Drug discovery efforts largely depend on access to structural diversity. Multicomponent reactions allow for time-efficient chemical transformations and provide advanced intermediates with three or four points of diversification for further expansion to a structural variety of organic molecules. This review is aimed at solid-phase syntheses of small molecules involving isocyanide-based multicomponent reactions. The majority of all reported syntheses employ the Ugi four-component reaction. The review also covers the Passerini and Groebke-Blackburn-Bienaymé reactions. To date, the main advantages of the solid-phase approach are the ability to prepare chemical libraries intended for biological screening and elimination of the isocyanide odor. However, the potential of multicomponent reactions has not been fully exploited. The unexplored avenues of these reactions, including chiral frameworks, DNA-encoded libraries, eco-friendly synthesis, and chiral auxiliary reactions, are briefly outlined.
A dodecadepsipeptide valinomycin (VLM) has been most recently reported to be a potential anti-coronavirus drug that could be efficiently produced on a large scale. It is thus of importance to study solid-phase forms of VLM in order to be able to ensure its polymorphic purity in drug formulations. The previously available solid-state NMR (SSNMR) data are combined with the plane-wave DFT computations in the NMR crystallography framework. Structural/spectroscopical predictions (the PBE functional/GIPAW method) are obtained to characterize four polymorphs of VLM. Interactions which confer a conformational stability to VLM molecules in these crystalline forms are described in detail. The way how various structural factors affect the values of SSNMR parameters is thoroughly analyzed, and several SSNMR markers of the respective VLM polymorphs are identified. The markers are connected to hydrogen bonding effects upon the corresponding (13C/15N/1H) isotropic chemical shifts of (CO, Namid, Hamid, Hα) VLM backbone nuclei. These results are expected to be crucial for polymorph control of VLM and in probing its interactions in dosage forms.
- MeSH
- Betacoronavirus chemistry isolation & purification metabolism MeSH
- Nitrogen Isotopes chemistry MeSH
- Carbon Isotopes chemistry MeSH
- Coronavirus Infections pathology virology MeSH
- Crystallography MeSH
- Magnetic Resonance Spectroscopy methods MeSH
- Pandemics MeSH
- Valinomycin chemistry metabolism MeSH
- Pneumonia, Viral pathology virology MeSH
- Hydrogen Bonding MeSH
- Publication type
- Journal Article MeSH
Electrochemical methods can be used not only for the sensitive analysis of proteins but also for deeper research into their structure, transport functions (transfer of electrons and protons), and sensing their interactions with soft and solid surfaces. Last but not least, electrochemical tools are useful for investigating the effect of an electric field on protein structure, the direct application of electrochemical methods for controlling protein function, or the micromanipulation of supramolecular protein structures. There are many experimental arrangements (modalities), from the classic configuration that works with an electrochemical cell to miniaturized electrochemical sensors and microchip platforms. The support of computational chemistry methods which appropriately complement the interpretation framework of experimental results is also important. This text describes recent directions in electrochemical methods for the determination of proteins and briefly summarizes available methodologies for the selective labeling of proteins using redox-active probes. Attention is also paid to the theoretical aspects of electron transport and the effect of an external electric field on the structure of selected proteins. Instead of providing a comprehensive overview, we aim to highlight areas of interest that have not been summarized recently, but, at the same time, represent current trends in the field.
Oxime reactivators of acetylcholinesterase are commonly used to treat highly toxic organophosphate poisoning. They are effective nucleophiles that can restore the catalytic activity of acetylcholinesterase; however, their main limitation is the difficulty in crossing the blood-brain barrier (BBB) because of their strongly hydrophilic nature. Various approaches to overcome this limitation and enhance the bioavailability of oxime reactivators in the CNS have been evaluated; these include structural modifications, conjugation with molecules that have transporters in the BBB, bypassing the BBB through intranasal delivery, and inhibition of BBB efflux transporters. A promising approach is the use of nanoparticles (NPs) as the delivery systems. Studies using mesoporous silica nanomaterials, poly (L-lysine)-graft-poly(ethylene oxide) NPs, metallic organic frameworks, poly(lactic-co-glycolic acid) NPs, human serum albumin NPs, liposomes, solid lipid NPs, and cucurbiturils, have shown promising results. Some NPs are considered as nanoreactors for organophosphate detoxification; these combine bioscavengers with encapsulated oximes. This study provides an overview and critical discussion of the strategies used to enhance the bioavailability of oxime reactivators in the central nervous system.
- MeSH
- Acetylcholinesterase * MeSH
- Biological Availability MeSH
- Biological Transport MeSH
- Central Nervous System * MeSH
- Blood-Brain Barrier MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Articular cartilage is a complex, anisotropic, stratified tissue with remarkable resilience and mechanical properties. It has been subject to extensive modelling as a multiphase medium, with many recent studies examining the impact of increasing detail in the representation of this tissue's fine scale structure. However, further investigation of simple models with minimal constitutive relations can nonetheless inform our understanding at the foundations of soft tissue simulation. Here, we focus on the impact of heterogeneity with regard to the volume fractions of solid and fluid within the cartilage. Once swelling pressure due to cartilage fixed charge is also present, we demonstrate that the multiphase modelling framework is substantially more complicated, and thus investigate this complexity, especially in the simple setting of a confined compression experiment. Our findings highlight the importance of locally, and thus heterogeneously, approaching pore compaction for load bearing in cartilage models, while emphasising that such effects can be represented by simple constitutive relations. In addition, simulation predictions are observed for the sensitivity of stress and displacement in the cartilage to variations in the initial state of the cartilage and thus the details of experimental protocol, once the tissue is heterogeneous. These findings are for the simplest models given only heterogeneity in volume fractions and swelling pressure, further emphasising that the complex behaviours associated with the interaction of volume fraction heterogeneity and swelling pressure are likely to persist for simulations of cartilage representations with more fine-grained structural detail of the tissue.
Impulsem k zahájení procesu, jenž postupně vedl až ke vzniku zdravotnické profese adiktologa v České repub- lice, byla reakce na nedostatek dostatečně vzdělaných profesionálů v nově vznikajících službách v 90. letech. Postupem času však došlo k natolik výrazné a úspěšné profilaci této nové profese, že byl uvedený rámec překročen a vznikl zcela svébytný a originální koncept studijního programu na pozadí emancipujícího se transdisciplinárního oboru. Jeho zaměření dostalo plný rozsah tematického záběru od prevence, přes léčbu a rehabilitaci, až procesu přirozené úzdravy. Své pevné místo zde má také celá oblast strategií a metod minimalizace rizik a škod. Cílem studie je popsat okolnosti vzniku, vývoje a současného ukotvení studijního oboru adiktologie na pozadí vývoje v oblasti závislostního chování v České republice. Dílčím cíle je upozornit na měnící se profil podobně zaměřených studijních programů a startující vlnu zájmu o ně ve světě, včetně vzniku prvních modelových mezinárodních kurikulí pro tento typ studia na univerzitách. Výzkumný soubor tvoří identifikované dokumenty a evaluační studie vztahující se k oboru adiktologie v ČR a související studie zaměřené na tento obor v zahraničí, mající vztah k formování mezinárodních kurikulí. Přestože byl vznik samotného původního konceptu studijního oboru ovlivněn dobovými požadavky poskytovatelů péče, ukázalo se rychle, že dynamika vývoje tohoto oboru překročila uvedený rámec a dala vzniknout zcela originálnímu konceptu studijního oboru pod názvem „pražský model adiktologického studia“. Následnými srovnáními se ukázalo, že podobnou cestou prošly také další země a že mnohé z těchto programů se podobají. Unikátnost tuzemského modelu tkví v jeho konzistentní stavbě a systematickém budování a následném pevném legislativním ukotvení. Současně se ukázala být velmi dobře nastavená vazba mezi tímto oborem a praxí, tj. především poskytovateli péči a dobře zvládnutému institucionálnímu rámci rodícího se nového oboru. Paralelním procesem se pak stalo formování mezinárodní spolupráce univerzit s těmito studijními programy a vznik prvních mezinárodních kurikulí. Česká republika se stala průkopníkem nového modelu studia oboru adiktologie a její model studijního programu na úrovni bakalářského, magisterského a doktorského se stal vzorovým pro rozvoj podobných programů v dalších zemích a pro ukotvení této nové profese v systému péče o osoby se závislostí.
A shortage of appropriately qualified and trained practitioners to staff the emerging addiction services in the 1990s initiated a process which eventually led to the establishment of the health profession of an addictologist in the Czech Republic. In the course of time, this new profession developed into a distinctive and well-acclaimed field of expertise which went beyond its original scope and gave rise to a unique concept of a study programme against the background of an emancipating transdisciplinary field of study. It is intended to address the full scope of relevant topics, ranging from prevention, treatment, and rehabilitation to the process of natural recovery. All aspects of harm reduction strategies and methods are also given significant attention. The Aim was to describe the details of the origin, development, and current status of the study programme in addictology in the context of the addictive behaviour-related developments in the Czech Republic. Another objective is to point out the changing profile of similarly-oriented study programmes and the emerging wave of interest in them internationally, including the development of the first international model curricula for this type of study at universities. The sample comprises retrieved documents and evaluation studies pertaining to the field of addictology in the Czech Republic and related studies on this discipline abroad which address the constitution of international curricula. While the development of the original concept of the discipline was influenced by the requirements of the service providers of the time, it became apparent before long that the dynamics of the development of the field had gone beyond its original scope and given rise to a brand-new concept of a study programme referred to as the “Prague Model of Addiction Studies”. Subsequent comparisons showed that other countries, too, followed a similar path and that many of these programmes were similar. The Czech model is unique in its consistent structure, systematic building, and subsequent legislative grounding. In addition, a firm link between the field of study and practice, especially service providers, and a solid institutional framework for the new field have been established. Finally, in parallel with the domestic efforts, activities aimed at establishing and maintaining networks of international universities offering relevant academic programmes and developing the first international curricula have been pursued. The Czech Republic has pioneered a new model of addiction studies, and its concept of bachelor’s, master’s, and doctoral study programmes has become a blueprint for the development of similar programmes and the integration of the new profession within the system of addiction services in other countries.
xiv, 1122 s. : il. ; 28 cm
- Conspectus
- Patologie. Klinická medicína
- NML Fields
- kardiologie
- NML Publication type
- kolektivní monografie
Impulsem k zahájení procesu, jenž postupně vedl až ke vzniku zdravotnické profese adiktologa v České repub- lice, byla reakce na nedostatek dostatečně vzdělaných profesionálů v nově vznikajících službách v 90. letech. Postupem času však došlo k natolik výrazné a úspěšné profilaci této nové profese, že byl uvedený rámec překročen a vznikl zcela svébytný a originální koncept studijního programu na pozadí emancipujícího se transdisciplinárního oboru. Jeho zaměření dostalo plný rozsah tematického záběru od prevence, přes léčbu a rehabilitaci, až procesu přirozené úzdravy. Své pevné místo zde má také celá oblast strategií a metod minimalizace rizik a škod. Cílem studie je popsat okolnosti vzniku, vývoje a současného ukotvení studijního oboru adiktologie na pozadí vývoje v oblasti závislostního chování v České republice. Dílčím cíle je upozornit na měnící se profil podobně zaměřených studijních programů a startující vlnu zájmu o ně ve světě, včetně vzniku prvních modelových mezinárodních kurikulí pro tento typ studia na univerzitách. Výzkumný soubor tvoří identifikované dokumenty a evaluační studie vztahující se k oboru adiktologie v ČR a související studie zaměřené na tento obor v zahraničí, mající vztah k formování mezinárodních kurikulí. Přestože byl vznik samotného původního konceptu studijního oboru ovlivněn dobovými požadavky poskytovatelů péče, ukázalo se rychle, že dynamika vývoje tohoto oboru překročila uvedený rámec a dala vzniknout zcela originálnímu konceptu studijního oboru pod názvem „pražský model adiktologického studia“. Následnými srovnáními se ukázalo, že podobnou cestou prošly také další země a že mnohé z těchto programů se podobají. Unikátnost tuzemského modelu tkví v jeho konzistentní stavbě a systematickém budování a následném pevném legislativním ukotvení. Současně se ukázala být velmi dobře nastavená vazba mezi tímto oborem a praxí, tj. především poskytovateli péči a dobře zvládnutému institucionálnímu rámci rodícího se nového oboru. Paralelním procesem se pak stalo formování mezinárodní spolupráce univerzit s těmito studijními programy a vznik prvních mezinárodních kurikulí. Česká republika se stala průkopníkem nového modelu studia oboru adiktologie a její model studijního programu na úrovni bakalářského, magisterského a doktorského se stal vzorovým pro rozvoj podobných programů v dalších zemích a pro ukotvení této nové profese v systému péče o osoby se závislostí.
A shortage of appropriately qualified and trained practitioners to staff the emerging addiction services in the 1990s initiated a process which eventually led to the establishment of the health profession of an addictologist in the Czech Republic. In the course of time, this new profession developed into a distinctive and well-acclaimed field of expertise which went beyond its original scope and gave rise to a unique concept of a study programme against the background of an emancipating transdisciplinary field of study. It is intended to address the full scope of relevant topics, ranging from prevention, treatment, and rehabilitation to the process of natural recovery. All aspects of harm reduction strategies and methods are also given significant attention. The Aim was to describe the details of the origin, development, and current status of the study programme in addictology in the context of the addictive behaviour-related developments in the Czech Republic. Another objective is to point out the changing profile of similarly-oriented study programmes and the emerging wave of interest in them internationally, including the development of the first international model curricula for this type of study at universities. The sample comprises retrieved documents and evaluation studies pertaining to the field of addictology in the Czech Republic and related studies on this discipline abroad which address the constitution of international curricula. While the development of the original concept of the discipline was influenced by the requirements of the service providers of the time, it became apparent before long that the dynamics of the development of the field had gone beyond its original scope and given rise to a brand-new concept of a study programme referred to as the “Prague Model of Addiction Studies”. Subsequent comparisons showed that other countries, too, followed a similar path and that many of these programmes were similar. The Czech model is unique in its consistent structure, systematic building, and subsequent legislative grounding. In addition, a firm link between the field of study and practice, especially service providers, and a solid institutional framework for the new field have been established. Finally, in parallel with the domestic efforts, activities aimed at establishing and maintaining networks of international universities offering relevant academic programmes and developing the first international curricula have been pursued. The Czech Republic has pioneered a new model of addiction studies, and its concept of bachelor’s, master’s, and doctoral study programmes has become a blueprint for the development of similar programmes and the integration of the new profession within the system of addiction services in other countries.
... 95 -- 5.4.3 Choice of Human Framework Sequences 97 -- 5.4.3.1 Fixed Frameworks or Best-Fit? ... ... 100 -- 5.4.3.2 VL/VH Frameworks from the Same or Different Clone? ... ... 100 -- 5.4.3.3 Human Subgroup Consensus or Expressed Framework? ... ... Martin and James Allen -- 9.1 Introduction 201 -- 9.1.1 Brief Review of Antibody Structure 201 -- 9.1.2 ... ... Resource 215 -- 9.8 Antibody Structure Prediction 216 -- 9.8.1 Build the Framework 216 -- 9.8.2 Build ...
2nd ed. 4 sv. (lxxxv, 2187 s.) : il., tab. ; 25 cm
- MeSH
- Biomarkers, Pharmacological MeSH
- Biotechnology methods MeSH
- Drug Evaluation, Preclinical MeSH
- Antibodies pharmacology therapeutic use MeSH
- Publication type
- Handbook MeSH
- Conspectus
- Farmacie. Farmakologie
- NML Fields
- farmacie a farmakologie
- alergologie a imunologie
- NML Publication type
- kolektivní monografie
... Regulate Cell Polarity Summary -- CELL POLARIZATION AND MIGRATION -- Many Cells Can Crawl Across a Solid ...
Sixth edition xxxiv, 1430 stran v různém stránkování : ilustrace (převážně barevné) ; 29 cm
- MeSH
- Cells * MeSH
- Molecular Biology MeSH
- Conspectus
- Biochemie. Molekulární biologie. Biofyzika
- NML Fields
- molekulární biologie, molekulární medicína
- NML Publication type
- učebnice vysokých škol
