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Found 34832 matches. Displaying 141-150
Hartweger H, McGuire AT, Horning M, Taylor JJ, Dosenovic P, Yost D, Gazumyan A, Seaman MS, Stamatatos L, Jankovic M, Nussenzweig MC
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HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells

A small number of HIV-1-infected individuals develop broadly neutralizing antibodies to the virus (bNAbs). These antibodies are protective against infection in animal models. However, they only emerge 1-3 yr after infection, and show a number of highly unusual features including exceedingly high levels of somatic mutations. It is therefore not surprising that elicitation of protective immunity to HIV-1 has not yet been possible. Here we show that mature, primary mouse and human B cells can be edited in vitro using CRISPR/Cas9 to express mature bNAbs from the endogenous Igh locus. Moreover, edited B cells retain the ability to participate in humoral immune responses. Immunization with cognate antigen in wild-type mouse recipients of edited B cells elicits bNAb titers that neutralize HIV-1 at levels associated with protection against infection. This approach enables humoral immune responses that may be difficult to elicit by traditional immunization.
Heselpoth RD, Euler CW, Schuch R, Fischetti VA
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Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria

The prevalence of multidrug-resistant Pseudomonas aeruginosa has stimulated development of alternative therapeutics. Bacteriophage peptidoglycan hydrolases, termed lysins, represent an emerging antimicrobial option for targeting Gram-positive bacteria. However, lysins against Gram-negatives are generally deterred by the outer membrane and their inability to work in serum. One solution involves exploiting evolved delivery systems used by colicin-like bacteriocins (e.g., S-type pyocins of P. aeruginosa) to translocate through the outer membrane. Following surface receptor binding, colicin-like bacteriocins form Tol- or TonB-dependent translocons to actively import bactericidal domains through outer membrane protein channels. With this understanding, we developed lysocins, which are bioengineered Iysin-bacteriocin fusion molecules capable of periplasmic import. In our proof-of-concept studies, components from the P. aeruginosa bacteriocin pyocin S2 (PyS2) responsible for surface receptor binding and outer membrane translocation were fused to the GN4 lysin to generate the PyS2-GN4 lysocin. PyS2-GN4 delivered the GN4 lysin to the periplasm to induce peptidoglycan cleavage and log-fold killing of P. aeruginosa with minimal endotoxin release. While displaying narrow-spectrum antipseudomonal activity in human serum, PyS2-GN4 also efficiently disrupted biofilms, outperformed standard-of-care antibiotics, exhibited no cytotoxicity toward eukaryotic cells, and protected mice from P. aeruginosa challenge in a bacteremia model. In addition to targeting P. aeruginosa, lysocins can be constructed to target other prominent Gram-negative bacterial pathogens.
Martel J, Ojcius DM, Ko YF, Ke PY, Wu CY, Peng HH, Young JD
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Hormetic Effects of Phytochemicals on Health and Longevity

Caloric restriction, intermittent fasting, and exercise activate defensive cellular responses such as autophagy, DNA repair, and the induction of antioxidant enzymes. These processes improve health and longevity by protecting cells and organs against damage, mutations, and reactive oxygen species. Consuming a diet rich in vegetables, fruits, and mushrooms can also improve health and longevity. Phytochemicals such as alkaloids, polyphenols, and terpenoids found in plants and fungi activate the same cellular processes as caloric restriction, fasting, and exercise. Many of the beneficial effects of fruits and vegetables may thus be due to activation of stress resistance pathways by phytochemicals. A better understanding of the mechanisms of action of phytochemicals may provide important insights to delay aging and prevent chronic diseases.
Funabiki H
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Correcting aberrant kinetochore microtubule attachments: a hidden

For equal chromosome segregation, a pair of kinetochores on each
Capoor MN, Lochman J, McDowell A, Schmitz JE, Solansky M, Zapletalova M, Alamin TF, Coscia MF, Garfin SR, Jancalek R, Ruzicka F, Shamie AN, Smrcka M, Wang JC, Birkenmaier C, Slaby O
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Intervertebral disc penetration by antibiotics used prophylactically in spinal surgery: implications for the current standards and treatment of disc infections (vol 28, pg 783, 2019)

EUROPEAN SPINE JOURNAL 2019 JUN; 28(6):1546-1547
Unfortunately, the complete conflict of interest statement was missed out in the original publication. The same is given below.
Jin J, Cheng J, Lee KW, Amreen B, McCabe KA, Pitcher C, Liebmann T, Greengard P, Flajolet M
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Cholinergic Neurons of the Medial Septum Are Crucial for Sensorimotor Gating

JOURNAL OF NEUROSCIENCE 2019 JUN 26; 39(26):5234-5242
Hypofunction of NMDA receptors has been considered a possible cause for the pathophysiology of schizophrenia. More recently, indirect ways to regulate NMDA that would be less disruptive have been proposed and metabotropic glutamate receptor subtype 5 (mGluR5) represents one such candidate. To characterize the cell populations involved, we demonstrated here that knock-out (KO) of mGluR5 in cholinergic, but not glutamatergic or parvalbumin (PV)-positive GABAergic, neurons reduced prepulse inhibition of the startle response (PPI) and enhanced sensitivity to MK801-induced locomotor activity. Inhibition of cholinergic neurons in the medial septum by DREADD (designer receptors exclusively activated by designer drugs) resulted in reduced PPI further demonstrating the importance of these neurons in sensorimotor gating. Volume imaging and quantification were used to compare PV and cholinergic cell distribution, density, and total cell counts in the different cell-type-specific KO lines. Electrophysiological studies showed reduced NMDA receptormediated currents in cholinergic neurons of the medial septum in mGluR5 KO mice. These results obtained from male and female mice indicate that cholinergic neurons in the medial septum represent a key cell type involved in sensorimotor gating and are relevant to pathologies associated with disrupted sensorimotor gating such as schizophrenia.
Stoeckle M
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The eDNA Revolution

SEA TECHNOLOGY 2019 JUN; 60(6):7-7
Litke JL, Jaffrey SR
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Highly efficient expression of circular RNA aptamers in cells using autocatalytic transcripts

NATURE BIOTECHNOLOGY 2019 JUN; 37(6):667-675
RNA aptamers and RNA aptamer-based devices can be genetically encoded and expressed in cells to probe and manipulate cellular function. However, their usefulness in the mammalian cell is limited by low expression and rapid degradation. Here we describe the Tornado (Twister-optimized RNA for durable overexpression) expression system for achieving rapid RNA circularization, resulting in RNA aptamers with high stability and expression levels. Tornado-expressed transcripts contain an RNA of interest flanked by Twister ribozymes. The ribozymes rapidly undergo autocatalytic cleavage, leaving termini that are ligated by the ubiquitous endogenous RNA ligase RtcB. Using this approach, protein-binding aptamers that otherwise have minimal effects in cells become potent inhibitors of cellular signaling. Additionally, an RNA-based fluorescent metabolite biosensor for S-adenosyl methionine (SAM) that is expressed at low levels when expressed as a linear RNA achieves levels sufficient for detection of intracellular SAM dynamics when expressed as a circular RNA. The Tornado expression system thus markedly enhances the utility of RNA-based approaches in the mammalian cell.
Matthews BJ
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Aedes aegypti

TRENDS IN GENETICS 2019 JUN; 35(6):470-471
Spalinger MR, Atrott K, Baebler K, Schwarzfischer M, Melhem H, Peres DR, Lalazar G, Rogler G, Scharl M, Frey-Wagner I
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Administration of the Hyper-immune Bovine Colostrum Extract IMM-124E Ameliorates Experimental Murine Colitis

JOURNAL OF CROHNS & COLITIS 2019 JUN; 13(6):785-797
Background and Aims Inflammatory bowel disease [IBD] is accompanied by lesions in the epithelial barrier, which allow translocation of bacterial products from the gut lumen to the host's circulation. IMM-124E is a colostrum-based product containing high levels of anti-E.coli-LPS IgG, and might limit exposure to bacterial endotoxins. Here, we investigated whether IMM-124E can ameliorate intestinal inflammation. Methods Acute colitis was induced in WT C57Bl/6J mice by administration of 2.5% dextran sodium sulphate [DSS] for 7 days. T cell transfer colitis was induced via transfer of 0.5 x 10(6) naive T cells into RAG2(-/-) C57Bl/6J mice. IMM-124E was administered daily by oral gavage, either preventively or therapeutically. Results Treatment with IMM-124E significantly ameliorated colitis in acute DSS colitis and in T cell transfer colitis. Maximum anti-inflammatory effects were detected at an IMM-124E concentration of 100 mg/kg body weight, whereas 25 mg/kg and 500 mg/kg were less effective. Histology revealed reduced levels of infiltrating immune cells and less pronounced mucosal damage. Flow cytometry revealed reduced numbers of effector T helper cells in the intestine, whereas levels of regulatory T cells were enhanced. IMM-124E treatment reduced the DSS-induced increase of serum levels of lipopolysaccharide [LPS]-binding protein, indicating reduced systemic LPS exposure. Conclusions Our results demonstrate that oral treatment with IMM-124E significantly reduces intestinal inflammation, via decreasing the accumulation of pathogenic T cells and concomitantly increasing the induction of regulatory T cells. Our study confirms the therapeutic efficacy of IMM-124E in acute colitis and suggests that administration of IMM-124E might represent a novel therapeutic strategy to induce or maintain remission in chronic colitis.