modular structure
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Phage tail fibres are elongated protein assemblies capable of specific recognition of bacterial surfaces during the first step of viral infection1-4. The folding of these complex trimeric structures often requires a phage-encoded tail fibre assembly (Tfa) protein5-7. Despite the wide occurrence of Tfa proteins, their functional mechanism has not been elucidated. Here, we investigate the tail fibre and Tfa of Escherichia coli phage Mu. We demonstrate that Tfa forms a stable complex with the tail fibre, and present a 2.1 Å resolution X-ray crystal structure of this complex. We find that Tfa proteins are comprised of two domains: a non-conserved N-terminal domain that binds to the C-terminal region of the fibre and a conserved C-terminal domain that probably mediates fibre oligomerization and assembly. Tfa forms rapidly exchanging multimers on its own, but not a stable trimer, implying that Tfa does not specify the trimeric state of the fibre. We propose that the key conserved role of Tfa is to ensure that fibre assembly and multimerization initiates at the C terminus, ensuring that the intertwined and repetitive structural elements of fibres come together in the correct sequence. The universal importance of correctly aligning the C termini of phage fibres is highlighted by our work.
- MeSH
- bakteriofágy klasifikace fyziologie MeSH
- Escherichia coli metabolismus virologie MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- multimerizace proteinu MeSH
- proteiny virových bičíků chemie genetika metabolismus MeSH
- sbalování proteinů MeSH
- sekvence aminokyselin MeSH
- sekvenční seřazení MeSH
- vazba proteinů MeSH
- virové proteiny chemie genetika metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Novel compounds termed lipophosphonoxins were prepared using a simple and efficient synthetic approach. The general structure of lipophosphonoxins consists of four modules: (i) a nucleoside module, (ii) an iminosugar module, (iii) a hydrophobic module (lipophilic alkyl chain), and (iv) a phosphonate linker module that holds together modules i-iii. Lipophosphonoxins displayed significant antibacterial properties against a panel of Gram-positive species, including multiresistant strains. The minimum inhibitory concentration (MIC) values of the best inhibitors were in the 1-12 μg/mL range, while their cytotoxic concentrations against human cell lines were significantly above this range. The modular nature of this artificial scaffold offers a large number of possibilities for further modifications/exploitation of these compounds.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- erytroidní prekurzorové buňky cytologie účinky léků MeSH
- fetální krev MeSH
- grampozitivní bakterie účinky léků MeSH
- hydrofobní a hydrofilní interakce MeSH
- kultivované buňky MeSH
- kyseliny fosforité chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mnohočetná bakteriální léková rezistence MeSH
- nukleosidy chemická syntéza chemie farmakologie MeSH
- stereoizomerie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Novel 4-aminoquinazoline-6-carboxamide derivatives bearing differently substituted aryl or heteroaryl groups at position 7 in the core were rationally designed, synthesized and evaluated for biological activity in vitro as phosphatidylinositol 4-kinase IIα (PI4K2A) inhibitors. The straightforward approach described here enabled the sequential, modular synthesis and broad functionalization of the scaffold in a mere six steps. The SAR investigation reported here is based on detailed structural analysis of the conserved binding mode of ATP and other adenine derivatives to the catalytic site of type II PI4Ks, combined with extensive docking studies. Several compounds exhibited significant activity against PI4K2A. Moreover, we solved a crystal structure of PI4K2B in complex with one of our lead ligand candidates, which validated the ligand binding site and pose predicted by our docking-based ligand model. These discoveries suggest that our structure-based approach may be further developed and employed to synthesize new inhibitors with optimized potency and selectivity for this class of PI4Ks.
Given the great biological importance and high diversity of temperate Staphylococcus aureus bacteriophages, a method is needed for the description of their genomic structure. Here we have updated a multiplex PCR strategy for the complex characterization of S. aureus phages of the family Siphoviridae. Based on the comparative genomic analysis of the available phage sequences, a multilocus PCR strategy for typing the major modules of the phage genome was designed. The genomic modules were classified on the basis of the genes for integrase (10 types), anti-repressor (five types), replication proteins polA, dnaC and dnaD (four types), dUTPase (four types), portal protein (eight types), tail appendices (four types) and endolysin (four types) corresponding to the integrase locus, lysogeny control region, and modules for DNA replication, transcription regulation, packaging, tail appendices and lysis respectively. The nine PCR assays designed for the above sequences were shown to be capable to identify the bacteriophage gene pool present both in the phage and bacterial genomes and their extensive mosaic structure. The established multiplex PCR-based multilocus diagnostic scheme is convenient for rapid and reliable phage and prophage classification and for the study of bacteriophage evolution.
- MeSH
- DNA virů genetika MeSH
- genom virový MeSH
- multilokusová sekvenční typizace MeSH
- polymerázová řetězová reakce metody MeSH
- profágy klasifikace genetika MeSH
- Siphoviridae klasifikace genetika MeSH
- srovnávací genomová hybridizace MeSH
- Staphylococcus aureus genetika virologie MeSH
- virové proteiny genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Seroins are small lepidopteran silk proteins known to possess antimicrobial activities. Several seroin paralogs and isoforms were identified in studied lepidopteran species and their classification required detailed phylogenetic analysis based on complete and verified cDNA sequences. We sequenced silk gland-specific cDNA libraries from ten species and identified 52 novel seroin cDNAs. The results of this targeted research, combined with data retrieved from available databases, form a dataset representing the major clades of Lepidoptera. The analysis of deduced seroin proteins distinguished three seroin classes (sn1-sn3), which are composed of modules: A (includes the signal peptide), B (rich in charged amino acids) and C (highly variable linker containing proline). The similarities within and between the classes were 31-50% and 22.5-25%, respectively. All species express one, and in exceptional cases two, genes per class, and alternative splicing further enhances seroin diversity. Seroins occur in long versions with the full set of modules (AB1C1B2C2B3) and/or in short versions that lack parts or the entire B and C modules. The classes and the modular structure of seroins probably evolved prior to the split between Trichoptera and Lepidoptera. The diversity of seroins is reflected in proposed nomenclature.
The concept of the phylotypic stage has been strongly integrated into developmental biology, thanks mostly to drawings presented by Haeckel (Anthropogenie oder Entwicklungsgeschichte des Menschen, 1874). They are printed in every textbook as proof of the existence of the phylotypic stage and the fact of its conservation, albeit many times criticized as misleading and simplifying (Richardson in Develop Biol 172:412-421, 1995, Richardson et al. in Anat Embryo 196:91-106, 1997; Bininda-Emons et al. in Proc R Soc Lond 270:341-346, 2003). Although generally accepted by modern biology, doubt still exists concerning the very existence or the usefulness of the concept. What kind of evolutionary and developmental horizons does it open indeed? This article begins with the history of the concept, discusses its validity and draws this into connotation with the idea of a memory activated throughout the development. Barbieri (The organic codes. An introduction to semantic biology, 2003) considers the phylotypic stage to be a crucial boundary when the genetic program ceases to suffice for further development of the embryo, and supracellular memory of the body plan is activated. This moment clearly coincides with the commencing of the modular development of the embryo. In this article the nature of such putative memory will be discussed.
