COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. T cells play a key role in the adaptive antiviral immune response by killing infected cells and facilitating the selection of virus-specific antibodies. However, neither the dynamics and cross-reactivity of the SARS-CoV-2-specific T-cell response nor the diversity of resulting immune memory is well understood. In this study, we use longitudinal high-throughput T-cell receptor (TCR) sequencing to track changes in the T-cell repertoire following two mild cases of COVID-19. In both donors, we identified CD4+ and CD8+ T-cell clones with transient clonal expansion after infection. We describe characteristic motifs in TCR sequences of COVID-19-reactive clones and show preferential occurrence of these motifs in publicly available large dataset of repertoires from COVID-19 patients. We show that in both donors, the majority of infection-reactive clonotypes acquire memory phenotypes. Certain T-cell clones were detected in the memory fraction at the pre-infection time point, suggesting participation of pre-existing cross-reactive memory T cells in the immune response to SARS-CoV-2.
- MeSH
- COVID-19 immunology physiopathology MeSH
- Gene Library MeSH
- Immunologic Memory * MeSH
- Humans MeSH
- Longitudinal Studies MeSH
- Epitope Mapping MeSH
- Receptors, Antigen, T-Cell chemistry genetics MeSH
- SARS-CoV-2 physiology MeSH
- Amino Acid Sequence MeSH
- Severity of Illness Index MeSH
- T-Lymphocytes immunology MeSH
- Histocompatibility Testing MeSH
- Cross Reactions MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
... .: Studies on the nature of immunogenicity employing soluble and particulate bacterial proteins 31 -- ... ... Structure of the antibody molecule and antibody combining site -- Press, E. ... ... C., Fudenberg, H., Frangione, B., Meltzer,M.: Structural basis for differ- A ences between y-globulins ... ... B.: Studies on the interaction of immunoglobulins towards protein anti gens with biological activity ... ... Onset and dynamics of antibody formation studied with isolated cells -- Berglund, K.: Studies on the ...
Symposia ČSAV
683 s. : il.
Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O2) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s-1 and 15 cm·s-1. In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation.NEW & NOTEWORTHY Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration.
- MeSH
- Hippocampus * metabolism MeSH
- Hypoxia metabolism physiopathology MeSH
- rho-Associated Kinases * metabolism genetics MeSH
- Rats MeSH
- Spinal Cord metabolism physiology MeSH
- Cerebral Cortex metabolism physiology MeSH
- Neuronal Plasticity physiology MeSH
- Rats, Wistar * MeSH
- rho GTP-Binding Proteins MeSH
- rhoA GTP-Binding Protein metabolism MeSH
- Signal Transduction * physiology MeSH
- High-Intensity Interval Training * MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
... 109 -- THE SHAPE AND STRUCTURE OF PROTEINS 109 -- The Shape of a Protein Is Specified by Its Amino Acid ... ... 127 -- Protein Molecules Often Serve as Subunits for the Assembly of Large Structures 127 -- Many Structures ... ... Protein Structure in Solution 461 -- Protein Sequence and Structure Provide Clues About Protein -- Function ... ... Can Be Fluorescently Tagged in Living Cells and Organisms 542 -- Protein Dynamics Can Be Followed in ... ... Assemble from Protein Subunits That Impart Specific -- Physical and Dynamic Properties 893 -- XXX -- ...
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
BACKGROUND: ALZ-801 is an oral, small-molecule inhibitor of beta amyloid (Aβ) oligomer formation in clinical development for Alzheimer's disease (AD). ALZ-801 is a prodrug of tramiprosate with improved pharmacokinetic properties and gastrointestinal tolerability. During clinical studies, we discovered that the primary metabolite of tramiprosate and its prodrug ALZ-801, 3-sulfopropanoic acid (3-SPA), is an endogenous molecule in the human brain and present in the cerebrospinal fluid (CSF) of patients with AD and other neurodegenerative brain diseases. OBJECTIVE: The objectives of this research were to (1) identify and confirm the presence of 3-SPA in CSF samples from elderly, drug-naïve patients with memory deficits; (2) quantify the levels of 3-SPA in the CSF of patients with AD from tramiprosate phase III North American (NA) trial; (3) evaluate the in vitro anti-Aβ42 oligomer activity of 3-SPA; and (4) characterize the pharmacokinetics and brain-penetration properties of 3-SPA. METHODS: Lumbar CSF samples from 64 drug-naïve patients with cognitive deficits (Mini-Mental State Examination [MMSE] score range 15-30) and six patients with AD treated with tramiprosate 150 mg twice daily in the phase III trial, at week 78, were analyzed. We used liquid chromatography-tandem mass spectrometry to confirm the structural molecular identity of endogenous 3-SPA with a 3-SPA reference standard and ion-mobility spectrometry-mass spectrometry with molecular dynamics to characterize interactions of 3-SPA with Aβ42 monomers, and the resultant conformational alterations. Rat studies using oral (30 mg/kg) and intravenous (10 mg/kg) doses were conducted to characterize the pharmacokinetic properties and brain penetration of 3-SPA. RESULTS: We confirmed the presence of 3-SPA in the CSF of drug-naïve patients with cognitive deficits (mean concentration 11.7 ± 4.3 nM). The mean concentration of 3-SPA in patients with AD treated with tramiprosate was 135 ± 51 nM. In vitro studies revealed a multi-ligand interaction of 3-SPA with monomeric Aβ42 that inhibits the aggregation of Aβ42 into small oligomers. Comparisons of the molecular interactions of tramiprosate and 3-SPA with Aβ42 are also presented. Furthermore, in rat preclinical studies, 3-SPA displayed 100% oral bioavailability and 25% brain penetration, indicating that the metabolite is well absorbed and crosses the blood-brain barrier. CONCLUSIONS: We confirmed the endogenous presence of 3-SPA, the major metabolite of tramiprosate, in the CSF of drug-naïve elderly patients with memory deficits due to AD and a variety of other neurodegenerative disorders. The levels of 3-SPA were up to 12.6-fold greater in patients with AD receiving tramiprosate than in drug-naïve patients. In addition, we showed that 3-SPA has potent anti-Aβ oligomer activity, inhibiting aggregation of Aβ42 into small oligomers with efficacy comparable to that of tramiprosate. 3-SPA displays excellent oral availability and brain penetration in rats, suggesting that the higher CSF concentrations of 3-SPA in the human brain after oral administration of ALZ-801 or tramiprosate (and subsequent conversion to 3-SPA) result from the penetration of the metabolite into the central nervous system. These data suggest that 3-SPA is an endogenous agent with potential activity stabilizing the conformational flexibility of Aβ monomers that, in turn, inhibit Aβ misfolding and formation of soluble toxic Aβ oligomers in humans, thereby preventing the initial pathogenic step in the progression of AD. Clinical improvements observed in patients with AD carrying the ε4 allele of the apolipoprotein E gene in tramiprosate phase III studies may in part be explained by the therapeutic effects of excess levels of the metabolite in the brains of these patients. The potential protective role of 3-SPA in AD pathogenesis, as well as its therapeutic role in AD and other neurodegenerative disorders, warrants further investigation.
- MeSH
- Alzheimer Disease complications drug therapy MeSH
- Amyloid beta-Peptides metabolism MeSH
- Models, Chemical MeSH
- Chromatography, Liquid MeSH
- Cognition Disorders etiology MeSH
- Rats MeSH
- Middle Aged MeSH
- Humans MeSH
- Brain drug effects metabolism MeSH
- Nonlinear Dynamics MeSH
- Peptide Fragments metabolism MeSH
- Computer Simulation MeSH
- Rats, Sprague-Dawley MeSH
- Prodrugs chemistry therapeutic use MeSH
- Propionates MeSH
- Aged MeSH
- Tandem Mass Spectrometry MeSH
- Taurine analogs & derivatives chemistry therapeutic use MeSH
- Valine analogs & derivatives chemistry therapeutic use MeSH
- Mental Status Schedule MeSH
- Drug Administration Routes MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Research Support, Non-U.S. Gov't MeSH
... Body 10 -- CHAPTER 2 -- The Cell and Its Functions 11 -- Organization of the Cell 11 -- Physical Structure ... ... -- Functional Systems of the Cell 19 -- Locomotion of Cells 24 -- CHAPTER 3 -- Genetic Control of Protein ... ... Synthesis, Cell Function, and Cell Reproduction 27 -- Genes in the Cell Nucleus Control Protein Synthesis ... ... Cell Membranes 47 -- The Cell Membrane Consists of a Lipid Bilayer With Cell Membrane Transport Proteins ... ... Roles of the Plasma Proteins 877 -- Hormonal Regulation of Protein Metabolism 880 -- CHAPTER 71 -- The ...
Thirteenth edition xix, 1145 stran : ilustrace (převážně barevné), grafy ; 29 cm
- MeSH
- Physiological Phenomena MeSH
- Publication type
- Textbook MeSH
- Conspectus
- Fyziologie člověka a srovnávací fyziologie
- NML Fields
- fyziologie
... Westbrook -- The Structural and Functional Blueprint of Neurons Is Similar to Epithelial Cells 69 -- ... ... Schwartz, Pietro De Camilli -- Most Proteins Are Synthesized in the Cell Body 88 -- Proteins May Be Modified ... ... During or After Synthesis 92 -- Some Proteins Are Synthesized in the Cytosol and Actively Imported by ... ... the Nucleus, Mitochondria, and Peroxisomes 93 -- Secretory Proteins and Proteins of the Vacuolar Apparatus ... ... and Plasmalemma Are Synthesized and Modified in the Endoplasmic Reticulum 94 -- Secretory Proteins Are ...
4th ed. xxxiii, 1414 s. : il., tab., grafy ; 30 cm
- MeSH
- Behavior MeSH
- Molecular Biology MeSH
- Nervous System Diseases MeSH
- Nervous System MeSH
- Neurochemistry MeSH
- Neurophysiology MeSH
- Neurons MeSH
- Neurosciences MeSH
- Publication type
- Monograph MeSH
- Conspectus
- Fyziologie člověka a srovnávací fyziologie
- NML Fields
- neurovědy
- biologie
... Structure -- 75 The Shape of a Protein Molecule Is Determined by Its Amino Acid Sequence -- 77 Common ... ... Folding Patterns Recur in Different Protein Chains -- 79 Proteins Are Enormously Versatile in Structure ... ... -- 80 Proteins Show Different Levels of Structural Organization -- 81 Relatively Few of the Many Possible ... ... Subunits Can Self-assemble into Large 84 Structures in the Cell -- A Single Type of Protein Subunit Can ... ... ’s Synthesis Produce a Stable -- “Memory” in a Bacterial Cell 442 -- Gene Regulatory Proteins That Act ...
xxxix, 1146 s. : il., tab. ; 28 cm
- MeSH
- Cell Biology MeSH
- Molecular Biology MeSH
- Publication type
- Monograph MeSH
- Conspectus
- Biochemie. Molekulární biologie. Biofyzika
- NML Fields
- biologie
- cytologie, klinická cytologie
... Helix 225 DNA Structure: Alternate Forms of the Double Helix 230 -- DNA Structure: Negative Supercoils ... ... in Vivo 232 Chromosome Structure in Prokaryotes and Viruses 233 -- Chromosome Structure in Eukaryotes ... ... Structure 327 -- Polypeptides: Twenty Different Amino Acid Subunits 327 Proteins: Complex Three-Dimensional ... ... Structures 329 -- Protein Synthesis: Translation 331 Overview of Protein Synthesis 331 Components Required ... ... of Green Fluorescent Protein as a Reporter of Protein Synthesis 574 Evolution of Genomes 577 -- Genome ...
2nd ed. xviii, 876 s. : il.
... 9: В-Cell Development 321 -- Chapter 10: Т-Cell Activation, Helper Subset Differentiation, and Memory ... ... 353 -- Chapter 11: В-Cell Activation, Differentiation, and Memory Generation 391 -- Chapter 12: Effector ... ... System -- 12 -- 12 -- 14 -- 15 -- 16 -- 17 -- 18 -- Adaptive Immune Responses Typically Generate Memory ... ... 63 -- 65 -- 66 67 -- 69 -- 70 -- 70 -- 71 -- 71 -- XI -- CONTENTS • Combinatorial Expression of Protein ... ... by Differences in Surface Protein Expression 383 -- Memory Cell Subpopulations Are Distinguished by ...
Eight edition různé stránkování : barevné ilustrace ; 28 cm
- MeSH
- Allergy and Immunology MeSH
- Immune System MeSH
- Publication type
- Textbook MeSH
- Conspectus
- Patologie. Klinická medicína
- Učební osnovy. Vyučovací předměty. Učebnice
- NML Fields
- alergologie a imunologie
