multicomponent signals
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In the complex network of cellular physiology, the maintenance of cellular proteostasis emerges as a critical factor for cell survival, particularly under stress conditions. This homeostasis is largely governed by a sophisticated network of molecular chaperones and co-chaperones, among which Bcl-2-associated athanogene 3 (BAG3), able to interact with the ATPase domain of Heat Shock Protein 70 (HSP70), plays a pivotal role. The BAG3-HSP70 functional module is not only essential for cellular homeostasis but is also involved in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and cardiac dysfunction, making it an attractive target for therapeutic intervention. Inspired by our continuous interest in the development of new chemical platforms able to interfere with BAG3 protein, herein we report the discovery of compound 16, the first-in-class BAG3/HSP70 dual modulator, obtained by combining the multicomponent Ugi reaction with the alkyne-azide Huisgen procedure in a sequential tandem reaction approach. Through a combination of biophysical analysis, biochemical assays, and cell-based studies, we elucidated the mechanism of action of this inhibitor and assessed its potential as a therapeutic agent. Hence, this study can open new avenues for the development of novel anticancer strategies that leverage the simultaneous disruption of multiple chaperone pathways.
- MeSH
- adaptorové proteiny signální transdukční * metabolismus antagonisté a inhibitory MeSH
- lidé MeSH
- molekulární chaperony metabolismus antagonisté a inhibitory chemie MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- proteiny regulující apoptózu * metabolismus antagonisté a inhibitory MeSH
- proteiny tepelného šoku HSP70 * antagonisté a inhibitory metabolismus MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- screeningové testy protinádorových léčiv MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization. OBJECTIVES: This study aimed to explore the ability of pretreatment parameters to predict fecal calprotectin (FCal) levels at EEN completion in a prospective study in children with CD. METHODS: In children with active CD, clinical parameters, dietary intake, cytokines, inflammation-related blood proteomics, and diet-related metabolites, metabolomics and microbiota in feces, were measured before initiation of 8 wk of EEN. Prediction of FCal levels at EEN completion was performed using machine learning. Data are presented with medians (IQR). RESULTS: Of 37 patients recruited, 15 responded (FCal < 250 μg/g) to EEN (responders) and 22 did not (nonresponders). Clinical and immunological parameters were not associated with response to EEN. Responders had lesser (μmol/g) butyrate [responders: 13.2 (8.63-18.4) compared with nonresponders: 22.3 (12.0-32.0); P = 0.03], acetate [responders: 49.9 (46.4-68.4) compared with nonresponders: 70.4 (57.0-95.5); P = 0.027], phenylacetate [responders: 0.175 (0.013-0.611) compared with nonresponders: 0.943 (0.438-1.35); P = 0.021], and a higher microbiota richness [315 (269-347) compared with nonresponders: 243 (205-297); P = 0.015] in feces than nonresponders. Responders consumed (portions/1000 kcal/d) more confectionery products [responders: 0.55 (0.38-0.72) compared with nonresponders: 0.19 (0.01-0.38); P = 0.045]. A multicomponent model using fecal parameters, dietary data, and clinical and immunological parameters predicted response to EEN with 78% accuracy (sensitivity: 80%; specificity: 77%; positive predictive value: 71%; negative predictive value: 85%). Higher taxon abundance from Ruminococcaceae, Lachnospiraceae, and Bacteroides and phenylacetate, butyrate, and acetate were the most influential variables in predicting lack of response to EEN. CONCLUSIONS: We identify microbial signals and diet-related metabolites in feces, which could comprise targets for pretreatment optimization and personalized nutritional therapy in pediatric CD.
