Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2's recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins.
- MeSH
- aktivace lymfocytů MeSH
- buněčná membrána metabolismus MeSH
- Drosophila melanogaster MeSH
- gating iontového kanálu MeSH
- HEK293 buňky MeSH
- konformace proteinů MeSH
- lidé MeSH
- membránové proteiny metabolismus MeSH
- mutace MeSH
- proteasy chemie MeSH
- protein ORAI1 chemie MeSH
- serinové endopeptidasy metabolismus MeSH
- signální transdukce MeSH
- stochastické procesy MeSH
- vápník metabolismus MeSH
- vápníková signalizace fyziologie MeSH
- vápníkové kanály chemie MeSH
- vazba proteinů MeSH
- výpočetní biologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
- biologické modely * MeSH
- datové soubory jako téma MeSH
- genové regulační sítě MeSH
- lidé MeSH
- počítačová simulace MeSH
- software * MeSH
- stochastické procesy MeSH
- systémová biologie metody MeSH
- ukládání a vyhledávání informací MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
In most temperate fruit trees, fruits are located on one-year old shoots. In Prunus species, flowers and fruits are born in axillary position along those shoots. The axillary bud fate and branching patterns are thus key components of the cultivar potential fruit production. The objective of this study was to analyze the branching and bearing behaviors of 1-year-old shoots of apricot cultivars and clones genetically closely related. Shoot structures were analyzed in terms of axillary bud fates using hidden semi-Markov chains and compared depending on the genotype, year and shoot length. The shoots were composed of three successive zones containing latent buds (basal zone), central flower buds (median zone) and vegetative buds (distal zone), respectively. The last two zones contained few associated flower buds. The zones length (in number of metamers) and occurrence strongly depended on shoot development in the two successive years. With decrease in the number of metamers per shoot, the last two zones become shorter or may not develop. While the number of metamers of the basal and distal zones and the number of associated flower buds correlated to the number of metamers of the shoot, the number of metamers of the median zone and the transition probability from the median to the distal zone were cultivar specific.
Ionizujícím zářením označujeme tok hmotných částic nebo fotonů elektromagnetického záření, jež mají schopnost ionizovat atomy prostředí, kterým procházejí. Na buněčné úrovni se poškození může projevit smrtí buňky či změnou její cytogenetické informace. Tyto děje mohou vést k nepříznivých tkáňovým reakcím (deterministickým účinkům), u kterých jsou projevy závislé na překročení dávkového prahu, nebo ke vzniku stochastických účinků, u nichž s dávkou stoupá pravděpodobnost poškození. Článek krátce shrnuje tyto účinky na lidský organismus.
Ionizing radiation refers to the flow of material particles or photons of electromagnetic radiation that can ionize atoms of the environment through which it passes. At the cellular level, damage can be manifested by cell death or changing their cytogenetic information. These events can lead to adverse tissue reactions (deterministic effects) in which manifestations depend on exceeding the dose threshold, or to the stochastic effects, when the probability of damage increases with the dose. This article briefly summarizes these effects on the human body.
- MeSH
- buňky * účinky záření MeSH
- ionizující záření * MeSH
- lidé MeSH
- poškození DNA účinky záření MeSH
- radiační účinky MeSH
- stochastické procesy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
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
- akční potenciály * MeSH
- algoritmy MeSH
- Bayesova věta MeSH
- interpretace statistických dat MeSH
- lidé MeSH
- modely neurologické MeSH
- neurony fyziologie MeSH
- pravděpodobnost MeSH
- stochastické procesy MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Heterozygous germline BRCA2 mutations predispose to breast, ovarian, pancreatic and other types of cancer. The presence of a pathogenic mutation in patients or their family members warrants close surveillance or prophylactic surgery. Besides clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. The influence of such variants on cancer risk is often unknown, making their presence a major clinical problem. When genetic methods are insufficient to classify these variants, functional assays with various cellular models are performed. We developed and applied a new syngeneic model of human cancer cells to test all variants of unknown significance in exon 18 identified by genetic testing of high-risk cancer patients in the Czech Republic, via introduction of constructs containing each of these variants into the wild-type allele of BRCA2-heterozygous DLD1 cells (BRCA2wt/Δex11). We found unaffected DNA repair function of BRCA2 in cell lines BRCA27997G>C/Δex11, BRCA28111C>T/Δex11, BRCA28149G>T/Δex11, BRCA28182G>A/Δex11, and BRCA28182G>T/Δex11, whereas the cell line BRCA28168A>G/Δex11 and the nonsense mutation carrying line BRCA28305G>T/Δex11 did affect protein function. Targeting the BRCA2 wild-type allele with a construct carrying the variant c.7988A> G resulted in incorporation exclusively into the already defective allele in all viable clones, strongly suggesting a detrimental phenotype. Our model thus offers a valuable tool for the functional evaluation of unclassified variants in the BRCA2 gene and provides a stable and distributable cellular resource for further research.
- MeSH
- anamnéza MeSH
- biologické modely * MeSH
- dospělí MeSH
- exony genetika MeSH
- genetická predispozice k nemoci * MeSH
- genetické testování metody MeSH
- hodnocení rizik metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- Markovovy řetězce MeSH
- mutace MeSH
- mutační analýza DNA metody MeSH
- nádorové buněčné linie MeSH
- nádory diagnóza genetika MeSH
- protein BRCA2 genetika MeSH
- senioři MeSH
- studie proveditelnosti MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
The nature of neural codes is central to neuroscience. Do neurons encode information through relatively slow changes in the firing rates of individual spikes (rate code) or by the precise timing of every spike (temporal code)? Here we compare the loss of information due to correlations for these two possible neural codes. The essence of Shannon's definition of information is to combine information with uncertainty: the higher the uncertainty of a given event, the more information is conveyed by that event. Correlations can reduce uncertainty or the amount of information, but by how much? In this paper we address this question by a direct comparison of the information per symbol conveyed by the words coming from a binary Markov source (temporal code) with the information per symbol coming from the corresponding Bernoulli source (uncorrelated, rate code). In a previous paper we found that a crucial role in the relation between information transmission rates (ITRs) and firing rates is played by a parameter s, which is the sum of transition probabilities from the no-spike state to the spike state and vice versa. We found that in this case too a crucial role is played by the same parameter s. We calculated the maximal and minimal bounds of the quotient of ITRs for these sources. Next, making use of the entropy grouping axiom, we determined the loss of information in a Markov source compared with the information in the corresponding Bernoulli source for a given word length. Our results show that in the case of correlated signals the loss of information is relatively small, and thus temporal codes, which are more energetically efficient, can replace rate codes effectively. These results were confirmed by experiments.
We investigate the impact of solar activity changes on mortality from cardiovascular causes of death in the period 1994-2011 in the Czech Republic. This period coincides with the time of solar cycle no. 23 and the surrounding minima when there was an unusually low level of solar activity. We use long-period daily time series of numbers of deaths by cause, solar activity indices (the relative sunspot number, and the intensity of solar radio flux), geomagnetic indices (Kp-the planetary index that indicates the fluctuation rate of horizontal components of the geomagnetic field, the Auroral Electrojet, and the disturbance storm time), and physical parameters describing the ionospheric effects (the critical frequency of the ionospheric F2 layer and the content of free electrons in the ionosphere). The results of the analysis confirm the hypothesis that there is no direct correlation between the geomagnetic solar index, Kp, and the number of deaths from acute myocardial infarction (code I21) or brain stroke (code I64) during the maxima of the solar cycle. On the other hand, the ionospheric parameters explain a greater part of the variability in the number of deaths for acute myocardial infarction or brain stroke than the model with solar parameters. The analysis shows that, because the values are geographically specific, the ionospheric parameters may describe the variability in the number of deaths from cardiovascular causes better than the solar indices. The cardiovascular diseases thus respond to the changes in the solar activity and to abnormal solar events indirectly through a concentration of electrical charges in the earth's environment.
- MeSH
- časové faktory MeSH
- cévní mozková příhoda diagnóza mortalita MeSH
- ekosystém * MeSH
- elektromagnetická pole MeSH
- infarkt myokardu diagnóza mortalita MeSH
- kardiovaskulární nemoci diagnóza mortalita MeSH
- kosmické záření MeSH
- lidé MeSH
- lineární modely MeSH
- příčina smrti MeSH
- prognóza MeSH
- rizikové faktory MeSH
- shluková analýza MeSH
- sluneční aktivita * MeSH
- sluneční energie MeSH
- stochastické procesy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika epidemiologie 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
- časoprostorová analýza * MeSH
- epidemický výskyt choroby * MeSH
- epidemiologické monitorování MeSH
- incidence MeSH
- Mycobacterium bovis izolace a purifikace MeSH
- skot MeSH
- statistické modely * MeSH
- stochastické procesy MeSH
- tuberkulóza skotu epidemiologie mikrobiologie přenos MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Spojené království MeSH
Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.
- MeSH
- biologické modely * MeSH
- databáze faktografické statistika a číselné údaje MeSH
- datové soubory jako téma MeSH
- dospělí MeSH
- interpretace statistických dat MeSH
- lidé MeSH
- mladý dospělý MeSH
- narkolepsie klasifikace diagnóza patofyziologie MeSH
- polysomnografie statistika a číselné údaje MeSH
- řízené strojové učení * MeSH
- ROC křivka MeSH
- spánek REM fyziologie MeSH
- spánková latence fyziologie MeSH
- stochastické procesy MeSH
- vzácné nemoci klasifikace diagnóza patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
