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Found 34362 matches. Displaying 41-50
Naik S, Larsen SB, Cowley CJ, Fuchs E
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Two to Tango: Dialog between Immunity and Stem Cells in Health and Disease

CELL 2018 NOV 1; 175(4):908-920
Stem cells regenerate tissues in homeostasis and under stress. By taking cues from their microenvironment or "niche,'' they smoothly transition between these states. Immune cells have surfaced as prominent members of stem cell niches across the body. Here, we draw parallels between different stem cell niches to explore the context-specific interactions that stem cells have with tissue-resident and recruited immune cells. We also highlight stem cells' innate ability to sense and respond to stress and the enduring memory that forms from such encounters. This fascinating crosstalk holds great promise for novel therapies in inflammatory diseases and regenerative medicine.
Belousov R, Jacobo A, Hudspeth AJ
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Fluctuation theory in space and time: White noise in reaction-diffusion models of morphogenesis

PHYSICAL REVIEW E 2018 NOV 21; 98(5):? Article 052125
The precision of reaction-diffusion models for mesoscopic physical systems is limited by fluctuations. To account for this uncertainty, Van Kampen derived a stochastic Langevin-like reaction-diffusion equation that incorporates spatiotemporal white noise. The resulting solutions, however, have infinite standard deviation. Ad hoc modifications that address this issue by introducing microscopic correlations are inconvenient in many physical contexts of wide interest. We instead estimate the magnitude of fluctuations by coarse-graining solutions of the Van Kampen equation at a relevant mesoscopic scale. The ensuing theory yields fluctuations of finite magnitude. Our approach is demonstrated for a specific biophysical model-the encoding of positional information. A numerical example is given for bicoid signaling in Drosophila. We discuss the properties of the fluctuations and the role played by the macroscopic parameters of the underlying reaction-diffusion model. The analysis and numerical methods developed here can be applied in physical problems to predict the magnitude of fluctuations. This general approach can also be extended to other classes of dynamical systems that are described by partial differential equations.
Fuchs E
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Mentoring the Next Generation: Elaine Fuchs

CELL STEM CELL 2018 NOV 1; 23(5):642-643
Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Elaine Fuchs about her views.
Song T, Pavel AB, Wen HC, Malik K, Estrada Y, Gonzalez J, Hashim PW, Nia JK, Baum D, Kimmel G, Singer GK, Krueger JG, Guttman-Yassky E
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An integrated model of alopecia areata biomarkers highlights both T(H)1 and T(H)2 upregulation

Ryan JD, Zhou Y, Contoreggi NH, Bshesh FK, Gray JD, Kogan JF, Ben KT, McEwen BS, Kreek MJ, Milner TA
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Sex Differences in the Rat Hippocampal Opioid System After Oxycodone Conditioned Place Preference

NEUROSCIENCE 2018 NOV 21; 393(?):236-257
Although opioid addiction has risen dramatically, the role of gender in addiction has been difficult to elucidate. We previously found sex-dependent differences in the hippocampal opioid system of Sprague-Dawley rats that may promote associative learning relevant to drug abuse. The present studies show that although female and male rats acquired conditioned place preference (CPP) to the mu-opioid receptor (MOR) agonist oxycodone (3 mg/kg, I.P.), hippocampal opioid circuits were differentially altered. In CA3, Leu-Enkephalin-containing mossy fibers had elevated levels in oxycodone CPP (Oxy) males comparable to those in females and sprouted in Oxy-females, suggesting different mechanisms for enhancing opioid sensitivity. Electron microscopy revealed that in Oxy-males delta opioid receptors (DORs) redistributed to mossy fiber-CA3 synapses in a manner resembling females that we previously showed is important for opioid-mediated long-term potentiation. Moreover, in Oxy-females DORs redistributed to CA3 pyramidal cell spines, suggesting the potential for enhanced plasticity processes. In Saline-injected (Sal) females, dentate hilar parvalbumin-containing basket interneuron dendrites had fewer MORs, however plasmalemmal and total MORs increased in Oxy-females. In dentate hilar GABAergic dendrites that contain neuropeptide Y, Sal-females compared to Sal-males had higher plasmalemmal DORs, and near-plasmalemmal DORs increased in Oxy-females. This redistribution of MORs and DORs within hilar interneurons in Oxy-females would potentially enhance disinhibition of granule cells via two different circuits. Together, these results indicate that oxycodone CPP induces sex-dependent redistributions of opioid receptors in hippocampal circuits in a manner facilitating opioid-associative learning processes and may help explain the increased susceptibility of females to opioid addiction acquisition and relapse. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
Linton SS, Abraham T, Liao J, Clawson GA, Butler PJ, Fox T, Kester M, Matters GL
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Tumor-promoting effects of pancreatic cancer cell exosomes on THP-1-derived macrophages

PLOS ONE 2018 NOV 1; 13(11):? Article e0206759
Pancreatic ductal adenocarcinoma (PDAC) tumor growth is enhanced by tumor-associated macrophages (TAMs), yet the mechanisms by which tumor cells and TAMs communicate are not fully understood. Here we show that exosomes secreted by PDAC cell lines differed in their surface proteins, lipid composition, and efficiency of fusing with THP-1-derived macrophages in vitro. Exosomes from AsPC-1, an ascites-derived human PDAC cell line, were enriched in ICAM-1, which mediated their docking to macrophages through interactions with surface-exposed CD11c on macrophages. AsPC-1 exosomes also contained much higher levels of arachidonic acid (AA), and they fused at a higher rate with THP-1-derived macrophages than did exosomes from other PDAC cell lines or from an immortalized normal pancreatic ductal epithelial cell line (HPDE) H6c7. Phospholipase A(2) enzymatic cleavage of arachidonic acid from AsPC-1 exosomes reduced fusion efficiency. PGE(2) secretion was elevated in macrophages treated with AsPC-1 exosomes but not in macrophages treated with exosomes from other cell lines, suggesting a functional role for the AsPC-1 exosome-delivered arachidonic acid in macrophages. Non-polarized (M0) macrophages treated with AsPC-1 exosomes had increased levels of surface markers indicative of polarization to an immunosuppressive M2-like phenotype (CD14(hi) CD163(hi) CD206(hi)). Furthermore, macrophages treated with AsPC-1 exosomes had significantly increased secretion of pro-tumoral, bioactive molecules including VEGF, MCP-1, IL-6, IL-1 beta, MMP-9, and TNF alpha. Together, these results demonstrate that compared to exosomes from other primary tumor-derived PDAC cell lines, AsPC-1 exosomes alter THP-1-derived macrophage phenotype and function. AsPC-1 exosomes mediate communication between tumor cells and TAMs that contributes to tumor progression.
Gejman RS, Chang AY, Jones HF, DiKun K, Hakimi AA, Schietinger A, Scheinberg DA
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Rejection of immunogenic tumor clones is limited by clonal fraction

ELIFE 2018 NOV 30; 7(?):? Article e41090
Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand the determinants of MHC-I peptide immunogenicity in nascent tumors, we tested the ability of thousands of MHC-I ligands to cause tumor subclone rejection in immunocompetent mice by use of a new 'PresentER' antigen presentation platform. Surprisingly, we show that immunogenic tumor antigens do not lead to immune-mediated cell rejection when the fraction of cells bearing each antigen ('clonal fraction') is low. Moreover, the clonal fraction necessary to lead to rejection of immunogenic tumor subclones depends on the antigen. These data indicate that tumor neoantigen heterogeneity has an underappreciated impact on immune elimination of cancer cells and has implications for the design of immunotherapeutics such as cancer vaccines.
Botkin JR, Appelbaum PS, Bakken S, Brown C, Burke W, Fabsitz R, Gamble VN, Gonsalves G, Kost R, Leonard DGB, McGuire A, Nichols JH, Patrick-Lake B, Wilkins CH, Zikmund-Fisher BJ
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Standardizing return of participant results

SCIENCE 2018 NOV 16; 362(6416):759-760
As members of the National Academies of Sciences, Engineering, and Medicine committee that wrote the report on the return of individual research results (1), we reject the allegations in the Policy Forum “Return of results and data to study participants” (S. M. Wolf and B. J. Evans, 12 October, p. 159) that the report is paternalistic, misunderstands the law, burdens Institutional Review Boards (IRBs), and creates barriers to the return of results.
Patel NP, Vukmanovic-Stejic M, Suarez-Farinas M, Chambers ES, Sandhu D, Fuentes-Duculan J, Mabbott NA, Rustin MHA, Krueger J, Akbar AN
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Impact of Zostavax Vaccination on T-Cell Accumulation and Cutaneous Gene Expression in the Skin of Older Humans After Varicella Zoster Virus Antigen-Specific Challenge

Background. The live attenuated vaccine Zostavax was developed to prevent varicella zoster virus (VZV) reactivation that causes herpes zoster (shingles) in older humans. However, the impact of vaccination on the cutaneous response to VZV is not known. Methods. We investigated the response to intradermal VZV antigen challenge before and after Zostavax vaccination in participants >70 years of age by immunohistological and transcriptomic analyses of skin biopsy specimens collected from the challenge site. Results. Vaccination increased the proportion of VZV-specific CD4(+) T cells in the blood and promoted the accumulation of both CD4(+) and CD8(+) T cells in the skin after VZV antigen challenge. However, Zostavax did not alter the proportion of resident memory T cells (CD4(+) and CD8(+)) or CD4(+) Foxp3(+) regulatory T cells in unchallenged skin. After vaccination, there was increased cutaneous T-cell proliferation at the challenge site and also increased recruitment of T cells from the blood, as indicated by an elevated T-cell migratory gene signature. CD8(+) T-cell-associated functional genes were also highly induced in the skin after vaccination. Conclusion. Zostavax vaccination does not alter the abundance of cutaneous resident memory T cells but instead increases the recruitment of VZV-specific T cells from the blood and enhances T-cell activation, particularly cells of the CD8(+) subset, in the skin after VZV antigen challenge.
Zhang Y, Liang YP, Randesi M, Yuferov V, Zhao C, Kreek MJ
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Chronic Oxycodone Self-administration Altered Reward-related Genes in the Ventral and Dorsal Striatum of C57BL/6J Mice: An RNA-seq Analysis

NEUROSCIENCE 2018 NOV 21; 393(?):333-349
Prescription opioid abuse, for example of oxycodone, is a pressing public health issue. This study focuses on how chronic oxycodone self-administration (SA) affects the reward pathways in the mouse brain. In this study, we tested the hypothesis that the expression of reward-related genes in the ventral and dorsal striatum, areas involved in different aspects of opioid addiction models, was altered within 1 h after chronic oxycodone SA, using transcriptome-wide sequencing (RNA-seq). Based on results from earlier human genetic and rodent preclinical studies, we focused on a set of genes that may be associated with the development of addictive diseases and the rewarding effect of drugs of abuse, primarily in the opioid, stress response and classical neurotransmitter systems. We found that 32 transcripts in the ventral striatum, and 7 in the dorsal striatum, were altered significantly in adult mice that had self-administered oxycodone (n = 5) for 14 consecutive days (4 hiday) compared with yoked saline controls (n = 5). The following 5 genes in the ventral striatum showed experiment-wise significant changes: proopiomelanocortin (Pomc) and serotonin 5-HT-2A receptor (Htr2a) were upregulated; serotonin receptor 7 (Htr7), galanin receptor1 (Galr1) and glycine receptor 1 (Glra1) were downregulated. Some genes detected by RNA-seq were confirmed by quantitative polymerase chain reaction (qPCR). Conclusion: A RNA-seq study shows that chronic oxycodone SA alters the expression of several reward-related genes in the dorsal and ventral striatum. These results suggest potential mechanisms underlying neuronal adaptation to chronic oxycodone self-exposure, of relevance to our mechanistic understanding of prescription opioid abuse. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.