CssRS is a two-component system that plays a pivotal role in mediating the secretion stress response in Bacillus subtilis. This system upregulates the synthesis of membrane-bound HtrA family proteases that cope with misfolded proteins that accumulate within the cell envelope as a result of overexpression or heat shock. Recent studies have shown the induction of CssRS-regulated genes in response to cell envelope stress. We investigated the induction of the CssRS-regulated htrA promoter in the presence of different cell wall- and membrane-active substances and observed induction of the CssRS-controlled genes by glycopeptides (vancomycin and teicoplanin), polymyxins B and E, certain β-lactams, and detergents. Teicoplanin was shown to elicit remarkably stronger induction than vancomycin and polymyxin B. Teicoplanin and polymyxin B induced the spxO gene expression in a CssRS-dependent fashion, resulting in increased activity of Spx, a master regulator of disulfide stress in Bacillus subtilis. The CssRS signaling pathway and Spx activity were demonstrated to be involved in Bacillus subtilis resistance to teicoplanin and polymyxin B.
- MeSH
- Anti-Bacterial Agents * pharmacology MeSH
- Bacillus subtilis * genetics drug effects metabolism MeSH
- Bacterial Proteins * genetics metabolism MeSH
- Polymyxin B * pharmacology MeSH
- Promoter Regions, Genetic MeSH
- Gene Expression Regulation, Bacterial * drug effects MeSH
- Signal Transduction MeSH
- Teicoplanin * pharmacology MeSH
- Publication type
- Journal Article MeSH
Poznatky, získané hlavne v posledných dvoch desaťročiach, umožnili lepšie porozumieť mechanizmom a dráham, prostredníctvom ktorých nervový systém, a tým aj stres, ovplyvňuje procesy súvisiace so vznikom a progresiou nádorových chorôb. Neurobiologický výskum nádorových chorôb pritom nie len rozšíril poznanie etiopatogenézy nádorového procesu, ale vytvoril podklady aj pre zavedenie nových terapeutických metód v onkológii, založených na modulácii prenosu signálov medzi nervovým systémom a nádorovým tkanivom. Bolo tiež zistené, že monitorovanie aktivity zložiek autonómneho nervového systému je možné využiť nie len na určenie miery stresu u daného pacienta, ale aj na posúdenie prognózy jeho onkologickej choroby. Jednu z efektívnych metód, umožňujúcich sledovanie flexibility a rovnováhy pôsobenia zložiek autonómneho nervového systému a nepriamo aj miery stresu u onkologických pacientov, predstavuje určovanie variability srdcovej frekvencie (HRV). Na opodstatnenosť využitia tejto metódy v onkológii poukazujú aj zistenia, že pacienti s vyššími hodnotami HRV vykazujú dlhšie prežívanie v porovnaní s pacientmi, u ktorých sú hodnoty HRV nižšie. Zámerom tohto textu je priblížiť súčasné poznatky týkajúce sa vplyvu stresu na nádory hlavy a krku a načrtnúť možnosti využitia stanovenia HRV ako prognostického markera u týchto pacientov. Diskutované sú aj možnosti využitia metód, ktoré sú zamerané na zvýšenie HRV a ich prípadné využitie v liečbe pacientov s nádormi hlavy a krku.
Knowledge, mainly gained in the last two decades, has provided a better understanding of the mechanisms and pathways through which the nervous system, and thus stress, influences processes related to cancer initiation and progression. Neurobiological research on cancer has not only increased the knowledge of the aetiopathogenesis of the tumour process, but also has laid the foundation for the introduction of new therapeutic methods in oncology based on the modulation of the transmission of signals between the nervous system andtumour tissue. It also has been found that monitoring the activity of components of the autonomic nervous system can be used not only to determine the degree of stress in a given patient, but also to assess the prognosis of his or her oncological disease. One of the effective methods to monitor the flexibility and balance of the autonomic nervous system components and indirectly the level of stress in cancer patients is the determination of heart rate variability (HRV). The validity of the use of this method in oncology is indicated by the findings that patients with higher HRV values show longer survival compared to patients with lower HRV values. The aim of this text is to review the current knowledge regarding the impact of stress on head and neck cancer and to outline the possibilities of using HRV determination as a prognostic marker in these patients. The potential use of methods aimed at increasing HRV and their potential use in the management of patients with head and neck tumours are also discussed.
Telomeres, essential for maintaining genomic stability, are typically preserved through the action of telomerase, a ribonucleoprotein complex that synthesizes telomeric DNA. One of its two core components, telomerase RNA (TR), serves as the template for this synthesis, and its evolution across different species is both complex and diverse. This review discusses recent advancements in understanding TR evolution, with a focus on plants (Viridiplantae). Utilizing novel bioinformatic tools and accumulating genomic and transcriptomic data, combined with corresponding experimental validation, researchers have begun to unravel the intricate pathways of TR evolution and telomere maintenance mechanisms. Contrary to previous beliefs, a monophyletic origin of TR has been demonstrated first in land plants and subsequently across the broader phylogenetic megagroup Diaphoretickes. Conversely, the discovery of plant-type TRs in insects challenges assumptions about the monophyletic origin of TRs in animals, suggesting evolutionary innovations coinciding with arthropod divergence. The review also highlights key challenges in TR identification and provides examples of how these have been addressed. Overall, this work underscores the importance of expanding beyond model organisms to comprehend the full complexity of telomerase evolution, with potential applications in agriculture and biotechnology.
- MeSH
- Phylogeny MeSH
- Evolution, Molecular * MeSH
- RNA * genetics metabolism MeSH
- Plants genetics MeSH
- Telomerase * genetics metabolism MeSH
- Telomere * metabolism genetics MeSH
- Viridiplantae genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The cytokine TNF can trigger highly proinflammatory RIPK1-dependent cell death. Here, we show that the two adapter proteins, TANK and AZI2, suppress TNF-induced cell death by regulating the activation of TBK1 kinase. Mice lacking either TANK or AZI2 do not show an overt phenotype. Conversely, animals deficient in both adapters are born in a sub-Mendelian ratio and suffer from severe multi-organ inflammation, excessive antibody production, male sterility, and early mortality, which can be rescued by TNFR1 deficiency and significantly improved by expressing a kinase-dead form of RIPK1. Mechanistically, TANK and AZI2 both recruit TBK1 to the TNF receptor signaling complex, but with distinct kinetics due to interaction with different complex components. While TANK binds directly to the adapter NEMO, AZI2 is recruited later via deubiquitinase A20. In summary, our data show that TANK and AZI2 cooperatively sustain TBK1 activity during different stages of TNF receptor assembly to protect against autoinflammation.
- MeSH
- Adaptor Proteins, Signal Transducing * metabolism genetics MeSH
- Cell Death MeSH
- Endopeptidases MeSH
- Intracellular Signaling Peptides and Proteins metabolism genetics MeSH
- Humans MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout * MeSH
- Mice MeSH
- Protein Serine-Threonine Kinases * metabolism genetics MeSH
- Receptors, Tumor Necrosis Factor, Type I * metabolism genetics MeSH
- Receptor-Interacting Protein Serine-Threonine Kinases * metabolism genetics MeSH
- Signal Transduction MeSH
- Tumor Necrosis Factor-alpha * metabolism MeSH
- Tumor Necrosis Factor alpha-Induced Protein 3 metabolism genetics MeSH
- Inflammation metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 Mb tandem duplication of chromosome 17 harbouring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To obtain better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication in cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing (RNA-seq) on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient-derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was downregulated in a dose-dependent manner throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signalling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane owing to an alteration in the lipid composition, which might ultimately lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of patients with CMT1A.
- MeSH
- Cell Membrane * metabolism MeSH
- Charcot-Marie-Tooth Disease * genetics metabolism pathology MeSH
- Gene Duplication MeSH
- Homeostasis * physiology MeSH
- Induced Pluripotent Stem Cells * metabolism MeSH
- Humans MeSH
- Lipid Metabolism * physiology MeSH
- Myelin Proteins * metabolism genetics MeSH
- Mice MeSH
- Sciatic Nerve metabolism MeSH
- Schwann Cells * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Quantitative maps of rotating frame relaxation (RFR) time constants are sensitive and useful magnetic resonance imaging tools with which to evaluate tissue integrity in vivo. However, to date, only moderate image resolutions of 1.6 x 1.6 x 3.6 mm3 have been used for whole-brain coverage RFR mapping in humans at 3 T. For more precise morphometrical examinations, higher spatial resolutions are desirable. Towards achieving the long-term goal of increasing the spatial resolution of RFR mapping without increasing scan times, we explore the use of the recently introduced Transform domain NOise Reduction with DIstribution Corrected principal component analysis (T-NORDIC) algorithm for thermal noise reduction. RFR acquisitions at 3 T were obtained from eight healthy participants (seven males and one female) aged 52 ± 20 years, including adiabatic T1ρ, T2ρ, and nonadiabatic Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n = 4 (RAFF4) with both 1.6 x 1.6 x 3.6 mm3 and 1.25 x 1.25 x 2 mm3 image resolutions. We compared RFR values and their confidence intervals (CIs) obtained from fitting the denoised versus nondenoised images, at both voxel and regional levels separately for each resolution and RFR metric. The comparison of metrics obtained from denoised versus nondenoised images was performed with a two-sample paired t-test and statistical significance was set at p less than 0.05 after Bonferroni correction for multiple comparisons. The use of T-NORDIC on the RFR images prior to the fitting procedure decreases the uncertainty of parameter estimation (lower CIs) at both spatial resolutions. The effect was particularly prominent at high-spatial resolution for RAFF4. Moreover, T-NORDIC did not degrade map quality, and it had minimal impact on the RFR values. Denoising RFR images with T-NORDIC improves parameter estimation while preserving the image quality and accuracy of all RFR maps, ultimately enabling high-resolution RFR mapping in scan times that are suitable for clinical settings.
- MeSH
- Algorithms MeSH
- Principal Component Analysis MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging * methods MeSH
- Brain Mapping MeSH
- Brain * diagnostic imaging MeSH
- Signal-To-Noise Ratio * MeSH
- Rotation MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
The pungency of chili peppers, the most popular hot spice used worldwide, is caused by capsaicinoids (CPDs), the content of which can vary greatly due to varietal differences and growing conditions. For the first time, a novel simple method for the fast determination of CPDs in chili peppers and chili products was developed based on adsorptive transfer cyclic square-wave voltammetry (AdTCSWV), using adsorption of lipophilic CPDs on an unmodified glassy carbon electrode surface from methanolic extracts of chili pepper samples. The CSWV is based on short oxidation of adsorbed CPDs to quinoid products, and their subsequent reduction and re-oxidation to provide specific analytical signals with a linear range from 0.05 to 1.00 mg L-1. This principle was also implemented in tandem coulometric and amperometric detection of CPDs after HPLC separation. The two-step electrochemical detection provides increased selectivity for CPDs in case of CPDs co-elution with other electrochemically oxidizable components that cannot be reversibly reduced.
