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Léonetti, Michel, Jérome Galon, Robert Thai, Catherine Sautès-Fridman, Gervaise Moine, and André Ménez. "Presentation of Antigen in Immune Complexes Is Boosted by Soluble Bacterial Immunoglobulin Binding Proteins." Journal of Experimental Medicine 189, no. 8 (April 19, 1999): 1217–28. http://dx.doi.org/10.1084/jem.189.8.1217.
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Using a snake toxin as a proteic antigen (Ag), two murine toxin–specific monoclonal antibodies (mAbs), splenocytes, and two murine Ag–specific T cell hybridomas, we showed that soluble protein A (SpA) from Staphylococcus aureus and protein G from Streptococcus subspecies, two Ig binding proteins (IBPs), not only abolish the capacity of the mAbs to decrease Ag presentation but also increase Ag presentation 20–100-fold. Five lines of evidence suggest that this phenomenon results from binding of an IBP–Ab–Ag complex to B cells possessing IBP receptors. First, we showed that SpA is likely to boost presentation of a free mAb, suggesting that the IBP-boosted presentation of an Ag in an immune complex results from the binding of IBP to the mAb. Second, FACS® analyses showed that an Ag–Ab complex is preferentially targeted by SpA to a subpopulation of splenocytes mainly composed of B cells. Third, SpA-dependent boosted presentation of an Ag–Ab complex is further enhanced when splenocytes are enriched in cells containing SpA receptors. Fourth, the boosting effect largely diminishes when splenocytes are depleted of cells containing SpA receptors. Fifth, the boosting effect occurs only when IBP simultaneously contains a Fab and an Fc binding site. Altogether, our data suggest that soluble IBPs can bridge immune complexes to APCs containing IBP receptors, raising the possibility that during an infection process by bacteria secreting these IBPs, Ag-specific T cells may activate IBP receptor–containing B cells by a mechanism of intermolecular help, thus leading to a nonspecific immune response.
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Özdemir and Gambetta. "The Role of Insulation in Patterning Gene Expression." Genes 10, no. 10 (September 28, 2019): 767. http://dx.doi.org/10.3390/genes10100767.
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Development is orchestrated by regulatory elements that turn genes ON or OFF in precise spatial and temporal patterns. Many safety mechanisms prevent inappropriate action of a regulatory element on the wrong gene promoter. In flies and mammals, dedicated DNA elements (insulators) recruit protein factors (insulator binding proteins, or IBPs) to shield promoters from regulatory elements. In mammals, a single IBP called CCCTC-binding factor (CTCF) is known, whereas genetic and biochemical analyses in Drosophila have identified a larger repertoire of IBPs. How insulators function at the molecular level is not fully understood, but it is currently thought that they fold chromosomes into conformations that affect regulatory element-promoter communication. Here, we review the discovery of insulators and describe their properties. We discuss recent genetic studies in flies and mice to address the question: Is gene insulation important for animal development? Comparing and contrasting observations in these two species reveal that they have different requirements for insulation, but that insulation is a conserved and critical gene regulation strategy.
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Natrus, Larysa V., Yulia S. Osadchuk, Olha O. Lisakovska, Dmytro O. Labudzinskyi, Yulia G. Klys, and Yuri B. Chaikovsky. "Effect of Propionic Acid on Diabetes-Induced Impairment of Unfolded Protein Response Signaling and Astrocyte/Microglia Crosstalk in Rat Ventromedial Nucleus of the Hypothalamus." Neural Plasticity 2022 (January 22, 2022): 1–26. http://dx.doi.org/10.1155/2022/6404964.
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Background. The aim was to investigate the influence of propionic acid (PA) on the endoplasmic reticulum (ER), unfolded protein response (UPR) state, and astrocyte/microglia markers in rat ventromedial hypothalamus (VMH) after type 2 diabetes mellitus (T2DM). Methods. Male Wistar rats were divided: (1) control, (2) T2DM, and groups that received the following (14 days, orally): (3) metformin (60 mg/kg), (4) PA (60 mg/kg), and (5) PA+metformin. Western blotting, RT-PCR, transmission electron microscopy, and immunohistochemical staining were performed. Results. We found T2DM-associated enlargement of ER cisterns, while drug administration slightly improved VMH ultrastructural signs of damage. GRP78 level was 2.1-fold lower in T2DM vs. control. Metformin restored GRP78 to control, while PA increased it by 2.56-fold and metformin+PA—by 3.28-fold vs. T2DM. PERK was elevated by 3.61-fold in T2DM, after metformin—by 4.98-fold, PA—5.64-fold, and metformin+PA—3.01-fold vs. control. A 2.45-fold increase in ATF6 was observed in T2DM. Metformin decreased ATF6 content vs. T2DM. Interestingly, PA exerted a more pronounced lowering effect on ATF6, while combined treatment restored ATF6 to control. IRE1 increased in T2DM (2.4-fold), metformin (1.99-fold), and PA (1.45-fold) groups vs. control, while metformin+PA fully normalized its content. The Iba1 level was upregulated in T2DM (5.44-fold) and metformin groups (6.88-fold). Despite PA treatment leading to a further 8.9-fold Iba1 elevation, PA+metformin caused the Iba1 decline vs. metformin and PA treatment. GFAP level did not change in T2DM but rose in metformin and PA groups vs. control. PA+metformin administration diminished GFAP vs. PA. T2DM-induced changes were associated with dramatically decreased ZO-1 levels, while PA treatment increased it almost to control values. Conclusions. T2DM-induced UPR imbalance, activation of microglia, and impairments in cell integrity may trigger VMH dysfunction. Drug administration slightly improved ultrastructural changes in VMH, normalized UPR, and caused an astrocyte activation. PA and metformin exerted beneficial effects for counteracting diabetes-induced ER stress in VMH.
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Hansen, Eva H., Mark A. Schembri, Per Klemm, Thomas Sch�fer, S�ren Molin, and Lone Gram. "Elucidation of the Antibacterial Mechanism of the Curvularia Haloperoxidase System by DNA Microarray Profiling." Applied and Environmental Microbiology 70, no. 3 (March 2004): 1749–57. http://dx.doi.org/10.1128/aem.70.3.1749-1757.2004.
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ABSTRACT A novel antimicrobial enzyme system, the Curvularia haloperoxidase system, was examined with the aim of elucidating its mechanism of antibacterial action. Escherichia coli strain MG1655 was stressed with sublethal concentrations of the enzyme system, causing a temporary arrest of growth. The expression of genes altered upon exposure to the Curvularia haloperoxidase system was analyzed by using DNA microarrays. Only a limited number of genes were involved in the response to the Curvularia haloperoxidase system. Among the induced genes were the ibpA and ibpB genes encoding small heat shock proteins, a gene cluster of six genes (b0301-b0306) of unknown function, and finally, cpxP, a member of the Cpx pathway. Knockout mutants were constructed with deletions in b0301-b0306, cpxP, and cpxARP, respectively. Only the mutant lacking cpxARP was significantly more sensitive to the enzyme system than was the wild type. Our results demonstrate that DNA microarray technology cannot be used as the only technique to investigate the mechanisms of action of new antimicrobial compounds. However, by combining DNA microarray analysis with the subsequent creation of knockout mutants, we were able to pinpoint one of the specific responses of E. coli—namely, the Cpx pathway, which is important for managing the stress response from the Curvularia haloperoxidase system.
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El-Fatatry, Hamed M., Mokhtar M. Mabrouk, Sherin F. Hammad, and Samah F. El-Malla. "A Validated Enantioselective HPLC Method for Determination of Ibuprofen Enantiomers in Bulk and Tablet Dosage Form." Journal of AOAC INTERNATIONAL 99, no. 3 (May 1, 2016): 604–11. http://dx.doi.org/10.5740/jaoacint.15-0273.
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Abstract A new chiral reversed-phase (RP)-HPLC method with UV detection was developed. Enantioselective resolution of ibuprofen (IBP) was achieved using (3R,4S)-4-(3,5-dinitrobenzamido)-3-(3-(trioxysilyl)-propyl)-1,2,3,4-tetrahydro-phenanthrene [(R,R)-Whelk-O2] chiral stationary phase (4.6 mm id × 250 mm, 10 μm) with a mobile phase composed of ethanol–water (30 + 70, v/v) containing 100 mM ammonium acetate at a flow rate of 1.3 mL/min using diode array detector at λ 220 nm. Calibration curves were linear over the concentration range of 20–180 μg/mL for both IBP enantiomers. Mean % recoveries ±SD of 99.74 ± 1.73 and 99.60 ± 0.93 were obtained for dexibuprofen (dex-IBP) and levoibuprofen (levo-IBP), respectively. Intra- and interday precision calculated as RSD, % were not more than 1.66% for dex-IBP and 1.93% for levo-IBP. The detection limits were 2.09 and 2.06 μg/mL for dex-IBP and levo-IBP, respectively. The method was successfully applied for the determination of dex-IBP in tablet dosage form.
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Cerantola, S., S. Faggin, V. Caputi, V. Cortese, A. Bosi, D. Banfi, A. Rambaldo, et al. "P044 Enteric dopaminergic pathways in mouse and human intestinal inflammation." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i160—i161. http://dx.doi.org/10.1093/ecco-jcc/jjab232.173.
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Abstract Background Changes in dopamine beta-hydroxylase (DBH) and anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and related animal models. Thus, we aimed to evaluate the dopaminergic pathways in IBD patients as well as in a mouse model of dextran sodium sulphate (DSS)-induced ileitis. Methods Colon biopsies (CB) obtained from healthy volunteers (N=3) and matched-IBD patients (N=3), were used to evaluate DBH immunoreactivity by confocal microscopy. Male C57/Bl6 (8±2 weeks old; N=16 mice) received 1.5% DSS in drinking water for 5 days, then switched to regular drinking water for 3 days. Inflammatory cytokines (IL-1β, TNFα, IL-6) were measured to assess ileitis severity. Changes in ileal muscle tension were isometrically recorded following 30 μM dopamine or 30 μM SKF38393 (a dopamine receptor 1 (D1R) agonist) or 30 μM bromocriptine (a D2R agonist). Immunofluorescence distribution of Iba1 (a macrophage specific marker), D1R, DBH and dopamine transporter (DAT) were determined in longitudinal muscle-myenteric plexus whole-mount preparations (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR. Results CB from IBD patients and LMMPs from DSS mice showed a significant increase of DBH immunoreactivity compared to healthy patients and sham mice (+25% [p<0.01], +20% [p<0.01], respectively). DSS treatment caused a significant increase of DAT and D1R immunoreactivity as well as D1R mRNA levels (+27% [p<0.05], +24% [p<0.05], +6-fold [p<0.05], respectively), accompanied by a significant reduction of dopamine-mediated relaxation (-27% [p<0.01]). SKF38393 determined a marked inhibitory response in ileal preparations from DSS mice compared to sham mice (+73% [p<0.01]), suggesting that dopamine responses are mainly mediated through D1R. A 2-fold increase of resident Iba1+ macrophages was observed in the myenteric plexus of DSS mice associated with a 2.9- and 1.5-fold enhancement of IL-6 and IL-1β mRNA levels, respectively. Conclusion Human colitis and mouse ileitis affect dopamine machinery in the enteric nervous system. Experimentally induced ileitis impairs dopaminergic neurotransmission altering D1R-mediated responses. These findings provide novel information on the involvement of dopaminergic pathways in IBD.
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Rodríguez-Lorenzo, Luis M., Blanca Vázquez, Julio San Román, and Kārlis A. Gross. "Incorporation of 2nd and 3rd Generation Bisphosphonates on Hydroxyfluorapatite." Key Engineering Materials 309-311 (May 2006): 899–902. http://dx.doi.org/10.4028/www.scientific.net/kem.309-311.899.
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Bisphosphonates (BPs) may play an important role in minimizing osteolysis. In this work two new bisphosphonates pertaining to second and third generations respectively, have been synthesized and incorporated onto a chemically enriched hydroxyapatite. BP synthesis has been performed by adding H3PO3, PCl3 and methanesulfonic acid over 4-aminophenyl acetic acid (APBP) and 1-H-indole-3-acetic acid (IBP) respectively at 65°C in a N2 atmosphere. These compounds bear a primary amine group bonded to an aromatic ring, and a secondary amine group within a heterocyclic ring respectively. A chemically enriched hydroxyapatite with a chemical content corresponding to a 50% fluorided hydroxyapatite has been synthesized. Ceramic bodies manufactured by uniaxial pressure followed by cold isostatic press have a 97% density and submicron grain size. The BP was adsorbed onto the surface by immersion in a stirred solution at 37°C for 48 hours. A 10-fold decrease of the surface energy was observed for bodies modified with the APBP whereas only a 25 % decrease is obtained for bodies loaded with the bisphosphonate loaded with the IBP.
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Holstein, Sarah A., Huaxiang Tong, and Raymond J. Hohl. "Biochemical Basis for Interactions Between Thalidomide and Inhibitors of the Isoprenoid Biosynthetic Pathway in Multiple Myeloma Cells." Blood 112, no. 11 (November 16, 2008): 2635. http://dx.doi.org/10.1182/blood.v112.11.2635.2635.
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Abstract Introduction: The isoprenoid biosynthetic pathway (IBP) is responsible for the production of key sterol and nonsterol species, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) which serve as substrates for protein isoprenylation reactions. Several agents known to target the IBP have been observed to have cytotoxic effects in multiple myeloma cells. Thalidomide (Thal) has emerged as an effective agent for treating multiple myeloma. While Thal has been noted to have a variety of direct and indirect effects on myeloma cells, the precise mechanism of action remains unknown. Aim: We examined interactions between inhibitors of the IBP and Thal in multiple myeloma cells. The mechanisms underlying the observed differential sensitivity to these agents were explored. Methods: Studies were performed in three human multiple myeloma cell lines (RPMI-8226, U266, H929). Cytotoxicity was assessed via MTT assays, while apoptosis induction was determined by Annexin V staining and evaluation of PARP cleavage. Western blot analysis was used to evaluate inhibition of protein isoprenylation. Intracellular FPP and GGPP levels were measured via enzymatic coupling to fluorescently-tagged peptides, HPLC fractionation and fluorescence detection. Pharmacologic manipulation of the IBP was achieved with the following agents: lovastatin (Lov) as an HMG-CoA reductase inhibitor, zoledronic acid (ZA) as a FPP synthase inhibitor, digeranyl bisphosphonate (DGBP) as a GGPP synthase inhibitor, FTI-277 as a farnesyl transferase inhibitor (FTI), and GGTI-286 as a geranylgeranyl transferase I inhibitor (GGTI). Results: Addition of Thal to Lov (at both 24 & 48h), zoledronic acid (at 48h), or DGBP (at 24 & 48h) in RPMI-8266 cells results in marked enhancement in cytotoxicity. Isobologram analysis could not be performed as Thal by itself does induce cytotoxicity in MTT assays. Although Lov induces cytotoxicity in a concentration- and time-dependent manner in the U266 and H929 cells, the addition of Thal did not result in increased cytotoxicity. Neither ZA nor DGBP induced cytotoxicity in the U266 cell line, while the H929 cell line showed effects only at 48 hours. Addition of Thal to FTI or GGTI did not result in enhanced cytotoxicity in tested cell lines. Annexin V experiments confirmed enhanced induction of apoptosis in RPMI-8226 cells incubated with the combination of Thal/Lov or Thal/DGBP. Add-back experiments revealed that the enhanced cytotoxicity/induction of apoptosis observed with the addition of Thal could be prevented with the addition of mevalonate or GGPP in Lov-treated cells or GGPP in DGBP-treated cells. PARP cleavage was demonstrated in RPMI-8226 and H929 cells treated with Lov or DGBP (with or without Thal) and in U266 cells treated with Lov. As expected, Lov resulted in the accumulation of unmodified forms of proteins normally farnesylated (Ras) and geranylgeranylated (Rap1a and Rab6) in these cells. Interestingly however, while DGBP led to accumulation of unmodified Rap1a and Rab6 in RPMI-8226 and H929 cells, no effect was seen in the U266 line. Examination of intracellular levels of FPP and GGPP revealed that the U266 line has markedly larger pools of FPP (8.5-fold) and GGPP (2.7-fold) compared to RPMI-8226 and that treatment with DGBP only partially depletes U266 cells of GGPP. Conclusions: These studies demonstrate an interaction between thalidomide and IBP inhibitors in multiple myeloma cells. These effects appear dependent on depletion of GGPP. Since treatment with a geranylgeranyl transferase-I inhibitor does not produce similar results, this suggests that substrates of geranylgeranyl transferase-II, such as the Rab proteins, may play critical roles in myeloma pathophysiology. The finding that intracellular levels of FPP and GGPP vary markedly amongst cell lines explains differential sensitivity of these cells to pharmacologic manipulation of the IBP and may also influence sensitivity to chemotherapeutic agents. Further studies will determine the extent to which isoprenoid pool sizes vary in primary samples and may ultimately allow for the identification of multiple myeloma patients who would benefit from the addition of an IBP inhibitor to their treatment plan. Figure Figure
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Rehman, Haneef Ur, Afsheen Aman, Mohammad Asif Nawaz, and Shah Ali Ul Qader. "Characterization of pectin degrading polygalacturonase produced by Bacillus licheniformis KIBGE-IB21." Food Hydrocolloids 43 (January 2015): 819–24. http://dx.doi.org/10.1016/j.foodhyd.2014.08.018.
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Burchard, Julja, Ashoka D. Polpitiya, Angela C. Fox, Todd L. Randolph, Tracey C. Fleischer, Max T. Dufford, Thomas J. Garite, et al. "Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth and Associated Clinical Outcomes: A Replication Study." Journal of Clinical Medicine 10, no. 21 (October 29, 2021): 5088. http://dx.doi.org/10.3390/jcm10215088.
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Preterm births are the leading cause of neonatal death in the United States. Previously, a spontaneous preterm birth (sPTB) predictor based on the ratio of two proteins, IBP4/SHBG, was validated as a predictor of sPTB in the Proteomic Assessment of Preterm Risk (PAPR) study. In particular, a proteomic biomarker threshold of −1.37, corresponding to a ~two-fold increase or ~15% risk of sPTB, significantly stratified earlier deliveries. Guidelines for molecular tests advise replication in a second independent study. Here we tested whether the significant association between proteomic biomarker scores above the threshold and sPTB, and associated adverse outcomes, was replicated in a second independent study, the Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TREETOP). The threshold significantly stratified subjects in PAPR and TREETOP for sPTB (p = 0.041, p = 0.041, respectively). Application of the threshold in a Kaplan–Meier analysis demonstrated significant stratification in each study, respectively, for gestational age at birth (p < 001, p = 0.0016) and rate of hospital discharge for both neonate (p < 0.001, p = 0.005) and mother (p < 0.001, p < 0.001). Above the threshold, severe neonatal morbidity/mortality and mortality alone were 2.2 (p = 0.0083,) and 7.4-fold higher (p = 0.018), respectively, in both studies combined. Thus, higher predictor scores were associated with multiple adverse pregnancy outcomes.
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Haugen, Brian J., Shahaireen Pellett, Peter Redford, Holly L. Hamilton, Paula L. Roesch, and Rodney A. Welch. "In Vivo Gene Expression Analysis Identifies Genes Required for Enhanced Colonization of the Mouse Urinary Tract by Uropathogenic Escherichia coli Strain CFT073 dsdA." Infection and Immunity 75, no. 1 (October 30, 2006): 278–89. http://dx.doi.org/10.1128/iai.01319-06.
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ABSTRACT Deletional inactivation of the gene encoding d-serine deaminase, dsdA, in uropathogenic Escherichia coli strain CFT073 results in a hypermotile strain with a hypercolonization phenotype in the bladder and kidneys of mice in a model of urinary tract infection (UTI). The in vivo gene expression profiles of CFT073 and CFT073 dsdA were compared by isolating RNA directly from the urine of mice challenged with each strain individually. Hybridization of cDNAs derived from these samples to CFT073-specific microarrays allowed identification of genes that were up- or down-regulated in the dsdA deletion strain during UTI. Up-regulated genes included the known d-serine-responsive gene dsdX, suggesting in vivo intracellular accumulation of d-serine by CFT073 dsdA. Genes encoding F1C fimbriae, both copies of P fimbriae, hemolysin, OmpF, a dipeptide transporter DppA, a heat shock chaperone IbpB, and clusters of open reading frames with unknown functions were also up-regulated. To determine the role of these genes as well as motility in the hypercolonization phenotype, mutants were constructed in the CFT073 dsdA background and tested in competition against the wild type in the murine model of UTI. Strains with deletions of one or both of the two P fimbrial operons, hlyA, fliC, ibpB, c0468, locus c3566 to c3568, or c2485 to c2490 colonized mouse bladders and kidneys at levels indistinguishable from wild type. CFT073 dsdA c2398 and CFT073 dsdA focA maintained a hypercolonization phenotype. A CFT073 dsdA dppA mutant was attenuated 10- to 50-fold in its colonization ability compared to CFT073. Our results support a role for d-serine catabolism and signaling in global virulence gene regulation of uropathogenic E. coli.
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Arques, M. Carmen, M. Carmen Marín-Manzano, L. Clarissa Brito da Rocha, Blanca Hernandez-Ledesma, Isidra Recio, and Alfonso Clemente. "Quantitative determination of active Bowman-Birk isoinhibitors, IBB1 and IBBD2, in commercial soymilks." Food Chemistry 155 (July 2014): 24–30. http://dx.doi.org/10.1016/j.foodchem.2014.01.024.
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Han, Sang-Kap, Min-Kyung Joo, Jeon-Kyung Kim, Woonhee Jeung, Heerim Kang, and Dong-Hyun Kim. "Bifidobacteria-Fermented Red Ginseng and Its Constituents Ginsenoside Rd and Protopanaxatriol Alleviate Anxiety/Depression in Mice by the Amelioration of Gut Dysbiosis." Nutrients 12, no. 4 (March 26, 2020): 901. http://dx.doi.org/10.3390/nu12040901.
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Gut dysbiosis is closely connected with the outbreak of psychiatric disorders with colitis. Bifidobacteria-fermented red ginseng (fRG) increases the absorption of ginsenoside Rd and protopanxatriol into the blood in volunteers and mice. fRG and Rd alleviates 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice. Therefore, to understand the gut microbiota-mediated mechanism of fRG against anxiety/depression, we examined the effects of red ginseng (RG), fRG, ginsenoside Rd, and protopanaxatriol on the occurrence of anxiety/depression, colitis, and gut dysbiosis in mice. Mice with anxiety/depression were prepared by being exposed to two stressors, immobilization stress (IS) or Escherichia coli (EC). Treatment with RG and fRG significantly mitigated the stress-induced anxiety/depression-like behaviors in elevated plus maze, light-dark transition, forced swimming (FST), and tail suspension tasks (TST) and reduced corticosterone levels in the blood. Their treatments also suppressed the stress-induced NF-κB activation and NF-κB+/Iba1+ cell population in the hippocampus, while the brain-derived neurotrophic factor (BDNF) expression and BDNF+/NeuN+ cell population were increased. Furthermore, treatment with RG or fRG suppressed the stress-induced colitis: they suppressed myeloperoxidase activity, NF-κB activation, and NF-κB+/CD11c+ cell population in the colon. In particular, fRG suppressed the EC-induced depression-like behaviors in FST and TST and colitis more strongly than RG. fRG treatment also significantly alleviated the EC-induced NF-κB+/Iba1+ cell population and EC-suppressed BDNF+/NeuN+ cell population in the hippocampus more strongly than RG. RG and fRG alleviated EC-induced gut dysbiosis: they increased Bacteroidetes population and decreased Proteobacteria population. Rd and protopanaxatriol also alleviated EC-induced anxiety/depression and colitis. In conclusion, fRG and its constituents Rd and protopanaxatriol mitigated anxiety/depression and colitis by regulating NF-κB-mediated BDNF expression and gut dysbiosis.
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Alatrash, Gheath, Luis M. Vence, Wendy Woodward, Naoto T. Ueno, and Jeffrey J. Molldrem. "Leukemia-Associated Primary Granule Proteins (PGPs) Elastase-2 and Proteinase-3 Are Aberrantly Expressed in Solid Tumors: A Potential Therapeutic Target for PR1-Directed Immunotherapy." Blood 112, no. 11 (November 16, 2008): 5440. http://dx.doi.org/10.1182/blood.v112.11.5440.5440.
