Biomolecular simulations are routinely used in biochemistry and molecular biology research; however, they often fail to match expectations of their impact on pharmaceutical and biotech industry. This is caused by the fact that a vast amount of computer time is required to simulate short episodes from the life of biomolecules. Several approaches have been developed to overcome this obstacle, including application of massively parallel and special purpose computers or non-conventional hardware. Methodological approaches are represented by coarse-grained models and enhanced sampling techniques. These techniques can show how the studied system behaves in long time-scales on the basis of relatively short simulations. This review presents an overview of new simulation approaches, the theory behind enhanced sampling methods and success stories of their applications with a direct impact on biotechnology or drug design.

• MeSH
• metody pro přípravu analytických vzorků metody   MeSH
• simulace molekulární dynamiky * MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Knowledge of the structure and conformational flexibility of carbohydrates in an aqueous solvent is important to improving our understanding of how carbohydrates function in biological systems. In this study, we extend a variant of the Hamiltonian replica-exchange molecular dynamics (MD) simulation to improve the conformational sampling of saccharides in an explicit solvent. During the simulations, a biasing potential along the glycosidic-dihedral linkage between the saccharide monomer units in an oligomer is applied at various levels along the replica runs to enable effective transitions between various conformations. One reference replica runs under the control of the original force field. The method was tested on disaccharide structures and further validated on biologically relevant blood group B, Lewis X and Lewis A trisaccharides. The biasing potential-based replica-exchange molecular dynamics (BP-REMD) method provided a significantly improved sampling of relevant conformational states compared with standard continuous MD simulations, with modest computational costs. Thus, the proposed BP-REMD approach adds a new dimension to existing carbohydrate conformational sampling approaches by enhancing conformational sampling in the presence of solvent molecules explicitly at relatively low computational cost.

• MeSH
• antigeny krevních skupin chemie   genetika   MeSH
• disacharidy chemie   genetika   MeSH
• konformace sacharidů MeSH
• lidé MeSH
• sekvenční analýza * MeSH
• simulace molekulární dynamiky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cíl. Cílem studie bylo stanovit diagnostickou výtěžnost kontrastní MR angiografie (MRA) s použitím paralelních akvizičních technik v diagnostice stenózy renální tepny. Metoda. Celkem bylo vyšetřeno 70 nemocných s hypertenzní chorobou a podezřením na stenózu renální tepny. Vyšetření byla prováděna na přístroji Magnetom Symphony Maestro Class 1,5 T s použitím array cívek. Průchod bolusu kontrastní látky byl monitorován metodou bolus tracking. Parametry MRA sekvence byly: TR 3,7 ms; TE 1,2 ms; flip angle 25o; akviziční doba 18 s; velikost voxelu 1,1× 1,0×1,1 mm; centrický náběr dat v k-prostoru; paralelní akviziční techniky s akceleračním faktorem 2 (GRAPPA). Za hemodynamicky významnou byla považována stenóza 60 % a více. Výsledky MRA byly porovnávány s nálezem na digitální subtrakční angiografii, která sloužila jako zlatý standard. Výsledky. Senzitivita a specificita MRA v detekci hemodynamicky významné stenózy renální tepny byla 92 %, respektive 95 %. Její prevalence v našem souboru činila 37 %. Závěr. Při splnění parametrů dostatečného geometrického rozlišení vykazuje kontrastní MR angiografie vysokou senzitivitu a specificitu v diagnostice stenózy renální tepny.

Aim. The aim of our study was to assess the diagnostic value of contrast-enhanced MR angiography (MRA) utilizing parallel acquisition techniques in the detection of renal artery stenosis. Method. Seventy hypertensive subjects with suspected renal artery stenosis were examined on a 1.5 Tesla MR system with body array coil. Bolus tracking was used to monitor the arrival of contrast agent to the abdominal aorta. The MRA sequence parameters were as follows: TR 3.7 ms; TE 1.2 ms; flip angle 25°; acquisition time 18 s; voxel size 1.1 × 1.0 × 1.1 mm; centric k-space sampling; parallel acquisition techniques with acceleration factor of 2 (GRAPPA). Renal artery stenosis of 60 % and more was considered hemodynamically significant. The results of MRA were compared to digital subtraction angiography serving as a standard of reference. Results. Sensitivity and specificity of MRA in the detection of hemodynamically significant renal artery stenosis were 92 % and 95 %, respectively. Its prevalence was 37 % in our study population. Conclusion. Contrast-enhanced MRA with high spatial resolution offers sufficient sensitivity and specificity for screening of renal artery stenosis.

