Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure

AbstractRisperidone is a second-generation antipsychotic that causes weight gain. We hypothesized that risperidone-induced shifts in the gut microbiome are mechanistically involved in its metabolic consequences. Wild-type female C57BL/6J mice treated with risperidone (80μg/day) exhibited significant excess weight gain, due to reduced energy expenditure, which correlated with an altered gut microbiome. Fecal transplant from risperidone-treated mice caused a 16% reduction in total resting metabolic rate in naïve recipients, attributable to suppression of non-aerobic metabolism. Risperidone inhibited growth of cultured fecal bacteria grown anaerobically more than those grown aerobically. Finally, transplant of the fecal phage fraction from risperidone-treated mice was sufficient to cause excess weight gain in naïve recipients, again through reduced energy expenditure. Collectively, these data highlight a major role for the gut microbiome in weight gain following chronic use of risperidone, and specifically implicates the modulation of non-aerobic resting metabolism in this mechanism

Abundances in planetary nebulae: NGC1535, NGC6629, He2-108, and Tc1

The aim of the paper is to determine abundances in a group of PNe with uniform morphology. The PNe discussed are circular excited by rather low-temperature central stars. The relation between abundance and evolution is discussed. The mid-infrared spectra of NGC1535, NGC6629, He2-108 and Tc1 taken with the Spitzer Space Telescope are presented. These spectra are combined with IUE and visual spectra to obtain complete extinction-corrected spectra from which the abundances are determined. These abundances are more accurate for several reasons, the most important is that the inclusion of the far infrared spectra increases the number of observed ions and makes it possible to include the nebular temperature gradient in the abundance calculation. The abundances of these PNe are compared to those found in five other PNe of similar properties and are further compared with predictions of evolutionary models. From this comparison we conclude that these PNe originated from low mass stars, probably between 1 and 2.5 solar masses and at present have core masses between 0.56 and 0.63 solar masses. A consistent description of the evolution of this class of PNe is found that agrees with the predictions of the present nebular abundances, the individual masses and the luminosities of these PNe. The distances to these nebulae can be found as well.Comment: 17 pages, 18 tables, 1 figure, Accepted for publication in A&

A Study of B0 -> J/psi K(*)0 pi+ pi- Decays with the Collider Detector at Fermilab

We report a study of the decays B0 -> J/psi K(*)0 pi+ pi-, which involve the creation of a u u-bar or d d-bar quark pair in addition to a b-bar -> c-bar(c s-bar) decay. The data sample consists of 110 1/pb of p p-bar collisions at sqrt{s} = 1.8 TeV collected by the CDF detector at the Fermilab Tevatron collider during 1992-1995. We measure the branching ratios to be BR(B0 -> J/psi K*0 pi+ pi-) = (8.0 +- 2.2 +- 1.5) * 10^{-4} and BR(B0 -> J/psi K0 pi+ pi-) = (1.1 +- 0.4 +- 0.2) * 10^{-3}. Contributions to these decays are seen from psi(2S) K(*)0, J/psi K0 rho0, J/psi K*+ pi-, and J/psi K1(1270)

Prospects for Studies of Stellar Evolution and Stellar Death in the JWST Era

I review the prospects for studies of the advanced evolutionary stages of low-, intermediate- and high-mass stars by the JWST and concurrent facilities, with particular emphasis on how they may help elucidate the dominant contributors to the interstellar dust component of galaxies. Observations extending from the mid-infrared to the submillimeter can help quantify the heavy element and dust species inputs to galaxies from AGB stars. JWST's MIRI mid-infrared instrument will be so sensitive that observations of the dust emission from individual intergalactic AGB stars and planetary nebulae in the Virgo Cluster will be feasible. The Herschel Space Observatory will enable the last largely unexplored spectral region, the far-IR to the submillimeter, to be surveyed for new lines and dust features, while SOFIA will cover the wavelength gap between JWST and Herschel, a spectral region containing important fine structure lines, together with key water-ice and crystalline silicate bands. Spitzer has significantly increased the number of Type II supernovae that have been surveyed for early-epoch dust formation but reliable quantification of the dust contributions from massive star supernovae of Type II, Type Ib and Type Ic to low- and high-redshift galaxies should come from JWST MIRI observations, which will be able to probe a volume over 1000 times larger than Spitzer.Comment: 24 pages, 19 figures. To appear in `Astrophysics in the Next Decade: JWST and Concurrent Facilities' (JWST Conference Proceedings), edited by H. A. Thronson, M. Stiavelli and A. G. G. M. Tielens; Springer Series: Astrophysics and Space Science Proceeding

Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities

Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). Approach and Results We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such asTP53(35.5%),KRAS(28.0%),CDKN2A(14.5%), andSMAD4(11.3%), as well as potentially druggable mutations (e.g.,HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.Peer reviewe

Search for Single-Top-Quark Production in p-pbar Collisions at sqrt(s)=1.8 TeV

We search for standard model single-top-quark production in the W-gluon fusion and W* channels using 106 pb^-1 of data from p-pbar collisions at sqrt(s)=1.8 TeV collected with the Collider Detector at Fermilab. We set an upper limit at 95% C.L. on the combined W-gluon fusion and W* single-top cross section of 14 pb, roughly six times larger than the standard model prediction. Separate 95% C.L. upper limits in the W-gluon fusion and W* channels are also determined and are found to be 13 and 18 pb, respectively.Comment: 6 pages, 2 figures; submitted to Phys. Rev. Let

Measurement of the polar-angle distribution of leptons from W boson decay as a function of the W transverse momentum in proton-antiproton collisions at sqrt{s}=1.8 TeV

We present a measurement of the coefficient alpha_2 of the leptonic polar-angle distribution from W boson decays, as a function of the W transverse momentum. The measurement uses an 80+/-4 pb^{-1} sample of proton-antiproton collisions at sqrt{s}=1.8 TeV collected by the CDF detector and includes data from both the W->e+nu and W->mu+nu decay channels. We fit the W boson transverse mass distribution to a set of templates from a Monte Carlo event generator and detector simulation in several ranges of the W transverse momentum. The measurement agrees with the Standard Model expectation, whereby the ratio of longitudinally to transversely polarized W bosons, in the Collins-Soper W rest frame, increases with the W transverse momentum at a rate of approximately 15% per 10 GeV/c.Comment: 47 pages, 16 figures, submitted to Physical Review

Measurement of the Ratio of b Quark Production Cross Sections in Antiproton-Proton Collisions at 630 GeV and 1800 GeV

We report a measurement of the ratio of the bottom quark production cross section in antiproton-proton collisions at 630 GeV to 1800 GeV using bottom quarks with transverse momenta greater than 10.75 GeV identified through their semileptonic decays and long lifetimes. The measured ratio sigma(630)/sigma(1800) = 0.171 +/- .024 +/- .012 is in good agreement with next-to-leading order (NLO) quantum chromodynamics (QCD)

Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice

Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans

Nicotinamide riboside (NR) is in wide use as an NAD(+) precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD(+) metabolism in humans. We report that human blood NAD(+) can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD(+) with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD(+) metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD(+), is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD(+) repletion