- MeSH
- acetáty MeSH
- butyráty MeSH
- Crohnova nemoc * terapie metabolismus MeSH
- dítě MeSH
- enterální výživa MeSH
- fenylacetáty MeSH
- indukce remise MeSH
- lidé MeSH
- metabolom MeSH
- mikrobiota * MeSH
- prospektivní studie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Mechanisms of change represent the cornerstone of the therapeutic process. This study aimed to investigate how network models could be used to test mechanisms of change at a group level. A secondary aim was to investigate which of the several hypothesized mechanisms (emotion regulation, interoceptive awareness, and acceptance) are related to changes in psychological well-being. The sample comprised adult patients suffering from psychological disorders (N=444; 70% women) from 7 clinical sites in the Czech Republic who were undergoing groupbased multicomponent treatment composed mainly of psychodynamic psychotherapy (lasting from 4 to 12 weeks depending on the clinical site). Data were collected weekly using the multidimensional assessment of interoceptive awareness, emotion regulation skills questionnaire, chronic pain acceptance questionnaire-symptoms and outcome rating scale. A lag-1 longitudinal network model was employed for exploratory analysis of the panel data. The pruned final model demonstrated a satisfactory fit. Three networks were computed, i.e., temporal, contemporaneous, and between-person networks. The most central node was the modification of negative emotions. Mechanisms that were positively associated with well-being included modification, readiness to confront negative emotions, activity engagement, and trust in bodily signals. Acceptance of negative emotions showed a negative association with well-being. Moreover, noticing bodily sensations, not worrying, and self-regulation contributed indirectly to changes in well-being. In conclusion, the use of network methodology to model panel data helped generate novel hypotheses for future research and practice; for instance, well-being could be actively contributing to other mechanisms, not just a passive outcome.
- Publikační typ
- časopisecké články MeSH
The participation of reactants undergoing a polarity inversion along a multicomponent reaction allows the continuation of the transformation with productive domino processes. Thus, indole aldehydes in Groebke-Blackburn-Bienaymé reactions lead to an initial adduct which spontaneously triggers a series of events leading to the discovery of novel reaction pathways together with direct access to a variety of linked, fused, and bridged polyheterocyclic scaffolds. Indole 3- and 4-carbaldehydes with suitable isocyanides and aminoazines afford fused adducts through oxidative Pictet-Spengler processes, whereas indole 2-carbaldehyde yields linked indolocarbazoles under mild conditions, and a bridged macrocycle at high temperature. These novel structures are potent activators of the human aryl hydrocarbon receptor signaling pathway.
Here, we present a new family of hierarchical porous hybrid materials as an innovative tool for ultrasensitive and selective sensing of enantiomeric drugs in complex biosamples via chiral surface-enhanced Raman spectroscopy (SERS). Hierarchical porous hybrid films were prepared by the combination of mesoporous plasmonic Au films and microporous homochiral metal-organic frameworks (HMOFs). The proposed hierarchical porous substrates enable extremely low limit of detection values (10-12 M) for pseudoephedrine in undiluted blood plasma due to dual enhancement mechanisms (physical enhancement by the mesoporous Au nanostructures and chemical enhancement by HMOF), chemical recognition by HMOF, and a discriminant function for bio-samples containing large biomolecules, such as blood components. We demonstrate the effect of each component (mesoporous Au and microporous AlaZnCl (HMOF)) on the analytical performance for sensing. The growth of AlaZnCl leads to an increase in the SERS signal (by around 17 times), while the use of mesoporous Au leads to an increase in the signal (by up to 40%). In the presence of a complex biomatrix (blood serum or plasma), the hybrid hierarchical porous substrate provides control over the transport of the molecules inside the pores and prevents blood protein infiltration, provoking competition with existing plasmonic materials at the limit of detection and enantioselectivity in the presence of a multicomponent biomatrix.
