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.
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.
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
Histone 3 K4 trimethylation (depositing H3K4me3 marks) is typically associated with active promoters yet paradoxically occurs at untranscribed domains. Research to delineate the mechanisms of targeting H3K4 methyltransferases is ongoing. The oocyte provides an attractive system to investigate these mechanisms, because extensive H3K4me3 acquisition occurs in nondividing cells. We developed low-input chromatin immunoprecipitation to interrogate H3K4me3, H3K27ac and H3K27me3 marks throughout oogenesis. In nongrowing oocytes, H3K4me3 was restricted to active promoters, but as oogenesis progressed, H3K4me3 accumulated in a transcription-independent manner and was targeted to intergenic regions, putative enhancers and silent H3K27me3-marked promoters. Ablation of the H3K4 methyltransferase gene Mll2 resulted in loss of transcription-independent H3K4 trimethylation but had limited effects on transcription-coupled H3K4 trimethylation or gene expression. Deletion of Dnmt3a and Dnmt3b showed that DNA methylation protects regions from acquiring H3K4me3. Our findings reveal two independent mechanisms of targeting H3K4me3 to genomic elements, with MLL2 recruited to unmethylated CpG-rich regions independently of transcription.
- MeSH
- chromatinová imunoprecipitace MeSH
- CpG ostrůvky MeSH
- genetická transkripce MeSH
- histonlysin-N-methyltransferasa chemie MeSH
- histony chemie MeSH
- Markovovy řetězce MeSH
- metylace DNA * MeSH
- multivariační analýza MeSH
- myší embryonální kmenové buňky cytologie MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- oocyty cytologie MeSH
- oogeneze MeSH
- promotorové oblasti (genetika) MeSH
- protoonkogenní protein MLL chemie MeSH
- sekvenční analýza RNA MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The P2X4 receptor (P2X4R) is a member of a family of purinergic channels activated by extracellular ATP through three orthosteric binding sites and allosterically regulated by ivermectin (IVM), a broad-spectrum antiparasitic agent. Treatment with IVM increases the efficacy of ATP to activate P2X4R, slows both receptor desensitization during sustained ATP application and receptor deactivation after ATP washout, and makes the receptor pore permeable to NMDG+, a large organic cation. Previously, we developed a Markov model based on the presence of one IVM binding site, which described some effects of IVM on rat P2X4R. Here we present two novel models, both with three IVM binding sites. The simpler one-layer model can reproduce many of the observed time series of evoked currents, but does not capture well the short time scales of activation, desensitization, and deactivation. A more complex two-layer model can reproduce the transient changes in desensitization observed upon IVM application, the significant increase in ATP-induced current amplitudes at low IVM concentrations, and the modest increase in the unitary conductance. In addition, the two-layer model suggests that this receptor can exist in a deeply inactivated state, not responsive to ATP, and that its desensitization rate can be altered by each of the three IVM binding sites. In summary, this study provides a detailed analysis of P2X4R kinetics and elucidates the orthosteric and allosteric mechanisms regulating its channel gating.
- MeSH
- adenosintrifosfát metabolismus MeSH
- algoritmy MeSH
- gating iontového kanálu účinky léků fyziologie MeSH
- HEK293 buňky MeSH
- ivermektin metabolismus MeSH
- lidé MeSH
- Markovovy řetězce MeSH
- metoda terčíkového zámku MeSH
- purinergní receptory P2X4 účinky léků metabolismus fyziologie MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: This study assessed the cost-effectiveness of the subcutaneous RANKL inhibitor, denosumab, vs the intravenous bisphosphonate, zoledronic acid, for the prevention of skeletal-related events (SREs) in patients with prostate cancer, breast cancer, and other solid tumors (OST) in the Czech Republic. MATERIALS AND METHODS: A lifetime Markov model was developed to compare the effects of denosumab and zoledronic acid on costs (including drug costs and administration, patient management, SREs, and adverse events), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from a national payer perspective. Different discount rates, time horizons, SRE rates, distributions, and nature (asymptomatic vs all SREs), and the inclusion of treatment discontinuation were considered in scenario analyses. The robustness of the model was tested using deterministic and probabilistic sensitivity analyses. RESULTS: Across tumor types, denosumab was associated with fewer SREs, improved QALYs, and higher total costs over a lifetime. The incremental cost per QALY gained for denosumab vs zoledronic acid was 382,673 CZK for prostate cancer, 408,450 CZK for breast cancer, and 608,133 CZK for OST. Incremental costs per SRE avoided for the same tumor type were 54,007 CZK, 51,765 CZK, and 94,426 CZK, respectively. In scenario analyses, the results remained similar to baseline, when different discount rates and time horizons were considered. At a non-official willingness-to-pay threshold of 1.2 million CZK, the probabilities of denosumab being cost-effective vs zoledronic acid were 0.64, 0.67, and 0.49 for prostate cancer, breast cancer, and OST, respectively. LIMITATIONS: The SRE rates used were obtained from clinical trials; studies suggest rates may be higher in clinical practice. Additional evidence on real-world SRE rates could further improve the accuracy of the modeling. CONCLUSIONS: Compared with zoledronic acid, denosumab provides a cost-effective treatment option for the prevention of SREs in patients with prostate cancer, breast cancer, and OST in the Czech Republic.
