Small Molecule Tools to Study Cellular Target Engagement for the Intracellular Allosteric Binding Site of GPCRs

Abstract A conserved intracellular allosteric binding site (IABS) has recently been identified at several G protein‐coupled receptors (GPCRs). Ligands targeting the IABS, so‐called intracellular allosteric antagonists, are highly promising compounds for pharmaceutical intervention and currently evaluated in several clinical trials. Beside co‐crystal structures that laid the foundation for the structure‐based development of intracellular allosteric GPCR antagonists, small molecule tools that enable an unambiguous identification and characterization of intracellular allosteric GPCR ligands are of utmost importance for drug discovery campaigns in this field. Herein, we discuss recent approaches that leverage cellular target engagement studies for the IABS and thus play a critical role in the evaluation of IABS‐targeted ligands as potential therapeutic agents

Cooperativity‐Driven Reactivity of a Dinuclear Copper Dimethylglyoxime Complex

In this report, we present the dinuclear copper(II) dimethylglyoxime (H$_2$dmg) complex [Cu$_2$(H$_2$dmg)(Hdmg)(dmg)]$^+$ (1), which, in contrast to its mononuclear analogue [Cu(Hdmg)$_2$] (2), is subject to a cooperativity-driven hydrolysis. The combined Lewis acidity of both copper centers increases the electrophilicity of the carbon atom in the bridging μ$_2$-O−N=C-group of H$_2$dmg and thus, facilitates the nucleophilic attack of H2O. This hydrolysis yields butane-2,3-dione monoxime (3) and NH$_2$OH that, depending on the solvent, is then either oxidized or reduced. In ethanol, NH$_2$OH is reduced to NH$_4$$^+$, yielding acetaldehyde as the oxidation product. In contrast, in CH$_3$CN, NH$_2$OH is oxidized by Cu$^{II}$ to form N$_2$O and [Cu(CH$_3$CN)4]$^+$. Herein are presented the combined synthetic, theoretical, spectroscopic and spectrometric methods that indicate and establish the reaction pathway of this solvent-dependent reaction

Landauer vs. Nernst: What is the True Cost of Cooling a Quantum System?

Thermodynamics connects our knowledge of the world to our capability to manipulate and thus to control it. This crucial role of control is exemplified by the third law of thermodynamics, Nernst's unattainability principle, stating that infinite resources are required to cool a system to absolute zero temperature. But what are these resources and how should they be utilised? And how does this relate to Landauer's principle that famously connects information and thermodynamics? We answer these questions by providing a framework for identifying the resources that enable the creation of pure quantum states. We show that perfect cooling is possible with Landauer energy cost given infinite time or control complexity. However, such optimal protocols require complex unitaries generated by an external work source. Restricting to unitaries that can be run solely via a heat engine, we derive a novel Carnot-Landauer limit, along with protocols for its saturation. This generalises Landauer's principle to a fully thermodynamic setting, leading to a unification with the third law and emphasising the importance of control in quantum thermodynamics.Comment: 15 pages, 4 figures, 46 pages of appendice

Fast and Not-so-Furious: Case Study of the Fast and Faint Type IIb SN 2021bxu

We present photometric and spectroscopic observations and analysis of SN~2021bxu (ATLAS21dov), a low-luminosity, fast-evolving Type IIb supernova (SN). SN~2021bxu is unique, showing a large initial decline in brightness followed by a short plateau phase. With $M_r = -15.93 \pm 0.16\, \mathrm{mag}$ during the plateau, it is at the lower end of the luminosity distribution of stripped-envelope supernovae (SE-SNe) and shows a distinct $\sim$10 day plateau not caused by H- or He-recombination. SN~2021bxu shows line velocities which are at least $\sim1500\,\mathrm{km\,s^{-1}}$ slower than typical SE-SNe. It is photometrically and spectroscopically similar to Type IIb SNe during the photospheric phases of evolution, with similarities to Ca-rich IIb SNe. We find that the bolometric light curve is best described by a composite model of shock interaction between the ejecta and an envelope of extended material, combined with a typical SN~IIb powered by the radioactive decay of $^{56}$Ni. The best-fit parameters for SN~2021bxu include a $^{56}$Ni mass of $M_{\mathrm{Ni}} = 0.029^{+0.004}_{-0.005}\,\mathrm{M_{\odot}}$, an ejecta mass of $M_{\mathrm{ej}} = 0.57^{+0.04}_{-0.03}\,\mathrm{M_{\odot}}$, and an ejecta kinetic energy of $K_{\mathrm{ej}} = 9.3^{+0.7}_{-0.6} \times 10^{49}\, \mathrm{erg}$. From the fits to the properties of the extended material of Ca-rich IIb SNe we find a trend of decreasing envelope radius with increasing envelope mass. SN~2021bxu has $M_{\mathrm{Ni}}$ on the low end compared to SE-SNe and Ca-rich SNe in the literature, demonstrating that SN~2021bxu-like events are rare explosions in extreme areas of parameter space. The progenitor of SN~2021bxu is likely a low mass He star with an extended envelope.Comment: 18 pages, 15 figures, submitted to MNRA

TESS Reveals HD 118203 b to be a Transiting Planet

The exoplanet HD 118203 b, orbiting a bright (V = 8.05) host star, was discovered using the radial velocity method by da Silva et al., but was not previously known to transit. Transiting Exoplanet Survey Satellite (TESS) photometry has revealed that this planet transits its host star. Nine planetary transits were observed by TESS, allowing us to measure the radius of the planet to be 1.136^(+0.029)_(-0.028) R_J, and to calculate the planet mass to be 2.166^(+0.074)_(-0.079) M_J. The host star is slightly evolved with an effective temperature of T_(eff) = 5683^(+84)_(-85) K and a surface gravity of log g = 3.889^(+0.017)_(-0.018). With an orbital period of 6.134985^(+0.000029_(-0.000030) days and an eccentricity of 0.314 ± 0.017, the planet occupies a transitional regime between circularized hot Jupiters and more dynamically active planets at longer orbital periods. The host star is among the 10 brightest known to have transiting giant planets, providing opportunities for both planetary atmospheric and asteroseismic studies

Sicherung von Dämmen, Deichen und Stauanlagen : Handbuch für Theorie und Praxis ; Vol. V - 2015

Die Universität Siegen beschäftigt sich seit über 15 Jahren wissenschaftlich und im Bereich der anwendungsorientierten Forschung mit diesem Thema und hat dazu mittlerweile fünf Symposien durchgeführt. Mit der Veröffentlichung soll die langjährige Tradition als etablierte wissenschaftliche Plattform mit einem Wissensaustausch auf europäischer Ebene fortgesetzt werden. Die Bearbeitung dieser Thematik erfolgt auf der Basis der bewährten Kooperation zwischen Geotechnik und Wasserbau an der Universität Siegen. Aktuelle Ereignisse, wie z.B. die aus England oder Australien im Februar des Jahres 2014, machen uns aber auch deutlich, dass ein absoluter Schutz gegen Extremereignisse nicht möglich ist. Sie zeigen aber auch, dass dort wo technischer Hochwasserschutz konsequent umgesetzt wurde Schäden vermieden werden konnten. Wir sind nach den Ereignissen in den vergangenen Jahren aufgefordert wissenschaftlich noch leistungsfähigere und duktilere Systeme zu entwickeln. Weiter ist die Wissenschaft in der Pflicht, die Zivile Sicherheit im Hochwasser-schutz permanent zu bewerten, zu bearbeiten und ganzheitliche-interdisziplinäre und länderübergreifende Lösungen für die Zivilgesellschaft einzufordern

The TESS-Keck Survey. III. A Stellar Obliquity Measurement of TOI-1726 c

We report the measurement of a spectroscopic transit of TOI-1726c, one of two planets transiting a G-type star with V = 6.9 in the Ursa Major Moving Group (~400 Myr). With a precise age constraint from cluster membership, TOI-1726 provides a great opportunity to test various obliquity excitation scenarios that operate on different timescales. By modeling the Rossiter–McLaughlin (RM) effect, we derived a sky-projected obliquity of −1^(+35)_(−32)∘. This result rules out a polar/retrograde orbit and is consistent with an aligned orbit for planet c. Considering the previously reported, similarly prograde RM measurement of planet b and the transiting nature of both planets, TOI-1726 tentatively conforms to the overall picture that compact multitransiting planetary systems tend to have coplanar, likely aligned orbits. TOI-1726 is also a great atmospheric target for understanding differential atmospheric loss of sub-Neptune planets (planet b 2.2 R⊕ and c 2.7 R⊕ both likely underwent photoevaporation). The coplanar geometry points to a dynamically cold history of the system that simplifies any future modeling of atmospheric escape

Mineral Detection of Neutrinos and Dark Matter 2024. Proceedings

The second "Mineral Detection of Neutrinos and Dark Matter" (MDvDM'24) meeting was held January 8-11, 2024 in Arlington, VA, USA, hosted by Virginia Tech's Center for Neutrino Physics. This document collects contributions from this workshop, providing an overview of activities in the field. MDvDM'24 was the second topical workshop dedicated to the emerging field of mineral detection of neutrinos and dark matter, following a meeting hosted by IFPU in Trieste, Italy in October 2022. Mineral detectors have been proposed for a wide variety of applications, including searching for dark matter, measuring various fluxes of astrophysical neutrinos over gigayear timescales, monitoring nuclear reactors, and nuclear disarmament protocols; both as paleo-detectors using natural minerals that could have recorded the traces of nuclear recoils for timescales as long as a billion years and as detectors recording nuclear recoil events on laboratory timescales using natural or artificial minerals. Contributions to this proceedings discuss the vast physics potential, the progress in experimental studies, and the numerous challenges lying ahead on the path towards mineral detection. These include a better understanding of the formation and annealing of recoil defects in crystals; identifying the best classes of minerals and, for paleo-detectors, understanding their geology; modeling and control of the relevant backgrounds; developing, combining, and scaling up imaging and data analysis techniques; and many others. During the last years, MDvDM has grown rapidly and gained attention. Small-scale experimental efforts focused on establishing various microscopic readout techniques are underway at institutions in North America, Europe and Asia. We are looking ahead to an exciting future full of challenges to overcome, surprises to be encountered, and discoveries lying ahead of us.Comment: Summary and proceedings of the MDvDM'24 conference, Jan 8-11 202

Searching for eV-scale sterile neutrinos with eight years of atmospheric neutrinos at the IceCube neutrino telescope

We report in detail on searches for eV-scale sterile neutrinos, in the context of a 3+1 model, using eight years of data from the IceCube neutrino telescope. By analyzing the reconstructed energies and zenith angles of 305,735 atmospheric $\nu_\mu$ and $\bar{\nu}_\mu$ events we construct confidence intervals in two analysis spaces: $\sin^2 (2\theta_{24})$ vs. $\Delta m^2_{41}$ under the conservative assumption $\theta_{34}=0$; and $\sin^2(2\theta_{24})$ vs. $\sin^2 (2\theta_{34})$ given sufficiently large $\Delta m^2_{41}$ that fast oscillation features are unresolvable. Detailed discussions of the event selection, systematic uncertainties, and fitting procedures are presented. No strong evidence for sterile neutrinos is found, and the best-fit likelihood is consistent with the no sterile neutrino hypothesis with a p-value of 8\% in the first analysis space and 19\% in the second.Comment: This long-form paper is a companion to the letter "An eV-scale sterile neutrino search using eight years of atmospheric muon neutrino data from the IceCube Neutrino Observatory". v2: update other experiments contours on results plo

LeptonInjector and LeptonWeighter: A neutrino event generator and weighter for neutrino observatories

We present a high-energy neutrino event generator, called LeptonInjector, alongside an event weighter, called LeptonWeighter. Both are designed for large-volume Cherenkov neutrino telescopes such as IceCube. The neutrino event generator allows for quick and flexible simulation of neutrino events within and around the detector volume, and implements the leading Standard Model neutrino interaction processes relevant for neutrino observatories: neutrino-nucleon deep-inelastic scattering and neutrino-electron annihilation. In this paper, we discuss the event generation algorithm, the weighting algorithm, and the main functions of the publicly available code, with examples.Comment: 28 pages, 10 figures, 3 table