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Abstract Neutrophil elastase (ELA2) and proteinase-3 (PRTN3) are the source proteins for the nonomeric HLA-A2-restricted peptide PR1 (VLQELNVTV), a recognized leukemia-associated antigen (LAA). In myeloid leukemia, high expression of ELA2 and PRTN3 has been correlated with improved clinical outcomes following hematopoietic stem cell transplant (HSCT). Vaccination with PR-1 peptide showed efficacy in myeloid leukemia and myelodysplastic syndrome, and was associated with immunologic response (≥ 2 fold increase in PR1-specific cytotoxic T lymphocytes (PR1-CTL)) and long-lasting clinical remissions. PR1-CTLwere shown to mediate immunity elicited by PR-1 vaccine, as they preferentially recognize and kill myeloid leukemia cells. Since ELA2 and PRTN3 have been reported in breast cancer biopsies, we hypothesized that ELA2 and PRTN3 may be mislocalized in solid tumors, leading to MHC-I presentation, therefore providing a therapeutic target for PR1 vaccine. To study the subcellular localization of ELA2 and PRTN3, the cytoplasmic, nuclear, membrane, and golgi/ER fractions were obtained from inflammatory breast cancer (IBC) (MDA-IBC1 and SUM149) and melanoma (526, 624, 888 and 926) cell lines. ELA2 was preferentially expressed in the cytoplasmic fraction in the IBC cell line SUM149, while PRTN3 was expressed in the membrane and cytoskeletal fractions of the IBC cell line MDA-IBC1. In the melanoma cell lines, ELA2 was expressed in the cytoplasmic fractions, while PRTN3 was noted in the nuclear, cytoplasmic and cytoskeletal fractions. Furthermore, the HLA-A2+ melanoma cell line 888 was susceptible to lysis by PR1-CTL (approximately 30% lysis; Effector:Target ratio=1:2). Together, these results demonstrate that ELA2 and PRTN3 are aberrantly localized in non-hematopoietic cell lines, and that this can be associated with susceptibility to PR1- CTL lysis. In particular, PR1 is a potential immunotherapeutic target for patients with melanoma and breast cancer.
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Jiang, Ping, Jing Cai, Xiaoqi He, Hongbo Wang, Weihong Dong, Yuan Zhang, Juergen Dunst, Kay C. Willborn, Bangxing Huang, and Zehua Wang. "Identification of risk factors associated with pelvic lymph node metastasis in patients with stage IB1 cervical cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e18005-e18005. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e18005.
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e18005 Background: Evaluation the distribution of nodal metastases in the stage IB1 cervical cancer and the risk factors associated with pelvic lymph node metastasis (LNM) at each anatomic location. Methods: 728 patients with stage IB1 cervical cancer who underwent radical hysterectomies and systemic pelvic lymphadenectomies from January 2008 to December 2017 were retrospectively studied. All removed pelvic lymph nodes were pathologically examined, and the risk factors for LNM at the obturator, internal iliac, external iliac, and common iliac regions were evaluated by univariate and multivariate logistic regression analyses. Results: 20,134 lymph nodes were analysed with the average number of 27.80 (± SD 9.43) lymph nodes per patient. Nodal metastases were present in 266 (14.6%) patients. The obturator was the most common site for nodal metastasis (42.5%) followed by the internal iliac nodes (20.3%) and the external iliac nodes (19.9%), while the common iliac (9.8%) and parametrial (7.5%) nodes were the least likely to be involved. Tumor size more than 2 cm, histologically proven lymphovascular space involvement (LVSI) and parametrial invasion correlated independently significantly with the higher risk of the lymphatic metastasis. Obesity (BMI≥25) was independently significantly negatively correlated with the risk of lymphatic metastases. All the positive common iliac nodes were found in patients with tumors greater than 2 cm. The multivariate analysis showed that tumor size greater than 3 cm was associated with a 16.6-fold increase in the risk for common iliac LNM. Interestingly, tumor size was not an independent risk factor for pelvic LNM in the lower regions, i.e., the obturator, internal iliac and external iliac areas, where LVSI was the most significant predictor for LNM. In addition, parametrial invasion was related to external and internal iliac LNM; deep stromal invasion and age less than 50 years were associated with obturator LNM. Conclusions: The incidence of lymph node metastasis in patients with stage IB1 cervical cancer is low but prognostically relevant. The data offer the opportunity for tailored individual treatment in selected patients with small tumors and obesity.
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Parvatiyar, Kislay, Eyad M. Alsabbagh, Urs A. Ochsner, Michelle A. Stegemeyer, Alan G. Smulian, Sung Hei Hwang, Colin R. Jackson, Timothy R. McDermott, and Daniel J. Hassett. "Global Analysis of Cellular Factors and Responses Involved in Pseudomonas aeruginosa Resistance to Arsenite." Journal of Bacteriology 187, no. 14 (July 2005): 4853–64. http://dx.doi.org/10.1128/jb.187.14.4853-4864.2005.
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ABSTRACT The impact of arsenite [As(III)] on several levels of cellular metabolism and gene regulation was examined in Pseudomonas aeruginosa. P. aeruginosa isogenic mutants devoid of antioxidant enzymes or defective in various metabolic pathways, DNA repair systems, metal storage proteins, global regulators, or quorum sensing circuitry were examined for their sensitivity to As(III). Mutants lacking the As(III) translocator (ArsB), superoxide dismutase (SOD), catabolite repression control protein (Crc), or glutathione reductase (Gor) were more sensitive to As(III) than wild-type bacteria. The MICs of As(III) under aerobic conditions were 0.2, 0.3, 0.8, and 1.9 mM for arsB, sodA sodB, crc, and gor mutants, respectively, and were 1.5- to 13-fold less than the MIC for the wild-type strain. A two-dimensional gel/matrix-assisted laser desorption ionization-time of flight analysis of As(III)-treated wild-type bacteria showed significantly (>40-fold) increased levels of a heat shock protein (IbpA) and a putative allo-threonine aldolase (GlyI). Smaller increases (up to 3.1-fold) in expression were observed for acetyl-coenzyme A acetyltransferase (AtoB), a probable aldehyde dehydrogenase (KauB), ribosomal protein L25 (RplY), and the probable DNA-binding stress protein (PA0962). In contrast, decreased levels of a heme oxygenase (HemO/PigA) were found upon As(III) treatment. Isogenic mutants were successfully constructed for six of the eight genes encoding the aforementioned proteins. When treated with sublethal concentrations of As(III), each mutant revealed a marginal to significant lag period prior to resumption of apparent normal growth compared to that observed in the wild-type strain. Our results suggest that As(III) exposure results in an oxidative stress-like response in P. aeruginosa, although activities of classic oxidative stress enzymes are not increased. Instead, relief from As(III)-based oxidative stress is accomplished from the collective activities of ArsB, glutathione reductase, and the global regulator Crc. SOD appears to be involved, but its function may be in the protection of superoxide-sensitive sulfhydryl groups.
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CARROLL, LAURA M., TERESA M. BERGHOLZ, IAN M. HILDEBRANDT, and BRADLEY P. MARKS. "Application of a Nonlinear Model to Transcript Levels of Upregulated Stress Response Gene ibpA in Stationary-Phase Salmonella enterica Subjected to Sublethal Heat Stress." Journal of Food Protection 79, no. 7 (July 1, 2016): 1089–96. http://dx.doi.org/10.4315/0362-028x.jfp-15-377.
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ABSTRACT Sublethal heating, which can occur during slow cooking of meat products, is known to induce increased thermal resistance in Salmonella. However, very few studies have addressed the kinetics of this response. Although several recent studies have reported improved thermal inactivation models that include the effect of prior sublethal history on subsequent thermal resistance, none of these models were based on cellular-level responses to sublethal thermal stress. The goal of this study was to determine whether a nonlinear model could accurately portray the response of Salmonella to heat stress induced by prolonged exposure to sublethal temperatures. To accomplish this, stationary-phase Salmonella Montevideo cultures were subjected to various heating profiles (held at either 40 or 45°C for 0, 5, 10, 15, 30, 60, 90, 180, or 240 min) using a PCR thermal cycler. Differential plating on selective and nonselective media was used to confirm the presence of cellular injury. Reverse transcription quantitative PCR was used to screen the transcript levels of six heat stress–related genes to find candidate genes for nonlinear modeling. Injury was detected in populations of Salmonella held at 45°C for 30, 60, and 90 min and at 40°C for 0, 5, and 90 min (P < 0.05), whereas no significant injury was found at 180 and 240 min (P > 0.05). The transcript levels of ibpA, which codes for a small heat shock protein associated with the ClpB and DnaK-DnaJ-GrpE chaperone systems, showed the greatest increase relative to the transcript levels at 0 min, which was significant at 5, 10, 15, 30, 60, 90, and 180 min at 45°C and at 5, 10, 15, 30, 60, and 90 min at 40°C (P < 0.05). Using ibpA transcript levels as an indicator of adaptation to thermal stress, a nonlinear model for sublethal injury is proposed. The use of variables indicating the physiological state of the pathogen during stress has the potential to increase the accuracy of thermal inactivation models that must account for prolonged exposure to sublethal temperatures.
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Yun, Soo-Won, Jeon-Kyung Kim, Kyung-Eon Lee, Young Joon Oh, Hak-Jong Choi, Myung Joo Han, and Dong-Hyun Kim. "A Probiotic Lactobacillus gasseri Alleviates Escherichia coli-Induced Cognitive Impairment and Depression in Mice by Regulating IL-1β Expression and Gut Microbiota." Nutrients 12, no. 11 (November 10, 2020): 3441. http://dx.doi.org/10.3390/nu12113441.
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Excessive expression of interleukin (IL)-1β in the brain causes depression and cognitive dysfunction. Herein, we investigated the effect of Lactobacillus gasseri NK109, which suppressed IL-1β expression in activated macrophages, on Escherichia coli K1-induced cognitive impairment and depression in mice. Germ-free and specific pathogen-free mice with neuropsychiatric disorders were prepared by oral gavage of K1. NK109 alleviated K1-induced cognition-impaired and depressive behaviors, decreased the expression of IL-1β and populations of NF-κB+/Iba1+ and IL-1R+ cells, and increased the K1-suppressed population of BDNF+/NeuN+ cells in the hippocampus. However, its effects were partially attenuated by celiac vagotomy. NK109 treatment mitigated K1-induced colitis and gut dysbiosis. Tyndallized NK109, even if lysed, alleviated cognitive impairment and depression. In conclusion, NK109 alleviated neuropsychiatric disorders and colitis by modulating IL-1β expression, gut microbiota, and vagus nerve-mediated gut–brain signaling.
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Ma, Xiao-Yang, Young-Hoo Son, Jong-Wook Yoo, Min-Kyung Joo, and Dong-Hyun Kim. "Citation: Tight Junction Protein Expression-Inducing Probiotics Alleviate TNBS-Induced Cognitive Impairment with Colitis in Mice." Nutrients 14, no. 14 (July 20, 2022): 2975. http://dx.doi.org/10.3390/nu14142975.
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A leaky gut is closely connected with systemic inflammation and psychiatric disorder. The rectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS) induces gut inflammation and cognitive function in mice. Therefore, we selected Bifidobacterium longum NK219, Lactococcus lactis NK209, and Lactobacillus rhamnosus NK210, which induced claudin-1 expression in TNBS- or lipopolysaccharide (LPS)-stimulated Caco-2 cells, from the fecal bacteria collection of humans and investigated their effects on cognitive function and systemic inflammatory immune response in TNBS-treated mice. The intrarectal injection of TNBS increased cognitive impairment-like behaviors in the novel object recognition and Y-maze tests, TNF-α, IL-1β, and IL-17 expression in the hippocampus and colon, and LPS level in the blood and feces, while the expression of hippocampal claudin-5 and colonic claudin-1 decreased. Oral administration of NK209, NK210, and NK219 singly or together decreased TNBS-impaired cognitive behaviors, TNF-α and IL-1β expression, NF-κB+Iba1+ cell and LPS+Iba1+ cell numbers in the hippocampus, and LPS level in the blood and feces, whereas BDNF+NeuN+ cell and claudin-5+ cell numbers and IL-10 expression increased. Furthermore, they suppressed TNBS-induced colon shortening and colonic TNF-α and IL-1β expression, while colonic IL-10 expression and mucin protein-2+ cell and claudin-1+ cell numbers expression increased. Of these, NK219 most strongly alleviated cognitive impairment and colitis. They additively alleviated cognitive impairment with colitis. Based on these findings, NK209, NK210, NK219, and their combinations may alleviate cognitive impairment with systemic inflammation by suppressing the absorption of gut bacterial products including LPS into the blood through the suppression of gut bacterial LPS production and alleviation of a leaky gut by increasing gut tight junction proteins and mucin-2 expression.
