Chem. Listy 2022; 116: 101−109. doi: 10.54779/ chl20220101 vladimir.pliska@biol.ethz.ch, parizek@porodnice.cz Došlo 12. 10. 2021, přijato 1. 11. 2021.

Abstract: Licence agreements between the Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague (IOCB), and the pharmaceutical company Ferring AB Malmö enabled the Swedish company to produce and commercialize worldwide a number of neurohypophyseal peptides designed at the IOCB. Several of them found therapeutic applications. dDAVP: 1-deamino-8-D-arginine-vasopressin was designed in one of the IOCB peptide laboratories (M. Zaoral and F. Šorm) in 1967. It displayed an extremely high antidiuretic activity (various tests indicate a 2- to 50-fold increase, as compared to arginine vasopressin) and a very low pressor activity. The peptide (covered by the U.S. Patent No. 3,497,491, 1970) has been used as a preferred drug in the substitution therapy of the central form of diabetes insipidus (Minirin®, today as Desmopressin INN). Besides, as later discovered (Mannucci et al. 1977), dDAVP increases the plasma concentration of the blood clottiing factor VIII. This fact extended its clinical use as haemostatics in cases of milder forms of haemophilia A, von Willebrand-Jürgens syndrome and some thrombocyte dysfunctions. Despite of the clinical success of dDAVP, a closer look reveals certain inadequacies in the presently available pharmacological data: several reports declare activity values and the prolongation effect (index of persistence) in very broad ranges. Triglycyl-8- -lysine-vasopressin (Terlipressin), a peptide with lysine vasopressin chain extended at the N-terminal by a triglycine residue, acts mainly as a prodrug (releasing lysine vasopressin after aminopeptidase splitting at the Na group). The analogue belongs to the so-called „synthetic hormonogens“; individual peptides carrying various acylating groups were synthesized in the midsixties at the IOCB and legally protected by U.S. Patent No. 3,558,590 (1968). It was a part of the licence agreements mentioned above. The activities of triglycyl-8-lysine-vasopressin (both antidiuretic and vasopressor) are about 100 times lower than those of lysine vasopressin, but its persistence is 5 times longer. As such, it is occasionally used in emergency medicine in cases of esophageal (and other gastroenteral) bleeding, traumatic or septic shock, in cirrhotic patients and patients with portal hypertension. Its use as an early abortion drug was discussed but not pursued. Carbetocin (deaminocarba1-2-O-methyltyrosin-oxytocin) was synthetized in the laboratory of Karel Jošt at the IOCB before 1971; its synthesis was covered by a Czechoslovak patent (CS-149,028 B1) in June 1973 (at that time, Czechoslovak patent law did not provide for the patentability of substances as such) and first published in a biophysical communication by Frič et al., 1974). As a part of the licence agreement, it was included in the production program of Ferring AB, but marketed later also by several other pharmaceutical companies due to an incomplete patent protection. The peptide is a moderately active uterotonic partial agonist and as such has been utilized in veterinary obstetrics for delivery induction in cows and (multiparous) pigs: its milder and better--controlled uterotonic action was found preferential as compared to oxytocin so far used for these purposes. In the last two decades, carbetocin has been commonly used also in the human obstetrics, especially to prevent the peri- and post-partum haemorrhage, from the maternal side the most frequent and most severe delivery complication. It became a life-saving drug in emergency obstetrics.

• Klíčová slova
• carbetocin,
• MeSH
• desmopresin aplikace a dávkování   dějiny   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• neurohypofyzární hormony * dějiny   farmakologie   klasifikace   MeSH
• oxytocin antagonisté a inhibitory   dějiny   farmakologie   MeSH
• poporodní krvácení farmakoterapie   MeSH
• terlipresin aplikace a dávkování   dějiny   farmakologie   terapeutické užití   MeSH
• uterotonika aplikace a dávkování   dějiny   farmakologie   klasifikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH
• Švédsko MeSH

Specific salts effect is intensively studied from the prospective of modification of different physico-chemical properties of biomacromolecules. Limited knowledge of the specific salts effect on enzymes led us to address the influence of five sodium anions: sulfate, phosphate, chloride, bromide, and perchlorate, on catalytic and conformational properties of human rhinovirus-14 (HRV) 3C protease. The enzyme conformation was monitored by circular dichroism spectrum (CD) and by tyrosines fluorescence. Stability and flexibility of the enzyme have been analyzed by CD in the far-UV region, differential scanning calorimetry and molecular dynamics simulations, respectively. We showed significant influence of the anions on the enzyme properties in accordance with the Hofmeister effect. The HRV 3C protease in the presence of kosmotropic anions, in contrast with chaotropic anions, exhibits increased stability, rigidity. Correlations of stabilization effect of anions on the enzyme with their charge density and the rate constant of the enzyme with the viscosity B-coefficients of anions suggest direct interaction of the anions with HRV 3C protease. The role of stabilization and decreased fluctuation of the polypeptide chain of HRV 3C protease on its activation in the presence of kosmotropic anions is discussed within the frame of the macromolecular rate theory.

