Bardet-Biedl syndrome (BBS) is an archetypal ciliopathy caused by dysfunction of primary cilia. BBS affects multiple tissues, including the kidney, eye and hypothalamic satiety response. Understanding pan-tissue mechanisms of pathogenesis versus those which are tissue-specific, as well as gauging their associated inter-individual variation owing to genetic background and stochastic processes, is of paramount importance in syndromology. The BBSome is a membrane-trafficking and intraflagellar transport (IFT) adaptor protein complex formed by eight BBS proteins, including BBS1, which is the most commonly mutated gene in BBS. To investigate disease pathogenesis, we generated a series of clonal renal collecting duct IMCD3 cell lines carrying defined biallelic nonsense or frameshift mutations in Bbs1, as well as a panel of matching wild-type CRISPR control clones. Using a phenotypic screen and an unbiased multi-omics approach, we note significant clonal variability for all assays, emphasising the importance of analysing panels of genetically defined clones. Our results suggest that BBS1 is required for the suppression of mesenchymal cell identities as the IMCD3 cell passage number increases. This was associated with a failure to express epithelial cell markers and tight junction formation, which was variable amongst clones. Transcriptomic analysis of hypothalamic preparations from BBS mutant mice, as well as BBS patient fibroblasts, suggested that dysregulation of epithelial-to-mesenchymal transition (EMT) genes is a general predisposing feature of BBS across tissues. Collectively, this work suggests that the dynamic stability of the BBSome is essential for the suppression of mesenchymal cell identities as epithelial cells differentiate.

• MeSH
• Bardet-Biedl Syndrome * genetics   metabolism   pathology   MeSH
• Cilia metabolism   MeSH
• Humans MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Microtubule-Associated Proteins metabolism   MeSH
• Proteins metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The turnover of microbial communities across space is dictated by local and regional factors. Locally, selection shapes community assembly through biological interactions between organisms and the environment, while regional factors influence microbial dispersion patterns. Methods used to disentangle the effects of local and regional factors typically do not aim to identify ecological processes underlying the turnover. In this paper, we identified and quantified these processes for three operational microbial subcommunities (cyanobacteria, particle-attached, and free-living bacteria) from a tropical cascade of freshwater reservoirs with decreasing productivity, over two markedly different dry and rainy seasons. We hypothesized that during the dry season communities would mainly be controlled by selection shaped by the higher environmental heterogeneity that results from low hydrological flow and connectivity between reservoirs. We expected highly similar communities shaped by dispersal and a more homogenized environment during the rainy season, enhanced by increased flow rates. Even if metacommunities were largely controlled by regional events in both periods, the selection had more influence on free-living communities during the dry period, possibly related to elevated dissolved organic carbon concentration, while drift as a purely stochastic factor, had more influence on cyanobacterial communities. Each subcommunity had distinct patterns of turnover along the cascade related to diversity (Cyanobacteria), lifestyle and size (Free-living), and spatial dynamics (particle-attached).

• Publication type
• Journal Article MeSH

Dynamic modeling of biological systems is essential for understanding all properties of a given organism as it allows us to look not only at the static picture of an organism but also at its behavior under various conditions. With the increasing amount of experimental data, the number of tools that enable dynamic analysis also grows. However, various tools are based on different approaches, use different types of data and offer different functions for analyses; so it can be difficult to choose the most suitable tool for a selected type of model. Here, we bring a brief overview containing descriptions of 50 tools for the reconstruction of biological models, their time-course simulation and dynamic analysis. We examined each tool using test data and divided them based on the qualitative and quantitative nature of the mathematical apparatus they use.

• MeSH
• Models, Biological * MeSH
• Datasets as Topic MeSH
• Gene Regulatory Networks MeSH
• Humans MeSH
• Computer Simulation MeSH
• Software * MeSH
• Stochastic Processes MeSH
• Systems Biology methods   MeSH
• Information Storage and Retrieval MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Objective: Conventional selection of pre-ictal EEG epochs for seizure prediction algorithm training data typically assumes a continuous pre-ictal brain state preceding a seizure. This is carried out by defining a fixed duration, pre-ictal time period before seizures from which pre-ictal training data epochs are uniformly sampled. However, stochastic physiological and pathological fluctuations in EEG data characteristics and underlying brain states suggest that pre-ictal state dynamics may be more complex, and selection of pre-ictal training data segments to reflect this could improve algorithm performance. Methods: We propose a semi-supervised technique to select pre-ictal training data most distinguishable from interictal EEG according to pre-specified data characteristics. The proposed method uses hierarchical clustering to identify optimal pre-ictal data epochs. Results: In this paper we compare the performance of a seizure forecasting algorithm with and without hierarchical clustering of pre-ictal periods in chronic iEEG recordings from six canines with naturally occurring epilepsy. Hierarchical clustering of training data improved results for Time In Warning (TIW) (0.18 vs. 0.23) and False Positive Rate (FPR) (0.5 vs. 0.59) when evaluated across all subjects (p<0.001, n=6). Results were mixed when evaluating TIW, FPR, and Sensitivity for individual dogs. Conclusion: Hierarchical clustering is a helpful method for training data selection overall, but should be evaluated on a subject-wise basis. Significance: The clustering method can be used to optimize results of forecasting towards sensitivity or TIW or FPR, and therefore can be useful for epilepsy management.

• Publication type
• Journal Article MeSH

• MeSH
• Neoplasms radiotherapy   MeSH
• Nuclear Medicine methods   MeSH
• Radiotherapy methods   MeSH
• Publication type
• Textbook MeSH

• Conspectus
• Učební osnovy. Vyučovací předměty. Učebnice
• Lékařské vědy. Lékařství
• NML Fields
• radiologie, nukleární medicína a zobrazovací metody
• onkologie
• NML Publication type
• kolektivní monografie

Neuronal firing rate is traditionally defined as the number of spikes per time window. The concept is essential for the rate coding hypothesis, which is still the most commonly investigated scenario in neuronal activity analysis. The estimation of dynamically changing firing rate from neural data can be challenging due to the variability of spike times, even under identical external conditions; hence a wide range of statistical measures have been employed to solve this particular problem. In this paper, we review established firing rate estimation methods, briefly summarize the technical aspects of each approach and discuss their practical applications.

• MeSH
• Action Potentials * MeSH
• Algorithms MeSH
• Bayes Theorem MeSH
• Data Interpretation, Statistical MeSH
• Humans MeSH
• Models, Neurological MeSH
• Neurons physiology   MeSH
• Probability MeSH
• Stochastic Processes MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

KEY MESSAGE: Standard pathways involved in the regulation of telomere stability do not contribute to gradual telomere elongation observed in the course of A. thaliana calli propagation. Genetic and epigenetic changes accompanying the culturing of plant cells have frequently been reported. Here we aimed to characterize the telomere homeostasis during long term callus propagation. While in Arabidopsis thaliana calli gradual telomere elongation was observed, telomeres were stable in Nicotiana tabacum and N. sylvestris cultures. Telomere elongation during callus propagation is thus not a general feature of plant cells. The long telomere phenotype in Arabidopsis calli was correlated neither with changes in telomerase activity nor with activation of alternative mechanisms of telomere elongation. The dynamics of telomere length changes was maintained in mutant calli with loss of function of important epigenetic modifiers but compromised in the presence of epigenetically active drug zebularine. To examine whether the cell culture-induced disruption of telomere homeostasis is associated with the modulated structure of chromosome ends, epigenetic properties of telomere chromatin were analysed. Albeit distinct changes in epigenetic modifications of telomere histones were observed, these were broadly stochastic. Our results show that contrary to animal cells, the structure and function of plant telomeres is not determined significantly by the epigenetic character of telomere chromatin. Set of differentially transcribed genes was identified in calli, but considering the known telomere- or telomerase-related functions of respective proteins, none of these changes per se was apparently related to the elongated telomere phenotype. Based on our data, we propose that the disruption in telomere homeostasis in Arabidopsis calli arises from the interplay of multiple factors, as a part of reprogramming of plant cells to long-term culture conditions.

• MeSH
• Arabidopsis drug effects   genetics   metabolism   MeSH
• Chromatin genetics   MeSH
• Cytidine analogs & derivatives   pharmacology   MeSH
• Species Specificity MeSH
• Ecotype MeSH
• Epigenesis, Genetic drug effects   MeSH
• Histones metabolism   MeSH
• Telomere Homeostasis * drug effects   MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Mutation genetics   MeSH
• Arabidopsis Proteins metabolism   MeSH
• Regeneration drug effects   MeSH
• Genes, Plant MeSH
• Nicotiana genetics   MeSH
• Tissue Culture Techniques * MeSH
• Telomerase metabolism   MeSH
• Telomere metabolism   MeSH
• Publication type
• Journal Article MeSH

Disease control strategies can have both intended and unintended effects on the dynamics of infectious diseases. Routine testing for the harmful pathogen Bovine Tuberculosis (bTB) was suspended briefly during the foot and mouth disease epidemic of 2001 in Great Britain. Here we utilize bTB incidence data and mathematical models to demonstrate how a lapse in management can alter epidemiological parameters, including the rate of new infections and duration of infection cycles. Testing interruption shifted the dynamics from annual to 4-year cycles, and created long-lasting shifts in the spatial synchrony of new infections among regions of Great Britain. After annual testing was introduced in some GB regions, new infections have become more de-synchronised, a result also confirmed by a stochastic model. These results demonstrate that abrupt events can synchronise disease dynamics and that changes in the epidemiological parameters can lead to chaotic patterns, which are hard to be quantified, predicted, and controlled.

• MeSH
• Spatio-Temporal Analysis * MeSH
• Disease Outbreaks * MeSH
• Epidemiological Monitoring MeSH
• Incidence MeSH
• Mycobacterium bovis isolation & purification   MeSH
• Cattle MeSH
• Models, Statistical * MeSH
• Stochastic Processes MeSH
• Tuberculosis, Bovine epidemiology   microbiology   transmission   MeSH
• Animals MeSH
• Check Tag
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• United Kingdom MeSH

Vital mitochondrial DNA (mtDNA) populations exist in cells and may consist of heteroplasmic mixtures of mtDNA types. The evolution of these heteroplasmic populations through development, ageing, and generations is central to genetic diseases, but is poorly understood in mammals. Here we dissect these population dynamics using a dataset of unprecedented size and temporal span, comprising 1947 single-cell oocyte and 899 somatic measurements of heteroplasmy change throughout lifetimes and generations in two genetically distinct mouse models. We provide a novel and detailed quantitative characterisation of the linear increase in heteroplasmy variance throughout mammalian life courses in oocytes and pups. We find that differences in mean heteroplasmy are induced between generations, and the heteroplasmy of germline and somatic precursors diverge early in development, with a haplotype-specific direction of segregation. We develop stochastic theory predicting the implications of these dynamics for ageing and disease manifestation and discuss its application to human mtDNA dynamics.

• MeSH
• Datasets as Topic MeSH
• Genome, Mitochondrial genetics   MeSH
• Haplotypes genetics   MeSH
• DNA, Mitochondrial genetics   MeSH
• Mitochondria metabolism   MeSH
• Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Oocytes cytology   immunology   MeSH
• DNA Copy Number Variations genetics   MeSH
• Age Factors MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Protein translocation across cell membranes is a ubiquitous process required for protein secretion and membrane protein insertion. In bacteria, this is mostly mediated by the conserved SecYEG complex, driven through rounds of ATP hydrolysis by the cytoplasmic SecA, and the trans-membrane proton motive force. We have used single molecule techniques to explore SecY pore dynamics on multiple timescales in order to dissect the complex reaction pathway. The results show that SecA, both the signal sequence and mature components of the pre-protein, and ATP hydrolysis each have important and specific roles in channel unlocking, opening and priming for transport. After channel opening, translocation proceeds in two phases: a slow phase independent of substrate length, and a length-dependent transport phase with an intrinsic translocation rate of ~40 amino acids per second for the proOmpA substrate. Broad translocation rate distributions reflect the stochastic nature of polypeptide transport.

• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Adenosine Triphosphatases chemistry   genetics   metabolism   MeSH
• Bacterial Proteins chemistry   genetics   metabolism   MeSH
• Cell Membrane metabolism   MeSH
• Escherichia coli genetics   metabolism   MeSH
• Microscopy, Fluorescence methods   MeSH
• Hydrolysis MeSH
• Protein Conformation MeSH
• Models, Molecular MeSH
• Mutation MeSH
• Protein Sorting Signals genetics   MeSH
• Escherichia coli Proteins chemistry   genetics   metabolism   MeSH
• Proton-Motive Force * MeSH
• SEC Translocation Channels chemistry   genetics   metabolism   MeSH
• Protein Transport MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH