The nucleoside analog entecavir (ETV) is a first-line pharmacotherapy for chronic hepatitis B in adult and pediatric patients. However, due to insufficient data on placental transfer and its effects on pregnancy, ETV administration is not recommended for women after conception. To expand knowledge of safety, we focused on evaluating the contribution of nucleoside transporters (NBMPR sensitive ENTs and Na+ dependent CNTs) and efflux transporters, P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance-associated transporter 2 (ABCC2), to the placental kinetics of ETV. We observed that NBMPR and nucleosides (adenosine and/or uridine) inhibited [3H]ETV uptake into BeWo cells, microvillous membrane vesicles, and fresh villous fragments prepared from the human term placenta, while Na+ depletion had no effect. Using a dual perfusion study in an open-circuit setup, we showed that maternal-to-fetal and fetal-to-maternal clearances of [3H]ETV in the rat term placenta were decreased by NBMPR and uridine. Net efflux ratios calculated for bidirectional transport studies performed in MDCKII cells expressing human ABCB1, ABCG2, or ABCC2 were close to the value of one. Consistently, no significant decrease in fetal perfusate was observed in the closed-circuit setup of dual perfusion studies, suggesting that active efflux does not significantly reduce maternal-to-fetal transport. In conclusion, ENTs (most likely ENT1), but not CNTs, ABCB1, ABCG2, and ABCC2, contribute significantly to the placental kinetics of ETV. Future studies should investigate the placental/fetal toxicity of ETV, the impact of drug-drug interactions on ENT1, and interindividual variability in ENT1 expression on the placental uptake and fetal exposure to ETV.

• MeSH
• ABC transportér z rodiny G, člen 2 metabolismus   MeSH
• dítě MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• membránové transportní proteiny metabolismus   MeSH
• nádorové proteiny metabolismus   MeSH
• nádory prsu * metabolismus   MeSH
• nukleosidy metabolismus   farmakologie   MeSH
• P-glykoprotein metabolismus   MeSH
• P-glykoproteiny metabolismus   MeSH
• placenta * metabolismus   MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející nukleosidy metabolismus   farmakologie   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• těhotenství MeSH
• uridin MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Ribavirin is a broad-spectrum nucleoside-derived antiviral drug used in combination pharmacotherapy treatment of hepatitis C virus infection. Current evidence indicates that ribavirin-associated teratogenicity is not significant in humans, but more information about the developmental toxicity and mechanisms involved in ribavirin placental kinetics is required to assure its safe use in pregnancy. Thus, we have investigated potential roles of equilibrative nucleoside transporters (ENTs, SLC29A), Na+-dependent influx-mediating concentrative nucleoside transporters (CNTs, SLC28A), and ATP-binding cassette (ABC) efflux pumps, in ribavirin placental pharmacokinetics. Our data indicate that ENT1 participates in uptake of ribavirin by BeWo cells, fresh human placental villous fragments and microvillous plasma membrane (MVM) vesicles while activity of CNTs (probably CNT2) was only observed in BeWo cells. In situ dual perfusion experiments with rat term placenta in an open circuit setup showed that ENT inhibition significantly decreases total ribavirin maternal-to-foetal and foetal-to-maternal clearances. In contrast, no contribution of ABC transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), or multidrug resistance-associated protein (ABCC2) was detected in assays with MDCKII cells overexpressing them, or in closed circuit dual perfusion experiments with rat term placenta. In summary, our data show that ribavirin placental pharmacokinetics are largely controlled by ENT1 activity and independent of ABCB1, ABCG2, and ABCC2 efflux pumps.

• MeSH
• ABC transportéry fyziologie   MeSH
• antimetabolity metabolismus   farmakologie   MeSH
• buňky MDCK MeSH
• druhová specificita MeSH
• ekvilibrační přenašeč nukleosidů 1 metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nukleosidy fyziologie   MeSH
• placenta účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• psi MeSH
• ribavirin metabolismus   farmakologie   MeSH
• těhotenství MeSH
• transport proteinů účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Modeling the cardiovascular system as an analogy of an electrical circuit composed of resistors, capacitors and inductors is introduced in many research papers. This contribution uses an object oriented and acausal approach, which was recently introduced by several other authors, for educational and research purpose. Examples of several hydraulic systems and whole system modeling hemodynamics of a pulsatile cardiovascular system are presented in Modelica language using Physiolibrary.

• MeSH
• fyziologie metody   výchova   MeSH
• kardiovaskulární fyziologické jevy * MeSH
• lidé MeSH
• modely kardiovaskulární * MeSH
• studenti lékařství MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• řešení modelových problémů MeSH

• Konspekt
• Biologické vědy
• NLK Obory
• biologie
• fyziologie

Modelica is an object-oriented language, in which models can be created and graphically represented by connecting instances of classes from libraries. These connections are not only assignments of values; they can also represent acausal equality. Even more, they can model Kirchhoff's laws of circuits. In Modelica it is possible to develop library classes which are an analogy of electrical circuit components. The result of our work in this field is Physiolibrary (www.physiolibrary.org) – a free, open-source Modelica library for human physiology. By graphical joining instances of Physiolibrary classes, user can create models of cardiovascular circulation, thermoregulation, metabolic processes, nutrient distribution, gas transport, electrolyte regulation, water distribution, hormonal regulation and pharmacological regulation. After simple setting of the parameters, the models are ready to simulate. After simulation, the user can examine variables as their values change over time. Representing the model as a diagram has also great educational advantages, because students are able to better understand physical principles when they see them modeled graphically.

• MeSH
• biologické modely * MeSH
• fyziologie * metody   MeSH
• lidé MeSH
• počítačová grafika MeSH
• počítačová simulace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

BACKGROUND: Boolean networks (BNs) provide an effective modelling formalism for various complex biochemical phenomena. Their long term behaviour is represented by attractors-subsets of the state space towards which the BN eventually converges. These are then typically linked to different biological phenotypes. Depending on various logical parameters, the structure and quality of attractors can undergo a significant change, known as a bifurcation. We present a methodology for analysing bifurcations in asynchronous parametrised Boolean networks. RESULTS: In this paper, we propose a computational framework employing advanced symbolic graph algorithms that enable the analysis of large networks with hundreds of Boolean variables. To visualise the results of this analysis, we developed a novel interactive presentation technique based on decision trees, allowing us to quickly uncover parameters crucial to the changes in the attractor landscape. As a whole, the methodology is implemented in our tool AEON. We evaluate the method's applicability on a complex human cell signalling network describing the activity of type-1 interferons and related molecules interacting with SARS-COV-2 virion. In particular, the analysis focuses on explaining the potential suppressive role of the recently proposed drug molecule GRL0617 on replication of the virus. CONCLUSIONS: The proposed method creates a working analogy to the concept of bifurcation analysis widely used in kinetic modelling to reveal the impact of parameters on the system's stability. The important feature of our tool is its unique capability to work fast with large-scale networks with a relatively large extent of unknown information. The results obtained in the case study are in agreement with the recent biological findings.

• MeSH
• algoritmy MeSH
• aniliny MeSH
• benzamidy MeSH
• COVID-19 * MeSH
• genové regulační sítě * MeSH
• lidé MeSH
• modely genetické MeSH
• naftaleny MeSH
• SARS-CoV-2 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Arytmie představují u dospělých nemocných s vrozenou vadou srdeční hlavní příčinu morbidity a mortality. V této skupině nemocných se charakteristicky objevují tzv. postincizionální tachykardie. Jejich příčinou je reentry kroužící okolo jizevnaté tkáně nebo protetického materiálu po chirurgickém zákroku. Nejčastěji se objevuje intraatriální reentry, při kterém vzruch krouží okolo jizvy po atriotomii v pravé síni. V případě komplexních srdečních vad je uložení reentry okruhu individuální a vzhledem k abnormální derivaci toku krve může být problematický katetrizační přístup do srdečních oddílů. Ostatní typy arytmií, jako jsou fokální tachykardie, arytmie na podkladě přídatné dráhy nebo fibrilace síní se objevují méně často. Analogickým mechanizmem jako intraatriální reentry mohou vznikat komorové postincizionální tachykardie, které obvykle vycházejí z okraje jizvy po ventrikulotomii. Díky použití trojrozměrných elektroanatomických mapovacích systémů a zobrazovacích metod (například intrakardiální echokardiografie) lze navzdory komplexním anatomickým poměrům dosáhnout vysoké úspěšnosti léčby u těchto poruch srdečního rytmu. Tento přehled se zabývá patofyziologií, klasifikací a současnými možnostmi katetrizační léčby tachyarytmií u nemocných s vrozenou srdeční vadou.

Arrhythmias are the leading cause of morbidity and mortality in adult patients with congenital heart defect. Patients in this group typically develop incisional tachycardias. They are caused by reentry circulating around scar tissue or prosthetic material following a surgical procedure. Most commonly, intra-atrial reentry occurs, in which the impulse circulates around a right atriotomy scar. In the case of complex heart defects, the location of the reentry circuit is individual and, given an abnormal diversion of blood flow, catheter access to the heart chambers may be difficult. The other types of arrhythmias, such as focal tachycardias, accessory pathway-mediated arrhythmias or atrial fibrillations, are encountered less frequently. Through a mechanism analogical to that in intra-atrial reentry, incisional ventricular tachycardias can occur that usually arise from the edge of a ventriculotomy scar. By using three-dimensional electroanatomic mapping systems and imaging techniques (e.g. intracardiac echocardiography), it is possible, despite the complex anatomic relations, to achieve a high success rate of treatment in these cardiac rhythm disorders. This review deals with the pathophysiology, classification, and current options of catheter treatment of tachyarrhythmias in patients with congenital heart defect.

• MeSH
• fibrilace síní diagnóza   etiologie   chirurgie   MeSH
• katetrizační ablace metody   MeSH
• lidé MeSH
• srdeční arytmie chirurgie   MeSH
• tachykardie diagnóza   etiologie   chirurgie   MeSH
• vrozené vady chirurgie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Blood is carried from the heart to all parts of your body in vessels called arteries. Blood pressure is the force of the blood pushing against the walls of the arteries. Each time the heart beats (about 60 to 70 times a minute at rest), it pumps out blood into the arteries with different value of systolic pressure SP (highest blood pressure when the heart beats) and different value of diastolic pressure DP (lowest blood pressure when the heart relaxes) [3]. Values of SP and DP change during the whole day with dependence on person’s physical and psychical activity. Accuracy of measurement with the modern automatic blood pressure (BP) monitors using oscillometric method is highly depended on condition of cardiovascular system of the monitored person [1]. Especially, with people who suffer from cardiovascular diseases (e.g. arteriosclerosis) the resulting accuracy is much lower when compared to auscultation method. A reasonable solution for improvement of quality of oscillometric method could be an intelligent universal measuring system for evaluation of BP taking into account condition of patient cardiovascular system (CS) of monitored person i.e. the hemodynamics parameters of CS (e.g. heart rate, stroke volume, total peripheral resistance, systemic arterial compliance). Such a system has to be based on an appropriate model of the considered diseases. To create the models, it is very important to establish a database of oscillometric pulsations waveforms (OPW) complemented by the values of “auscultation” blood pressure and information about patients (age, sex, etc.) as well as their diagnosis. This requires a special HW device for measurement of the OPW – we have developed such a device and it has been validated in Czech Certified Metrological Centre, its accuracy is ± 0.5 mmHg in the measuring range 0 to 300 mmHg. We have introduced the concept of oscillometric pulsations waveform (OPW) database that allows testing of oscillometric algorithms for healthy people and mainly for people whose cardiovascular system is not in standard state (arteriosclerosis etc.). The concept is based on oscillometric data retrieving during cuff deflation and on reference BP measurements by auscultation as in [2]. Together with the data, oscillometric pulsations and cuff pressure are saved into the database. For records of OPW we have developed a special HW device that consists of an arm cuff, a pressure sensor, two regulation valves, batteries and electronic circuits. The device can be controlled from PC by a special SW. The connection with the PC is via USB port. The microcontroller controls the pneumatic and the electronic circuits. Cuff pressure is converted into analog voltage by pressure sensor (Piezoresistive Bridge). The analog voltage is amplified by an amplifier TLV2422 and the amplified cuff pressure signal is then separated into 2 channels by a hi-pass filter. Channel 1 is cuff pressure signal (0-300 mm Hg) and channel 2 represents amplified and filtered cuff pulsations (OPW). The 2 signals are digitized by a 12-bit A/D converter in microcontroller ADuC814 with sampling frequency of 200 Hz. The deflation of the cuff is controlled by the regulations valves. The microcontroller communicates with the notebook computer via FTDI chip. Our OPW monitor is connected through the T-pieces and tubes to the cuff, mercury sphygmomanometer and automatic oscillometric blood pressure monitor. Auscultation values are measured by educated staff. Cuff inflation is controlled by microcontroller of the monitor. Then we can directly compare oscillometric and reference (auscultation) method. Moreover, we exactly know the OPW. Nowadays, we have already collected 950 OPW records of 250 people. There are mainly people older than 60 years in the group and we have tried several algorithms (designed in MATLAB ver. 7.00) for evaluation of systolic and diastolic BP [3] and others hemodynamics parameters of the cardiovascular system (mean arterial pressure, heart rate etc.). We have compared values of BP measured by mercury sphygmomanometer and the commercial oscillometric monitor and we have got less than 80% of the measurements results in range of ± 5 mmHg for systolic and diastolic pressure. In more than 20% for both pressures the differences between oscillometric and reference method were greater than ± 5 mmHg. Difference more than -5 mmHg as well as + 5 mmHg was distributed approximately similar. This is a strong motivation for the creation of our database. We have begun apply on measured values some methods of artificial intelligence (AI), especially data mining with system WEKA [5]. We used correlation and searched some association rules. We validated results of standard statistical analysis but we did not find any other strong rules in the data. Nowadays we plan apply these statistical and AI methods directly on measured oscillometric pulsations. This pilot project could be very useful for development of new blood pressure measurement (BPM) methods and also for determination of correct BPM for each group of cardiovascular condition of patients what can be considerable improvement in medical care and patient satisfaction.

