated in serum and liver extracts. We found that storing dry extracts at -24 °C and partially at -0.5 °C provided comparable results to -80 °C (reference condition). However, increasing the storage temperatures led to significant changes in oxidized triacylglycerols, phospholipids, and fatty acids within three days. Polar metabolites were mainly affected at storage temperatures of +23 °C and +30 °C.
- Publikační typ
- časopisecké články MeSH
Giardia duodenalis (syn. G. intestinalis, G. lamblia) is a widespread gastrointestinal protozoan parasite with debated taxonomic status. Currently, eight distinct genetic sub-groups, termed assemblages A-H, are defined based on a few genetic markers. Assemblages A and B may represent distinct species and are both of human public health relevance. Genomic studies are scarce and the few reference genomes available, in particular for assemblage B, are insufficient for adequate comparative genomics. Here, by combining long- and short-read sequences generated by PacBio and Illumina sequencing technologies, we provide nine annotated genome sequences for reference from new clinical isolates (four assemblage A and five assemblage B parasite isolates). Isolates chosen represent the currently accepted classification of sub-assemblages AI, AII, BIII and BIV. Synteny over the whole genome was generally high, but we report chromosome-level translocations as a feature that distinguishes assemblage A from B parasites. Orthologue gene group analysis was used to define gene content differences between assemblage A and B and to contribute a gene-set-based operational definition of respective taxonomic units. Giardia is tetraploid, and high allelic sequence heterogeneity (ASH) for assemblage B vs. assemblage A has been observed so far. Noteworthy, here we report an extremely low ASH (0.002%) for one of the assemblage B isolates (a value even lower than the reference assemblage A isolate WB-C6). This challenges the view of low ASH being a notable feature that distinguishes assemblage A from B parasites, and low ASH allowed assembly of the most contiguous assemblage B genome currently available for reference. In conclusion, the description of nine highly contiguous genome assemblies of new isolates of G. duodenalis assemblage A and B adds to our understanding of the genomics and species population structure of this widespread zoonotic parasite.
- MeSH
- genomika MeSH
- Giardia lamblia * genetika MeSH
- Giardia genetika MeSH
- giardiáza * parazitologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
V komentované kazuistice je popsán případ pacientky s ulcerózní kolitidou (UC), která byla v úvodu stonání pro selhání konvenční terapie úspěšně léčena infliximabem. Pro dlouhodobou remisi UC bylo v třetím trimestru gravidity rozhodnuto o ukončení terapie biologikem. Pro relaps UC po porodu jsme indikovali zahájení terapie vedolizumabem (VDZ), na němž bylo dosaženo remise UC, a proto pacientka v následujícím průběhu pokračovala v udržovací léčbě VDZ. Na této terapii došlo k novému otěhotnění, které se vyvíjelo bez komplikací na uvedené léčbě. V práci je hodnocen přínos a možná rizika biologické léčby v graviditě.
The annotated case report describes the case of a patient with ulcerative colitis (UC) who was successfully treated with infliximab at the beginning of disease due to failure of conventional therapy. For a long-term remission of UC, it was decided to end biological therapy during the third trimester of pregnancy. For the relapse of UC after the delivery, the initiation of vedolizumab therapy was indicated, after which a remission of UC was achieved, and therefore VDZ maintenance treatment was continued in the following course. A new pregnancy occurred on this therapy, which developed without complications to the indicated treatment. This thesis evaluates the benefits and possible risks of biological treatment during pregnancy.
- MeSH
- dospělí MeSH
- gastrointestinální látky MeSH
- humanizované monoklonální protilátky aplikace a dávkování terapeutické užití MeSH
- indukce remise MeSH
- infliximab * aplikace a dávkování terapeutické užití MeSH
- komplikace těhotenství MeSH
- lidé MeSH
- maternofetální výměna látek účinky léků MeSH
- recidiva MeSH
- těhotenství účinky léků MeSH
- ulcerózní kolitida * farmakoterapie komplikace MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- těhotenství účinky léků MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: Distal embolization (DE) is a common complication of endovascular treatment (EVT). We investigated the association of radiological thrombus characteristics and treatment details with DE. METHODS: Patients with thin-slice (≤2.5 mm) baseline noncontrast computed tomography and computed tomography angiography from the ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke) were included. Thrombus annotation was performed manually on coregistered scans by experienced readers. We assessed thrombus location, distance from internal carotid artery terminus, length, perviousness, absolute attenuation, and hyperdense artery sign. In addition, we evaluated balloon guide catheter use during EVT, first-line EVT approach, the number of thrombectomy passes, and prior intravenous thrombolysis administration. DE was defined as the occurrence of emboli distal to the target artery or in new territories during EVT. The association between thrombus characteristics, treatment details, and DE was evaluated using descriptive statistics and multivariable mixed-effects logistic regression, resulting in adjusted odds ratios (aOR) with 95% CI. Interaction between IVT and radiological thrombus characteristics was assessed by adding interaction terms in separate models. RESULTS: In total, 496 out of 1105 (44.9%) ESCAPE-NA1 patients were included. DE was detected in 251 out of 496 patients (50.6%). Patients with DE had longer thrombi (median, 28.5 [interquartile range, 20.8-42.3] mm versus 24.4 [interquartile range, 17.1-32.4] mm; P<0.01). There were no statistically significant differences in the other thrombus characteristics. Factors associated with DE were thrombus length (aOR, 1.02 [95% CI, 1.01-1.04]), balloon guide catheter use (aOR, 0.49 [95% CI, 0.29-0.85]), and number of passes (aOR, 1.24 [95% CI, 1.04-1.47]). In patients with hyperdense artery sign, IVT was associated with reduced odds of DE (aOR, 0.55 [95% CI, 0.31-0.97]), P for interaction=0.04. CONCLUSIONS: DE was associated with longer thrombi, no balloon guide catheter use, and more EVT passes. IVT was associated with a reduced risk of DE in patients with hyperdense artery sign. These findings may support treatment decisions on IVT and EVT approaches.
- MeSH
- cévní mozková příhoda * terapie MeSH
- endovaskulární výkony * škodlivé účinky MeSH
- ischemická cévní mozková příhoda * etiologie MeSH
- ischemie mozku * terapie MeSH
- lidé MeSH
- trombektomie MeSH
- trombolytická terapie metody MeSH
- trombóza * etiologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
