777 research outputs found
Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.
Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the β cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in β cells from the earliest expression of the Ins1 gene (∼E11.5) we have therefore used a Cre recombinase introduced at the Ins1 locus. Tcfl2(fl/fl)::Ins1Cre mice display impaired oral and intraperitoneal glucose tolerance by 8 and 16 weeks, respectively, and defective responses to the GLP-1 analogue liraglutide at 8 weeks. Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca(2+) increases, and connectivity between individual β cells, were both lowered by Tcf7l2 deletion in islets from mice maintained on a high (60%) fat diet. Finally, analysis by optical projection tomography revealed ∼30% decrease in β cell mass in pancreata from Tcfl2(fl/fl)::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination. The possible relevance of these findings for the action of TCF7L2 polymorphisms associated with Type 2 diabetes in man is discussed
The clustering of ultra-high energy cosmic rays and their sources
The sky distribution of cosmic rays with energies above the 'GZK cutoff'
holds important clues to their origin. The AGASA data, although consistent with
isotropy, shows evidence for small-angle clustering, and it has been argued
that such clusters are aligned with BL Lacertae objects, implicating these as
sources. It has also been suggested that clusters can arise if the cosmic rays
come from the decays of very massive relic particles in the Galactic halo, due
to the expected clumping of cold dark matter. We examine these claims and show
that both are in fact not justified.Comment: 13 pages, 8 figures, version in press at Phys. Rev.
Non-crossing dependencies: Least effort, not grammar
The use of null hypotheses (in a statistical sense) is common in hard sciences but not in theoretical linguistics. Here the null hypothesis that the low frequency of syntactic dependency crossings is expected by an arbitrary ordering of words is rejected. It is shown that this would require star dependency structures, which are both unrealistic and too restrictive. The hypothesis of the limited resources of the human brain is revisited. Stronger null hypotheses taking into account actual dependency lengths for the likelihood of crossings are presented. Those hypotheses suggests that crossings are likely to reduce when dependencies are shortened. A hypothesis based on pressure to reduce dependency lengths is more parsimonious than a principle of minimization of crossings or a grammatical ban that is totally dissociated from the general and non-linguistic principle of economy.Postprint (author's final draft
LKB1 and AMPK differentially regulate pancreatic β-cell identity.
Fully differentiated pancreatic β cells are essential for normal glucose homeostasis in mammals. Dedifferentiation of these cells has been suggested to occur in type 2 diabetes, impairing insulin production. Since chronic fuel excess ("glucotoxicity") is implicated in this process, we sought here to identify the potential roles in β-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly β-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis. Loss of LKB1 strikingly (2.0-12-fold, E<0.01) increased the expression of subsets of hepatic (Alb, Iyd, Elovl2) and neuronal (Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamate signaling. These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell "disallowed" genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E<0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P=1.3×10(-33)) and hypoxia-regulated (HIF1; P=2.5×10(-16)) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics. Selective targeting of these enzymes may provide a new approach to maintaining β-cell function in some forms of diabetes.-Kone, M., Pullen, T. J., Sun, G., Ibberson, M., Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S., Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J., Thorens, B., Reimann, F., Gribble, F., McGinty, J. A., Chen, L., French, P. M., Birzele, F., Hildebrandt, T., Uphues, I., Rutter, G. A. LKB1 and AMPK differentially regulate pancreatic β-cell identity
Search for composite and exotic fermions at LEP 2
A search for unstable heavy fermions with the DELPHI detector at LEP is
reported. Sequential and non-canonical leptons, as well as excited leptons and
quarks, are considered. The data analysed correspond to an integrated
luminosity of about 48 pb^{-1} at an e^+e^- centre-of-mass energy of 183 GeV
and about 20 pb^{-1} equally shared between the centre-of-mass energies of 172
GeV and 161 GeV. The search for pair-produced new leptons establishes 95%
confidence level mass limits in the region between 70 GeV/c^2 and 90 GeV/c^2,
depending on the channel. The search for singly produced excited leptons and
quarks establishes upper limits on the ratio of the coupling of the excited
fermio
Search for charginos in e+e- interactions at sqrt(s) = 189 GeV
An update of the searches for charginos and gravitinos is presented, based on
a data sample corresponding to the 158 pb^{-1} recorded by the DELPHI detector
in 1998, at a centre-of-mass energy of 189 GeV. No evidence for a signal was
found. The lower mass limits are 4-5 GeV/c^2 higher than those obtained at a
centre-of-mass energy of 183 GeV. The (\mu,M_2) MSSM domain excluded by
combining the chargino searches with neutralino searches at the Z resonance
implies a limit on the mass of the lightest neutralino which, for a heavy
sneutrino, is constrained to be above 31.0 GeV/c^2 for tan(beta) \geq 1.Comment: 22 pages, 8 figure
Search for lightest neutralino and stau pair production in light gravitino scenarios with stau NLSP
Promptly decaying lightest neutralinos and long-lived staus are searched for
in the context of light gravitino scenarios. It is assumed that the stau is the
next to lightest supersymmetric particle (NLSP) and that the lightest
neutralino is the next to NLSP (NNLSP). Data collected with the Delphi detector
at centre-of-mass energies from 161 to 183 \GeV are analysed. No evidence of
the production of these particles is found. Hence, lower mass limits for both
kinds of particles are set at 95% C.L.. The mass of gaugino-like neutralinos is
found to be greater than 71.5 GeV/c^2. In the search for long-lived stau,
masses less than 70.0 to 77.5 \GeVcc are excluded for gravitino masses from 10
to 150 \eVcc . Combining this search with the searches for stable heavy leptons
and Minimal Supersymmetric Standard Model staus a lower limit of 68.5 \GeVcc
may be set for the stau mas
Hadronization properties of b quarks compared to light quarks in e+e- -> q qbar from 183 to 200 GeV
The DELPHI detector at LEP has collected 54 pb^{-1} of data at a
centre-of-mass energy around 183 GeV during 1997, 158 pb^{-1} around 189 GeV
during 1998, and 187 pb^{-1} between 192 and 200 GeV during 1999. These data
were used to measure the average charged particle multiplicity in e+e- -> b
bbar events, _{bb}, and the difference delta_{bl} between _{bb} and the
multiplicity, _{ll}, in generic light quark (u,d,s) events: delta_{bl}(183
GeV) = 4.55 +/- 1.31 (stat) +/- 0.73 (syst) delta_{bl}(189 GeV) = 4.43 +/- 0.85
(stat) +/- 0.61 (syst) delta_{bl}(200 GeV) = 3.39 +/- 0.89 (stat) +/- 1.01
(syst). This result is consistent with QCD predictions, while it is
inconsistent with calculations assuming that the multiplicity accompanying the
decay of a heavy quark is independent of the mass of the quark itself.Comment: 13 pages, 2 figure
Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector
A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results
Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC
Measurements of inclusive jet suppression in heavy ion collisions at the LHC
provide direct sensitivity to the physics of jet quenching. In a sample of
lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated
luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with
a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the
transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the
anti-kt algorithm with values for the distance parameter that determines the
nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of
the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp.
Jet production is found to be suppressed by approximately a factor of two in
the 10% most central collisions relative to peripheral collisions. Rcp varies
smoothly with centrality as characterized by the number of participating
nucleons. The observed suppression is only weakly dependent on jet radius and
transverse momentum. These results provide the first direct measurement of
inclusive jet suppression in heavy ion collisions and complement previous
measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables,
submitted to Physics Letters B. All figures including auxiliary figures are
available at
http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02
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