X-Box Binding Protein 1 Is Essential for Insulin Regulation of Pancreatic α-Cell Function

Patients with type 2 diabetes (T2D) often exhibit hyperglucagonemia despite hyperglycemia, implicating defective α-cell function. Although endoplasmic reticulum (ER) stress has been suggested to underlie β-cell dysfunction in T2D, its role in α-cell biology remains unclear. X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), and its deficiency in β-cells has been reported to impair insulin secretion, leading to glucose intolerance. To evaluate the role of XBP1 in α-cells, we created complementary in vivo (α-cell–specific XBP1 knockout [αXBPKO] mice) and in vitro (stable XBP1 knockdown α-cell line [αXBPKD]) models. The αXBPKO mice exhibited glucose intolerance, mild insulin resistance, and an inability to suppress glucagon secretion after glucose stimulation. αXBPKD cells exhibited activation of inositol-requiring enzyme 1, an upstream activator of XBP1, leading to phosphorylation of Jun NH2-terminal kinase. Interestingly, insulin treatment of αXBPKD cells reduced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) (pY896) and phosphorylation of Akt while enhancing serine phosphorylation (pS307) of IRS1. Consequently, the αXBPKD cells exhibited blunted suppression of glucagon secretion after insulin treatment in the presence of high glucose. Together, these data indicate that XBP1 deficiency in pancreatic α-cells induces altered insulin signaling and dysfunctional glucagon secretion

Assessment, Usability, and Sociocultural Impacts of DataONE

DataONE, funded from 2009-2019 by the U.S. National Science Foundation, is an early example of a large-scale project that built both a cyberinfrastructure and culture of data discovery, sharing, and reuse. DataONE used a Working Group model, where a diverse group of participants collaborated on targeted research and development activities to achieve broader project goals. This article summarizes the work carried out by two of DataONE’s working groups: Usability & Assessment (2009-2019) and Sociocultural Issues (2009-2014). The activities of these working groups provide a unique longitudinal look at how scientists, librarians, and other key stakeholders engaged in convergence research to identify and analyze practices around research data management through the development of boundary objects, an iterative assessment program, and reflection. Members of the working groups disseminated their findings widely in papers, presentations, and datasets, reaching international audiences through publications in 25 different journals and presentations to over 5,000 people at interdisciplinary venues. The working groups helped inform the DataONE cyberinfrastructure and influenced the evolving data management landscape. By studying working groups over time, the paper also presents lessons learned about the working group model for global large-scale projects that bring together participants from multiple disciplines and communities in convergence research

Unification of Luminous Type 1 Quasars through CIV Emission

Using a sample of 30,000 quasars from SDSS-DR7, we explore the range of properties exhibited by high-ionization, broad emission lines, such as CIV 1549. Specifically we investigate the anti-correlation between L_UV and emission line EQW (the Baldwin Effect) and the "blueshifting" of high-ionization emission lines. The blueshift of the CIV emission line is nearly ubiquitous, with a mean shift of 810 km/s for radio-quiet (RQ) quasars and 360 km/s for radio-loud (RL) quasars, and the Baldwin Effect is present in both RQ and RL samples. Composite spectra are constructed as a function of CIV emission line properties in attempt to reveal empirical relationships between different line species and the SED. Within a two-component disk+wind model of the broad emission line region (BELR), where the wind filters the continuum seen by the disk component, we find that RL quasars are consistent with being dominated by the disk component, while BALQSOs are consistent with being dominated by the wind component. Some RQ objects have emission line features similar to RL quasars; they may simply have insufficient black hole (BH) spin to form radio jets. Our results suggest that there could be significant systematic errors in the determination of L_bol and BH mass that make it difficult to place these findings in a more physical context. However, it is possible to classify quasars in a paradigm where the diversity of BELR parameters are due to differences in an accretion disk wind between quasars (and over time); these differences are underlain primarily by the SED, which ultimately must be tied to BH mass and accretion rate.Comment: 51 pages, 18 figures, accepted by AJ, revised version includes various modifications based on the referee's comment

Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound

Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (\u3e24 h) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state

Leptin receptor signaling regulates protein synthesis pathways and neuronal differentiation in pluripotent stem cells

The role of leptin receptor (OB-R) signaling in linking pluripotency with growth and development and the consequences of dysfunctional leptin signaling on progression of metabolic disease is poorly understood. Using a global unbiased proteomics approach we report that embryonic fibroblasts (MEFs) carrying the db/db mutation exhibit metabolic abnormalities, while their reprogrammed induced pluripotent stem cells (iPSCs) show altered expression of proteins involved in embryonic development. An upregulation in expression of eukaryotic translation initiation factor 4e (Eif4e) and Stat3 binding to the Eif4e promoter was supported by enhanced protein synthesis in mutant iPSCs. Directed differentiation of db/db iPSCs toward the neuronal lineage showed defects. Gene editing to correct the point mutation in db/db iPSCs using CRISPR-Cas9, restored expression of neuronal markers and protein synthesis while reversing the metabolic defects. These data imply a direct role for OB-R in regulating metabolism in embryonic fibroblasts and key developmental pathways in iPSCs.publishedVersio

Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes

Contributions D.D., A.H., S.G., S.P. and M.D. conceived the study and together with L.v.L., G.L., F.T. obtained the grant funding. AM executed the patient screening, recruitment, intervention planning, carried out all study investigations under respective specialist supervision (A.H./D.C./D.D. for magnetic resonance spectroscopy, F.T./G.L./D.D. for stable isotope investigation, S.G. for exercise intervention, S.P. for clinical supervision/management of diabetes as required, M.D. for all molecular laboratory analyses, A.M. analysed all data and performed statistical analysis under the supervision of G.H. L.v.L. provided expert advice in athletic physiology. Lipidomic analyses were carried out in P.W. laboratory. Blood/skeletal muscle enrichment analyses were carried out in B.F./F.T.-G.L. laboratories respectively, with practical input from R.G. A.R. and L.C. contributed as overall help to deliver study assessments in a technical role. M.K.H. analysed the food diaries. D.E.N. contributed to manuscript writing. D.D. and M.D. were the PhD supervisors for A.M. whose PhD thesis was based on this work. All authors contributed their respective specialist sections in drafting the manuscript.Peer reviewe

Epitaxial Graphene Growth on SiC Wafers

An in vacuo thermal desorption process has been accomplished to form epitaxial graphene (EG) on 4H- and 6H-SiC substrates using a commercial chemical vapor deposition reactor. Correlation of growth conditions and the morphology and electrical properties of EG are described. Raman spectra of EG on Si-face samples were dominated by monolayer thickness. This approach was used to grow EG on 50 mm SiC wafers that were subsequently fabricated into field effect transistors with fmax of 14 GHz.Comment: 215th Meeting of the Electrochemical Society, 8 pages, 8 figure

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected