Autori prezentujú prípad I. trimestrového potratu s klinicky suponovanou skorou formou kompletnej moly hydatidózy. Histopatologická a imunohistochemická analýza vylúčila kompletnú molu, ale histomorfologický profil naznačoval parciálnu hydatidóznu molu. Genetická analýza vylúčila parciálnu molu na základe biparentálnej kompozície genómu, ďalšie genetické analýzy odhalili trizómiu chromozómu 16. Trizómia chromozómu 16 je častou príčinou potratov v I. trimestri a môže viesť k vysoko abnormálnej histomorfológii placenty napodobňujúcej parciálnu molu. Genetické analýzy sú v týchto prípadoch rozhodujúce pre správnu diferenciálnu dia gnostiku, a teda pre stanovenie adekvátnej dispenzárnej starostlivosti a prognózy pre ďalšie gravidity.
The authors present a case of 1st trimester miscarriage where an early, complete hydatidiform mole was clinically suspected. Histopathological and immunohistochemical analyses excluded a complete mole, but the histomorphological profile was in concordance with a partial hydatidiform mole. Genetic analysis excluded a partial mole based on biparental genome composition, where further genetic analyses detected trisomy of chromosome 16. Trisomy of chromosome 16 is a frequent cause of 1st trimester abortions and may lead to highly abnormal placental histomorphology mimicking a partial mole. Genetic analyses are crucial for proper differential diagnosis and for the determination of adequate follow-up and prognosis for further pregnancies.
- MeSH
- dospělí MeSH
- lidé MeSH
- lidské chromozomy, pár 16 genetika MeSH
- mola hydatidosa * diagnóza genetika klasifikace komplikace MeSH
- molekulární mimikry genetika MeSH
- mutační analýza DNA klasifikace metody MeSH
- placenta anatomie a histologie patologie MeSH
- samovolný potrat etiologie genetika MeSH
- trizomie * genetika patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
Neurotropic pathogens, notably, herpesviruses, have been associated with significant neuropsychiatric effects. As a group, these pathogens can exploit molecular mimicry mechanisms to manipulate the host central nervous system to their advantage. Here, we present a systematic computational approach that may ultimately be used to unravel protein-protein interactions and molecular mimicry processes that have not yet been solved experimentally. Toward this end, we validate this approach by replicating a set of pre-existing experimental findings that document the structural and functional similarities shared by the human cytomegalovirus-encoded UL144 glycoprotein and human tumor necrosis factor receptor superfamily member 14 (TNFRSF14). We began with a thorough exploration of the Homo sapiens protein database using the Basic Local Alignment Search Tool (BLASTx) to identify proteins sharing sequence homology with UL144. Subsequently, we used AlphaFold2 to predict the independent three-dimensional structures of UL144 and TNFRSF14. This was followed by a comprehensive structural comparison facilitated by Distance-Matrix Alignment and Foldseek. Finally, we used AlphaFold-multimer and PPIscreenML to elucidate potential protein complexes and confirm the predicted binding activities of both UL144 and TNFRSF14. We then used our in silico approach to replicate the experimental finding that revealed TNFRSF14 binding to both B- and T-lymphocyte attenuator (BTLA) and glycoprotein domain and UL144 binding to BTLA alone. This computational framework offers promise in identifying structural similarities and interactions between pathogen-encoded proteins and their host counterparts. This information will provide valuable insights into the cognitive mechanisms underlying the neuropsychiatric effects of viral infections.
Human immunodeficiency virus type 1 (HIV-1) vaccine immunogens capable of inducing broadly neutralizing antibodies (bNAbs) remain obscure. HIV-1 evades immune responses through enormous diversity and hides its conserved vulnerable epitopes on the envelope glycoprotein (Env) by displaying an extensive immunodominant glycan shield. In elite HIV-1 viremic controllers, glycan-dependent bNAbs targeting conserved Env epitopes have been isolated and are utilized as vaccine design templates. However, immunological tolerance mechanisms limit the development of these antibodies in the general population. The well characterized bNAbs monoclonal variants frequently exhibit extensive levels of somatic hypermutation, a long third heavy chain complementary determining region, or a short third light chain complementarity determining region, and some exhibit poly-reactivity to autoantigens. This review elaborates on the obstacles to engaging and manipulating the Env glycoprotein as an effective immunogen and describes an alternative reverse vaccinology approach to develop a novel category of bNAb-epitope-derived non-cognate immunogens for HIV-1 vaccine design.