- MeSH
- aktivace transkripce MeSH
- anatomické modely MeSH
- biologická evoluce MeSH
- biologické modely MeSH
- DNA metabolismus MeSH
- Drosophila melanogaster MeSH
- fylogeneze MeSH
- homeoboxové geny MeSH
- lidé MeSH
- mutace MeSH
- myši MeSH
- reprodukovatelnost výsledků MeSH
- signální transdukce MeSH
- vývojová biologie metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Úvod: Dlouhodobé výsledky přežití endoprotéz kloubů jsou pro praxi nejdůležitější informací, která operatérovi ukazuje, zda zvolil správný implantát. Autoři hodnotí dlouhodobé výsledky kondylární totální endoprotézy kolenních kloubů typu Universal 16-22 let od implantace. Soubor a metodika: Soubor zahrnuje celkem 121 totálních náhrad kolenního kloubu u 107 pacientů s průměrným věkem 71,3 roku (52-86 roků). K operaci bylo indikováno celkem 115 kolen s diagnózou osteoartrózy 3.-4. stupně a šest pacientů s diagnózou revmatoidní artritidy. Výsledky byly zhodnoceny statistickou metodou podle Kaplanovy-Meierovy křivky přežití a kumulativní incidence. Výsledky: V pozdním období nastaly infekční komplikace kolenního kloubu u 4 kolenních kloubů (3,3 %). Aseptické uvolnění z počtu 117 endoprotéz bylo pozorováno ve 4 případech (3,4 %). Vždy šlo o uvolnění tibiální komponenty. Uvolnění femorální komponenty nebylo pozorováno. Od implantace do současnosti (červen 2014), což je 16-22 let od implantace přežívá celkem 16 pacientů, u kterých bylo implantováno celkem 21 endoprotéz, u nichž nejsou známky uvolnění jen u 4 pacientů (19 %), byla patrná radiolucentní linie do 2 mm se sklerotickým lemem pod tibiálním platem. Šest pacientek (28,5 %) udává obtíže z oblasti femoropatelárního kloubu, kde je na rentgenových snímcích patrná lateralizace pately. U dvou pacientů (1,6 %) došlo v období sledování k periprotetické zlomenině femuru. Tento stav bylo možné řešit osteosyntézou hřebem (Distal Femoral Nail). Při hodnocení Kaplanovy-Meierovy křivky uvolnění a kumulativní incidence našeho souboru ukazuje po sedmi letech shodně incidenci uvolnění 1,3 %, ale po 12 letech je podle Kaplanovy-Meierovy křivky 8,2 % a podle kumulativní incidence 5,2 %, což přetrvává i po 22 letech. Diskuze: Naše závěry ukazují, že totální endoprotéza kolenního kloubu typu UNIVERSAL patří mezi spolehlivé endoprotézy kolenního kloubu, která má dlouhodobě shodné či lepší výsledky než další renomované implantáty.
Introduction: Long-term survival outcomes of joint replacements are a crucial piece of practical information that shows the surgeon if he had chosen the correct implant. The authors evaluate the long-term results of total condylar knee replacements from the Universal series at 16 to 22 years after implantation. Patients and methods: The sample includes a total of 121 total knee arthroplasties in 107 patients with the mean age of 71.3 (52-86). The operation was indicated in 115 knees with a diagnosis of 3rd to 4th degree osteoarthritis and in 6 patients diagnosed with rheumatoid arthritis. The results were evaluated by statistical methods according to Kaplan-Meier survival curves and cumulative incidence. Results: Late onset infectious complications occurred in 4 knees (3.3%). Aseptic loosening of was observed in 4 cases (3.4%). The tibial component was the part getting loose all of those times. Loosening of the femoral component was not observed at all. Since the time of the implantation to the present (June 2014), which is 16 to 22 years since implantation, 16 patients still survive, who were implanted with 21 endoprostheses in total, from which only 4 patients (19%) were without signs of loosening of the implant. A radiolucent line up to 2mm thick with sclerotic rim below the tibial plate was visible in all patients without clinical signs of loosening. Six patients (28.5 %) indicate difficulties in the area of the patellofemoral joint, with lateralization of the patella being visible on x-ray images. Two patients (1.6 %) suffered from periprosthetic femoral fractures during the observed period of time. This situation can be addressed with nail osteosynthesis (Distal femoral Nail). When evaluating the Kaplan - Meier curves for loosening and the cumulative incidence, our sample shows identical incidence of loosening - 1.3%. But after 12 years it rises to 8.2% according to the Kaplan - Meier curves and to 5.2% according to a cumulative incidence, which persists after 22 years as well. Discussion: Our findings show that total knee arthroplasty implants from the UNIVERSAL series are reliable and that they have the same or better long-term results in comparison to other renowned implants.
- Klíčová slova
- Dlouhodobé přežívání endoprotéz kolenního kloubu typu UNIVERSAL,
- MeSH
- analýza přežití * MeSH
- artróza kolenních kloubů diagnóza chirurgie komplikace MeSH
- hodnotící studie jako téma MeSH
- infekční nemoci komplikace MeSH
- Kaplanův-Meierův odhad MeSH
- lidé MeSH
- nervus peroneus chirurgie zranění MeSH
- paréza diagnóza terapie MeSH
- pooperační období MeSH
- protézy a implantáty * využití MeSH
- radiografie MeSH
- revmatoidní artritida diagnóza chirurgie komplikace MeSH
- statistika jako téma MeSH
- totální endoprotéza kolene * metody využití MeSH
- výsledky a postupy - zhodnocení (zdravotní péče) metody trendy využití MeSH
- Check Tag
- lidé MeSH
Complex spatiotemporal patterns, called chimera states, consist of coexisting coherent and incoherent domains and can be observed in networks of coupled oscillators. The interplay of synchrony and asynchrony in complex brain networks is an important aspect in studies of both the brain function and disease. We analyse the collective dynamics of FitzHugh-Nagumo neurons in complex networks motivated by its potential application to epileptology and epilepsy surgery. We compare two topologies: an empirical structural neural connectivity derived from diffusion-weighted magnetic resonance imaging and a mathematically constructed network with modular fractal connectivity. We analyse the properties of chimeras and partially synchronized states and obtain regions of their stability in the parameter planes. Furthermore, we qualitatively simulate the dynamics of epileptic seizures and study the influence of the removal of nodes on the network synchronizability, which can be useful for applications to epileptic surgery.
- MeSH
- difuzní magnetická rezonance MeSH
- epilepsie diagnostické zobrazování MeSH
- lidé MeSH
- mozek * fyziologie MeSH
- nervová síť fyziologie MeSH
- nervové vedení fyziologie MeSH
- teoretické modely MeSH
- záchvaty diagnostické zobrazování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
BACKGROUND: Treponema pallidum subsp. pertenue (TPE) is the causative agent of yaws, a multistage disease endemic in tropical regions in Africa, Asia, Oceania, and South America. To date, seven TPE strains have been completely sequenced and analyzed including five TPE strains of human origin (CDC-2, CDC 2575, Gauthier, Ghana-051, and Samoa D) and two TPE strains isolated from the baboons (Fribourg-Blanc and LMNP-1). This study revealed the complete genome sequences of two TPE strains, Kampung Dalan K363 and Sei Geringging K403, isolated in 1990 from villages in the Pariaman region of Sumatra, Indonesia and compared these genome sequences with other known TPE genomes. METHODOLOGY/PRINCIPAL FINDINGS: The genomes were determined using the pooled segment genome sequencing method combined with the Illumina sequencing platform resulting in an average coverage depth of 1,021x and 644x for the TPE Kampung Dalan K363 and TPE Sei Geringging K403 genomes, respectively. Both Indonesian TPE strains were genetically related to each other and were more distantly related to other, previously characterized TPE strains. The modular character of several genes, including TP0136 and TP0858 gene orthologs, was identified by analysis of the corresponding sequences. To systematically detect genes potentially having a modular genetic structure, we performed a whole genome analysis-of-occurrence of direct or inverted repeats of 17 or more nucleotides in length. Besides in tpr genes, a frequent presence of repeats was found in the genetic regions spanning TP0126-TP0136, TP0856-TP0858, and TP0896 genes. CONCLUSIONS/SIGNIFICANCE: Comparisons of genome sequences of TPE Kampung Dalan K363 and Sei Geringging K403 with other TPE strains revealed a modular structure of several genomic loci including the TP0136, TP0856, and TP0858 genes. Diversification of TPE genomes appears to be facilitated by intra-strain genome recombination events.
- MeSH
- genom bakteriální * MeSH
- lidé MeSH
- pořadí genů MeSH
- rekombinace genetická MeSH
- repetitivní sekvence nukleových kyselin MeSH
- sekvenční analýza DNA * MeSH
- Treponema pallidum genetika MeSH
- výpočetní biologie MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Indonésie MeSH