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Barrera, I., D. Bloom, and M. Challberg. "An Intertypic Herpes Simplex Virus Helicase-Primase Complex Associated with a Defect in Neurovirulence Has Reduced Primase Activity." Journal of Virology 72, no. 2 (February 1, 1998): 1203–9. http://dx.doi.org/10.1128/jvi.72.2.1203-1209.1998.
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ABSTRACT R13-1 is an intertypic recombinant virus in which the left-hand 18% of the herpes simplex virus type 1 (HSV-1) genome is replaced by homologous sequences from HSV-2. R13-1 is nonneurovirulent and defective in DNA replication in neurons. The defect was localized to the UL5 open reading frame by using marker rescue analysis (D. C. Bloom and J. G. Stevens, J. Virol. 68:3761–3772, 1994). To provide conclusive evidence that UL5 is the only HSV-2 gene involved in the restricted replication phenotype of R13-1, we have characterized the phenotype of a recombinant virus (IB1) in which only the UL5 gene of HSV-1 was replaced by HSV-2 UL5. Data from 50% lethal dose determinations and the in vivo yields of virus suggested that IB1 has the same phenotypic characteristics as R13-1. UL5 is the helicase component of a complex with helicase and primase activities. All three subunits of this complex (UL5, UL8, and UL52) are required for viral DNA replication in all cell types. The intertypic complex HSV-2 UL5–HSV-1 UL8–HSV-1 UL52 was purified and biochemically characterized. The primase activity of the intertypic complex was 10-fold lower than that of HSV-1 UL5–HSV-1 UL8–HSV-1 UL52. The ATPase activity was comparable to that of the HSV-1 enzyme complex, and although the helicase activity was threefold lower, this did not interfere with the synthesis of leading strands by the HSV polymerase. One explanation for these findings is that the interactions between the subunits of the helicase-primase intertypic complex that are important for the full function of each subunit are inappropriate or weak.
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Rehman, Haneef Ur, Afsheen Aman, Alba Silipo, Shah Ali Ul Qader, Antonio Molinaro, and Asma Ansari. "Degradation of complex carbohydrate: Immobilization of pectinase from Bacillus licheniformis KIBGE-IB21 using calcium alginate as a support." Food Chemistry 139, no. 1-4 (August 2013): 1081–86. http://dx.doi.org/10.1016/j.foodchem.2013.01.069.
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Bathini, Praveen, Tao Sun, Mathias Schenk, Stephan Schilling, Nathan J. McDannold, and Cynthia A. Lemere. "Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses." Biomolecules 12, no. 7 (July 6, 2022): 951. http://dx.doi.org/10.3390/biom12070951.
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Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aβ antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5–6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics.
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Bianchi, Allison A., and François Baneyx. "Stress Responses as a Tool To Detect and Characterize the Mode of Action of Antibacterial Agents." Applied and Environmental Microbiology 65, no. 11 (November 1, 1999): 5023–27. http://dx.doi.org/10.1128/aem.65.11.5023-5027.1999.
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ABSTRACT Single-copy gene fusions between the lacZ reporter gene and Escherichia coli strains containing promoters induced by cold shock (cspA), cytoplasmic stress (ibp), or protein misfolding in the cell envelope (P3rpoH) were constructed and tested to determine their ability to detect antibacterial agents while simultaneously providing information on their cellular targets. Antibiotics that affect prokaryotic ribosomes selectively induced the cspA::lacZ oribp::lacZ gene fusion, depending on their mode of action. The membrane-damaging peptide polymyxin B induced both the P3rpoH::lacZ andibp::lacZ fusions, while the β-lactam antibacterial agent carbenicillin activated only the P3rpoH promoter. Nalidixic acid, a compound that causes DNA damage, downregulated β-galactosidase synthesis from P3rpoH but had little effect on expression of the reporter enzyme from either the cspA or ibp promoter. All model antibiotics could be identified over a wide range of sublethal concentrations with signal-to-noise ratios between 2 and 11. A blue halo assay was developed to rapidly characterize the modes of action of antibacterial agents by visual inspection, and this assay was used to detect chloramphenicol secreted into the growth medium ofStreptomyces venezuelae cultures. This simple system holds promise for screening natural or combinatorial libraries of antimicrobial compounds.
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Olías, Raquel, Carmen Becerra-Rodríguez, Jorge R. Soliz-Rueda, F. Javier Moreno, Cristina Delgado-Andrade, and Alfonso Clemente. "Glycation affects differently the main soybean Bowman–Birk isoinhibitors, IBB1 and IBBD2, altering their antiproliferative properties against HT29 colon cancer cells." Food & Function 10, no. 9 (2019): 6193–202. http://dx.doi.org/10.1039/c9fo01421g.
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Browne, Alice, Miranda Clements, Wei Ju, Daniel Brock, and Rosandra Kaplan. "Abstract B007: Remodeling the hyaluronan-rich tumor extracellular matrix using hyaluronidase-expressing genetically engineered MSCs for tumor regression and metastasis prevention in sarcomas." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): B007. http://dx.doi.org/10.1158/1538-7445.metastasis22-b007.
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Abstract Sarcomas are a diverse group of rare malignant tumors the develop in the bone and connective tissue and are often aggressive with ~50% of patients developing metastases. Due to their rarity and diversity, there is a great lack of standard therapies resulting in a 65% and 15% 5-year survival rate for regional and metastatic disease, respectively. Tumorigenesis is largely influenced by communication between the tumor microenvironment (TME), cancer cells, and the extracellular matrix (ECM). The ECM promotes cancer initiation and dissemination from the primary tumor and fosters a favorable microenvironment for metastatic colonization of tumor cells. Due to their mesenchymal origin, sarcomas are thought to produce and deposit large quantities of ECM. One component of the tumor-ECM known to promote an aggressive cancer phenotype is hyaluronan (HA). Abundant HA in the TME arises from overactive HA synthases that produce HA or downregulation of hyaluronidases (Hyals) that catalyze HA degradation. HA-rich tumor ECM promote cancer progression by regulating chemokine and cytokine trafficking, increasing hypoxia and interstitial pressure, and limiting delivery of antitumor therapies. In-silico profiling of sarcomas revealed an increase in HA synthase mRNA expression in 50.78% and correlated with 35% decrease in overall patient survival (P = 0.0027), compared to sarcomas with low HA synthase expression. To target this HA-rich tumor ECM, we sought to develop a cell-based approach to locally deliver HA-remodeling enzymes to minimize the drawbacks of systemic therapy and enhance anti-tumor responses. We developed genetically engineered mesenchymal stromal cells (GEMesys) that express Hyal, using mesenchymal stem cells derived from mouse lungs. We hypothesized that the Hyal-GEMesys would home to and degrade the HA-rich ECM preventing cancer progression. The therapeutic efficacy of Hyal-GEMesys was tested in osteosarcoma (F42010) and rhabdomyosarcoma (M-3-9M) syngeneic murine models. Preliminary data demonstrated encouraging efficacy of Hyal-GEMesys in reducing tumor volume in the osteosarcoma (up to 1.4-fold, p=0.0035-0.0172) and rhabdomyosarcoma M-3-9M model (up to 2-fold, P= 0.0428). Further, analysis of osteosarcoma tumors revealed reduced HA (up to 2.3-fold, P=0.0078) and collagen-I content (up to 3-fold, P= 0.0025) indicating our Hyal-GEMesys functionally remodel the ECM in vivo. Changes in ECM in GEMesy treated group were associated with changes in immune infiltration with an increase in CD4+ (P=0.0221) and CD8+ (P=0.0087) T cells and a decrease in IBA1+ (P=0.0144) macrophages. Analysis of rhabdomyosarcoma tumors revealed reduced HA content (up to 2-fold, P-0.00206). Future studies will more deeply explore the mechanisms of ECM-mediated immune changes and impact on metastatic progression. Our cell-based approach to deliver hyaluronidases holds promise of effectively degrading and remodel the HA-rich tumor ECM to enhance anti-tumor responses, prevent metastases and improve clinical outcomes for patients with high-risk sarcoma malignancies. Citation Format: Alice Browne, Miranda Clements, Wei Ju, Daniel Brock, Rosandra Kaplan. Remodeling the hyaluronan-rich tumor extracellular matrix using hyaluronidase-expressing genetically engineered MSCs for tumor regression and metastasis prevention in sarcomas [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B007.
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Lee, Dong-Yun, Jeon-Kyung Kim, Soo-Won Yun, Myung Joo Han, and Dong-Hyun Kim. "DW2009 Elevates the Efficacy of Donepezil against Cognitive Impairment in Mice." Nutrients 13, no. 9 (September 19, 2021): 3273. http://dx.doi.org/10.3390/nu13093273.
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Lactobacillus plantarum C29 and DW2009 (C29-fermented soybean) alleviate cognitive impairment through the modulation of the microbiota-gut-brain axis. Therefore, we examined whether combining donepezil, a well-known acetylcholinesterase inhibitor, with C29 or DW2009 could synergistically alleviate cognitive impairment in mice. Oral administration of donepezil combined with or without C29 (DC) or DW2009 (DD) alleviated lipopolysaccharide (LPS)-induced cognitive impairment-like behaviors more strongly than treatment with each one alone. Their treatments significantly suppressed the NF-κB+/Iba1+ (activated microglia) population, NF-κB activation, and tumor necrosis factor-α and interleukin-1β expression in the hippocampus, while the brain-derived neurotropic factor (BDNF)+/NeuN+ cell population and BDNF expression increased. Their treatments strongly suppressed LPS-induced colitis. Moreover, they increased the Firmicutes population and decreased the Cyanobacteria population in gut microbiota. Of these, DD most strongly alleviated cognitive impairment, followed by DC. In conclusion, DW2009 may synergistically or additively increase the effect of donepezil against cognitive impairment and colitis by regulating NF-κB-mediated BDNF expression.
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Oyedeji, Olaoluwa, Mufutau Kolawole Bakare, Isaac Olusanjo Adewale, Patrick Ojo Olutiola, and Olumide Owolabi Omoboye. "Optimized production and characterization of thermostable invertase from Aspergillus niger IBK1, using pineapple peel as alternate substrate." Biocatalysis and Agricultural Biotechnology 9 (January 2017): 218–23. http://dx.doi.org/10.1016/j.bcab.2017.01.001.
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Zhou, Jihong, Limin Mao, Ping Xu, and Yuefei Wang. "Effects of (−)-Epigallocatechin Gallate (EGCG) on Energy Expenditure and Microglia-Mediated Hypothalamic Inflammation in Mice Fed a High-Fat Diet." Nutrients 10, no. 11 (November 5, 2018): 1681. http://dx.doi.org/10.3390/nu10111681.
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Obesity is an escalating global epidemic caused by an imbalance between energy intake and expenditure. (−)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been reported to be conducive to preventing obesity and alleviating obesity-related chronic diseases. However, the role of EGCG in energy metabolism disorders and central nervous system dysfunction induced by a high-fat diet (HFD) remains to be elucidated. The aim of this study was to evaluate the effects of EGCG on brown adipose tissue (BAT) thermogenesis and neuroinflammation in HFD-induced obese C57BL/6J mice. Mice were randomly divided into four groups with different diets: normal chow diet (NCD), normal chow diet supplemented with 1% EGCG (NCD + EGCG), high-fat diet (HFD), and high-fat diet supplemented with 1% EGCG (HFD + EGCG). Investigations based on a four-week experiment were carried out including the BAT activity, energy consumption, mRNA expression of major inflammatory cytokines in the hypothalamus, nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and immunofluorescence staining of microglial marker Iba1 in hypothalamic arcuate nucleus (ARC). Experimental results demonstrated that dietary supplementation of EGCG significantly inhibited HFD-induced obesity by enhancing BAT thermogenesis, and attenuated the hypothalamic inflammation and microglia overactivation by regulating the NF-κB and STAT3 signaling pathways.
