Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, ...and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. Oral administration of either A-784168 (1-3-(trifluoromethyl)pyridin-2-yl-N-4-(trifluoromethylsulfonyl)phenyl-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N'-(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-ylurea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.
Background & Aims Protein misfolding and endoplasmic reticulum (ER) stress have been observed in intestinal secretory cells from patients with inflammatory bowel diseases and induce intestinal ...inflammation in mice. However, it is not clear how immune factors affect ER stress and therefore disease symptoms. Methods We analyzed the effects of interleukin (IL)-10 on ER stress in intestinal tissues in wild-type C57BL/6, Winnie , IL-10 −/− , and Winnie × IL-10 +/− mice. In Winnie mice, misfolding of the intestinal mucin Muc2 initiates ER stress and inflammation. We also analyzed the effects of different inhibitors of IL-10 signaling and the N -glycosylation inhibitor tunicamycin in cultured human LS174T goblet cells. Results Administration of neutralizing antibodies against IL-10 or its receptor (IL-10R1) to Winnie mice rapidly exacerbated ER stress and intestinal inflammation compared with mice given vehicle (controls). Antibodies against IL-10 also increased accumulation of misfolded Muc2 in the ER of goblet cells of Winnie mice and increased T-cell production of inflammatory cytokines. Winnie × IL-10 +/− mice and IL-10 −/− mice with a single Winnie allele each developed more severe inflammation than Winnie mice or IL-10 −/− mice. Administration of tunicamycin to wild-type mice caused intestinal ER stress, which increased when IL-10R1 was blocked. In LS174T cells, induction of ER stress with tunicamycin and misfolding of MUC2 were reduced by administration of IL-10; this reduction required STAT1 and STAT3. In LS174T cells incubated with tunicamycin, IL-10 up-regulated genes involved in MUC2 folding and in ER-associated degradation and maintained correct folding of MUC2, its transport from the ER, and its O -glycosylation and secretion. Conclusions IL-10 prevents protein misfolding and ER stress by maintaining mucin production in goblet cells and helps the intestine preserve the mucus barrier.
Using a sample of four galaxy clusters at 1.35 < z < 1.65 and 10 galaxy clusters at 0.85 < z < 1.35, we measure the environmental quenching timescale, tQ, corresponding to the time required after a ...galaxy is accreted by a cluster for it to fully cease star formation. Cluster members are selected by a photometric-redshift criterion, and categorized as star-forming, quiescent, or intermediate according to their dust-corrected rest-frame colors and magnitudes. We employ a "delayed-then-rapid" quenching model that relates a simulated cluster mass accretion rate to the observed numbers of each type of galaxy in the cluster to constrain tQ. For galaxies of mass M* 1010.5 M , we find a quenching timescale of tQ = Gyr in the z ∼ 1.5 cluster sample, and Gyr at z ∼ 1. Using values drawn from the literature, we compare the redshift evolution of tQ to timescales predicted for different physical quenching mechanisms. We find tQ to depend on host halo mass such that quenching occurs over faster timescales in clusters relative to groups, suggesting that properties of the host halo are responsible for quenching high-mass galaxies. Between z = 0 and z = 1.5, we find that tQ evolves faster than the molecular gas depletion timescale and slower than an estimated star formation rate-outflow timescale, but is consistent with the evolution of the dynamical time. This suggests that environmental quenching in these galaxies is driven by the motion of satellites relative to the cluster environment, although due to uncertainties in the atomic gas budget at high redshift, we cannot rule out quenching due to simple gas depletion.
The advent of reprogramming and its impact on stem cell biology has renewed interest in lineage restriction in mammalian embryos, the source of embryonic (ES), epiblast (EpiSC), trophoblast (TS), and ...extraembryonic endoderm (XEN) stem cell lineages. Isolation of specific cell types during stem cell differentiation and reprogramming, and also directly from embryos, is a major technical challenge because few cell-surface proteins are known that can distinguish each cell type. We provide a large-scale proteomic resource of cell-surface proteins for the four embryo-derived stem cell lines. We validated 27 antibodies against lineage-specific cell-surface markers, which enabled investigation of specific cell populations during ES-EpiSC reprogramming and ES-to-XEN differentiation. Identified markers also allowed prospective isolation and characterization of viable lineage progenitors from blastocysts by flow cytometry. These results provide a comprehensive stem cell proteomic resource and enable new approaches to interrogate the mechanisms that regulate cell fate specification.
► Cell-surface proteome for four embryo-derived stem cell lineages ► Comprehensive resource of signaling, adhesion and migration proteins ► Enables isolation of specific cell types during differentiation and reprogramming ► Allows prospective isolation of lineage progenitors directly from blastocysts
Rugg-Gunn et al. provide a large-scale proteomic resource of cell-surface proteins for four embryo-derived stem cell lines: ES, EpiSC, TS, and XEN. Antibodies against lineage-specific cell-surface markers allowed investigation of specific cell populations during differentiation and reprogramming and also prospective isolation of viable lineage progenitors from blastocysts by flow cytometry.
Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although ...FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.
We present ALMA CO (2-1) detections in 11 gas-rich cluster galaxies at z ∼ 1.6, constituting the largest sample of molecular gas measurements in z > 1.5 clusters to date. The observations span three ...galaxy clusters, derived from the Spitzer Adaptation of the Red-sequence Cluster Survey. We augment the >5 detections of the CO (2-1) fluxes with multi-band photometry, yielding stellar masses and infrared-derived star formation rates, to place some of the first constraints on molecular gas properties in z ∼ 1.6 cluster environments. We measure sizable gas reservoirs of 0.5-2 × 1011 M☉ in these objects, with high gas fractions (fgas) and long depletion timescales (τ), averaging 62% and 1.4 Gyr, respectively. We compare our cluster galaxies to the scaling relations of the coeval field, in the context of how gas fractions and depletion timescales vary with respect to the star-forming main sequence. We find that our cluster galaxies lie systematically off the field scaling relations at z = 1.6 toward enhanced gas fractions, at a level of ∼4 , but have consistent depletion timescales. Exploiting CO detections in lower-redshift clusters from the literature, we investigate the evolution of the gas fraction in cluster galaxies, finding it to mimic the strong rise with redshift in the field. We emphasize the utility of detecting abundant gas-rich galaxies in high-redshift clusters, deeming them as crucial laboratories for future statistical studies.
Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical ...hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10
) and thalamus (d=-0.148; P=4.27 × 10
) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10
) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.
We report on the discovery of WASP-12b, a new transiting extrasolar planet with R pl = 1.79+0.09 -0.09 RJ and M pl = 1.41+0.10 -0.10 M J. The planet and host star properties were derived from a Monte ...Carlo Markov Chain analysis of the transit photometry and radial velocity data. Furthermore, by comparing the stellar spectrum with theoretical spectra and stellar evolution models, we determined that the host star is a supersolar metallicity (M/H = 0.3+0.05 -0.15), late-F (T eff = 6300+200 -100 K) star which is evolving off the zero-age main sequence. The planet has an equilibrium temperature of T eq = 2516 K caused by its very short period orbit (P = 1.09 days) around the hot, twelfth magnitude host star. WASP-12b has the largest radius of any transiting planet yet detected. It is also the most heavily irradiated and the shortest period planet in the literature.
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