- MeSH
- epitopy imunologie MeSH
- genové produkty env - virus lidské imunodeficience imunologie MeSH
- HIV infekce imunologie MeSH
- HIV protilátky * imunologie MeSH
- HIV-1 * imunologie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární mimikry imunologie MeSH
- neutralizující protilátky * imunologie MeSH
- polysacharidy imunologie MeSH
- vakcíny proti AIDS * imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Virové infekce jsou považovány za jeden z hlavních spouštěčů autoimunitních onemocnění u geneticky predisponovaných jedinců. Mechanismy, které se účastní prolomení imunitní tolerance, jsou velmi komplexní a v dnešní době se předpokládá několik základních principů, jimiž viry indukují rozvoj klinicky manifestního autoimunitního onemocnění. Mezi tyto principy patří především molekulární mimikry, takzvaná bystander aktivace a šíření antigenních determinant. Bylo prokázáno, že strukturálně komplexnější viry vyvolávají častěji zkříženou reaktivitu imunitního systému vůči vlastním tkáním. Nejvýznamnější úloha virových agens v rozvoji autoimunitního onemocnění je popisována u roztroušené sklerózy, diabetes mellitus 1. typu a Guillainova-Barrého syndromu. Samotné působení viru je však významně ovlivněno individuálními vlastnostmi imunitního systému, nastavením mikrobiomu a dalšími vlivy prostředí. V tomto přehledovém článku vysvětlujeme základní mechanismy, které viry využívají za účelem prolomení imunitní tolerance, a popisujeme též vybraná autoimunitní onemocnění a jejich vztah ke konkrétním virovým infekcím.
Viral infections were described to be one of the major triggers of autoimmune diseases in individuals with a genetic predisposition. The functional impairment of immune tolerance involves multiple steps and to date, several principles were discussed. The principles of virus-induced autoimmunity include particularly molecular mimicry, bystander activation and determinant spreading. It is generally accepted that structurally complex viruses are more likely to cause cross-reactivity of the immune system with self-structures. The most important role of viral agents in the initiation of autoimmune disease was described in multiple sclerosis, type 1 diabetes mellitus and Guillain-Barre syndrome. However, the clinical manifestation of the disease largely depends on the individual properties of the immune system, the microbiome setting and other environmental factors. In this review, we describe the major mechanisms by which viruses break down the immune tolerance and trigger autoimmunity. We also describe selected autoimmune diseases and discuss their association to specific viral infections.
In Batesian mimicry, the mimic gains protection from predators by imitating a noxious model. Some myrmecomorphic species use ants as models as ants have strong defensive capabilities. Ants are highly mobile models, and besides colour, shape, and size, mimics also imitate their movement. Yet, former studies focused mainly on static traits. Here, I tested the hypothesis that artificially increased speed of movement reduces the probability of the mimic being identified. First, images of 14 myrmecomorphic spider species and their models were used for humans to rank their mimetic accuracy. Humans were used as surrogate predators to obtain scores for each mimetic pair. In the second experiment, the effect of movement playback speed on the probability of identification was investigated, again using humans. Videos of mimics were played at different speeds, and the identification probability was recorded. While ants were correctly identified at any playback speed, the identification of myrmecomorphic spiders declined with increasing playback speed. In other words, the latency to correct identification increased with playback speed. Overall, mimics with higher accuracy scores were more difficult to identify while moving. The natural speed of movement of accurate mimics was similar to that of inaccurate ones. Movement is thus an important trait for myrmecomorphic species.
Microbial metabolite mimicry is a new concept that promises to deliver compounds that have minimal liabilities and enhanced therapeutic effects in a host. In a previous publication, we have shown that microbial metabolites of L-tryptophan, indoles, when chemically altered, yielded potent anti-inflammatory pregnane X Receptor (PXR)-targeting lead compounds, FKK5 and FKK6, targeting intestinal inflammation. Our aim in this study was to further define structure-activity relationships between indole analogs and PXR, we removed the phenyl-sulfonyl group or replaced the pyridyl residue with imidazolopyridyl of FKK6. Our results showed that while removal of the phenyl-sulfonyl group from FKK6 (now called CVK003) shifts agonist activity away from PXR towards the aryl hydrocarbon receptor (AhR), the imidazolopyridyl addition preserves PXR activity in vitro. However, when these compounds are administered to mice, that unlike the parent molecule, FKK6, they exhibit poor induction of PXR target genes in the intestines and the liver. These data suggest that modifications of FKK6 specifically in the pyridyl moiety can result in compounds with weak PXR activity in vivo. These observations are a significant step forward for understanding the structure-activity relationships (SAR) between indole mimics and receptors, PXR and AhR.
- MeSH
- adenokarcinom MeSH
- antiflogistika chemie farmakologie MeSH
- hepatocyty MeSH
- indoly chemie farmakologie MeSH
- játra MeSH
- konformace proteinů MeSH
- lidé středního věku MeSH
- lidé MeSH
- molekulární mimikry MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory tračníku MeSH
- pregnanový X receptor chemie metabolismus MeSH
- racionální návrh léčiv MeSH
- střeva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls-hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.
- MeSH
- Bacteria chemie MeSH
- biologické přípravky chemie MeSH
- indoly chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární mimikry MeSH
- objevování léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Mimicry is a hot spot of evolutionary research, but de novo origins of aposematic patterns, the persistence of multiple patterns in Müllerian communities, and the persistence of imperfect mimics still need to be investigated. Local mimetic assemblages can contain up to a hundred of species, their structure can be a result of multiple dispersal events, and the gradual build-up of the communities. Here, we investigate the structure of lowland and mountain mimetic communities of net-winged beetles by sampling the Crocker Range in north-eastern Borneo and neighbouring regions. The local endemics evolved from the Bornean lowland fauna which is highly endemic at the species level. We inferred that metriorrhynchine net-winged beetles evolved in high elevations yellow/black and reticulate aposematic high-contrast signals from a widespread low-contrast brown/black pattern. As the mountain range is ~ 6 million years old, and these patterns do not occur elsewhere, we assume their in situ origins. We demonstrate that a signal with increased internal contrast can evolve de novo in a mimetic community and can persist despite its low frequency. Additionally, a similar aposematic signal evolves from different structures and its similarity is imperfect. The community with multiple patterns sets conditions for the evolution of aposematic sexual dimorphism as demonstrated by the yellow/black male and reticulate female pattern of Micronychus pardus. These insights elucidate the complex character of the evolution of mimetic signalling in the dynamically diversifying biota of high tropical mountains.
- MeSH
- barva MeSH
- biologická evoluce * MeSH
- brouci anatomie a histologie fyziologie MeSH
- křídla zvířecí anatomie a histologie fyziologie MeSH
- mimikry * MeSH
- pohlavní dimorfismus * MeSH
- rozšíření zvířat MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Borneo MeSH
Humans started to drinkmammal's milk 11,000 years ago. Nowadays, cow, goat and sheep milks account for about 87% of the world milk production. The high incidence of allergies to cow's milk components and autoimmune diseases is rising in the Western industrialized countries, where milk is a major dietary component, especially in processed foods. When allergenic milk proteins face immature and susceptible immune system in children it might represent a threat for future health. Several studies support strong evidences that exposure to dietary allergens during childhood can increase the risk of developing autoimmune diseases, such as type 1 diabetes, celiac disease, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, neuropsychiatric disorders, among others. The "Mosaic of Autoimmunity" elucidates the diversity and multifactorial origin of autoimmune disease expression in humans. Growing evidence suggests a large overlap between oral tolerance, food antigens and autoimmune diseases. Assorted mechanisms have been hypothesized to explain the connection between these entities, mainly involving molecular mimicry, shared epitopes, cross-reactivity phenomena, enhanced hosts gut permeability, change in microbiome/ dysbiome ratio and even involving Mycobacterium avium subspecies paratuberculosis infection. Nowadays, different kinds of milk and dairy products are being evaluated for a potential benefit in human health. Likewise, milk derived nutraceutical products, such as bovine colostrum, claim many clinical advantages especially for its immune modulatory capabilities. The aim of this review is to explore the impact of cow's milk protein son human health, emphasizing its relationship with immune mediated and autoimmune diseases.
The concept of small-molecule mimicry even of weak microbial metabolites present in rodents and humans, as a means to expand drug repertoires, is new. Hitherto, there are few proof-of-concept papers demonstrating utility of this concept. More recently, papers demonstrating mimicry of intestinal microbial metabolites could expand the drug repertoire for diseases such as inflammatory bowel disease (IBD). We opine that, as more functional metabolite-receptor pairings are discovered, small-molecule metabolite mimicry could be a significant effort in drug discovery.
- MeSH
- lidé MeSH
- mikrobiota * MeSH
- molekulární mimikry * MeSH
- objevování léků * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
