In this study, we investigated the stability of the fully activated conformation of the orexin receptor 2 (OX2R) embedded in a pure POPC bilayer using MD simulations. Various thermodynamic ensembles (i.e., NPT, NVT, NVE, NPAT, μVT, and NPγT) were employed to explore the dynamical heterogeneity of the system in a comprehensive way. In addition, informational similarity metrics (e.g., Jensen-Shannon divergence) as well as Markov state modeling approaches were utilized to elucidate the receptor kinetics. Special attention was paid to assessing surface tension within the simulation box, particularly under NPγT conditions, where 21 nominal surface tension constants were evaluated. Our findings suggest that traditional thermodynamic ensembles such as NPT may not adequately control physical properties of the POPC membrane, impacting the plausibility of the OX2R model. In general, the performed study underscores the importance of employing the NPγT ensemble for computational investigations of membrane-embedded receptors, as it effectively maintains zero surface tension in the simulated system. These results offer valuable insights for future research aimed at understanding receptor dynamics and designing targeted therapeutics.
OBJECTIVES: Human papillomavirus (HPV) infections are highly prevalent sexually transmitted infections, notably associated with various cancers. This study analyses the health and economic impacts of HPV-associated diseases in the Czech Republic and evaluates the cost-effectiveness of a catch-up vaccination program. METHODS: Utilizing a Markov multistate model, the study assesses the lifetime impacts and costs related to HPV infections. Cohorts of ages 15-21 were simulated to assess the impact of catch-up vaccination outside the 11-year-old age group. RESULTS: The total quality-adjusted life years (QALYs) for the female and male cohorts (together 119,362 individuals) were higher in the vaccination scenario compared to the non-vaccination scenario. The increase in QALYs was 122,246 and 200,852 respectively, when considering the actual vaccination rates. Across both cohorts, 329 cancer-related deaths were prevented. In the probabilistic sensitivity analysis for the female population, vaccination was the dominant strategy in 99.3% of iterations. In the male population, vaccination was the dominant strategy in 80.3% of iterations. The implementation of catch-up vaccination for the 15-21 age group significantly increased QALY gains and reduced life-years-lost (LYLs). In the female cohort, all analysed rates of catch-up vaccination were the dominant strategy, while in the male cohort, the incremental cost-effectiveness ratios (ICERs) remained consistently below 42,000 CZK/QALY. CONCLUSIONS: The catch-up vaccination program for 15-21-year-olds is cost-effective and can prevent a significant number of HPV-related cancers in both men and women.
- MeSH
- Cost-Effectiveness Analysis MeSH
- Cost-Benefit Analysis * MeSH
- Adult MeSH
- Papillomavirus Infections * prevention & control economics MeSH
- Quality-Adjusted Life Years * MeSH
- Humans MeSH
- Markov Chains * MeSH
- Adolescent MeSH
- Young Adult MeSH
- Immunization Programs economics MeSH
- Cost of Illness MeSH
- Papillomavirus Vaccines * economics administration & dosage MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
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
- Lymphocyte Activation MeSH
- Cell Membrane metabolism MeSH
- Drosophila melanogaster MeSH
- Ion Channel Gating MeSH
- HEK293 Cells MeSH
- Protein Conformation MeSH
- Humans MeSH
- Membrane Proteins metabolism MeSH
- Mutation MeSH
- Peptide Hydrolases chemistry MeSH
- ORAI1 Protein chemistry MeSH
- Serine Endopeptidases metabolism MeSH
- Signal Transduction MeSH
- Stochastic Processes MeSH
- Calcium metabolism MeSH
- Calcium Signaling physiology MeSH
- Calcium Channels chemistry MeSH
- Protein Binding MeSH
- Computational Biology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
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.
- MeSH
- Chromosome Aberrations radiation effects MeSH
- Humans MeSH
- Mutagenesis radiation effects MeSH
- DNA Repair radiation effects MeSH
- DNA Damage radiation effects MeSH
- Radiation Injuries pathology MeSH
- Radiation Effects * MeSH
- Risk Factors MeSH
- Stochastic Processes MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
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
- Cells * radiation effects MeSH
- Radiation, Ionizing * MeSH
- Humans MeSH
- DNA Damage radiation effects MeSH
- Radiation Effects MeSH
- Stochastic Processes MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review 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
- 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
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.
