Due to the adverse effects of unpredictable environmental disturbances on real control systems, robustness of control performance becomes a substantial asset for control system design. This study introduces a v-domain optimal design scheme for Fractional Order Proportional-Integral-Derivative (FOPID) controllers with adoption of Genetic Algorithm (GA) optimization. The proposed design scheme performs placement of system pole with minimum angle to the first Riemann sheet in order to obtain improved disturbance rejection control performance. In this manner, optimal placement of the minimum angle system pole is conducted by fulfilling a predefined reference to disturbance rate (RDR) design specification. For a computer-aided solution of this optimal design problem, a multi-objective controller design strategy is presented by adopting GA. Illustrative design examples are demonstrated to evaluate performance of designed FOPID controllers.

• Klíčová slova
• Computer aided optimal controller design, Disturbance rejection control, FOPID controller, Fractional order control system, Stability,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The paper describes a novel control strategy for simultaneous manipulation of several microscale particles over a planar microelectrode array using dielectrophoresis. The approach is based on a combination of numerical nonlinear optimization, which gives a systematic computational procedure for finding the voltages applied to the individual electrodes, and exploitation of the intrinsic noise, which compensates for the loss of controllability when two identical particles are exposed to identical forces. Although interesting on its own, the proposed functionality can also be seen as a preliminary achievement in a quest for a technique for separation of two particles. The approach is tested experimentally with polystyrene beads (50 microns in diameter) immersed in deionized water on a flat microelectrode array with parallel electrodes. A digital camera and computer vision algorithm are used to measure the positions. Two distinguishing features of the proposed control strategy are that the range of motion is not limited to interelectrode gaps and that independent manipulation of several particles simultaneously is feasible even on a simple microelectrode array.

• Klíčová slova
• Dielectrophoresis, Feedback control, Micromanipulation, Parallel manipulation, Visual feedback,
• MeSH
• algoritmy MeSH
• design vybavení MeSH
• elektrody MeSH
• elektroforéza metody   MeSH
• hluk MeSH
• mikromanipulace přístrojové vybavení   metody   MeSH
• mikrosféry MeSH
• počítačové zpracování signálu přístrojové vybavení   MeSH
• teoretické modely MeSH
• zpětná vazba * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

This study aimed to reveal interactions of the stress response sigma subunits (factors) σD and σH of RNA polymerase and promoters in Gram-positive bacterium Corynebacterium glutamicum by combining wet-lab obtained data and in silico modeling. Computer modeling-guided point mutagenesis of C. glutamicum σH subunit led to the creation of a panel of σH variants. Their ability to initiate transcription from naturally occurring hybrid σD/σH-dependent promoter Pcg0441 and two control canonical promoters (σD-dependent PrsdA and σH-dependent PuvrD3) was measured and interpreted using molecular dynamics simulations of homology models of all complexes. The results led us to design the artificial hybrid promoter PD35H10 combining the -10 element of the PuvrD3 promoter and the -35 element of the PrsdA promoter. This artificial hybrid promoter PD35-rsdAH10-uvrD3 showed almost optimal properties needed for the bio-orthogonal transcription (not interfering with the native biological processes).

• Klíčová slova
• Bio-orthogonal transcription, Corynebacterium, Promoter, Sigma factor,
• MeSH
• bakteriální proteiny * genetika   metabolismus   chemie   MeSH
• bodová mutace * MeSH
• Corynebacterium glutamicum * genetika   MeSH
• DNA řízené RNA-polymerasy genetika   metabolismus   chemie   MeSH
• fyziologický stres genetika   MeSH
• genetická transkripce MeSH
• počítačová simulace MeSH
• promotorové oblasti (genetika) * MeSH
• regulace genové exprese u bakterií MeSH
• sigma faktor * genetika   metabolismus   chemie   MeSH
• simulace molekulární dynamiky * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bakteriální proteiny * MeSH
• DNA řízené RNA-polymerasy MeSH
• sigma faktor * MeSH

Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

• Klíčová slova
• Neuroblastoma, clinical trials, drug development, phase I, preclinical testing,
• MeSH
• časové faktory MeSH
• cílená molekulární terapie MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• neuroblastom farmakoterapie   patologie   MeSH
• preklinické hodnocení léčiv metody   MeSH
• prognóza MeSH
• protinádorové látky škodlivé účinky   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protinádorové látky MeSH

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.

• MeSH
• ABC transportéry metabolismus   MeSH
• biologický transport MeSH
• komplikace těhotenství farmakoterapie   patofyziologie   MeSH
• léčivé přípravky aplikace a dávkování   metabolismus   MeSH
• lékové interakce MeSH
• lidé MeSH
• maternofetální výměna látek fyziologie   MeSH
• membránové transportní proteiny metabolismus   MeSH
• placenta metabolismus   MeSH
• racionální návrh léčiv MeSH
• těhotenství MeSH
• trofoblasty metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ABC transportéry MeSH
• léčivé přípravky MeSH
• membránové transportní proteiny MeSH

Clinical procedure for mild cognitive impairment (MCI) is mainly based on clinical records and short cognitive tests. However, low suspicion and difficulties in understanding test cut-offs make diagnostic accuracy being low, particularly in primary care. Artificial neural networks (ANNs) are suitable to design computed aided diagnostic systems because of their features of generating relationships between variables and their learning capability. The main aim pursued in that work is to explore the ability of a hybrid ANN-based system in order to provide a tool to assist in the clinical decision-making that facilitates a reliable MCI estimate. The model is designed to work with variables usually available in primary care, including Minimental Status Examination (MMSE), Functional Assessment Questionnaire (FAQ), Geriatric Depression Scale (GDS), age, and years of education. It will be useful in any clinical setting. Other important goal of our study is to compare the diagnostic rendering of ANN-based system and clinical physicians. A sample of 128 MCI subjects and 203 controls was selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The ANN-based system found the optimal variable combination, being AUC, sensitivity, specificity, and clinical utility index (CUI) calculated. The ANN results were compared with those from medical experts which include two family physicians, a neurologist, and a geriatrician. The optimal ANN model reached an AUC of 95.2%, with a sensitivity of 90.0% and a specificity of 84.78% and was based on MMSE, FAQ, and age inputs. As a whole, physician performance achieved a sensitivity of 46.66% and a specificity of 91.3%. CUIs were also better for the ANN model. The proposed ANN system reaches excellent diagnostic accuracy although it is based only on common clinical tests. These results suggest that the system is especially suitable for primary care implementation, aiding physicians work with cognitive impairment suspicions.

• MeSH
• databáze faktografické statistika a číselné údaje   MeSH
• diagnóza počítačová metody   statistika a číselné údaje   MeSH
• kognitivní dysfunkce diagnóza   psychologie   MeSH
• lidé MeSH
• neuronové sítě * MeSH
• neuropsychologické testy * statistika a číselné údaje   MeSH
• plocha pod křivkou MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• studie případů a kontrol MeSH
• systémy pro podporu klinického rozhodování * statistika a číselné údaje   MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

The cell division cycle is controlled by cyclin-dependent kinases (cdk), which consist of a catalytic subunit (cdk1-cdk8) and a regulatory subunit (cyclin A-H). Purine-like inhibitors of cyclin-dependent kinases have recently been found to be of potential use as anticancer drugs. Rigid and flexible docking techniques were used for analysis of binding mode and design of new inhibitors. X-ray structures of three (ATP, olomoucine, roscovitine) cdk2 complexes were available at the beginning of the study and were used to optimize the docking parameters. The new potential inhibitors were then docked into the cdk2 enzyme, and the enzyme/inhibitor interaction energies were calculated and tested against the assayed activities of cdk1 (37 compounds) and cdk2 (9 compounds). A significant rank correlation between the activity and the rigid docking interaction energy has been found. This implies that (i) the rigid docking can be used as a tool for qualitative prediction of activity and (ii) values obtained by the rigid docking technique into the cdk2 active site can also be used for the prediction of cdk1 activity. While the resulting geometries obtained by the rigid docking are in good agreement with the X-ray data, the flexible docking did not always produce the same inhibitor conformation as that found in the crystal.

• MeSH
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   chemie   MeSH
• inhibitory enzymů chemická syntéza   chemie   MeSH
• katalytická doména MeSH
• kinasy CDC2-CDC28 * MeSH
• ligandy MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   chemie   MeSH
• proteinkinasa CDC2 antagonisté a inhibitory   chemie   MeSH
• puriny chemie   MeSH
• racionální návrh léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasy MeSH
• inhibitory enzymů MeSH
• kinasy CDC2-CDC28 * MeSH
• ligandy MeSH
• protein-serin-threoninkinasy MeSH
• proteinkinasa CDC2 MeSH
• puriny MeSH