• MeSH
• diagnostické techniky urologické využití   MeSH
• digitální subtrakční angiografie metody   využití   MeSH
• lidé MeSH
• magnetická rezonanční angiografie metody   přístrojové vybavení   využití   MeSH
• obstrukce renální arterie diagnóza   etiologie   patofyziologie   MeSH
• renální hypertenze diagnóza   MeSH
• senzitivita a specificita MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

The RNA recognition motif (RRM) is the most common RNA binding domain across eukaryotic proteins. It is therefore of great value to engineer its specificity to target RNAs of arbitrary sequence. This was recently achieved for the RRM in Rbfox protein, where four mutations R118D, E147R, N151S, and E152T were designed to target the precursor to the oncogenic miRNA 21. Here, we used a variety of molecular dynamics-based approaches to predict specific interactions at the binding interface. Overall, we have run approximately 50 microseconds of enhanced sampling and plain molecular dynamics simulations on the engineered complex as well as on the wild-type Rbfox·pre-miRNA 20b from which the mutated systems were designed. Comparison with the available NMR data on the wild type molecules (protein, RNA, and their complex) served to establish the accuracy of the calculations. Free energy calculations suggest that further improvements in affinity and selectivity are achieved by the S151T replacement.

• MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• mikro RNA chemie   genetika   metabolismus   MeSH
• molekulární modely MeSH
• motiv rozpoznávající RNA * genetika   MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• proteinové inženýrství MeSH
• proteiny vázající RNA chemie   genetika   metabolismus   MeSH
• RNA chemie   metabolismus   MeSH
• sekvence aminokyselin MeSH
• simulace molekulární dynamiky MeSH
• stabilita RNA MeSH
• vazba proteinů MeSH
• vazebná místa genetika   MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Since its early days in the 19th century, medicinal chemistry has concentrated its efforts on the treatment of diseases, using tools from areas such as chemistry, pharmacology, and molecular biology. The understanding of biological mechanisms and signaling pathways is crucial information for the development of potential agents for the treatment of diseases mainly because they are such complex processes. Given the limitations that the experimental approach presents, computational chemistry is a valuable alternative for the study of these systems and their behavior. Thus, classical molecular dynamics, based on Newton's laws, is considered a technique of great accuracy, when appropriated force fields are used, and provides satisfactory contributions to the scientific community. However, as many configurations are generated in a large MD simulation, methods such as Statistical Inefficiency and Optimal Wavelet Signal Compression Algorithm are great tools that can reduce the number of subsequent QM calculations. Accordingly, this review aims to briefly discuss the importance and relevance of medicinal chemistry allied to computational chemistry as well as to present a case study where, through a molecular dynamics simulation of AMPK protein (50 ns) and explicit solvent (TIP3P model), a minimum number of snapshots necessary to describe the oscillation profile of the protein behavior was proposed. For this purpose, the RMSD calculation, together with the sophisticated OWSCA method was used to propose the minimum number of snapshots.

• MeSH
• algoritmy MeSH
• farmaceutická chemie MeSH
• kvantová teorie MeSH
• lidé MeSH
• proteinkinasy aktivované AMP metabolismus   chemie   MeSH
• simulace molekulární dynamiky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The temporomandibular joint (TMJ) is typically involved in 45-87% of children with Juvenile Idiopathic Arthritis (JIA). Accurate diagnosis of JIA is difficult as various clinical tests, including MRI, disagree. The purpose of this study is to optimize the methodological aspects of Dynamic Contrast Enhanced (DCE) MRI of the TMJ in children. In this cross-sectional study, including data from 73 JIA affected children, aged 6-15 years, effects of motion correction, sampling rate and parametric modelling on DCE-MRI data is investigated. Consensus among three radiologists determined the regions of interest. Quantitative perfusion parameters were estimated using four perfusion models; the Adiabatic Approximation to Tissue Homogeneity (AATH), Distributed Capillary Adiabatic Tissue Homogeneity (DCATH), Gamma Capillary Transit Time (GCTT) and Two Compartment Exchange (2CXM) models. Effects of motion correction were evaluated by a sum of least squares between corrected raw data and the GCTT model. The effect of systematically down sampling the raw data was tested. The sum of least squares was computed across all pharmacokinetic models. Relative difference perfusion parameters between the left and right TMJ were used for an unsupervised k-means based stratification of the data based on a principal component analysis, as well as for a supervised random forest classification. Diagnostic sensitivity and specificity were computed relative to structural image scorings. Paired sample t-tests, as well as ANOVA tests, were used (significant threshold: p < 0.05) with Tukeys post hoc test. High-level elastic motion correction provides the best least square fit to the GCTT model (percental improvement: 72-84%). A 4 s sampling rate captures more of the potentially disease relevant signal variations. The various parametric models all leave comparable residues (relative standard deviation: 3.4%). In further evaluation of DCE-MRI as a potential diagnostic tool for JIA a high-level elastic motion correction scheme should be adopted, with a sampling rate of at least 4 s. Results suggest that DCE-MRI data can be a valuable part in JIA diagnostics in the TMJ.

• MeSH
• artefakty MeSH
• dítě MeSH
• juvenilní artritida diagnostické zobrazování   MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• mladiství MeSH
• počítačové zpracování obrazu * MeSH
• pohyb * MeSH
• předškolní dítě MeSH
• průřezové studie MeSH
• senzitivita a specificita MeSH
• statistické modely * MeSH
• temporomandibulární kloub diagnostické zobrazování   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cíl: Vliv protokolu zrychlené zotavení po operaci (ERAS) na pooperační výsledky po urogynekologické operaci zatím zůstává předmětem zkoumání. Tato studie se snažila zhodnotit toto téma srovnáním pacientů, kteří měli konvenční nebo ERAS – řízenou perioperační péči, a to u několika klinických endpointů vč. chůze, délky pobytu v nemocnici (LOS), opětovné hospitalizace a pooperačních komplikací. Materiál a metody: Celkem 121 pacientů podstupujících operaci z důvodu prolapsu pánevního orgánu bylo rozděleno do dvou větví studie – protokol ERAS (skupina E) a konvenční péče (skupina C). Mezi skupinami byly porovnány proměnné zahrnující obnovení chuti k jídlu, vyprazdňování, krvácivé příhody, další komplikace, LOS a opětovné hospitalizaci. Výsledky: Pacienti skupiny C dostávali významně intenzivněji intravenózní tekutinovou léčbu ve srovnání se skupinou E (2 760 ± 656 vs. 1 045 ± 218 ml, p < 0,001). Doba potřebná k prvnímu flatusu, první defekaci, požití pevné stravy a chůzi (p < 0,001) byla také delší u první skupiny pacientů. Při použití protokolu ERAS byla významně snížena délka pobytu v nemocnici (2,5 ± 1,1 vs. 2,0 ± 0,6 dne, p < 0,001). Na druhou stranu se obě skupiny ukázaly jako srovnatelné co se týče pooperačních komplikací, včetně infekcí v místě provedení chirurgického výkonu, kardiovaskulárních komplikací, nespecifických bolestí břicha, subileu, krevních ztrát a míry opětovné hospitalizace. Závěr: V námi zkoumané populaci vedl protokol ERAS k časnému zahájení perorálního příjmu, časnému obnovení funkce střev, časné mobilizaci a dřívějšímu propuštění pacientů bez snížení bezpečnosti po urogynekologické operaci.

Objective: The impact of enhanced recovery after surgery (ERAS) protocol on postoperative outcomes after urogynecological surgery is yet to be a matter of investigation. This study sought to evaluate this issue by comparing the patients who had conventional or ERAS--guided perioperative care for several clinical end-points including ambulation, length of hospital stay (LOS), readmissions, and postoperative complications. Materials and methods: A total of 121 patients undergoing pelvic organ prolapse surgery were allocated to two study arms, ERAS protocol (Group E) or conventional care (Group C). Variables reflecting the restoration of appetite and bowel movements, bleeding events, other complications, LOS and readmissions were compared between the groups. Results: The patients in Group C significantly received a more intensive intravenous fluid treatment compared to Group E (2,760 ± 656 vs. 1,045 ± 218 mL, P < 0.001). Time required for first flatus, first defecation, eating solid food, and ambulation (P < 0.001) were also longer in the former group of patients. Moreover, LOS was significantly reduced when the ERAS protocol was applied (2.5 ± 1.1 vs. 2.0 ± 0.6 days, P < 0.001). On the other hand, the two groups were similar with respect to the frequency of the postoperative complications, including surgical site infections, cardiovascular complications, non-specific abdominal pain, sub-ileus, blood loss and readmission rate. Conclusion: In our sample population, ERAS protocol led to early initiation of oral intake, early recovery of bowel function, early mobilization, and early discharge of patients without compromise in safety concerns after urogynecological surgery.

• MeSH
• délka pobytu MeSH
• lidé MeSH
• perioperační péče MeSH
• pooperační komplikace etiologie   MeSH
• prolaps pánevních orgánů * chirurgie   komplikace   MeSH
• retrospektivní studie MeSH
• urychlená pooperační rehabilitace * MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

Significant renal artery stenosis (RAS) is a potentially curable cause of renovascular hypertension and/or renal impairment. It is caused by either atherosclerosis or fibromuscular dysplasia. Correct and timely diagnosis remains a diagnostic challenge. MR angiography (MRA) as a minimally invasive method seems to be suitable for RAS detection, however, its diagnostic value widely differs in the literature (sensitivity 62-100% and specificity 75-100%). The aim of our prospective study was to compare the diagnostic value of contrast-enhanced MRA utilizing parallel acquisition techniques in the detection of significant RAS with digital subtraction angiography (DSA). A total of 78 hypertensive subjects with suspected renal artery stenosis were examined on a 1.5 Tesla MR system using a body array coil. Bolus tracking was used to monitor the arrival of contrast agent to the abdominal aorta. The MRA sequence parameters were as follows: TR 3.7 ms; TE 1.2 ms; flip angle 25 degrees; acquisition time 18s; voxel size 1.1 mm x1.0 mm x 1.1 mm; centric k-space sampling; parallel acquisition technique with acceleration factor of 2 (GRAPPA). Renal artery stenosis of 60% and more was considered hemodynamically significant. The results of MRA were compared to digital subtraction angiography serving as a standard of reference. Sensitivity and specificity of MRA in the detection of hemodynamically significant renal artery stenosis were 90% and 96%, respectively. Prevalence of RAS was 39% in our study population. Contrast-enhanced MRA with high spatial resolution offers sufficient sensitivity and specificity for screening of RAS.

• MeSH
• algoritmy MeSH
• dospělí MeSH
• interpretace obrazu počítačem metody   MeSH
• kontrastní látky MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční angiografie metody   MeSH
• mladý dospělý MeSH
• obstrukce renální arterie diagnóza   MeSH
• organokovové sloučeniny diagnostické užití   MeSH
• reprodukovatelnost výsledků MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• vylepšení obrazu metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

In this article, we present an enhanced sampling method based on a hybrid Hamiltonian which combines experimental distance restraints with a bias dependent from multiple path-dependent variables. This simulation method determines the bias-coordinates on the fly and does not require a priori knowledge about reaction coordinates. The hybrid Hamiltonian accelerates the sampling of proteins, and, combined with experimental distance information, the technique considers the restraints adaptively and in dependency of the system's intrinsic dynamics. We validate the methodology on the dipole relaxation of two water models and the conformational landscape of dialanine. Using experimental NMR-restraint data, we explore the folding landscape of the TrpCage mini-protein and in a second example apply distance restraints from chemical crosslinking/mass spectrometry experiments for the sampling of the conformation space of the Killer Cell Lectin-like Receptor Subfamily B Member 1A (NKR-P1A). The new methodology has the potential to adaptively introduce experimental restraints without affecting the conformational space of the system along an ergodic trajectory. Since only a limited number of input- and no-order parameters are required for the setup of the simulation, the method is broadly applicable and has the potential to be combined with coarse-graining methods.

• MeSH
• časové faktory MeSH
• magnetická rezonanční spektroskopie MeSH
• peptidy chemie   MeSH
• simulace molekulární dynamiky * MeSH
• Publikační typ
• časopisecké články MeSH

A pilot study aimed on possible occurrence of elevated activity of non-exchangable organically bound tritium (NE-OBT) in biota was performed. The first results showed a significant surplus of NE-OBT activity in biota of the valley of Mohelno reservoir and Jihlava river. The liquid releases of HTO from the nuclear power plant Dukovany is the source of tritium in this area. This area can be a source of various types of natural samples for future studies of tritium pathways.

• MeSH
• jaderné elektrárny MeSH
• lidé MeSH
• monitorování radiace přístrojové vybavení   metody   MeSH
• pilotní projekty MeSH
• radioaktivní látky znečišťující vodu analýza   MeSH
• radioaktivní znečišťující látky analýza   metabolismus   MeSH
• řeky chemie   MeSH
• rostliny metabolismus   MeSH
• scintilace - počítání přístrojové vybavení   metody   MeSH
• společenstvo MeSH
• tritium analýza   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH