scholarly journals Human Norovirus Epitope D Plasticity Allows Escape from Antibody Immunity without Loss of Capacity for Binding Cellular Ligands

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Lisa C. Lindesmith ◽  
Paul D. Brewer-Jensen ◽  
Michael L. Mallory ◽  
Boyd Yount ◽  
Matthew H. Collins ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Consensus Sequence ◽  
Antibody Binding ◽  
Carbohydrate Binding ◽  
Human Norovirus ◽  
Capsid Sequence ◽  
Relative Affinity ◽  
Over Time

ABSTRACT Emergent strains of human norovirus seed pandemic waves of disease. These new strains have altered ligand binding and antigenicity characteristics. Study of viral variants isolated from immunosuppressed patients with long-term norovirus infection indicates that initial virus in vivo evolution occurs at the same antigenic sites as in pandemic strains. Here, cellular ligand binding and antigenicity of two cocirculating strains isolated from a patient with long-term norovirus infection were characterized. The isolated GII.4 viruses differed from previous strains and from each other at known blockade antibody epitopes. One strain had a unique sequence in epitope D, including loss of an insertion at residue 394, corresponding to a decreased relative affinity for carbohydrate ligands. Replacement of 394 with alanine or restoration of the contemporary strain epitope D consensus sequence STT improved ligand binding relative affinity. However, monoclonal antibody blockade of binding potency was only gained for the consensus sequence, not by the alanine insertion. In-depth study of unique changes in epitope D indicated that ligand binding, but not antibody blockade of ligand binding, is maintained despite sequence diversity, allowing escape from blockade antibodies without loss of capacity for binding cellular ligands. IMPORTANCE Human norovirus causes ∼20% of all acute gastroenteritis and ∼200,000 deaths per year, primarily in young children. Most epidemic and all pandemic waves of disease over the past 30 years have been caused by type GII.4 human norovirus strains. The capsid sequence of GII.4 strains is changing over time, resulting in viruses with altered ligand and antibody binding characteristics. The carbohydrate binding pocket of these strains does not vary over time. Here, utilizing unique viral sequences, we study how residues in GII.4 epitope D balance the dual roles of variable antibody binding site and cellular ligand binding stabilization domain, demonstrating that amino acid changes in epitope D can result in loss of antibody binding without ablating ligand binding. This flexibility in epitope D likely contributes to GII.4 strain persistence by both allowing escape from antibody-mediated herd immunity and maintenance of cellular ligand binding and infectivity.

scholarly journals Normal cycling patterns of hematopoietic stem cell subpopulations: an assay using long-term in vivo BrdU infusion

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1460-1462 ◽  
Author(s):  
ME Pietrzyk ◽  
GV Priestley ◽  
NS Wolf
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Improved Method ◽  
Hematopoietic Stem ◽  
Infusion Study ◽  
A Cell ◽  
Cell Subpopulations ◽  
Over Time

It was found in a long-term bromodeoxyuridine (BrdU) infusion study that two or more different subpopulations of bone marrow stem cells exist in mice. One of these subpopulations appears to be noncycling and forms approximately 10% of eight-day CFU-S. Another one, a subpopulation of slowly cycling bone marrow cells, is represented as 14- day CFU-S. The 14-day CFU-S have a regular increment in the percentage of the subpopulation entering the cycle over time, with a cell generation half-time of 21 days. The cycling status in these experiments was ascertained by in vivo continuous long-term BrdU infusion. An improved method is presented for long-term BrdU infusion with UV killing of cycled cells.

scholarly journals Growth factor–induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells

2005 ◽  
Vol 171 (4) ◽  
pp. 729-738 ◽  
Author(s):  
Kan Ding ◽  
Martha Lopez-Burks ◽  
José Antonio Sánchez-Duran ◽  
Murray Korc ◽  
Arthur D. Lander
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Surface ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Sulfate Proteoglycan ◽  
Matrix Metalloproteinase 7 ◽  
Over Time

The cell surface heparan sulfate proteoglycan (HSPG) glypican-1 is up-regulated by pancreatic and breast cancer cells, and its removal renders such cells insensitive to many growth factors. We sought to explain why the cell surface HSPG syndecan-1, which is also up-regulated by these cells and is a known growth factor coreceptor, does not compensate for glypican-1 loss. We show that the initial responses of these cells to the growth factor FGF2 are not glypican dependent, but they become so over time as FGF2 induces shedding of syndecan-1. Manipulations that retain syndecan-1 on the cell surface make long-term FGF2 responses glypican independent, whereas those that trigger syndecan-1 shedding make initial FGF2 responses glypican dependent. We further show that syndecan-1 shedding is mediated by matrix metalloproteinase-7 (MMP7), which, being anchored to cells by HSPGs, also causes its own release in a complex with syndecan-1 ectodomains. These results support a specific role for shed syndecan-1 or MMP7–syndecan-1 complexes in tumor progression and add to accumulating evidence that syndecans and glypicans have nonequivalent functions in vivo.

scholarly journals A novel suprachoroidal microinvasive glaucoma implant: in vivo biocompatibility and biointegration

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Ian Grierson ◽  
Don Minckler ◽  
Marian K. Rippy ◽  
Andrew J. Marshall ◽  
Nathalie Collignon ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Time Course ◽  
Structural Changes ◽  
Ocular Tissues ◽  
Tissue Integration ◽  
Drainage Channels ◽  
Pressure Lowering ◽  
Over Time

Abstract Background A major challenge for any glaucoma implant is their ability to provide long-term intraocular pressure lowering efficacy. The formation of a low-permeability fibrous capsule around the device often leads to obstructed drainage channels, which may impair the drainage function of devices. These foreign body-related limitations point to the need to develop biologically inert biomaterials to improve performance in reaching long-term intraocular pressure reduction. The aim of this study was to evaluate in vivo (in rabbits) the ocular biocompatibility and tissue integration of a novel suprachoroidal microinvasive glaucoma implant, MINIject™ (iSTAR Medical, Wavre, Belgium). Results In two rabbit studies, no biocompatibility issue was induced by the suprachoroidal, ab-externo implantation of the MINIject™ device. Clinical evaluation throughout the 6 post-operative months between the sham and test groups were similar, suggesting most reactions were related to the ab-externo surgical technique used for rabbits, rather than the implant material itself. Histological analysis of ocular tissues at post-operative months 1, 3 and 6 revealed that the implant was well-tolerated and induced only minimal fibroplasia and thus minimal encapsulation around the implant. The microporous structure of the device became rapidly colonized by cells, mostly by macrophages through cell migration, which do not, by their nature, impede the flow of aqueous humor through the device. Time-course analysis showed that once established, pore colonization was stable over time. No fibrosis nor dense connective tissue development were observed within any implant at any time point. The presence of pore colonization may be the process by which encapsulation around the implant is minimized, thus preserving the permeability of the surrounding tissues. No degradation nor structural changes of the implant occurred during the course of both studies. Conclusions The novel MINIject™ microinvasive glaucoma implant was well-tolerated in ocular tissues of rabbits, with observance of biointegration, and no biocompatibility issues. Minimal fibrous encapsulation and stable cellular pore colonization provided evidence of preserved drainage properties over time, suggesting that the implant may produce a long-term ability to enhance aqueous outflow.

scholarly journals Normal cycling patterns of hematopoietic stem cell subpopulations: an assay using long-term in vivo BrdU infusion

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1460-1462 ◽  
Author(s):  
ME Pietrzyk ◽  
GV Priestley ◽  
NS Wolf
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Improved Method ◽  
Hematopoietic Stem ◽  
Infusion Study ◽  
A Cell ◽  
Cell Subpopulations ◽  
Over Time

