Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity

Ghrelin, the natural ligand of the growth hormone secretagogue receptor type la (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing epsilon-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes

Studies toward the Development of New Silicon-Containing Building Blocks for the Direct ¹⁸F‑Labeling of Peptides

Silicon-containing prosthetic groups have been conjugated to peptides to allow for a single-step labeling with ¹⁸F radioisotope. The fairly lipophilic di-<i>tert</i>-butylphenylsilane building block contributes unfavorably to the pharmacokinetic profile of bombesin conjugates. In this article, theoretical and experimental studies toward the development of more hydrophilic silicon-based building blocks are presented. Density functional theory calculations were used to predict the hydrolytic stability of di-<i>tert</i>-butylfluorosilanes <b>2</b>–<b>23</b> with the aim to improve the in vivo properties of ¹⁸F-labeled silicon-containing biomolecules. As a further step toward improving the pharmacokinetic profile, hydrophilic linkers were introduced between the lipophilic di-<i>tert</i>-butylphenylsilane building block and the bombesin congeners. Increased tumor uptake was shown with two of these peptides in xenograft-bearing mice using positron emission tomography and biodistribution studies. The introduction of a hydrophilic linker is thus a viable approach to improve the tumor uptake of ¹⁸F-labeled silicon–bombesin conjugates

Design, Synthesis, and Initial Evaluation of a High Affinity Positron Emission Tomography Probe for Imaging Matrix Metalloproteinases <b>2</b> and <b>9</b>

The activity of matrix metalloproteinases (MMPs) is elevated locally under many pathological conditions. Gelatinases MMP2 and MMP9 are of particular interest because of their implication in angiogenesis, cancer cell proliferation and metastasis, and atherosclerotic plaque rupture. The aim of this study was to identify and develop a selective gelatinase inhibitor for imaging active MMP2/MMP9 in vivo. We synthesized a series of <i>N</i>-sulfonylamino acid derivatives with low to high nanomolar inhibitory potencies. (<i>R</i>)-2-(4-(4-Fluorobenzamido)­phenylsulfonamido)-3-(1<i>H</i>-indol-3-yl)­propanoic acid (<b>7</b>) exhibited the best in vitro binding properties: MMP2 IC₅₀ = 1.8 nM, MMP9 IC₅₀ = 7.2 nM. Radiolabeling of <b>7</b> with no carrier added ¹⁸F-radioisotope was accomplished starting from iodonium salts as precursors. The radiochemical yield strongly depended on the iodonium counteranion (ClO₄^– > Br^– > TFA^– > tosylate). ¹⁸F-<b>7</b> was obtained in up to 20% radiochemical yield (decay corrected), high radiochemical purity, and >90 GBq/μmol specific radioactivity. The radiolabeled compound showed excellent stability in vitro and in mice in vivo

Two-particle Bose-Einstein correlations and their Lévy parameters in PbPb collisions at sNN\sqrt{s_\mathrm{NN}} = 5.02 TeV

Two-particle Bose-Einstein momentum correlation functions are studied for charged-hadron pairs in lead-lead collisions at a center-of-mass energy per nucleon pair of $\sqrt{s_\mathrm{NN}}$ = 5.02 TeV. The data sample, containing 4.27$\times10^{9}$ minimum bias events corresponding to an integrated luminosity of 0.607 nb$^{-1}$, was collected by the CMS experiment in 2018. The experimental results are discussed in terms of a L\'evy-type source distribution. The parameters of this distribution are extracted as functions of particle pair average transverse mass and collision centrality. These parameters include the L\'evy index or shape parameter ($\alpha$), the L\'evy scale parameter ($R$), and the correlation strength parameter ($\lambda$). The source shape, characterized by $\alpha$, is found to be neither Cauchy nor Gaussian, implying the need for a full L\'evy analysis. Similarly to what was previously found for systems characterized by Gaussian source radii, a hydrodynamical scaling is observed for the L\'evy $R$ parameter. The $\lambda$ parameter is studied in terms of the core-halo model.Comment: Submitted to Physical Review C. All figures and tables can be found at http://cms-results.web.cern.ch/cms-results/public-results/publications/HIN-21-011 (CMS Public Pages

Search for high-mass resonances decaying to a jet and a Lorentz-boosted resonance in proton-proton collisions at $\sqrt{s}=13\text{ }\text{ }\mathrm{TeV}

Physics letters / B 832, 137263 (2022). doi:10.1016/j.physletb.2022.137263 Published by North-Holland Publ., Amsterda