- MeSH
- analýza nákladů a výnosů MeSH
- bisfosfonáty aplikace a dávkování ekonomika MeSH
- denosumab aplikace a dávkování ekonomika MeSH
- dvojitá slepá metoda MeSH
- ekonometrické modely MeSH
- imidazoly aplikace a dávkování ekonomika MeSH
- inhibitory kostní resorpce aplikace a dávkování ekonomika MeSH
- kvalita života MeSH
- kvalitativně upravené roky života MeSH
- lidé MeSH
- Markovovy řetězce MeSH
- nádory prostaty komplikace MeSH
- nádory prsu komplikace MeSH
- nádory komplikace MeSH
- nemoci kostí etiologie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: This study aims to compare the cost-effectiveness of treatment sequences with available biologics, including adalimumab (ADA), biosimilar infliximab (bsIFX), originator infliximab (IFX) and vedolizumab (VEDO) for luminal Crohn's disease in nine European countries. METHODS: A Markov-model was constructed to simulate five-year medical costs and quality-adjusted life years (QALYs). Data on clinical efficacy were obtained from randomised controlled trials. Country-specific unit costs, discount rates and a third-party payer perspective were applied. RESULTS: The bsIFX versus conventional therapy resulted in the most favourable incremental cost-utility ratios (ICURs) ranging from €34,580 (Hungary) to €77,062/QALY (Sweden). Compared to bsIFX, the bsIFX-ADA sequence was more cost-effective than the bsIFX-VEDO sequence with ICURs varying between €70,277 (France) and €162,069/QALY (Germany). The ICURs of the bsIFX-ADA-VEDO sequence versus the bsIFX-ADA strategy were between €206,266 (The Netherlands) and €363,232/QALY (Spain). CONCLUSION: We are the first to compare cost-effectiveness of multiple biological sequences for luminal Crohn's disease. Based on our findings, bsIFX can be recommended as a first-line treatment in patients unresponsive to conventional treatments. While biological sequences only slightly differ in their associated health gains, their costs vary greatly. The bsIFX-ADA-VEDO seems to be the most cost-effective sequence of the available biologics across Europe.