• Publikační typ
• abstrakty MeSH

Previous studies that focused on treating major depressive disorder with conventional deep brain stimulation (DBS) paradigms produced inconsistent results. In this proof-of-concept preclinical study in rats (n = 8), we used novel paradigms of orientation selective DBS for stimulating the complex circuitry crossing the infralimbic cortex, an area considered analogous to human subgenual cingulate cortex. Using functional MRI at 9.4 T, we monitored whole brain responses to varying the electrical field orientation of DBS within the infralimbic cortex. Substantial alterations of functional MRI responses in the amygdala, a major node connected to the infralimbic cortex implicated in the pathophysiology of depression, were observed. As expected, the activation cluster near the electrode was insensitive to the changes of the stimulation orientation. Hence, our findings substantiate the ability of orientation selective stimulation (OSS) to recruit neuronal pathways of distinct orientations relative to the position of the electrode, even in complex circuits such as those involved in major depressive disorder. We conclude that OSS is a promising approach for stimulating brain areas that inherently require individualisation of the treatment approach.

• Publikační typ
• časopisecké články MeSH

Invasive cell growth and migration is usually considered a specifically metazoan phenomenon. However, common features and mechanisms of cytoskeletal rearrangements, membrane trafficking and signalling processes contribute to cellular invasiveness in organisms as diverse as metazoans and plants - two eukaryotic realms genealogically connected only through the last common eukaryotic ancestor (LECA). By comparing current understanding of cell invasiveness in model cell types of both metazoan and plant origin (invadopodia of transformed metazoan cells, neurites, pollen tubes and root hairs), we document that invasive cell behavior in both lineages depends on similar mechanisms. While some superficially analogous processes may have arisen independently by convergent evolution (e.g. secretion of substrate- or tissue-macerating enzymes by both animal and plant cells), at the heart of cell invasion is an evolutionarily conserved machinery of cellular polarization and oriented cell mobilization, involving the actin cytoskeleton and the secretory pathway. Its central components - small GTPases (in particular RHO, but also ARF and Rab), their specialized effectors, actin and associated proteins, the exocyst complex essential for polarized secretion, or components of the phospholipid- and redox- based signalling circuits (inositol-phospholipid kinases/PIP2, NADPH oxidases) are aparently homologous among plants and metazoans, indicating that they were present already in LECA.Reviewer: This article was reviewed by Arcady Mushegian, Valerian Dolja and Purificacion Lopez-Garcia.

• MeSH
• aktiny metabolismus   MeSH
• cytoskelet metabolismus   MeSH
• lidé MeSH
• pohyb buněk fyziologie   MeSH
• pylová láčka cytologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH