Knowledge of the active pharmaceutical ingredient (API) solubility in a polymer is imperative for successful amorphous solid dispersion design and formulation but acquiring this information at storage temperature is challenging. Various solubility determination methods have been established, which utilize differential scanning calorimetry (DSC). In this work, three commonly used DSC-based protocols [i.e., melting point depression (MPD), recrystallization, and zero-enthalpy extrapolation (Z-EE)] and a method that we have developed called "step-wise dissolution" (S-WD) were analyzed. For temperature-composition phase diagram construction, two glass-transition temperature equations (i.e., those of Gordon-Taylor and Kwei) and three solid-liquid equilibrium curve modeling approaches [i.e., the Flory-Huggins model, an empirical equation, and the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS)] were considered. Indomethacin (IND) and Kollidon 12 PF (PVP K12) were selected as the API and polymer, respectively. An annealing time investigation revealed that the IND-PVP K12 dissolution process was remarkably faster than demixing, which contradicted previously published statements. Thus, the recrystallization method overestimated the solubility of IND in PVP K12 when a 2-h time of annealing was set as the benchmark. Likewise, the MPD and Z-EE methods overestimated the API solubility because of unreliable IND melting endotherm evaluation at lower API loadings and a relatively slow heating rate, respectively. When the experimental results obtained using the S-WD method (in conjunction with the Kwei equation) were applied to the PC-SAFT EOS, which was regarded as the most reliable combination, the predicted IND solubility in PVP K12 at T = 25 °C was approximately 40 wt %. When applicable, the S-WD method offers the advantage of using a limited number of DSC sample pans and API-polymer physical mixture compositions, which is both cost- and time-effective.

• MeSH
• Models, Chemical MeSH
• Calorimetry, Differential Scanning MeSH
• Chemistry, Pharmaceutical methods   MeSH
• Crystallization MeSH
• Polymers chemistry   MeSH
• Excipients chemistry   MeSH
• Solubility MeSH
• Transition Temperature MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study 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.

• MeSH
• Action Potentials * MeSH
• Information Theory * MeSH
• Markov Chains * MeSH
• Models, Neurological * MeSH
• Uncertainty * MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Human populations tend to grow steadily, because of the ability of people to make innovations, and thus overcome and extend the limits imposed by natural resources. It is therefore questionable whether traditional concepts of population ecology, including environmental carrying capacity, can be applied to human societies. The existence of carrying capacity cannot be simply inferred from population time-series, but it can be indicated by the tendency of populations to return to a previous state after a disturbance. So far only indirect evidence at a coarse-grained scale has indicated the historical existence of human carrying capacity. We analysed unique historical population data on 88 settlements before and after the Thirty Years War (1618-1648), one the longest and most destructive conflicts in European history, which reduced the population of Central Europe by 30-50%. The recovery rate of individual settlements after the war was positively correlated with the extent of the disturbance, so that the population size of the settlements after a period of regeneration was similar to the pre-war situation, indicating an equilibrium population size (i.e. carrying capacity). The carrying capacity of individual settlements was positively determined mostly by the fertility of the soil and the area of the cadastre, and negatively by the number of other settlements in the surroundings. Pre-industrial human population sizes were thus probably controlled by negative density dependence mediated by soil fertility, which could not increase due to limited agricultural technologies.

• MeSH
• History, 17th Century MeSH
• History, 18th Century MeSH
• Humans MeSH
• Population Dynamics * MeSH
• Technology MeSH
• Rural Population statistics & numerical data   MeSH
• Conservation of Natural Resources * MeSH
• Agriculture instrumentation   MeSH
• Check Tag
• History, 17th Century MeSH
• History, 18th Century MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

For decades, a vast majority of biogerontologists assumed that aging is not and cannot be an adaptation. In recent years, however, several authors opposed this predominant view and repeatedly suggested that not only is aging an adaptation but that it is the result of a specific aging program. This issue almost instantaneously became somewhat controversial and many important authors produced substantial works refuting the notion of the aging program. In this article we review the current state of the debate and list the most important arguments proposed by both sides. Furthermore, although classical interpretations of the evolution of aging are in sharp contrast with the idea of programmed aging, we suggest that the truth might in fact very well lie somewhere in between. We also propose our own interpretation which states that although aging is in essence inevitable and results from damage accumulation rather than from a specific program, the actual rate of aging in nature may still be adaptive to some extent.

• MeSH
• Biological Evolution * MeSH
• Models, Biological MeSH
• Adaptation, Physiological * MeSH
• Humans MeSH
• Population Dynamics MeSH
• Gene Expression Regulation MeSH
• Aging genetics   metabolism   physiology   MeSH
• Age Factors MeSH
• Health Status MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

In photosynthesis, electron transport-coupled proton movement initiates the formation of the light-induced electric potential difference, ΔΨ, across the thylakoid membrane (TM). Ions are transported across the TM to counterbalance the charge of protons accumulated in the lumen. The objective of this work is to construct range of mathematical models for simulation of ΔΨ, using the transition state rate theory (TSRT) for description of movement of ions through the channels. The TSRT considers either single-ion (TSRT-SI) or multi-ion occupancy (TSRT-MI) in the channels. Movement of ions through the channel pore is described by means of energy barriers and binding sites; ions move in and out of vacant sites with rate constants that depend on the barrier heights and well depths, as well as on the interionic repulsion in TSRT-MI model. Three energy motifs are used to describe the TSRT-SI model: two-barrier one-site (2B1S), three-barrier two-site (3B2S), and four-barrier three-site (4B3S). The 3B2S energy motif is used for the TSRT-MI model. The accumulation of cations due to the TM surface negative fixed charges is also taken into account. A model employing the electro-diffusion theory instead of the TSRT is constructed for comparison. The dual wavelength transmittance signal (ΔA515-560nm) measuring the electrochromic shift (ECS) provides a proxy for experimental light-induced ΔΨ. The simulated ΔΨ traces qualitatively agree with the measured ECS traces. The models can simulate different channel conducting regimes and assess their impact on ΔΨ. The ionic flux coupling in the TSRT-MI model suggests that an increase in the internal or external K(+) concentration may block the outward or the inward Mg(2+) current, respectively.

• MeSH
• Models, Biological * MeSH
• Biological Transport radiation effects   MeSH
• Electric Conductivity MeSH
• Ions chemistry   MeSH
• Membrane Potentials radiation effects   MeSH
• Light MeSH
• Thylakoids chemistry   metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Biochemistry MeSH
• Chemistry MeSH
• Chemistry, Organic MeSH

• Conspectus
• Chemie. Mineralogické vědy
• NML Fields
• chemie, klinická chemie
• NML Publication type
• kolektivní monografie

• MeSH
• Cell Biology MeSH
• Genetic Predisposition to Disease MeSH
• Molecular Biology MeSH
• Neoplastic Processes MeSH
• Neoplasms MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Publication type
• monografie

Haloalkane dehalogenases catalyze the hydrolysis of carbon-halogen bonds in various chlorinated, brominated and iodinated compounds. These enzymes have a conserved pair of halide-stabilizing residues that are important in substrate binding and stabilization of the transition state and the halide ion product via hydrogen bonding. In all previously known haloalkane dehalogenases, these residues are either a pair of tryptophans or a tryptophan-asparagine pair. The newly-isolated haloalkane dehalogenase DatA from Agrobacterium tumefaciens C58 (EC 3.8.1.5) possesses a unique halide-stabilizing tyrosine residue, Y109, in place of the conventional tryptophan. A variant of DatA with the Y109W mutation was created and the effects of this mutation on the structure and catalytic properties of the enzyme were studied using spectroscopy and pre-steady-state kinetic experiments. Quantum mechanical and molecular dynamics calculations were used to obtain a detailed analysis of the hydrogen-bonding patterns within the active sites of the wild-type and the mutant, as well as of the stabilization of the ligands as the reaction proceeds. Fluorescence quenching experiments suggested that replacing the tyrosine with tryptophan improves halide binding by 3.7-fold, presumably as a result of the introduction of an additional hydrogen bond. Kinetic analysis revealed that the mutation affected the substrate specificity of the enzyme and reduced its K(0.5) for selected halogenated substrates by a factor of 2-4, without impacting the rate-determining hydrolytic step. We conclude that DatA is the first natural haloalkane dehalogenase that stabilizes its substrate in the active site using only a single hydrogen bond, which is a new paradigm in catalysis by this enzyme family.