Abstract It was found in a long-term bromodeoxyuridine (BrdU) infusion study that two or more different subpopulations of bone marrow stem cells exist in mice. One of these subpopulations appears to be noncycling and forms approximately 10% of eight-day CFU-S. Another one, a subpopulation of slowly cycling bone marrow cells, is represented as 14- day CFU-S. The 14-day CFU-S have a regular increment in the percentage of the subpopulation entering the cycle over time, with a cell generation half-time of 21 days. The cycling status in these experiments was ascertained by in vivo continuous long-term BrdU infusion. An improved method is presented for long-term BrdU infusion with UV killing of cycled cells.

scholarly journals Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

2019 ◽  
Author(s):  
V. Korzhova ◽  
P. Marinković ◽  
P. M. Goltstein ◽  
J. Herms ◽  
S. Liebscher
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Activity ◽  
Calcium Imaging ◽  
Amyloid Plaque ◽  
Activity Levels ◽  
Highly Active ◽  
Over Time

SummaryAlzheimer’s disease (AD) is associated with aberrant neuronal activity levels. How those activity alterations emerge and how stable they are over time in vivo, however, remains elusive to date. To address these questions we chronically recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice and their non-transgenic littermates over the course of 4 weeks by means of calcium imaging. Surprisingly, aberrant neuronal activity was very stable over time. Moreover, we identified a slow progressive gain of activity of former intermediately active neurons as the main source of new highly active neurons. Interestingly, fluctuations in neuronal activity were independent from amyloid plaque proximity, but aberrant activity levels were more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in AD patients is the consequence of stable single cell aberrant neuronal activity, a finding of potential therapeutic relevance.

scholarly journals Long Term Evaluation of Biodegradation and Biocompatibility In-Vivo the Mg-0.5Ca-xZr Alloys in Rats

Crystals ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 54
Author(s):  
Eusebiu-Viorel Sindilar ◽  
Corneliu Munteanu ◽  
Sorin Aurelian Pasca ◽  
Iuliana Mihai ◽  
Madalina Elena Henea ◽  
...  
Keyword(s):  
Bone Fractures ◽  
Tissue Reaction ◽  
Term Effect ◽  
Metallic Materials ◽  
Long Term Effect ◽  
Term Evaluation ◽  
Laboratory Examinations ◽  
Over Time

Biodegradable alloys in Mg have the advantages of traditional metallic materials and those of biodegradable polymers with superior strength, lower density and ideal rigidity for fixing bone fractures. The biocompatibility and biodegradability of the five concentrations of Mg-0.5Ca-xZr alloys used were assessed using clinical and laboratory examinations that followed over time: tissue reaction, histological and imaging (RX, CT and SEM) evolution at 1, 2, 4 and 8 weeks after implant. The main purpose of this study was to investigate in vivo the long-term effect of Mg-0.5Ca-xZr alloys in rats. The results confirmed that Mg-0.5Ca-xZr alloys are biocompatible and biodegradable and are recommended to be used as possible materials for new orthopedics devices.

EGFP Is a Useful Long-Term Expression Tracer for Hematopoietic Stem Cells While DsRed Fluorescent Protein Is Not.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3057-3057
Author(s):  
Wen Tao ◽  
Barbara Graham-Evans ◽  
Scott Cooper ◽  
Kenneth Cornetta ◽  
Christopher B. Ballas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Fluorescent Protein ◽  
Fluorescent Proteins ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Over Time

Abstract In the post-genome era, precise functions of the vast majority of human and mouse genes and their interactions remain to be elucidated and defined. To assess the contributions of many different genes to hematopoiesis and to determine how they function in hematopoietic stem and progenitor cells, often requires introduction of the gene of interests or its derivative mutants into these cells along with a marker gene which is used to track the transduced cells over time. An ideal expression tracer should be easy to track and non-toxic to cells with minimal perturbation of cell metabolism. Although the enhanced green fluorescent protein (EGFP) has been widely used as an expression tracer and other fluorescent proteins were occasionally used in this capacity as well, their suitability for long-term marking of hematopoietic stem cells and their unintended side-effects on the functions of these cells have not been systematically investigated. In this study, we have performed a series of in vitro and in vivo experiments to evaluate whether two fluorescent proteins, EGFP and DsRed-Express which is an optimized variant of a red fluorescent protein from coral, are suitable for use as expression tracers in hematopoietic stem and progenitor cells. We first constructed a pair of MSCV based retroviral vectors with an identical backbone expressing either EGFP or DsRed-Express. These vectors were intended to be used for multicolor tracking of separate genes simultaneously and accurately in a single cell or mouse since the emission spectra of EGFP and DsRed-Express have minimal overlap. We used these vectors to transduce mouse mononuclear bone marrow cells, and the results demonstrated that the EGFP vector transduced green cells and DsRed-Express vector transduced red cells from single color or mixed dual color cell populations are clearly discerned by flow cytometry and fluorescent microscopy. Our results from in vivo competitive repopulation assay showed that under the experimental condition, mouse hematopoietic stem cells expressing EGFP alone are maintained nearly throughout the lifespan of the transplanted mice and appear to function normally. About 15 months after bone marrow transplantation, on average, 24% total peripheral white blood cells in recipient mice expressed EGFP. This initial donor population prior to injection contained 25.2% EGFP positive cells and all 5 mice assessed at 15 months were EGFP positive. Most EGFP transplanted mice lived at least 22 months and appeared normal at sacrifice. In contrast, the percentage of DsRed expressing donor cells transplanted either alone or mixed with EGFP expressing cells unexpectedly declined in recipient mice over time. By 3 months post-transplantation, the decrease of the percentage of DsRed expressing cells was dramatic. Therefore, EGFP itself has no detectable deteriorative effects on hematopoietic stem cells and is nearly an ideal long-term expression tracer for hematopoietic cells. However, the number of detectable DsRed expressing hematopoietic stem and progenitor cells, for reasons not yet known, decreases over time; therefore, DsRed fluorescent protein should not be used as a long-term tracer for these cells. This study also points out the importance of using correct expression tracers for accurately defining the functions of any genes.

Long-Term In Vivo Studies in Mice Unexpectedly Reveal That Prolonged Growth Hormone (GH) and Insulin/Insulin-Like Growth Factor-1 (IGF-1) Signaling Have a Negative Effect on Normal Bone Marrow Hematopoiesis – Implications for GH-Based “rejuvenation” Therapies,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3422-3422
Author(s):  
Janina Ratajczak ◽  
Rui Liu ◽  
Magda Kucia ◽  
Andrzej Bartke ◽  
Mariusz Z Ratajczak
Keyword(s):  
Bone Marrow ◽  
Growth Hormone ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Ames Dwarf Mice ◽  
Ames Dwarf ◽  
Dwarf Mice ◽  
Over Time

Abstract Abstract 3422 Background: Growth hormone (GH) has been proposed as a rejuvenation factor that delays aging in older patients. The long-term results of such therapy, however, have recently become controversial. It is known that GH action is mediated by release of insulin-like growth factor-1 (IGF-1, also known as somatomedin C) from the liver. IGF-1 is an important factor affecting proliferation of several types of cells, including malignant hematopoietic blasts. A role for the GH-IGF-1 axis in normal hematopoiesis still remains controversial and some stimulatory effects to the clonogenicity of normal hematopoiteic stem/progenitor cells (HSPCs) have been described. We have previously reported that IGF-1 does not directly stimulate proliferation of normal clonogenic hematopoietic progenitors (J Clin Invest. 1994;94:320); however, it may promote erythroid differentiation and hemoglobinization of erythroblasts (Leukemia 1998;12:371). Aim of the study: Since long-term studies on the effect of GH-IGF-1 signaling on normal hematopoiesis in vivo have not been performed yet, we investigated the influence of these factors on the hematopoietic system in appropriate mouse models that express low or high levels of plasma GH and IGF-1. Experimental approach: We employed two mutant mouse strains that have low circulating plasma levels of IGF-1 due to a GH-receptor mutation (Laron dwarf mice) or to a defect in GH synthesis in the pituitary gland (Ames dwarf mice). We also employed transgenic mice that express the bovine GH gene (bGH), which results in a constitutively high level of circulating plasma IGF-1. In some experiments, normal wild type or Laron and Ames dwarf mice, with low circulating plasma IGF-1 levels, were injected for a prolonged period of time with recombinant GH or IGF-1. All these animals were analyzed by FACS for the presence of Sca-1+Lin–CD45+ HSPCs in bone marrow (BM) and the clonogenic growth of progenitors from all hematopoietic lineages monitored in standard methylcellulose (CFU-GM and BFU-E) and plasma clot (CFU-Meg) cultures. We also analyzed changes in peripheral blood count by Hemavet. The mice employed in our studies were at different ages (2 months, 6 months, and 2 years), and both female and male mice were analyzed. Results: We observed that Laron and Ames dwarf mice, with low circulating plasma levels of IGF-1, at the age of 1–2 years had ∼3–5 times more Sca-1+Lin–CD45+ in the BM than normal control littermates of the same age. Similarly, these mice also had ∼3–5 times more CFU-GM, BFU-E, and CFU-Meg in BM. The number of Sca-1+Lin–CD45+ cells and clonogenic progenitors from all lineages declined ∼5 fold in these animals (at 2 months and 8 months of age) after 4 weeks of treatment by daily injection of GH or IGF-1. However, interestingly, if this treatment was ceased the number of these cells showed over time a tendency to normalize. In another set of experiments, we evaluated the number of HSPCs in BM of 6-month- and 1-year-old mice that express the bovine GH transgene. We found that these mice have an ∼6-fold and ∼12-fold lower number in the BM of Sca-1+Lin–CD45+ and clonogenic progenitors, respectively, than control transgenic littermates expressing empty vector. Overall, a decrease in the number of HSPCs was accompanied by microcytic anemia. Conclusions: Our data, obtained from several in vivo animal models, show that prolonged exposure to GH-IGF-1 signaling depletes the number of HSPCs in the BM over time. This observation is highly relevant to GH rejuvenation therapies currently employed in humans. Our data indicate that this may lead to the premature depletion of HSPCs, and we also envision that prolonged stimulation of HSPCs by GH-IGF-1 may result in development of leukemias. In support of this notion, Laron dwarf mice and Laron dwarf patients do not develop hematological malignancies, while leukemias are often seen in bGH transgenic mice and in acromegalic patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Rhesus Macaques As a Preclinical Model Organism for RUNX1-FPD

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2185-2185
Author(s):  
Byung-Chul Lee ◽  
Yifan Zhou ◽  
Erica Bresciani ◽  
Neval Ozkaya ◽  
Taehoon Shin ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Gene Correction ◽  
Hematopoietic Stem ◽  
Human Phenotype ◽  
Runx1 Gene ◽  
Platelet Disorder ◽  
Control Locus ◽  
Over Time

Abstract Germline loss-of-function (LOF) heterozygous mutations in the central hematopoietic transcription factor RUNX1 gene cause the marrow failure/malignancy predisposition syndrome Familial Platelet Disorder with associated Myeloid Malignancies (FPDMM, or FPD). Patients with FPD have defective megakaryocytic development, low platelet counts, and a very high (35-50%) life-long risk of hematological malignancies, particularly MDS/AML. Murine heterozygous gene knockout models do not recapitulate the human phenotype in terms of thrombocytopenia or myeloid leukemia progression. Although gene correction of the RUNX1 mutation in hematopoietic stem and progenitor cells (HSPCs) is being considered as a possible treatment approach, it is unknown whether mutation-corrected HSPCs will have the hoped for advantage over RUNX1 mutant HSCs in vivo, likely necessary to significantly lower leukemia risk. In order to study the relative function of wildtype and RUNX1-mutated HSPCs in vivo in a model with close hematopoietic similarity to humans, we generated a rhesus macaque FPD competitive repopulation model via CRISPR/Cas9 NHEJ editing of the RUNX1 gene versus the AAVS1 safe-harbor control locus. We transplanted mixtures of autologous HSPCs edited at the two loci: 75% RUNX1-edited/25% AAVS1- edited CD34+ HSPCs in animal 1 and 25% RUNX1-edited/75% AAVS1-edited CD34+ HSPCs in animal 2, following conditioning with total body irradiation. Both animals engrafted tri-lineage hematopoiesis promptly following transplantation. However, platelet numbers remained below the normal range long-term in animal 1 receiving a higher ration of RUNX1-edited HSPCS and below counts of macaques receiving HSPCs edited at other loci (Figure 1). Bone marrow morphology at 6 months was normal. To assess the HSPC function of RUNX1 mutant versus AAV1 control and unedited WT cells we tracked RUNX1 and AAVS1-mutated allele frequencies in blood cells over time via deep sequencing (Figure 2). In the infusion products (IP), allele fractions reflected the desired ratios. In both animals, AAVS1-edited cells dominated compared to RUNX1-edited cells. However, in animal 1, RUNX1-mutated cells expanded over time eventually exceeding the ratio in the IP, and in animal 2, levels of RUNX1 and AAVS1-mutated cells were equivalent long-term. Marrow analyzed at 6 months showed heterozygous RUNX1-mutated CFU at levels concordant with mutation frequencies in the blood, but no homozygous RUNX1 mutated CFU, suggesting homozygous LOF is not compatible with long-term HSPC function. In conclusion, we have created pre-clinical model for FPD via CRISPR/Cas editing of HSPCs in rhesus macaques. The lack of a competitive advantage for wildtype or control-locus edited HSPCs over RUNX1 heterozygous-mutated HSPCs long-term in our model suggests that gene correction approaches for FPD will be challenging, particularly to reverse the MDS/AML predisposition phenotype. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

CarR, a MarR-family regulator from Corynebacterium glutamicum, modulated antibiotic and aromatic compound resistance

2019 ◽  
Vol 476 (21) ◽  
pp. 3141-3159 ◽  
Author(s):  
Meiru Si ◽  
Can Chen ◽  
Zengfan Wei ◽  
Zhijin Gong ◽  
GuiZhi Li ◽  
...  
Keyword(s):  
Stress Response ◽  
Ligand Binding ◽  
Corynebacterium Glutamicum ◽  
Conformational Changes ◽  
Cysteine Oxidation ◽  
Transcriptional Regulatory ◽  
Ligand Free ◽  
Redox Sensing

Abstract MarR (multiple antibiotic resistance regulator) proteins are a family of transcriptional regulators that is prevalent in Corynebacterium glutamicum. Understanding the physiological and biochemical function of MarR homologs in C. glutamicum has focused on cysteine oxidation-based redox-sensing and substrate metabolism-involving regulators. In this study, we characterized the stress-related ligand-binding functions of the C. glutamicum MarR-type regulator CarR (C. glutamicum antibiotic-responding regulator). We demonstrate that CarR negatively regulates the expression of the carR (ncgl2886)–uspA (ncgl2887) operon and the adjacent, oppositely oriented gene ncgl2885, encoding the hypothetical deacylase DecE. We also show that CarR directly activates transcription of the ncgl2882–ncgl2884 operon, encoding the peptidoglycan synthesis operon (PSO) located upstream of carR in the opposite orientation. The addition of stress-associated ligands such as penicillin and streptomycin induced carR, uspA, decE, and PSO expression in vivo, as well as attenuated binding of CarR to operator DNA in vitro. Importantly, stress response-induced up-regulation of carR, uspA, and PSO gene expression correlated with cell resistance to β-lactam antibiotics and aromatic compounds. Six highly conserved residues in CarR were found to strongly influence its ligand binding and transcriptional regulatory properties. Collectively, the results indicate that the ligand binding of CarR induces its dissociation from the carR–uspA promoter to derepress carR and uspA transcription. Ligand-free CarR also activates PSO expression, which in turn contributes to C. glutamicum stress resistance. The outcomes indicate that the stress response mechanism of CarR in C. glutamicum occurs via ligand-induced conformational changes to the protein, not via cysteine oxidation-based thiol modifications.

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