• MeSH
• anionty chemie   MeSH
• lidé MeSH
• prospektivní studie MeSH
• proteasy * MeSH
• soli * chemie   MeSH
• srdeční frekvence MeSH
• virové proteasy 3C MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Licence agreements between the Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague (IOCB), and the pharmaceutical company Ferring AB Malmö enabled the Swedish company to produce and commercialize worldwide a number of neurohypophyseal peptides designed at the IOCB. Several of them found therapeutic applications. dDAVP: 1-deamino-8-ᴅ-arginine-vasopressin was designed in one of the IOCB peptide laboratories (M. Zaoral and F. Šorm) in 1967. It displayed an extremely high antidiuretic activity (various tests indicate a 2- to 50-fold increase, as compared to arginine vasopressin) and a very low pressor activity. The peptide (covered by the U.S. Patent No. 3,497,491, 1970) has been used as a preferred drug in the substitution therapy of the central form of diabetes insipidus (Minirin®, today as Desmopressin INN). Besides, as later discovered (Mannucci et al. 1977), dDAVP increases the plasma concentration of the blood-clotting factor VIII. This fact extended its clinical use as haemostatics in cases of milder forms of haemophilia A, von Willebrand-Jürgens syndrome and some thrombocyte dysfunctions. Despite of the clinical success of dDAVP, a closer look reveals certain inadequacies in the presently available pharmacological data: several reports declare activity values and the prolongation effect (index of persistence) in very broad ranges. Triglycyl-8-lysine-vasopressin (Terlipressin), a peptide with lysine vasopressin chain extended at the N‐terminal by a triglycine residue, acts mainly as a prodrug (releasing lysine vasopressin after aminopeptidase splitting at the Nα group). The analogue belongs to the so-called „synthetic hormonogens“; individual peptides carrying various acylating groups were synthesized in the mid-sixties at the IOCB and legally protected by U.S. Patent No. 3,558,590 (1968). It was a part of the licence agreements mentioned above. The activities of triglycyl-8-lysine-vasopressin (both antidiuretic and vasopressor) are about 100 times lower than those of lysine vasopressin, but its persistence is 5 times longer. As such, it is occasionally used in emergency medicine in cases of esophageal (and other gastroenteral) bleeding, traumatic or septic shock, in cirrhotic patients and patients with portal hypertension. Its use as an early abortion drug was discussed but not pursued. Carbetocin (deaminocarba1-2-O-methyltyrosin-oxytocin) was synthetized in the laboratory of Karel Jošt at the IOCB before 1971; its synthesis was covered by a Czechoslovak patent (CS-149,028 B1) in June 1973 (at that time, Czechoslovak patent law did not provide for the patentability of substances as such) and first published in a biophysical communication by Frič et al., 1974). As a part of the licence agreement, it was included in the production program of Ferring AB, but marketed later also by several other pharmaceutical companies due to an incomplete patent protection. The peptide is a moderately active uterotonic partial agonist and as such has been utilized in veterinary obstetrics for delivery induction in cows and (multiparous) pigs: its milder and better-controlled uterotonic action was found preferential as compared to oxytocin so far used for these purposes. In the last two decades, carbetocin has been commonly used also in the human obstetrics, especially to prevent the peri- and post-partum haemorrhage, from the maternal side the most frequent and most severe delivery complication. It became a life-saving drug in emergency obstetrics.