• MeSH
• Agrobacterium tumefaciens enzymology   metabolism   MeSH
• Principal Component Analysis MeSH
• Bacterial Proteins chemistry   genetics   metabolism   MeSH
• Biocatalysis MeSH
• Hydrocarbons, Halogenated chemistry   metabolism   MeSH
• Halogens chemistry   metabolism   MeSH
• Hydrolases chemistry   genetics   metabolism   MeSH
• Hydrolysis MeSH
• Catalytic Domain MeSH
• Protein Conformation MeSH
• Quantum Theory MeSH
• Models, Molecular MeSH
• Mutagenesis, Site-Directed MeSH
• Mutant Proteins chemistry   metabolism   MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Enzyme Stability MeSH
• Amino Acid Substitution MeSH
• Substrate Specificity MeSH
• Tyrosine chemistry   MeSH
• Hydrogen Bonding MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Cílem studie je přiblížit vývoj demografické reprodukce obyvatelstva v České republice v uplynulém čtvrtstoletí. Pozornost je věnována především procesu demografického stárnutí, který je determinován vývojem dvou hlavních složek reprodukce obyvatelstva – porodnosti a úmrtnosti. Tyto základní demografické procesy prošly ve sledovaném období nemalými změnami, a to v důsledku společenských i ekonomických faktorů. Především jde o významný pokles plodnosti, ačkoliv se do rodivého věku dostaly početně silné populační ročníky ze 70. let minulého století, a snižování intenzity úmrtnosti, které má za následek neustálý nárůst naděje dožití. Vliv na počet, strukturu i rozmístění obyvatelstva má také migrace, která především ke konci sledovaného období měla výrazný vliv na meziroční změny početního stavu obyvatelstva. S procesem demografického stárnutí také souvisí otázka, v jakém zdravotním stavu se obyvatelstvo vyššího věku dožívá. Zdravotní stav se dá obecně hodnotit jak podle objektivních, tak subjektivních ukazatelů. Objektivní ukazatele často ale narážejí na ne příliš kvalitní datovou základnu, jelikož se jedná pouze o lékařem objektivně dokumentované skutečnosti, přičemž je zřejmé, že ne se všemi nemocemi lidé navštěvují své lékaře. Proto se čím dál tím více pozornosti zaměřuje na subjektivní ukazatele, kdy pomocí výběrových šetření obyvatelstvo přímo hodnotí svůj zdravotní stav. Z provedených průzkumů je patrné, že subjektivní hodnocení zdraví se za posledních dvacet let zlepšilo, přičemž je ale patrný trend zvyšování chronické nemocnosti obyvatelstva, a to nejen s věkem, ale i časem. Tato skutečnost může mít v souvislosti s procesem dalšího prohlubování demografického stárnutí výrazný vliv na fungování zdravotnického a sociálního systému v České republice.

The aim of the article is to describe the demographic development of the population in the Czech Republic in the last quarter-century. Particular attention is paid to the process of demographic ageing, which is determined by the development of two main components of population reproduction – fertility and mortality. These basic demographic processes had undergone considerable changes in the monitored period as a result of social and economic factors. In particular, there is a significant decrease in fertility, although the baby boomers generation from the 70s of the last century got into the reproductive age, and reduction of mortality, which has resulted in a constant increase of life expectancy. The number, structure and distribution of the population are also affected by migration; especially at the end of the monitored period migration had a significant effect on the annual change of numbers in the population. The process of demographic ageing is also related to the matter of health condition of the population which is growing old. State of health can be generally evaluated according to both objective and subjective indicators. Objective indicators do not have a good data base, since it is only a fact objectively documented by a doctor, and it is evident that people do not go the doctor with all their diseases. Therefore, more and more attention is paid to subjective indicators when surveyors directly assess their health status. According to the performed surveys, it is evident that the subjective evaluation of health over the last twenty years has improved, but there is also the trend of increasing chronic illness rate in the population, not only with age, but also in time. This fact may have a significant impact on the functioning of the medical and social system in the Czech Republic in connection with the process of demographic aging and its further deepening.

• MeSH
• Emigration and Immigration trends   MeSH
• Humans MeSH
• Morbidity * trends   MeSH
• Mortality trends   MeSH
• Population Dynamics * statistics & numerical data   trends   MeSH
• Population Growth * MeSH
• Birth Rate * trends   MeSH
• Health Status Indicators * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Review MeSH

Latitude gradients and secular trends in Europe and North America have been found in the male-female ratio at birth (M/F: male births divided by total births) which is expected to be 0.515. Annual national data for Czechoslovakia and the post-Czechoslovakian (Czech Republic and Slovakia) countries for male and female live births were obtained from the World Health Organisation and analysed with contingency tables. This study analysed 13,123,538 live births. An overall decreasing trend in M/F was found (p < 00001). No latitude gradient was noted. There was an overall deficit of 15,232 male births based on an M/F of 0.515. M/F is declining in this region, despite well developing economies that have resisted the worldwide slowdown. An interplay of several poorly understood factors is likely.

• MeSH
• Data Interpretation, Statistical MeSH
• Humans MeSH
• Sex Ratio * MeSH
• Population Dynamics MeSH
• Birth Rate trends   MeSH
• Statistics as Topic * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Geographicals
• Czech Republic MeSH
• Czechoslovakia MeSH
• Slovakia MeSH