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Found 34725 matches. Displaying 41-50
Xu M, Kolding J, Cohen JE
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Sequential analysis and design of fixed-precision sampling of Lake Kariba fishes using Taylor's power law

Taylor's power law (TPL), which states that the variance of abundance is a power function of mean abundance, has been used to design sampling of agricultural pests and fish species. We show that TPL holds for means and variances of abundance of accumulated fish samples in the fished and unfished areas separately of Lake Kariba (between Zambia and Zimbabwe), measuring abundance indices by number and weight separately. We use TPL parameters estimated from sequentially accumulated samples to update a stopping line of fixed precision 0.1 after each new sample from a sampling day. In these Lake Kariba data, depending on the sampling area and abundance measure, our updated stopping-line method requires 21% to 41% of the number of sampling days and 19% to 40% of the number of samples that are planned a priori and performed under systematic sampling. Our novel method yields mean abundance estimates similar to those from systematic sampling and provides a conservative approach to reaching a fixed sampling precision level with reduced sampling labor and time. Using mixed-effect modeling for cumulative means and variances with either number or weight from both fished and unfished areas, we find that fishing increases the slope of TPL. This study provides the conceptual framework and an empirical case study for implementing a sequential sampling method for fish assemblages of an inland lake. The possible limitations and applications of our method for sampling in other environments are discussed.
Zhou Y, Leri F, Low MJ, Kreek MJ
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Sex differences in the effect of bupropion and naltrexone combination on alcohol drinking in mice

A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave((R)), is an FDA approved pharmacotherapy for the treatment of obesity. A recent study found that combining BPP with low-dose NTX reduced alcohol drinking in alcohol-preferring male rats. To explore potential pharmacological effects of the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J mice were tested on one-week drinking-in-the dark (DID) and three-week intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer knockout (nPE(-/-)) mice with hypothalamic-specific deficiency of POMC, and its bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used as a genetic control for the effects of the BPP + NTX. A single administration of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPP + NTX had no effect on alcohol DID in nPE(-/-) males. Pretreatment with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested were not effective in females. Furthermore, our results suggest a hypothalamic POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol drinking in male mice.
Pillay BA, Avery DT, Smart JM, Cole T, Choo S, Chan D, Gray PE, Frith K, Mitchell R, Phan TG, Wong M, Campbell DE, Hsu P, Ziegler JB, Peake J, Alvaro F, Picard C, Bustamante J, Neven B, Cant AJ, Uzel G, Arkwright PD, Casanova JL, Su HC, Freeman AF, Shah N, Hickstein DD, Tangye SG, Ma CS
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Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients

JCI INSIGHT 2019 JUN 6; 4(11):? Article e127527
Biallelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterized by severe pathogen infections, eczema, allergies, malignancy, and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplant (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of alpha beta T and MAIT cells were reduced, while gamma delta T cells were increased in DOCK8-deficient patients. HSCT improved abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalog of cellular defects in DOCK8-deficient patients and the efficacy of HSCT in correcting these defects, concurrent with improvements in clinical phenotypes. Overall, our findings reveal mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency after HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.
Escolano A, Gristick HB, Abernathy ME, Merkenschlager J, Gautam R, Oliveira TY, Pai J, West AP, Barnes CO, Cohen AA, Wang HQ, Golijanin J, Yost D, Keeffe JR, Wang ZJ, Zhao P, Yao KH, Bauer J, Nogueira L, Gao H, Voll AV, Montefiori DC, Seaman MS, Gazumyan A, Silva M, McGuire AT, Stamatatos L, Irvine DJ, Wells L, Martin MA, Bjorkman PJ, Nussenzweig MC
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Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques

NATURE 2019 JUN 27; 570(7762):468-473
Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires.
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.
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.
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.