This study investigates the factors modulating the reactivity of 5'-deoxyadenosyl (5'dAdo ̇) radical, a potent hydrogen atom abstractor that forms in the active sites of radical SAM enzymes and that otherwise undergoes a rapid self-decay in aqueous solution. Here, we compare hydrogen atom abstraction (HAA) reactions between native substrates of radical SAM enzymes and 5'dAdo ̇ in aqueous solution and in two enzymatic microenvironments. With that we reveal that HAA efficiency of 5'dAdo ̇ is due to (i) the in situ formation of 5'dAdo ̇ in a pre-ordered complex with a substrate, which attenuates the unfavorable effect of substrate:5'dAdo ̇ complex formation, and (ii) the prevention of the conformational changes associated with self-decay by a tight active-site cavity. The enzymatic cavity, however, does not have a strong effect on the HAA activity of 5'dAdo ̇. Thus, we performed an analysis of in-water HAA performed by 5'dAdo ̇ based on a three-component thermodynamic model incorporating the diagonal effect of the free energy of reaction, and the off-diagonal effect of asynchronicity and frustration. To this aim, we took advantage of the straightforward relationship between the off-diagonal thermodynamic effects and the electronic-structure descriptor - the redistribution of charge between the reactants during the reaction. It allows to access HAA-competent redox and acidobasic properties of 5'dAdo ̇ that are otherwise unavailable due to its instability upon one-electron reduction and protonation. The results show that all reactions feature a favourable thermodynamic driving force and tunneling, the latter of which lowers systematically barriers by ∼2 kcal mol-1. In addition, most of the reactions experience a favourable off-diagonal thermodynamic contribution. In HAA reactions, 5'dAdo ̇ acts as a weak oxidant as well as a base, also 5'dAdo ̇-promoted HAA reactions proceed with a quite low degree of asynchronicity of proton and electron transfer. Finally, the study elucidates the crucial and dual role of asynchronicity. It directly lowers the barrier as a part of the off-diagonal thermodynamic contribution, but also indirectly increases the non-thermodynamic part of the barrier by presumably controlling the adiabatic coupling between proton and electron transfer. The latter signals that the reaction proceeds as a hydrogen atom transfer rather than a proton-coupled electron transfer.
Combining proton and phosphorus magnetic resonance spectroscopy offers a unique opportunity to study the oxidative and glycolytic components of metabolism in working muscle. This paper presents a 7 T proton calf coil design that combines dipole and loop elements to achieve the high performance necessary for detecting metabolites with low abundance and restricted visibility, specifically lactate, while including the option of adding a phosphorus array. We investigated the transmit, receive, and parallel imaging performance of three transceiver dipoles with six pair-wise overlap-decoupled standard or twisted pair receive-only coils. With a higher SNR and more efficient transmission decoupling, standard loops outperformed twisted pair coils. The dipoles with standard loops provided a four-fold-higher image SNR than a multinuclear reference coil comprising two proton channels and 32% more than a commercially available 28-channel proton knee coil. The setup enabled up to three-fold acceleration in the right-left direction, with acceptable g-factors and no visible aliasing artefacts. Spectroscopic phantom measurements revealed a higher spectral SNR for lactate with the developed setup than with either reference coil and fewer restrictions in voxel placement due to improved transmit homogeneity. This paper presents a new use case for dipoles and highlights their advantages for the integration in multinuclear calf coils.
- MeSH
- Phantoms, Imaging * MeSH
- Muscle, Skeletal * diagnostic imaging chemistry MeSH
- Lactic Acid chemistry metabolism MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy methods MeSH
- Magnetic Resonance Imaging * methods MeSH
- Signal-To-Noise Ratio MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Applications of causal techniques to neural time series have increased extensively over last decades, including a wide and diverse family of methods focusing on electroencephalogram (EEG) analysis. Besides connectivity inferred in defined frequency bands, there is a growing interest in the analysis of cross-frequency interactions, in particular phase and amplitude coupling and directionality. Some studies show contradicting results of coupling directionality from high frequency to low frequency signal components, in spite of generally considered modulation of a high-frequency amplitude by a low-frequency phase. We have compared two widely used methods to estimate the directionality in cross frequency coupling: conditional mutual information (CMI) and phase slope index (PSI). The latter, applied to infer cross-frequency phase-amplitude directionality from animal intracranial recordings, gives opposite results when comparing to CMI. Both metrics were tested in a numerically simulated example of unidirectionally coupled Rössler systems, which helped to find the explanation of the contradictory results: PSI correctly estimates the lead/lag relationship which, however, is not generally equivalent to causality in the sense of directionality of coupling in nonlinear systems, correctly inferred by using CMI with surrogate data testing.
- MeSH
- Electroencephalography * methods MeSH
- Humans MeSH
- Models, Neurological MeSH
- Brain physiology MeSH
- Nonlinear Dynamics * MeSH
- Computer Simulation MeSH
- Signal Processing, Computer-Assisted MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