BACKGROUND: Carotenoid plumage is of widespread use in bird communication. Carotenoid-based feather colouration has recently been shown to be dependent on both pigment concentration and feather structure. If these two components are determined differently, one plumage patch may potentially convey different aspects of individual quality. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the effects of genetic and environmental factors on carotenoid-based yellow breast colouration of Great Tit (Parus major) nestlings. By partial cross-fostering, we separated the genetic and pre-natal vs. post-natal parental effects on both the structural and the pigment-based component of carotenoid-based plumage colouration. We also simultaneously manipulated the post-hatching environment by brood size manipulation. The structural component of nestling colouration reflected features of female colouration. On the other hand, the pigment-based component was more affected by rearing conditions presumably representing food quality. While the structural component was related to both origin- and environment-related factors, the pigment-based component seemed to be environment-dependent only. These results support the notion that pigment-based and structural components of feather colouration are determined differently. CONCLUSIONS/SIGNIFICANCE: Chromatic and achromatic components of carotenoid-based feather colouration reflected different aspects of individual quality and history, and thus may potentially form a multicomponent signal.
- MeSH
- biologické pigmenty genetika metabolismus MeSH
- interakce genů a prostředí MeSH
- karotenoidy genetika metabolismus MeSH
- komunikace zvířat MeSH
- Passeriformes genetika metabolismus MeSH
- peří metabolismus MeSH
- pigmentace fyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Aggregation of the high-affinity IgE receptor (FcεRI) initiates a cascade of signaling events leading to release of preformed inflammatory and allergy mediators and de novo synthesis and secretion of cytokines and other compounds. The first biochemically well defined step of this signaling cascade is tyrosine phosphorylation of the FcεRI subunits by Src family kinase Lyn, followed by recruitment and activation of spleen tyrosine kinase (Syk). Activity of Syk is decisive for the formation of multicomponent signaling assemblies, the signalosomes, in the vicinity of the receptors. Formation of the signalosomes is dependent on the presence of transmembrane adaptor proteins (TRAPs). These proteins are characterized by a short extracellular domain, a single transmembrane domain, and a cytoplasmic tail with various motifs serving as anchors for cytoplasmic signaling molecules. In mast cells five TRAPs have been identified [linker for activation of T cells (LAT), non-T cell activation linker (NTAL), linker for activation of X cells (LAX), phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (PAG), and growth factor receptor-bound protein 2 (Grb2)-binding adaptor protein, transmembrane (GAPT)]; engagement of four of them (LAT, NTAL, LAX, and PAG) in FcεRI signaling has been documented. Here we discuss recent progress in the understanding of how TRAPs affect FcεRI-mediated mast cell signaling. The combined data indicate that individual TRAPs have irreplaceable roles in important signaling events such as calcium response, degranulation, cytokines production, and chemotaxis.
- Publikační typ
- časopisecké články MeSH
Blind inversion of a linear and instantaneous mixture of source signals is a problem often encountered in many signal processing applications. Efficient fastICA (EFICA) offers an asymptotically optimal solution to this problem when all of the sources obey a generalized Gaussian distribution, at most one of them is Gaussian, and each is independent and identically distributed (i.i.d.) in time. Likewise, weights-adjusted second-order blind identification (WASOBI) is asymptotically optimal when all the sources are Gaussian and can be modeled as autoregressive (AR) processes with distinct spectra. Nevertheless, real-life mixtures are likely to contain both Gaussian AR and non-Gaussian i.i.d. sources, rendering WASOBI and EFICA severely suboptimal. In this paper, we propose a novel scheme for combining the strengths of EFICA and WASOBI in order to deal with such hybrid mixtures. Simulations show that our approach outperforms competing algorithms designed for separating similar mixtures.
... Watanabe (Japan) 15 -- A new method of small signal gain measurement in CW C02 laser -- F. ... ... Zavalov (Russia) 132 -- Time behavior of small-signal gain on high vibrational transitions for pulsed ... ... Seryogin (Russia) 151 -- Bandwidth increase by controlled angular dispersion of signal beam in optical ... ... Barvíř (Czech Republic) 197 -- Tunable C02 laser measurements of composition and concentrations in multicomponent ...
1st ed. 209 s. ; 30 cm