- MeSH
- adalimumab aplikace a dávkování ekonomika terapeutické užití MeSH
- analýza nákladů a výnosů MeSH
- biosimilární léčivé přípravky aplikace a dávkování ekonomika terapeutické užití MeSH
- Crohnova nemoc farmakoterapie ekonomika MeSH
- ekonomické modely MeSH
- gastrointestinální látky aplikace a dávkování ekonomika terapeutické užití MeSH
- humanizované monoklonální protilátky aplikace a dávkování ekonomika terapeutické užití MeSH
- infliximab aplikace a dávkování ekonomika terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- kvalitativně upravené roky života MeSH
- lidé MeSH
- Markovovy řetězce MeSH
- randomizované kontrolované studie jako téma MeSH
- rozvrh dávkování léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Geografické názvy
- Evropa MeSH
MOTIVATION: Proteins often recognize their interaction partners on the basis of short linear motifs located in disordered regions on proteins' surface. Experimental techniques that study such motifs use short peptides to mimic the structural properties of interacting proteins. Continued development of these methods allows for large-scale screening, resulting in vast amounts of peptide sequences, potentially containing information on multiple protein-protein interactions. Processing of such datasets is a complex but essential task for large-scale studies investigating protein-protein interactions. RESULTS: The software tool presented in this article is able to rapidly identify multiple clusters of sequences carrying shared specificity motifs in massive datasets from various sources and generate multiple sequence alignments of identified clusters. The method was applied on a previously published smaller dataset containing distinct classes of ligands for SH3 domains, as well as on a new, an order of magnitude larger dataset containing epitopes for several monoclonal antibodies. The software successfully identified clusters of sequences mimicking epitopes of antibody targets, as well as secondary clusters revealing that the antibodies accept some deviations from original epitope sequences. Another test indicates that processing of even much larger datasets is computationally feasible. AVAILABILITY AND IMPLEMENTATION: Hammock is published under GNU GPL v. 3 license and is freely available as a standalone program (from http://www.recamo.cz/en/software/hammock-cluster-peptides/) or as a tool for the Galaxy toolbox (from https://toolshed.g2.bx.psu.edu/view/hammock/hammock). The source code can be downloaded from https://github.com/hammock-dev/hammock/releases. CONTACT: muller@mou.cz SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
- MeSH
- algoritmy * MeSH
- databáze proteinů * MeSH
- epitopy chemie MeSH
- interakční proteinové domény a motivy * MeSH
- lidé MeSH
- Markovovy řetězce MeSH
- molekulární sekvence - údaje MeSH
- monoklonální protilátky chemie MeSH
- peptidy chemie MeSH
- sekvence aminokyselin MeSH
- sekvenční seřazení MeSH
- shluková analýza MeSH
- software MeSH
- src homologní domény MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. METHODS: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. RESULTS: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinib-first incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. CONCLUSION: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.
- MeSH
- analýza nákladů a výnosů MeSH
- analýza přežití MeSH
- antitumorózní látky ekonomika terapeutické užití MeSH
- chronická myeloidní leukemie farmakoterapie ekonomika mortalita MeSH
- dospělí MeSH
- ekonometrické modely MeSH
- generika * ekonomika terapeutické užití MeSH
- imatinib mesylát ekonomika terapeutické užití MeSH
- inhibitory proteinkinas ekonomika terapeutické užití MeSH
- kvalitativně upravené roky života MeSH
- lékařská praxe - způsoby provádění * normy trendy MeSH
- lidé středního věku MeSH
- lidé MeSH
- Markovovy řetězce MeSH
- senioři MeSH
- tyrosinkinasy antagonisté a inhibitory MeSH
- výsledek terapie 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
- Research Support, N.I.H., Extramural MeSH
- srovnávací studie MeSH
- Geografické názvy
- Spojené státy americké MeSH
This paper reports the first study applying a triple-isotope approach for source apportionment of polycyclic aromatic hydrocarbons (PAHs). The (13)C/(12)C, (14)C/(12)C, and (2)H/(1)H isotope ratios of PAHs were determined in forest soils from mountainous areas of the Czech Republic, European Union. Statistical modeling applying a Bayesian Markov chain Monte Carlo (MCMC) framework to the environmental triple isotope PAH data and an end-member PAH isotope database allowed comprehensive accounting of uncertainties and quantitative constraints on the PAH sources among biomass combustion, liquid fossil fuel combustion, and coal combustion at low and high temperatures. The results suggest that PAHs in this central European region had a clear predominance of coal combustion sources (75 ± 6%; uncertainties represent 1 SD), mainly coal pyrolysis at low temperature (∼650 °C; 61 ± 8%). Combustion of liquid fossil fuels and biomass represented 16 ± 3 and 9 ± 3% of the total PAH burden (∑PAH14), respectively. Although some soils were located close to potential PAH point sources, the source distribution was within a narrow range throughout the region. These observation-based top-down constraints on sources of environmental PAHs provide a reference for both improved bottom-up emission inventories and guidance for efforts to mitigate PAH emissions.
- MeSH
- Bayesova věta MeSH
- deuterium chemie MeSH
- izotopy uhlíku MeSH
- látky znečišťující půdu analýza MeSH
- Markovovy řetězce MeSH
- metoda Monte Carlo MeSH
- počítačová simulace MeSH
- polycyklické aromatické uhlovodíky analýza MeSH
- půda chemie MeSH
- zeměpis MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