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Jang, Hyo-Min, Kyung-Eon Lee, and Dong-Hyun Kim. "The Preventive and Curative Effects of Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 on Immobilization Stress-Induced Anxiety/Depression and Colitis in Mice." Nutrients 11, no. 4 (April 11, 2019): 819. http://dx.doi.org/10.3390/nu11040819.
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The gut dysbiosis by stressors such as immobilization deteriorates psychiatric disorders through microbiota-gut-brain axis activation. To understand whether probiotics could simultaneously alleviate anxiety/depression and colitis, we examined their effects on immobilization stress (IS)-induced anxiety/depression and colitis in mice. The probiotics Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 were isolated from healthy human feces. Mice with anxiety/depression and colitis were prepared by IS treatment. NK33 and NK98 potently suppressed NF-κB activation in lipopolysaccharide (LPS)-induced BV-2 cells. Treatment with NK33 and/or NK98, which were orally gavaged in mice before or after IS treatment, significantly suppressed the occurrence and development of anxiety/depression, infiltration of Iba1+ and LPS+/CD11b+ cells (activated microglia) into the hippocampus, and corticosterone, IL-6, and LPS levels in the blood. Furthermore, they induced hippocampal BDNF expression while NF-κB activation was suppressed. NK33 and/or NK98 treatments suppressed IS-induced colon shortening, myeloperoxidase activity, infiltration of CD11b+/CD11c+ cells, and IL-6 expression in the colon. Their treatments also suppressed the IS-induced fecal Proteobacteria population and excessive LPS production. They also induced BDNF expression in LPS-induced SH-SY5Y cells in vitro. In conclusion, NK33 and NK98 synergistically alleviated the occurrence and development of anxiety/depression and colitis through the regulation of gut immune responses and microbiota composition.
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Roque, Dario R., Beth Cronin, Katina Robison, Vrishali Lopes, Tina Rizack, and Don S. Dizon. "The effects of age on treatment and outcomes in women with stage IB-IIB cervical cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 5100. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.5100.
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5100 Background: Advanced age may affect the treatment choice and subsequent outcome in elderly patients with cervical cancer. Given the potential for cure with either surgery or chemoradiation in early stage disease, we aimed to determine whether a patient’s age influenced the treatment received and the outcome. Methods: Our retrospective cohort identified a total of 303 patients diagnosed with Stage IB1 through IIB cervical carcinoma who were treated at our institution between 2000 and 2010. The eligible patients were divided into two groups based on age at the time of diagnosis: <65 and > 65 years. Adjusted odd ratios were calculated to determine variables associated with treatment received (chemoradiation or surgery). Single and multivariate Cox proportional hazards modeling were used to estimate hazard ratios for variables associated with disease specific survival. Results: Of the patients meeting inclusion criteria, 253 were <65 years and 50 were > 65 years. The distribution of tumor histology, stage and grade was not different between the two groups. After adjusting for histology, stage and a validated comorbidity score, the odds ratio of receiving chemoradiation vs. surgery for the cohort > 65 years was 1.69 (OR 95% CI: 0.68-4.17). There was no significant difference in the type of primary treatment received between the two groups (P = 0.16). Persistent disease was seen in 46 (18%) of the younger patients and in 19 (38%) of the older patients (P = 0.02). In the elderly cohort the treatment received did not influence disease-specific or all-cause mortality. However, compared to women under 65, older women treated surgically had increased disease specific (HR 3.18, 95% CI: 0.98-10.3) and all-cause mortality (HR 6.53, 95% CI: 2.57-16.6). Conclusions: Age does not appear to be a factor influencing the treatment received by patients with Stage IB1-IIB cervical cancer. The type of treatment received does not seem to affect disease-specific mortality among older versus younger women. However, surgery was associated with a 6.5-fold increased risk of all cause mortality among older women when compared to women under 65 years.
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Wise, Kimber, Sophie N. B. Selby-Pham, Jamie Selby-Pham, and Harsharn Gill. "Development of intestinal bioavailability prediction (IBP) and phytochemical relative antioxidant potential prediction (PRAPP) models for optimizing functional food value of Cannabis sativa (hemp)." International Journal of Food Properties 23, no. 1 (January 1, 2020): 1287–95. http://dx.doi.org/10.1080/10942912.2020.1797783.
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Ishii, Tomohiro, Toshikatsu Mitsui, Sadafumi Suzuki, Yumi Matsuzaki, and Tomonobu Hasegawa. "A Genome-Wide Expression Profile of Adrenocortical Cells in Knockout Mice Lacking Steroidogenic Acute Regulatory Protein." Endocrinology 153, no. 6 (April 23, 2012): 2714–23. http://dx.doi.org/10.1210/en.2011-1627.
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Steroidogenic acute regulatory protein (StAR) facilitates cholesterol transfer into the inner mitochondrial membrane in the acute phase of steroidogenesis. Mice lacking StAR (Star−/−) share phenotypes with human individuals having congenital lipoid adrenal hyperplasia including compromised production of steroid hormones and florid accumulation of cholesterol esters in adrenal glands and gonads. To define a specific pattern of molecular changes with StAR deficiency, we performed transcriptome analysis of adrenal cells selectively isolated by fluorescent-activated cell sorting at embryonic d 17.5 or 18.5 in seven wild-type (Star+/+) or four Star−/− mice having the transgene targeting the enhanced green fluorescent protein to cell lineages that express StAR. A gene expression profile was obtained by whole-mouse genome microarray and confirmed by quantitative real-time PCR, identifying 1206 and 767 significantly up-regulated and down-regulated genes, respectively, in Star−/− mice compared with Star+/+ mice (fold difference ≥ 2 and P value < 0.05 with false discovery rate < 0.2). In Star−/− mice, expression levels of genes involved in cholesterol efflux and the inflammatory response were significantly up-regulated, whereas those related to steroid hormone biosynthesis or cholesterol biosynthesis and influx were not significantly changed. Immunoreactive Iba1 or F4/80 (macrophage marker) in adrenal glands of Star−/− mice was detected not only in an increased number of resident macrophages but also in most adrenocortical cells. These findings expand our understanding of the pathophysiology of adrenal glands with the disruption of StAR and propose a reciprocal interaction between adrenocortical cells and resident macrophages inside adrenal glands of Star−/− mice.
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Goncalves, Kevin A., Shuping Li, Melissa L. Brooks, Sharon L. Hyzy, Anthony E. Boitano, and Michael P. Cooke. "MGTA-456, a First-in-Class Cell Therapy Produced from a Single Cord Blood Unit, Enables a Reduced Intensity Conditioning Regimen and Enhances Speed and Level of Human Microglia Engraftment in the Brains of NSG Mice." Blood 132, Supplement 1 (November 29, 2018): 115. http://dx.doi.org/10.1182/blood-2018-99-118258.
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Abstract Background. Allogeneic bone marrow transplant (BMT) is a promising, curative approach for patients with inherited metabolic disorders (IMDs), a class of pediatric diseases characterized by a single enzyme deficiency. The goal of transplant is to provide cells that produce functional enzymes otherwise deficient in these patients, and thereby prevent or ameliorate neurological complications associated with selected IMDs. Donor-derived microglial cells are protective, limiting neurological disease progression. For IMD patients who do not have an HLA matched, non-carrier related donor, cord blood (CB) is the preferred HSPC source given its rapid availability and superior clinical outcomes compared to other graft sources. CB, however, is associated with delayed hematopoietic recovery and relatively poor engraftment due to the limited numbers of hematopoietic stem cells (HSCs) in a CB unit, delaying enzyme/protein reconstitution and cross-correction of non-hematopoietic cells. An aryl hydrocarbon receptor antagonist (AHRa)-based culture has been shown to expand CB CD34+ and CD34+CD90+ cells 330-fold and 100-fold, respectively, leading to rapid hematopoietic recovery after infusion of the clinical product, MGTA-456 (Wagner et al., Cell Stem Cell 2016 and Orchard et al., ASH 2018). As microglia are thought to be derived from HSCs, we hypothesized that MGTA-456 might lead to faster and greater microglial engraftment and potentially enable reduced intensity conditioning. Here, we assessed human hematopoietic and brain engraftment in NSG mice after transplant with MGTA-456 and showed that microglia engrafted faster with MGTA-456, less conditioning was needed, and that, mechanistically, these cells are derived from the CD34+CD90+ cell fraction. Methods. CB CD34+ cells were expanded in growth factor-supplemented media with or without an AHRa for 10 days. NSG mice were transplanted with unmanipulated CB CD34+ cells or the expanded product after 200 cGy total body irradiation or busulfan (BU) dosed at 20 or 40 mg/kg ip. Microglial engraftment was measured by flow cytometry of homogenized brains, quantitating the number of CD45+CD11b+Iba1+ cells, and by immunohistochemistry of brain sections. Results. Relative to naïve, unmanipulated CB CD34+ cells, transplant of MGTA-456 into sublethally irradiated mice led to an 8-fold increase in hematopoietic engraftment and a 10-fold increase in microglial engraftment in the brain (p<0.0001, n=15 mice), with histology consistent with engrafting microglia. As high dose BU enables enhanced microglia engraftment relative to irradiation by crossing the blood brain barrier and clearing host microglia (Capotondo et al., PNAS 2013), we evaluated the effectiveness of MGTA-456 after BU conditioning at 20 or 40 mg/kg. Transplant of MGTA-456 led to a 37-fold increase in engraftment relative to mice transplanted with unmanipulated CB CD34+ cells (p<0.001, n=8). Notably, transplant of MGTA-456 into mice conditioned with low-dose BU (20 mg/kg) led to a 15-fold increase in engraftment relative to high-dose BU (40 mg/kg)-conditioned animals transplanted with unmanipulated CB CD34+ cells (p<0.001, n=8). To evaluate speed of microglial engraftment, we evaluated brains weekly to 16 weeks after transplant. A 28-fold increase in microglial engraftment was demonstrated as early as 2 weeks post-transplant with MGTA-456 (p<0.0001, n=8). Number of engrafting hematopoietic cells in the periphery correlated with number of engrafting microglia in the brain (p<0.0001). Lastly, subpopulations of MGTA-456 were evaluated to determine the source of microglial engraftment. Only CD34+CD90+ cells, but not CD34+CD90- or CD34- cells, led to brain engraftment, consistent with the subpopulation of cells that result in hematopoietic engraftment following transplant of unexpanded cells (Radtke et al., Sci Trans Med 2017 and Goncalves et al., Blood 2017 130:659). Conclusions. These studies demonstrate that microglial engraftment is faster and greater in recipients of MGTA-456 even after lower dose BU conditioning, that microglial engraftment correlates with peripheral blood recovery, and that microglia cells are derived from CD34+CD90+ cells. These results suggest that lower dose BU may improve safety without jeopardizing efficacy in IMD recipients of MGTA-456. A Phase 2 clinical trial is ongoing to evaluate transplant of MGTA-456 in patients with select IMDs. Disclosures Goncalves: Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Li:Magenta Therapeutics: Employment, Equity Ownership. Brooks:Magenta Therapeutics: Employment, Equity Ownership. Hyzy:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties.
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Liu, Sihan, Qianru He, Xiaodan Xing, Tingting Sun, and Chuang Qi. "Changes of immune microenvironment before and after chemoradiotherapy in cervical cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e17503-e17503. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e17503.
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e17503 Background: Cervical cancer is the fourth most common cancer in women worldwide. Metastasis and invasion of cervical cancer are closely related to the tumor microenvironment. As an effective treatment, chemoradiotherapy plays a vital role in immune-related cells and factors. However, little is known about the effect of chemoradiotherapy on the immune microenvironment in cervical cancers. Therefore, we studied the immune microenvironment alterations before and after chemoradiotherapy and analyzed their prognostic significance in cervical cancer patients. Methods: We recruited 15 patients with stage IB1-IVA cervical squamous cell carcinoma. Pelvic intensity-modulated radiotherapy (IMRT) was performed with conventional segmentation of 2Gy per irradiation (IB3 stage was treated with synchronous cisplatin for weeks), FFPE samples pre-treatment, and one-week after-chemoradiotherapy were conducted an exploratory biomarker analysis based on gene expression profiling (GEP). The panel of 289 genes was customized based on critical genes and pathways during tumor immunoregulation (e.g., tumor antigen release, T cell activation, and immune metabolism). The differential expressed genes between these two groups were then assessed. Results: Forty-two genes were found to be differentially expressed, with 21 genes having > 1.5-fold mean expression difference after chemoradiotherapy. Analysis of important GO terms and KEGG pathways indicated that the pathways enriched by different genes are located in immune-related pathways, specifically, T cell activation (GO-BP), cytokine activity (GO-MF), and cytokine-cytokine receptor interaction (KEGG). After-chemoradiotherapy, the enrichment of tumor-infiltrating lymphocytes (TILs) varied greatly, especially the macrophages. Conclusions: This study preliminarily demonstrated that chemoradiotherapy caused the release of pro-inflammatory like CCR7 and CD69 and immune cell (macrophages) infiltration alterations after chemoradiotherapy in cervical cancer patients.
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Kim, H. W., and M. S. Rhee. "Influence of Low-Shear Modeled Microgravity on Heat Resistance, Membrane Fatty Acid Composition, and Heat Stress-Related Gene Expression in Escherichia coli O157:H7 ATCC 35150, ATCC 43889, ATCC 43890, and ATCC 43895." Applied and Environmental Microbiology 82, no. 10 (March 4, 2016): 2893–901. http://dx.doi.org/10.1128/aem.00050-16.
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ABSTRACTWe previously showed that modeled microgravity conditions alter the physiological characteristics ofEscherichia coliO157:H7. To examine how microgravity conditions affect bacterial heat stress responses, D values, membrane fatty acid composition, and heat stress-related gene expression (clpB,dnaK,grpE,groES,htpG,htpX,ibpB, andrpoH),E. coliO157:H7 ATCC 35150, ATCC 43889, ATCC 43890, and ATCC 43895 were cultured under two different conditions: low-shear modeled microgravity (LSMMG, an analog of spaceflight conditions) and normal gravity (NG, Earth-like conditions). When 24-h cultures were heated to 55°C, cells cultured under LSMMG conditions showed reduced survival compared with cells cultured under NG conditions at all time points (P< 0.05). D values of all tested strains were lower after LSMMG culture than after NG culture. Fourteen of 37 fatty acids examined were present in the bacterial membrane: nine saturated fatty acids (SFA) and five unsaturated fatty acids (USFA). The USFA/SFA ratio, a measure of membrane fluidity, was higher under LSMMG conditions than under NG conditions. Compared with control cells grown under NG conditions, cells cultured under LSMMG conditions showed downregulation of eight heat stress-related genes (average, −1.9- to −3.7-fold). The results of this study indicate that in a simulated space environment, heat resistance ofE. coliO157:H7 decreased, and this might be due to the synergistic effects of the increases in membrane fluidity and downregulated relevant heat stress genes.IMPORTANCEMicrogravity is a major factor that represents the environmental conditions in space. Since infectious diseases are difficult to deal with in a space environment, comprehensive studies on the behavior of pathogenic bacteria under microgravity conditions are warranted. This study reports the changes in heat stress resistance ofE. coliO157:H7, the severe foodborne pathogen, under conditions that mimic microgravity. The results provide scientific clues for further understanding of the bacterial response under the simulated microgravity conditions. It will contribute not only to the improvement of scientific knowledge in the academic fields but also ultimately to the development of a prevention strategy for bacterial disease in the space environment.
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Müller, Luisa, Nicole Power Guerra, Jan Stenzel, Claire Rühlmann, Tobias Lindner, Bernd J. Krause, Brigitte Vollmar, Stefan Teipel, and Angela Kuhla. "Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice." Nutrients 13, no. 3 (March 18, 2021): 985. http://dx.doi.org/10.3390/nu13030985.
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Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer’s disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism—a hallmark of AD—and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.
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Yoo, Jong-Wook, Yoon-Jung Shin, Xiaoyang Ma, Young-Hoo Son, Hyo-Min Jang, Chang Kyun Lee, and Dong-Hyun Kim. "The Alleviation of Gut Microbiota-Induced Depression and Colitis in Mice by Anti-Inflammatory Probiotics NK151, NK173, and NK175." Nutrients 14, no. 10 (May 16, 2022): 2080. http://dx.doi.org/10.3390/nu14102080.
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Gut microbiota dysbiosis is strongly associated with psychiatric disorders and inflammatory bowel disease (IBD). Herein, we examined whether the fecal microbiota of IBD patients with depression (IBDD) and their gut microbiota culture (iGm) could cause depression and colitis in mice and anti-inflammatory probiotics could mitigate depression in iGm-transplanted or immobilization stress (IS)-exposed mice. Fecal microbiota transplantation (FMT) from IBDD patients, which exhibited Enterobacteriaceae-rich gut microbiota, and its gut microbiota culture (iGm) increased depression-like behaviors in mice. Their treatments heightened the blood lipopolysaccharide (LPS) level and colonic IL-1β and IL-6 expression. However, FMT from healthy volunteers or sulfasalazine treatment alleviated cGm-induced depressive-like behaviors and hippocampal and colonic inflammation in mice. Moreover, oral administration of Lactobacillus plantarum NK151, Bifidobacterium longum NK173, and Bifidobacterium bifidum NK175, which inhibited LPS-induced IL-6 expression in macrophages, alleviated cGm-induced depression-like behaviors, hippocampal NF-κB+Iba1+ cell numbers and IL-1β and IL-6 expression, blood LPS, IL-6, and creatinine levels, and colonic NF-κB+CD11c+ number and IL-1β and IL-6 expression in mice. Treatment with NK151, NK173, or NK175 mitigated immobilization stress (IS)-induced depressive-like behaviors, neuroinflammation, and gut inflammation in mice. NK151, NK173, or NK175 also decreased IS-induced blood LPS, IL-6, and creatinine levels. The transplantation of Enterobacteriaceae-rich gut microbiota can cause depression and colitis, as IS exposure, and anti-inflammatory NK151, NK173, and NK175, may alleviate stress-induced fatigue, depression, and colitis by regulating the expression of proinflammatory and anti-inflammatory cytokines through the suppression of gut bacterial LPS.
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Nikolopoulos, D., T. Manolakou, A. Polissidis, A. Filia, Y. Koutmani, and D. Boumpas. "POS0461 DISRUPTED HIPPOCAMPAL NEUROGENESIS MEDIATED BY IL-6 AND IL-18 INDUCE NEUROPSYCHIATRIC CHANGES IN MURINE LUPUS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 484.1–484. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2908.
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BackgroundSystemic lupus erythematosus (SLE) frequently affects the nervous system (NPSLE), however, its pathogenesis is only partly understood. We have previously characterized the behavioral phenotype of the NZΒ/W-F1 lupus-prone mouse which recapitulates the NPSLE phenotype exhibiting hippocampal-linked behavior including depressive-like disorder, anxiety and cognitive impairment both at early and late stages of the disease characterized by a profound hippocampal inflammatory response1,2. Defective hippocampal neural stem cell (hNSC) response is associated with cognitive dysfunction, depression and anxiety, all of which represent common neuropsychiatric features of both human and murine SLE.ObjectivesTo further investigate the hippocampal neurogenesis in lupus mice and determine its involvement in disease pathogenesis.MethodsAll experiments were performed in female NZW/NZB F1 and C57BL/6 (WT) mice at the age of 3 months (pre-nephritic) and 6 months (nephritic stage) (n=5-8/condition/experiment). Neurogenesis was assessed in sagittal sections of hippocampus by immunohistochemical staining (DCX, Sox2, GFAP, Iba1) and morphological criteria. RNA-sequencing was performed in hippocampal tissue followed by pathway and enrichment analysis. Apoptosis (cleaved-caspase 3) and immune cell infiltration (CD11b, CD45, Ly6G, Ly6C, MHC-II, CD4, CD8, B220, Iba1, CD80, CD86, Argianse-1, iNOS) were assessed by flow-cytometry. Cytokines levels were measured by Legendplex. Ex vivo assays were performed in adult hippocampal neural stem cells extracted by 2-month-old female WT mice.ResultsWe identified a profound disruption (~2-fold) of hippocampal neurogenesis (decreased DCX+ cells) both at 3 ad 6 month-old lupus mice together with decreased differentiated cells in both time-points, suggesting that lupus mice exhibit impaired neuronal differentiation. Although the number of the neuronal precursors radial glial-like cells (RGLs) was normal at pre-nephritic stage, lupus mice express increased number of both activated RGLs (Sox2+/GFAP+) and proliferating neuronal progenitors (Sox2+ cells) indicating enhanced self-renewal ability of neural precursors and augmented proliferation. Levels of cleaved-caspase 3 were elevated in lupus hippocampus supporting increased hippocampal apoptosis. Transcriptomic analysis of hippocampal tissue revealed a profound inflammatory response in lupus mice. Flow-cytometry analyses showed a pronounced immune cell trafficking in lupus hippocampus with a myeloid predominant response –involving predominantly the microglia- both at early and late stages of the disease. Multiplex assays revealed elevated levels of IL-6 and IL-18 in lupus hippocampus. Ex vivo exposure of adult hNSCs to IL-6 or IL-18 promoted cell proliferation and induced apoptosis.ConclusionThe NZB/W-F1 mouse model of SLE exhibits defective neurogenesis due to increased apoptosis, and decreased differentiation of neuronal progenitors. Inflammation in lupus hippocampus results in elevated levels of IL-6 and IL-18 with both cytokines negatively affecting the hNSCs response. IL-6 and IL-18 may induce behavioral changes in NZB/W-F1 lupus mediated by altered neurogenesis and may represent therapeutic targets in NPSLE.References[1]Nikolopoulos, D., et al. “THU0223 THE NEUROPSYCHIATRIC PHENOTYPE OF NZB/W LUPUS-PRONE MOUSE MODEL AT PRE-NEPHRITIC AND NEPHRITIC STAGES OF THE DISEASE: MURINE MODEL RECAPITULATES HUMAN DISEASE.” (2020): 334-335. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1807[2]Nikolopoulos D. et al. “OP0040 HIPPOCAMPAL IMMUNE CELL TRAFFICKING AND A MYELOID PREDOMINANT INFLAMMATORY RESPONSE WITH ENHANCED ANTIGEN PRESENTATION AND DECREASED LEVELS OF NEUROTRANSMITTERS UNDERLY THE NEUROPSYCHIATRIC PHENOTYPE OF THE NZW/NZB MURINE LUPUS MODEL.” (2021): 2021. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3972AcknowledgementsThis project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390)Disclosure of InterestsNone declared.
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Parra-Flores, Julio, Adriana Cabal-Rosel, Beatriz Daza-Prieto, Pamela Chavarria, Eduard Maury-Sintjago, Alejandra Rodriguez-Fernández, Sergio Acuña, and Werner Ruppitsch. "Are Enterobacteriaceae and Enterococcus Isolated from Powdered Infant Formula a Hazard for Infants? A Genomic Analysis." Foods 11, no. 22 (November 8, 2022): 3556. http://dx.doi.org/10.3390/foods11223556.
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Powdered infant formulas (PIF) are the most used dietary substitutes that are used in order to supplement breastfeeding. However, PIF are not sterile and can be contaminated with different microorganisms. The objective of this study was to genomically characterize Enterobacteriaceae (ENT) and Enterococcus strains that were isolated from PIF. Strains were identified by matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI-TOF MS) and whole-genome sequencing (WGS). Genomic typing, detection of virulence, and resistance profiles and genes were performed with the Ridom SeqSphere+ software; the comprehensive antibiotic resistance database (CARD) platform; ResFinder and PlasmidFinder tools; and by the disk diffusion method. Nineteen isolates from PIF were analyzed, including ENT such as Kosakonia cowanii, Enterobacter hormaechei, Franconibacter helveticus, Mixta calida, and lactic acid bacteria such as Enterococcus faecium. The strains exhibited resistance to beta-lactams, cephalosporins, and macrolides. Resistance genes such as AcrAB-TolC, marA, msbA, knpEF, oqxAB, fosA, blaACT-7, blaACT-14, qacJ, oqxAB, aac(6’)-Ii, and msr(C); and virulence genes such as astA, cheB, cheR, ompA ompX, terC, ironA, acm, and efaAfm, adem were also detected. All the analyzed strains possessed genes that produced heat-shock proteins, such as IbpA and ClpL. In PIF, the presence of ENT and Enterococcus that are multiresistant to antibiotics—together with resistance and virulence genes—pose a health risk for infants consuming these food products.
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Carter, J. N., P. A. Ludden, M. S. Kerley, E. Berg, M. Ellersieck, and W. O. Herring. "Intramuscular Fat Deposition in Steers Is Accelerated at a Set Body Weight11Appreciation is expressed to the staff of IBP, Inc. (Emporia, KS) and to Walt Krier of Prime Ultrasound, LLC (Shawnee, KS)." Professional Animal Scientist 18, no. 2 (June 2002): 135–40. http://dx.doi.org/10.15232/s1080-7446(15)31501-1.
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Raymond, James A., Michael G. Janech, and Marco Mangiagalli. "Ice-Binding Proteins Associated with an Antarctic Cyanobacterium, Nostoc sp. HG1." Applied and Environmental Microbiology 87, no. 2 (November 6, 2020). http://dx.doi.org/10.1128/aem.02499-20.
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ABSTRACT Ice-binding proteins (IBPs) have been identified in numerous polar algae and bacteria, but so far not in any cyanobacteria, despite the abundance of cyanobacteria in polar regions. We previously reported strong IBP activity associated with an Antarctic Nostoc species. In this study, to identify the proteins responsible, as well as elucidate their origin, we sequenced the DNA of an environmental sample of this species, designated Nostoc sp. HG1, and its bacterial community and attempted to identify IBPs by looking for known IBPs in the metagenome and by looking for novel IBPs by tandem mass spectrometry (MS/MS) proteomics analyses of ice affinity-purified proteins. The metagenome contained over 116 DUF3494-type IBP genes, the most common type of IBP identified so far. One of the IBPs could be confidently assigned to Nostoc, while the others could be attributed to diverse bacteria, which, surprisingly, accounted for the great majority of the metagenome. Recombinant Nostoc IBPs (nIBPs) had strong ice-structuring activities, and their circular dichroism spectra were consistent with the secondary structure of a DUF3494-type IBP. nIBP is unusual in that it is the only IBP identified so far to have a PEP (amino acid motif) C-terminal signal, a signal that has been associated with anchoring to the outer cell membrane. These results suggest that the observed IBP activity of Nostoc sp. HG1 was due to a combination of endogenous and exogenous IBPs. Amino acid and nucleotide sequence analyses of nIBP raise the possibility that it was acquired from a planctomycete. IMPORTANCE The horizontal transfer of genes encoding ice-binding proteins (IBPs), proteins that confer freeze-thaw tolerance, has allowed many microorganisms to expand their ranges into polar regions. One group of microorganisms for which nothing is known about its IBPs is cyanobacteria. In this study, we identified a cyanobacterial IBP and showed that it was likely acquired from another bacterium, probably a planctomycete. We also showed that a consortium of IBP-producing bacteria living with the Nostoc contribute to its IBP activity.
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Liu, Lulu, Virginie Gueguen-Chaignon, Isabelle R. Gonçalves, Christine Rascle, Martine Rigault, Alia Dellagi, Elise Loisel, et al. "A secreted metal-binding protein protects necrotrophic phytopathogens from reactive oxygen species." Nature Communications 10, no. 1 (October 24, 2019). http://dx.doi.org/10.1038/s41467-019-12826-x.
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Abstract Few secreted proteins involved in plant infection common to necrotrophic bacteria, fungi and oomycetes have been identified except for plant cell wall-degrading enzymes. Here we study a family of iron-binding proteins that is present in Gram-negative and Gram-positive bacteria, fungi, oomycetes and some animals. Homolog proteins in the phytopathogenic bacterium Dickeya dadantii (IbpS) and the fungal necrotroph Botrytis cinerea (BcIbp) are involved in plant infection. IbpS is secreted, can bind iron and copper, and protects the bacteria against H2O2-induced death. Its 1.7 Å crystal structure reveals a classical Venus Fly trap fold that forms dimers in solution and in the crystal. We propose that secreted Ibp proteins binds exogenous metals and thus limit intracellular metal accumulation and ROS formation in the microorganisms.
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Pang, Jian, Zhanying Liu, Qiancheng Zhang, Xuemei Lu, and Qingsheng Qi. "Systematic Analysis of Escherichia coli Isolates from Sheep and Cattle Suggests Adaption to the Rumen Niche." Applied and Environmental Microbiology 86, no. 20 (August 14, 2020). http://dx.doi.org/10.1128/aem.01417-20.
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ABSTRACT The commonly used laboratory bacterium Escherichia coli normally does not produce and secrete cellulases due to its complex bilayer membrane structure and poor secretory apparatus. In our previous study, the cellulolytic E. coli strain ZH-4 with extracellular cellulase activity was found in the bovine rumen. In this study, we demonstrate that the secretion of cellulase is a common feature of E. coli isolates from the rumen of animals such as sheep and cattle. Physiological phenotype characterization of these E. coli isolates, together with genome, transcriptome, and comparative genomics analysis, suggests their adaption to the rumen niche. The higher growth rate of the isolated strains under aerobic conditions meets the competitive requirements of the strains in rumen microecosystem, while anaerobic accumulation of reduced H2 and succinate is hypothesized to be the results of adaptation to the rumen environment. Cellulase secretion increased significantly when the molecular chaperone genes ibpA and ibpB were overexpressed. This was also revealed by the transcriptomic data. A possible mechanism for cellulase secretion by E. coli isolates was proposed based on the transcriptomic data and molecular experiments. IMPORTANCE As an important intestinal microorganism, E. coli is present in the intestinal tract of animals and in many other environments. However, it normally does not produce and secret cellulases due to its complex bilayer membrane structure and poor secretory apparatus. Here, we proved that E. coli is widely present in the rumen of sheep and cattle. Systematic analysis of the isolates indicated that they have adapted to the rumen niche, with phenotypes that include secretion of cellulase and fermentative accumulation of succinate and H2. The finding that overexpression of small heat shock protein genes ibpA and ibpB could facilitate cellulase BcsZ secretion, which provides a possible insight into the protein secretion mechanism of rumen-colonizing E. coli.
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Biancardi, Vinicia C., and Javier E. Stern. "Abstract 032: Microglial TLR4 Mediate Angiotensin II-induced Reactive Oxygen Species Production within the Paraventricular Nucleus in Hypertension." Hypertension 66, suppl_1 (September 2015). http://dx.doi.org/10.1161/hyp.66.suppl_1.032.
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Angiotensin II (AngII) contribution to hypertension involves CNS inflammation that includes cytokine release and reactive oxygen species (ROS) production. The innate immune system, via TLR4 signaling, has been implicated in AngII-mediated inflammatory responses. Yet, whether microglia, the immune cells of the CNS, are key cell targets mediating these effects is still unknown. Thus, we studied here whether TLR4 is a molecular link connecting AngII mediated microglia activation and ROS production within the paraventricular nucleus (PVN) during hypertension. TLR4 and AngII type 1 receptor (AT1) mRNA expression was found in isolated PVN microglia, providing molecular evidence for AT1/TLR4 crosstalk. Isolated microglia TLR4 mRNA expression was 2.56*-fold higher in hypertension. TLR4 and microglia (IBA1) immunoreactivity density were increased in the PVN of SHR vs WKY (TLR4 1.8±0.02 vs 1.3±0.1*; IBA1 23±3.03 vs 13.6±0.6* Arbitrary units - AU). Altered density was attenuated in SHR treated with AT1 blocker Losartan (1.3±0.05 and 14.9±0.9 AU). Higher TLR4/IBA1 co-localization was found in SHR vs WKY (4.6±0.9 vs 1.3±0.2* AU), supporting microglia activation and TLR4 upregulation in hypertension. To study whether AngII-induced microglia activation and ROS production involved TLR4, we used TLR4 deficient (TLR4-D, C3H/HeJ) and sufficient (TLR4-S, C3H/OuJ) mice. Acute hypothalamic slices exposed to AngII (1μM, 60 min) showed increased IBA1 density in the PVN of TLR4-S (3.9±0.1 to 6.5±0.3*%) and WKY (9.8±1.1 to 16.2±1.4*%). This effect was blunted in TLR4-D (4.3±0.1 to 5.2±0.5%). In SHR, AngII failed to further promote microglia activation (17.3±1.8 vs 14.1±1.1 AU). AngII (1 μΜ) increased dihydroethidium (DHE) staining (an indirect measure of ROS) in the PVN of WKY (166±2*) and TLR4-S (129±2*) compared to vehicle (100±3%). This effect was blunted in TLR4-D (102±2%). AngII-induced ROS production was attenuated by the microglia inhibitor minocycline (100 μΜ, 131±2*%) and blunted by Losartan (2 μΜ, 111±6%), suggesting AngII-ROS production involves microglia and AT1. Our results support a major contribution of microglial TLR4 to AngII-mediated ROS and microglia activation within the PVN, actions that are upregulated in hypertension. *P<0.05.
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Kim, Soojin, Jiwon Yang, Jaewon Jeong, Siyun Jeong, Hyesun Jeong, Bokyung Kim, Jeong-Soo Kim, and Yun Seon Song. "Abstract WP109: Glucagon-Like Peptide-1 Has Anti-Inflammatory Effects Through Increasing IB1, A Scaffold Regulator Of JNK, In Cerebral Ischemia." Stroke 44, suppl_1 (February 2013). http://dx.doi.org/10.1161/str.44.suppl_1.awp109.
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Background and Purpose: Hyperglycemia is frequently observed in patients with acute ischemic stroke, and conversely, diabetic patients showed a high frequency of stroke. This correlation indicates shared mechanisms in pathology. Glucagon like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion and is used to treat type 2 diabetes mellitus. Recently, beyond the glucose-lowering effect, GLP-1 has been reported to possess neuroprotective effects. We therefore investigated the neuroprotective mechanism of GLP-1 receptor (GLP-1R) agonist exendin-4 (ex-4) after cerebral ischemia-reperfusion injury. Methods: Male Sprague-Dawley rats were subjected to 60 min of middle cerebral artery occlusion (MCAO) with intracerebroventricular (i.c.v) pretreatment of ex-4. Oxygen glucose deprivation was induced to primary neuron cultures in an anaerobic chamber. Changes of genes were further confirmed by QPCR and Western blot, and siRNA was used to ascertain the mechanism. Results: Ischemia-reperfusion injury reduced the expressions of GLP-1R by 46.3% (p<0.01) ; higher oxidative stress in SOD2 KO mice induced lower expression of GLP-1R, but higher in SOD1 Tg mice. Down regulated GLP-1R by ischemic injury was 70% restored by GLP-1R agonist, ex-4 (p<0.01), which resulted in significant reduction of infarct volume. Intracellular cyclic AMP levels, a second messenger of GLP-1R, were also increased by 2.7 fold according to a high GLP-1R expression (p<0.01). Moreover, our results showed that ex-4 attenuated pro-inflammatory Cyclooxygenase-2 (Cox-2) by 85% (p<0.001) and prostaglandin E2 by 27% (p<0.01) after MCAO. The c-Jun NH 2 terminal kinase (JNK) signaling that stimulates activation of Cox-2 was 36% inhibited by the i.c.v injection of ex-4 at 24 h (p<0.05). Islet-brain 1 (IB1), a scaffold regulator of JNK, was 1.7 fold increased by ex-4 at 24 h. Suppression of IB1 levels with the use of siRNA impaired the anti-inflammatory effects of ex-4 against ischemic injury. Conclusions: GLP-1R activation by ex-4 resulted in reduction of Cox-2 through increasing IB1, which led to anti-inflammatory neuroprotection in stroke. Our study suggests that anti-inflammatory action of GLP-1 could be a new strategy for the treatment of stroke accompanied by hyperglycemia.
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Zingaro, Kyle A., and Eleftherios Terry Papoutsakis. "Toward a Semisynthetic Stress Response System To Engineer Microbial Solvent Tolerance." mBio 3, no. 5 (October 2, 2012). http://dx.doi.org/10.1128/mbio.00308-12.
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ABSTRACT Strain tolerance to toxic metabolites is an important trait for many biotechnological applications, such as the production of solvents as biofuels or commodity chemicals. Engineering a complex cellular phenotype, such as solvent tolerance, requires the coordinated and tuned expression of several genes. Using combinations of heat shock proteins (HSPs), we engineered a semisynthetic stress response system in Escherichia coli capable of tolerating high levels of toxic solvents. Simultaneous overexpression of the HSPs GrpE and GroESL resulted in a 2-fold increase in viable cells (CFU) after exposure to 5% (vol/vol) ethanol for 24 h. Co-overexpression of GroESL and ClpB on coexisting plasmids resulted in 1,130%, 78%, and 25% increases in CFU after 24 h in 5% ethanol, 1% n-butanol, and 1% i-butanol, respectively. Co-overexpression of GrpE, GroESL, and ClpB on a single plasmid produced 200%, 390%, and 78% increases in CFU after 24 h in 7% ethanol, 1% n-butanol, or 25% 1,2,4-butanetriol, respectively. Overexpression of other autologous HSPs (DnaK, DnaJ, IbpA, and IbpB) alone or in combinations failed to improve tolerance. Expression levels of HSP genes, tuned through inducible promoters and the plasmid copy number, affected the effectiveness of the engineered stress response system. Taken together, these data demonstrate that tuned co-overexpression of GroES, GroEL, ClpB, and GrpE can be engaged to engineer a semisynthetic stress response system capable of greatly increasing the tolerance of E. coli to solvents and provides a starting platform for engineering customized tolerance to a wide variety of toxic chemicals. IMPORTANCE Microbial production of useful chemicals is often limited by the toxicity of desired products, feedstock impurities, and undesired side products. Improving tolerance is an essential step in the development of practical platform organisms for production of a wide range of chemicals. By overexpressing autologous heat shock proteins in Escherichia coli, we have developed a modular semisynthetic stress response system capable of improving tolerance to ethanol, n-butanol, and potentially other toxic solvents. Using this system, we demonstrate that a practical stress response system requires both tuning of individual gene components and a reliable framework for gene expression. This system can be used to seek out new interacting partners to improve the tolerance phenotype and can be used in the development of more robust solvent production strains.
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Shtaya, Anan, Leslie R. Bridges, Rebecca Williams, Sarah Trippier, Liqun Zhang, Anthony C. Pereira, James A. R. Nicoll, Delphine Boche, and Atticus H. Hainsworth. "Innate Immune Anti-Inflammatory Response in Human Spontaneous Intracerebral Hemorrhage." Stroke, July 20, 2021. http://dx.doi.org/10.1161/strokeaha.121.034673.
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Background and Purpose: Spontaneous intracerebral hemorrhage (sICH) is a common form of hemorrhagic stroke, with high mortality and morbidity. Pathophysiological mechanisms in sICH are poorly understood and treatments limited. Neuroinflammation driven by microglial-macrophage activation contributes to brain damage post-sICH. We aim to test the hypothesis that an anti-inflammatory (repair) process occurs in parallel with neuroinflammation in clinical sICH. Methods: We performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, and CD206) in brain tissue biospecimens 1 to 12 days post-sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (CRP [C-reactive protein], total white cell, and monocyte count) over 1 to 12 days following sICH. Results: In 27 supratentorial sICH cases (n=27, median [interquartile range] age: 59 [52–80.5], 14F/13M) all microglia-macrophage markers increased post-sICH, relative to control brains. Anti-inflammatory markers (CD163 and CD206) were elevated alongside proinflammatory markers (CD68 and TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7–12 days, P <0.001). CD206 increased at 3 to 5 days (5.2-fold, P <0.001) then returned to control levels at 7 to 12 days. The parenchymal immune response combined brain-derived microglia (TMEM119 positive) and invading monocyte-derived macrophages (CD206 positive). In a prospective sICH patient cohort (n=26, age 74 [66–79], National Institutes of Health Stroke Scale on admission: 8 [4–17]; 14F/12M) blood CRP concentration and monocyte density (but not white blood cell) increased post-sICH. CRP increased from 0 to 2 to 3 to 5 days (8.3-fold, P =0.020) then declined at 7 to 12 days. Monocytes increased from 0 to 2 to 3 to 5 days (1.8-fold, P <0.001) then declined at 7 to 12 days. Conclusions: An anti-inflammatory pathway, enlisting native microglia and blood monocytes, occurs alongside neuroinflammation post-sICH. This novel pathway offers therapeutic targets and a window of opportunity (3–5 days post-sICH) for delivery of therapeutics via invading monocytes.
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Rong, Zijie, Yuliang Huang, Honghua Cai, Min Chen, Hao Wang, Guihua Liu, Zhiwen Zhang, and Jiawen Wu. "Gut Microbiota Disorders Promote Inflammation and Aggravate Spinal Cord Injury Through the TLR4/MyD88 Signaling Pathway." Frontiers in Nutrition 8 (September 13, 2021). http://dx.doi.org/10.3389/fnut.2021.702659.
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Background: In spinal cord injury (SCI), systemic inflammation and the death of nerve cells in the spinal cord are life threatening. The connection between gut microbiota and signaling pathways has been a hot research topic in recent years. The Toll-like receptor 4/Myeloid differentiation factor 88 (TLR4/MyD88) signaling pathway is closely related to the inflammatory response. This study explored whether the gut microbiota imbalance could affect the TLR4/MyD88 signaling pathway to regulate SCI to provide a new basis for SCI research and treatment.Methods: An SCI model was constructed to study the influence on the injury of gut microbiota. 16S amplicon sequencing was used to identify the diversity and abundance of gut microbes. Fecal microbiota transplantation was performed in mice with SCI. ELISA was used to detect the serum levels of pro-inflammatory and anti-inflammatory factors in mice. Hematoxylin and eosin staining was used to observe SCI in mice. Immunofluorescence was used to detect the rates of loss glial fibrillary acidic protein (GFAP), neuronal nuclear protein (NeuN), and ionized calcium-binding adapter molecule 1 (IBA1) in the spinal cord as indicators of apoptosis. The expression of the TLR4/MyD88 signaling pathway was detected by qRT-PCR and western blotting.Results: Significant differences were observed in the gut microbiota of SCI mice and normal mice. The gut microbiota of SCI mice was imbalanced. The levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in SCI mice were increased, as was the level of the toxic induced nitric oxide synthase. The levels of anti-inflammatory factors IL-4, transforming growth factor-β, and IL-10 were decreased, as was the level of arginase-1. The apoptosis rates of GFAP, NeuN, and IBA1 were increased. The TLR4/MyD88 signaling pathway was activated. In the SCI group, inflammation increased after fecal transplantation, apoptosis of GFAP, NeuN, and IBA1 increased, and SCI was more serious.Conclusion: The TLR4/MyD88 signaling pathway promotes the death of nerve cells by inducing inflammation. Gut microbiota dysregulation can lead to aggravated SCI by activating the TLR4/MyD88 signaling pathway.
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Kim, Han Rae, and Colin N. Young. "Abstract 055: Lipid Droplet Accumulating Microglia Involvement In Non-Alcoholic Fatty Liver Disease During Obesity." Hypertension 79, Suppl_1 (September 2022). http://dx.doi.org/10.1161/hyp.79.suppl_1.055.
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Non-alcoholic fatty liver disease (NAFLD), characterized by excess fat accumulation in the liver (i.e. steatosis), is directly associated with obesity and a risk factor for hypertension development. In addition to peripheral mechanisms, accumulating evidence points to alterations in the central nervous system as a NAFLD contributor. In this context, we recently demonstrated that selective inhibition of microglia, the resident immune cells of the brain, specifically in the subfornical organ (SFO), attenuated obesity-related hepatic steatosis by ~50%. However, underlying SFO microglia alterations that may contribute to NAFLD remain unknown. The SFO is a circumventricular nucleus situated outside of the blood-brain-barrier that is chronically exposed to circulating factors such as lipids. Interestingly, lipid droplet-accumulating microglia (LDAM) have been implicated in conditions such as Alzheimer's disease and aging. Based on this, we hypothesized that SFO LDAM may be a unique contributor to hepatic steatosis during obesity. To investigate this, 6 wk old C57Bl/6J male mice were fed a high fat diet (HFD, 60% kCal fat) or normal chow for 11 wks (Body weight: 33±1 vs 47±2 g, normal chow vs HFD, p<0.05, n=4-5/group). Immunohistochemistry for ionized calcium-binding adapter molecule 1 (Iba1) as a microglia indicator demonstrated an increase in SFO microglia of HFD fed mice (330±6 vs 393±18, normal chow vs HFD, p<0.05). Furthermore, combined immunohistochemistry for Iba1 and Perilipin-2 (Plin2) as a lipid droplet marker revealed an approximate doubling of SFO microglia with lipid droplet inclusion (Plin2+ microglia #: 80±11 vs 191±21; Plin2+ microglia %total: 23±3.2 vs 49±4.1, normal chow vs HFD, p<0.05). This increase in SFO LDAM was additionally confirmed with comprehensive 3-dimensional analysis of up to 400 microglia per animal using BODIPY, a dye that labels neutral lipids (e.g. HFD: 1.6±0.2 BODIPY+ microglia fold normal chow, p<0.05). Collectively, these findings indicate marked SFO microglia activation and microglia lipid accumulation during obesity and point to the possibility for SFO LDAM in the pathogenesis of NAFLD and associated hypertension development.
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Cercone, Marta, Jacqueline Chevalier, John G. Kennedy, Andrew D. Miller, and Lisa A. Fortier. "Early Failure of a Polyvinyl Alcohol Hydrogel Implant With Osteolysis and Foreign Body Reactions in an Ovine Model of Cartilage Repair." American Journal of Sports Medicine, August 23, 2021, 036354652110336. http://dx.doi.org/10.1177/03635465211033601.
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Background: Hemiarthroplasty using a polyvinyl alcohol (PVA) hydrogel synthetic implant has been suggested as a good alternative to arthrodesis for the treatment of hallux rigidus. However, failure rates as high as 20% have been recorded. Purpose: To characterize the pathological processes in bone, cartilage, and the synovial membrane after PVA hemiarthroplasty in an ovine model with 6 months of follow-up. Study Design: Controlled laboratory study. Methods: A unilateral osteochondral defect (8-mm diameter × 10-mm depth) was made in the medial femoral condyle in 6 sheep. Animals were randomized to receive a PVA implant (n = 4) or to have an empty defect (n = 2) and were monitored for 6 months. Patellofemoral radiographs were obtained at monthly intervals, and quantitative computed tomography was performed at the end of the study. After death, the joints were macroscopically evaluated and scored. Osteochondral and synovial membrane histological findings were assessed using modified Osteoarthritis Research Society International (OARSI) and aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) scoring systems. Immunohistochemistry using Iba1 was performed to evaluate activated macrophage infiltration. Results: Overall, 2 sheep with PVA implants were euthanized at 1 and 5 months because of uncontrollable pain and lameness (failed implants). Quantitative computed tomography showed that sheep with failed implants had 2.1-fold more osteolysis than those with successful implants. The sheep with failed implants had osteoarthritis with extensive glycosaminoglycan loss and cartilage fibrillation of the condyle and opposing tibial surface on histological examination. A foreign body reaction with severe chronic lymphoplasmacytic and granulomatous inflammation with giant cells was detected surrounding the implant. The synovial membrane ALVAL score was 9 of 19 and 14 of 19 in failed implants with synovial hyperplasia and lymphoplasmacytic and macrophage infiltration. In contrast, the synovial membrane in successful implants and empty defects was normal (ALVAL score = 0/19). Immunolabeling for Iba1 in failed implants confirmed extensive and dense macrophage infiltration within the condyle and synovial membrane, with the highest immunoreactive score (9/9). Conclusion: PVA hydrogel implants had a 50% failure rate with uncontrollable pain, severe osteolysis, inflammation, and foreign body reactions. Clinical Relevance: The failure rate and pathological characteristics of the PVA implants suggest that their use should not be continued in human patients without further in vivo safety studies.