• MeSH
• dějiny 20. století MeSH
• lidé MeSH
• neurohypofyzární hormony dějiny   MeSH
• oxytocin dějiny   MeSH
• vasopresiny dějiny   MeSH
• vyvíjení léků * dějiny   MeSH
• Check Tag
• dějiny 20. století MeSH
• lidé MeSH
• Publikační typ
• historické články MeSH
• Geografické názvy
• Československo MeSH
• Švédsko MeSH

The archiving and dissemination of protein and nucleic acid structures as well as their structural, functional and biophysical annotations is an essential task that enables the broader scientific community to conduct impactful research in multiple fields of the life sciences. The Protein Data Bank in Europe (PDBe; pdbe.org) team develops and maintains several databases and web services to address this fundamental need. From data archiving as a member of the Worldwide PDB consortium (wwPDB; wwpdb.org), to the PDBe Knowledge Base (PDBe-KB; pdbekb.org), we provide data, data-access mechanisms, and visualizations that facilitate basic and applied research and education across the life sciences. Here, we provide an overview of the structural data and annotations that we integrate and make freely available. We describe the web services and data visualization tools we offer, and provide information on how to effectively use or even further develop them. Finally, we discuss the direction of our data services, and how we aim to tackle new challenges that arise from the recent, unprecedented advances in the field of structure determination and protein structure modeling.

• MeSH
• databáze proteinů MeSH
• konformace proteinů MeSH
• nukleové kyseliny * MeSH
• proteiny * chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

Dynamics underlying epileptic seizures span multiple scales in space and time, therefore, understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. In this view, mathematical models have been developed, ranging from single neuron to neural population. In this study, we consider a neural mass model able to exactly reproduce the dynamics of heterogeneous spiking neural networks. We combine mathematical modeling with structural information from non invasive brain imaging, thus building large-scale brain network models to explore emergent dynamics and test the clinical hypothesis. We provide a comprehensive study on the effect of external drives on neuronal networks exhibiting multistability, in order to investigate the role played by the neuroanatomical connectivity matrices in shaping the emergent dynamics. In particular, we systematically investigate the conditions under which the network displays a transition from a low activity regime to a high activity state, which we identify with a seizure-like event. This approach allows us to study the biophysical parameters and variables leading to multiple recruitment events at the network level. We further exploit topological network measures in order to explain the differences and the analogies among the subjects and their brain regions, in showing recruitment events at different parameter values. We demonstrate, along with the example of diffusion-weighted magnetic resonance imaging (dMRI) connectomes of 20 healthy subjects and 15 epileptic patients, that individual variations in structural connectivity, when linked with mathematical dynamic models, have the capacity to explain changes in spatiotemporal organization of brain dynamics, as observed in network-based brain disorders. In particular, for epileptic patients, by means of the integration of the clinical hypotheses on the epileptogenic zone (EZ), i.e., the local network where highly synchronous seizures originate, we have identified the sequence of recruitment events and discussed their links with the topological properties of the specific connectomes. The predictions made on the basis of the implemented set of exact mean-field equations turn out to be in line with the clinical pre-surgical evaluation on recruited secondary networks.

• Publikační typ
• časopisecké články MeSH

Gangliosides are glycosphingolipids consisting of a ceramide base and a bulky sugar chain that contains one or more sialic acids. This unique structure endows gangliosides with a strong tendency to self-aggregate in solution, as well as in cellular membranes, where they can form nanoscopic assemblies called ganglioside nanodomains. As gangliosides are important biological molecules involved in a number of physiological processes, characterization of their lateral organization in membranes is essential. This review aims at providing comprehensive information about the nanoscale organization of gangliosides in various synthetic models. To this end, the impact of the hydrophobic backbone and the headgroup on the segregation of gangliosides into nanodomains are discussed in detail, as well as the way in which the properties of nanodomains are affected by ligand binding. Small size makes the characterization of ganglioside nanodomains challenging, and we thus highlight the biophysical methods that have advanced this research, such as Monte Carlo Förster resonance energy transfer, atomic force microscopy and approaches based on molecular diffusion.

• MeSH
• buněčná membrána chemie   MeSH
• gangliosidy chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• ligandy MeSH
• lipidové dvojvrstvy chemie   MeSH
• mikroskopie atomárních sil MeSH
• rezonanční přenos fluorescenční energie MeSH
• sacharidové sekvence MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Spinal cord injury (SCI) is a serious trauma, which often results in a permanent loss of motor and sensory functions, pain and spasticity. Despite extensive research, there is currently no available therapy that would restore the lost functions after SCI in human patients. Advanced treatments use regenerative medicine or its combination with various interdisciplinary approaches such as tissue engineering or biophysical methods. This review summarizes and critically discusses the research from specific interdisciplinary fields in SCI treatment such as the development of biomaterials as scaffolds for tissue repair, and using a magnetic field for targeted cell delivery. We compare the treatment effects of synthetic non-degradable methacrylate-based hydrogels and biodegradable biological scaffolds based on extracellular matrix. The systems using magnetic fields for magnetically guided delivery of stem cells loaded with magnetic nanoparticles into the lesion site are then suggested and discussed.

• MeSH
• biokompatibilní materiály farmakologie   terapeutické užití   MeSH
• hydrogely terapeutické užití   MeSH
• lidé MeSH
• magnetoterapie metody   trendy   MeSH
• poranění míchy patofyziologie   terapie   MeSH
• regenerace nervu účinky léků   fyziologie   MeSH
• transplantace kmenových buněk metody   trendy   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Ceramides, the principal building blocks of all sphingolipids, have attracted the attention of many scientists around the world interested in developing treatments for cystic fibrosis, the most common genetic disease of Caucasians. Many years of fruitful research in this field have produced some fundamentally important, yet controversial results. Here, we aimed to summarize the current knowledge on the role of long- and very-long- chain ceramides, the most abundant species of ceramides in animal cells, in cystic fibrosis and other diseases. We also aim to explain the importance of the length of their side chain in the context of stability of transmembrane proteins through a concise synthesis of their biophysical chemistry, cell biology, and physiology. This review also addresses several remaining riddles in this field. Finally, we discuss the technical challenges associated with the analysis and quantification of ceramides. We provide the evaluation of the antibodies used for ceramide quantification and we demonstrate their lack of specificity. Results and discussion presented here will be of interest to anyone studying these enigmatic lipids.

• MeSH
• bronchiální astma metabolismus   MeSH
• ceramidy chemie   metabolismus   MeSH
• cystická fibróza metabolismus   MeSH
• lidé MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

It is often suggested that Life may lay outside the normal laws of Physics and particularly of Thermodynamics, though this point of view is refuted by many. As the Living State may be thought of as an open system, often far from equilibrium, most attempts at placing Life under the umbrella of the laws of Physics have been based, particularly in recent years, on non-equilibrium Thermodynamics and particularly the Maximum Entropy Production Principle. In this view it is the dissipation of entropy (heat) which permits the ever increasing complexity of Living Systems in biological evolution and the maintenance of this complexity. However, these studies usually consider such biological entities as whole cells, organs, whole organisms and even Life itself at the entire terrestrial level. This requires making assumptions concerning the Living State, which are often not soundly based on observation and lack a defined model structure. The present study is based on an entirely different approach, in which a classical thermodynamic analysis of a well-defined biological nanoparticle, plant Photosystem I, is performed. This photosynthetic structure, which absorbs light and performs primary and secondary charge separation, operates with a quantum efficiency close to one. It is demonstrated that when monochromatic light is absorbed by the lowest lying electronic transition, the chlorophyll Qy transition, entropy production in the system bath plus entropy changes internal to the system are numerically less than the entropy decrease of the light field. A Second Law violation is therefore suggested for these experimental conditions. This conclusion, while at first sight is supportive of the famous and much discussed statement of Schroedinger, that "Life feeds on negentropy", is analysed and the conditions in which this statement may be considered valid for a Plant Photosystem are defined and delimited. The remarkably high quantum efficiency, leading to minimal entropy production (energy wastage), seems to suggest that evolution of Photosystem I has gone down the road of maximal energy efficiency as distinct from maximal entropy production. Photosystem I cannot be considered a maximum entropy dissipation structure.

• MeSH
• chlorofyl chemie   MeSH
• entropie * MeSH
• fotosystém I (proteinový komplex) chemie   MeSH
• fotosystém II (proteinový komplex) chemie   MeSH
• fyziologická absorpce MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The value of Shannon's mutual information is commonly used to describe the total amount of information that the neural code transfers between the ensemble of stimuli and the ensemble of neural responses. In addition, it is often desirable to know which features of the stimulus or response are most informative. The literature offers several different decompositions of the mutual information into its stimulus or response-specific components, such as the specific surprise or the uncertainty reduction, but the number of mutually distinct measures is in fact infinite. We resolve this ambiguity by requiring the specific information measures to be invariant under invertible coordinate transformations of the stimulus and the response ensembles. We prove that the Kullback-Leibler divergence is then the only suitable measure of the specific information. On a more general level, we discuss the necessity and the fundamental aspects of the coordinate invariance as a selection principle. We believe that our results will encourage further research into invariant statistical methods for the analysis of neural coding.

• MeSH
• biofyzika MeSH
• fyzická vytrvalost MeSH
• informační teorie * MeSH
• lidé MeSH
• modely neurologické * MeSH
• neurony fyziologie   MeSH
• pravděpodobnost MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH