Cx3cr1-deficient microglia exhibit a premature aging transcriptome.

CX3CR1, one of the highest expressed genes in microglia in mice and humans, is implicated in numerous microglial functions. However, the molecular mechanisms underlying Cx3cr1 signaling are not well understood. Here, we analyzed transcriptomes of Cx3cr1-deficient microglia under varying conditions by RNA-sequencing (RNA-seq). In 2-mo-old mice, Cx3cr1 deletion resulted in the down-regulation of a subset of immune-related genes, without substantial epigenetic changes in markers of active chromatin. Surprisingly, Cx3cr1-deficient microglia from young mice exhibited a transcriptome consistent with that of aged Cx3cr1-sufficient animals, suggesting a premature aging transcriptomic signature. Immunohistochemical analysis of microglia in young and aged mice revealed that loss of Cx3cr1 modulates microglial morphology in a comparable fashion. Our results suggest that CX3CR1 may regulate microglial function in part by modulating the expression levels of a subset of inflammatory genes during chronological aging, making Cx3cr1-deficient mice useful for studying aged microglia

Credneramides A and B: Neuromodulatory Phenethylamine and Isopentylamine Derivatives of a Vinyl Chloride-Containing Fatty Acid from cf. Trichodesmium sp. nov.

Credneramides A (1) and B (2), two vinyl chloride-containing metabolites, were isolated from a Papua New Guinea collection of cf. Trichodesmium sp. nov. and expand a recently described class of vinyl chloride-containing natural products. The precursor fatty acid, credneric acid (3), was isolated from both the aqueous and organic fractions of the parent fraction as well as from another geographically and phylogenetically distinct cyanobacterial collection (Panama). Credneramides A and B inhibited spontaneous calcium oscillations in murine cerebrocortical neurons at low micromolar concentrations (1, IC 50 4.0 μM; 2, IC 50 3.8 μM).Credneramides A (1) and B (2), two vinyl chloride-containing metabolites, were isolated from a Papua New Guinea collection of cf. Trichodesmium sp. nov. and expand a recently described class of vinyl chloride-containing natural products. The precursor fatty acid, credneric acid (3), was isolated from both the aqueous and organic fractions of the parent fraction as well as from another geographically and phylogenetically distinct cyanobacterial collection (Panama). Credneramides A and B inhibited spontaneous calcium oscillations in murine cerebrocortical neurons at low micromolar concentrations (1, IC 50 4.0 μM; 2, IC 50 3.8 μM)

(R)-N-Methyl-4-[2-(methyl­sulfan­yl)pyrimidin-4-yl]-1-(tetra­hydro­furan-3-yl)-1H-pyrazol-5-amine

The chiral center at the substituted atom of the tetra­hydro­furanyl ring in the title compound, C13H17N5OS, has an R configuration. The methyl­sulfanylpyrimidine group and the pyrazole ring are almost coplanar [the maximum deviation from this plane is 0.070 (4) Å], the N—Me substituent being displaced from the methyl­sulfanylpyrimidine-pyrazole plane by 0.880 (4) Å. The secondary amine group participates in an intra­molecular hydrogen bond with the pyrimidine N atom in position 3

Chimeric Antigen Receptors Based on Low Affinity Mutants of FcεRI Re-direct T Cell Specificity to Cells Expressing Membrane IgE

IgE is the key mediator of allergic responses. Omalizumab, an IgE-specific monoclonal antibody that depletes IgE, is effective for treating severe allergic asthma. The need for frequent administration of the expensive drug, however, limits its applications. Taking advantage of T cell memory, adoptive T cell therapy (ACT) targeting IgE-producing cells has the potential to achieve long-term suppression of IgE and relief of symptoms for severe allergic diseases. The transmembrane form of IgE (mIgE), which is present on all IgE-producing cells, serves as an excellent molecular target for ACT that employs chimeric antigen receptors (CARs). Here, we designed and tested CARs that use the extracellular domain of high affinity IgE receptor, FcεRIα, for mIgE recognition. When expressed on Jurkat T cells, FcεRIα-based CARs mediated robust responses in terms of CD69 upregulation to U266 myeloma cells expressing low levels of mIgE. FcεRIα-based CARs specifically recognized cells expressing mIgE, but not cells with secreted IgE captured through Fcε receptors. CAR+ Jurkat cells did not respond to LAD2 mast cells with secreted IgE bound through FcεRI or Ramos cells with secreted IgE bound through FcεRII. Co-culture of CAR+ Jurkat cells and LAD2 mast cells with IgE bound did not trigger LAD2 cell degranulation. The activity of CAR using wild type FcεRIα for mIgE binding was inhibited by the presence secreted IgE, which likely blocked CAR-mIgE interaction. The activities of CARs using low affinity mutants of FcεRIα, however, tolerated secreted IgE at relatively high concentrations. Moreover, primary human CD8+ T cells expressing a low affinity mutant CAR responded to U266 cells with INFγ production and cytotoxicity despite the presence of secreted IgE. The potency, specificity, and robustness of our CAR design, combined with repaid advances in the safety of ACT, hold promise for novel and highly effective cell-based therapies against severe allergic diseases

Investigating the Direct Meltwater Effect in Terrestrial Oxygenâ Isotope Paleoclimate Records Using an Isotopeâ Enabled Earth System Model

Variations in terrestrial oxygenâ isotope reconstructions from ice cores and speleothems have been primarily attributed to climatic changes of surface air temperature, precipitation amount, or atmospheric circulation. Here we demonstrate with the fully coupled isotopeâ enabled Community Earth System Model an additional process contributing to the oxygenâ isotope variations during glacial meltwater events. This process, termed â the direct meltwater effect,â involves propagating large amounts of isotopically depleted meltwater throughout the hydrological cycle and is independent of climatic changes. We find that the direct meltwater effect can make up 15â 35% of the δ18O signals in precipitation over Greenland and eastern Brazil for large freshwater forcings (0.25â 0.50 sverdrup (106 m3/s)). Model simulations further demonstrate that the direct meltwater effect increases with the magnitude and duration of the freshwater forcing and is sensitive to both the location and shape of the meltwater. These new modeling results have important implications for past climate interpretations of δ18O.Key PointsA portion of the δ18O signal in landâ based paleoclimate proxies can be attributed to the direct meltwater effect instead of climatic changesThe direct meltwater effect can make up 15â 35% of the δ18O signals in precipitation in Greenland and eastern Brazil for large meltwater eventsThe direct meltwater effect increases with the magnitude and duration of the freshwater forcing and is sensitive to location and shape dependentPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141374/1/grl56782_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141374/2/grl56782-sup-0001-Supporting_Information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141374/3/grl56782.pd

Regional and global forcing of glacier retreat during the last deglaciation

The ongoing retreat of glaciers globally is one of the clearest manifestations of recent global warming associated with rising greenhouse gas concentrations. By comparison, the importance of greenhouse gases in driving glacier retreat during the most recent deglaciation, the last major interval of global warming, is unclear due to uncertainties in the timing of retreat around the world. Here we use recently improved cosmogenic-nuclide production-rate calibrations to recalculate the ages of 1,116 glacial boulders from 195 moraines that provide broad coverage of retreat in mid-to-low-latitude regions. This revised history, in conjunction with transient climate model simulations, suggests that while several regional-scale forcings, including insolation, ice sheets and ocean circulation, modulated glacier responses regionally, they are unable to account for global-scale retreat, which is most likely related to increasing greenhouse gas concentrations.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Nature Publishing Group. The published article can be found at: http://www.nature.com/ncomms/2015/150821/ncomms9059/full/ncomms9059.htm

Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling

Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention

Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer