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The ILC as a natural SUSY discovery machine and precision microscope: from light higgsinos to tests of unification
No full textThe requirement of electroweak naturalness in simple supersymmetric models implies the existence of a cluster of four light Higgsinos with a mass ∼100–300 GeV, the lighter the better. While such light compressed spectra may be challenging to observe at the LHC, the International Linear e+e- Collider (ILC) with s>2mHiggsino would serve as both a SUSY discovery machine and a precision microscope. We study Higgsino pair production signatures at the ILC based on a full, geant4-based simulation of the ILD detector concept. We examine several benchmark scenarios that may be challenging for discovery at the HL-LHC due to mass differences between the Higgsino states between 20 and 4 GeV. Assuming s=500 GeV and 1000 fb-1 of integrated luminosity, the individual Higgsino masses can be measured to 1%–2% precision in the case of the larger mass differences, and at the level of 5% for the smallest mass difference case. The Higgsino mass splittings are sensitive to the electroweak gaugino masses and allow extraction of gaugino masses to ∼3%–20% (depending on the model). Extrapolation of gaugino masses via renormalization group running can test the hypothesis of gaugino mass unification. We also examine a case with natural generalized mirage mediation, where the unification of gaugino masses at an intermediate scale apparently gives rise to a natural SUSY spectrum somewhat beyond the reach of HL-LHC
Enhancing hydrogenation activity of Ni-Mo sulfide hydrodesulfurization catalysts
No full textUnsupported Ni-Mo sulfides have been hydrothermally synthesized and purified by HCl leaching to remove Ni sulfides. Unblocking of active sites by leaching significantly increases the catalytic activity for dibenzothiophene hydrodesulfurization. The site-specific rates of both direct (hydrogenolytic) and hydrogenative desulfurization routes on these active sites that consist of coordinatively unsaturated Ni and sulfhydryl groups were identical for all unsupported sulfides. The hydrogenative desulfurization rates were more than an order of magnitude higher on unsupported Ni-Mo sulfides than on AlO-supported catalysts, while they were similar for the direct (hydrogenolytic) desulfurization. The higher activity is concluded to be caused by the lower average electronegativity, i.e., higher base strength and polarity, of Ni-Mo sulfides in the absence of the alumina support and the modified adsorption of reactants enabled by multilayer stacking. Beyond the specific catalytic reaction, the synthesis strategy points to promising scalable routes to sulfide materials broadly applied in hydrogenation and hydrotreating
Structural Characterization of an S-enantioselective Imine Reductase from Mycobacterium Smegmatis
No full textNADPH-dependent imine reductases (IREDs) are enzymes capable of enantioselectively reducing imines to chiral secondary amines, which represent important building blocks in the chemical and pharmaceutical industry. Since their discovery in 2011, many previously unknown IREDs have been identified, biochemically and structurally characterized and categorized into families. However, the catalytic mechanism and guiding principles for substrate specificity and stereoselectivity remain disputed. Herein, we describe the crystal structure of S-IRED-Ms from Mycobacterium smegmatis together with its cofactor NADPH. S-IRED-Ms belongs to the S-enantioselective superfamily 3 (SFam3) and is the first IRED from SFam3 to be structurally described. The data presented provide further evidence for the overall high degree of structural conservation between different IREDs of various superfamilies. We discuss the role of Asp170 in catalysis and the importance of hydrophobic amino acids in the active site for stereospecificity. Moreover, a separate entrance to the active site, potentially functioning according to a gatekeeping mechanism regulating access and, therefore, substrate specificity is described
Structure-based design approach to rational site-directed mutagenesis of β-lactoglobulin
No full textRecombinant proteins play an important role in medicine and have diverse applications in industrial biotechnology. Lactoglobulin has shown great potential for use in targeted drug delivery and body fluid detoxification because of its ability to bind a variety of molecules. In order to modify the biophysical properties of β-lactoglobulin, a series of single-site mutations were designed using a structure-based approach. A 3-dimensional structure alignment of homologous molecules led to the design of nine β-lactoglobulin variants with mutations introduced in the binding pocket region. Seven stable and correctly folded variants (L39Y, I56F, L58F, V92F, V92Y, F105L, M107L) were thoroughly characterized by fluorescence, circular dichroism, isothermal titration calorimetry, size-exclusion chromatography, and X-ray structural investigations. The effects of the amino acid substitutions were observed as slight rearrangements of the binding pocket geometry, but they also significantly influenced the global properties of the protein. Most of the mutations increased the thermal/chemical stability without altering the dimerization constant or pH-dependent conformational behavior. The crystal structures reveal that the I56F and F105L mutations reduced the depth of the binding pocket, which is advantageous since it can reduce the affinity to endogenous fatty acids. The F105L mutant created a unique binding mode for a fatty acid, supporting the idea that lactoglobulin can be altered to bind unique molecules. Selected variants possessing a unique combination of their individual properties can be used for further, more advanced mutagenesis, and the presented results support further research using β-lactoglobulin as a therapeutic delivery agent or a blood detoxifying molecule
Molecular basis of MKLP2-dependent Aurora B transport from chromatin to the anaphase central spindle
No full textThe Aurora B chromosomal passenger complex (CPC) is a conserved regulator of mitosis. Its functions require localization first to the chromosome arms and then centromeres in mitosis and subsequently the central spindle in anaphase. Here, we analyze the requirements for core CPC subunits, survivin and INCENP, and the mitotic kinesin-like protein 2 (MKLP2) in targeting to these distinct localizations. Centromere recruitment of the CPC requires interaction of survivin with histone H3 phosphorylated at threonine 3, and we provide a complete structure of this assembly. Furthermore, we show that the INCENP RRKKRR-motif is required for both centromeric localization of the CPC in metaphase and MKLP2-dependent transport in anaphase. MKLP2 and DNA bind competitively to this motif, and INCENP T59 phosphorylation acts as a switch preventing MKLP2 binding in metaphase. In anaphase, CPC binding promotes the microtubule-dependent ATPase activity of MKLP2. These results explain how centromere targeting of the CPC in mitosis is coupled to its movement to the central spindle in anaphase
From spin chains to real-time thermal field theory using tensor networks
No full textOne of the most interesting directions in theoretical high-energy and condensed-matter physics is understanding dynamical properties of collective states of quantum field theories. The most elementary tool in this quest is retarded equilibrium correlators governing the linear response theory. In this article we examine tensor networks as a way of determining them in a fully ab initio way in a class of (1 + 1)-dimensional quantum field theories arising as infrared descriptions of quantum Ising chains. We show that, complemented with signal analysis using the Prony method, tensor network calculations for intermediate times provide a powerful way to explore the structure of singularities of the correlator in the complex frequency plane and to make predictions about the thermal response to perturbations in a class of nonintegrable interacting quantum field theories
Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering
No full textB29Nε-lithocholyl-γ-l-βGlu-desB30 human insulin [NN344] belongs to a group of insulins with fatty acid or sterol modifications. These insulin analogues have been found to form subcutaneous depots upon injection and hereby have a protracted release profile in vivo. In the present study, B29Nε-lithocholyl-γ-l-Glu-desB30 human insulin was investigated using in-solution small-angle X-ray scattering (SAXS) at chemical conditions designed to mimic three stages during treatment in vivo: in-vial/pen, postinjection, and longer times after injection. We found that the specific insulin analogue formed a mixture of mono- and dihexamers under in-vial/pen conditions of low salt and stabilizing phenol. At postinjection, conditions mimicking a subcutaneous depot, B29Nε-lithocholyl-γ-l-Glu-desB30 human insulin, formed very long straight soluble hexamer-based rods stacked along the Zn(II)-axis. The self-assembly was triggered by an increase in salt concentration when going from vial to physiological conditions. Mimicking longer times after injection and the additional removal of phenol caused the length of the rods to decrease significantly. Finally, we found that the self-assembly could be controlled by varying the amount of modification at the interaction interface by making mixed hexamers of B29Nε-lithocholyl-γ-l-Glu-desB30 and desB30 human insulin. This opens extra possibilities for controlling the release profile of very-long-acting insulins
Rapidly Forming Early Intermediate Structures Dictate the Pathway of Capsid Assembly
No full textThere are ∼10 possible intermediates on the assembly path from hepatitis B capsid protein dimers to the 120-dimer capsid. If every intermediate was tested, assembly would often get stuck in an entropic trap and essentially every capsid would follow a unique assembly path. Yet, capsids assemble rapidly with minimal trapped intermediates, a realization of the Levinthal paradox. To understand the fundamental mechanisms of capsid assembly, it is critical to resolve the early stages of the reaction. We have used time-resolved small angle X-ray scattering, which is sensitive to solute size and shape and has millisecond temporal resolution. Scattering curves were fit to a thermodynamically curated library of assembly intermediates, using the principle of maximum entropy. Maximum entropy also provides a physical rationale for the selection of species. We found that the capsid assembly pathway was exquisitely sensitive to initial assembly conditions. With the mildest conditions tested, the reaction appeared to be two-state from dimer to 120-dimer capsid with some dimers-of-dimers and trimers-of-dimers. In slightly more aggressive conditions, we observed transient accumulation of a decamer-of-dimers and the appearance of 90-dimer capsids. In conditions where there is measurable kinetic trapping, we found that highly diverse early intermediates accumulated within a fraction of a second and propagated into long-lived kinetically trapped states (≥90-mer). In all cases, intermediates between 35 and 90 subunits did not accumulate. These results are consistent with the presence of low barrier paths that connect early and late intermediates and direct the ultimate assembly path to late intermediates where assembly can be paused
Search for dark matter signals towards a selection of recently detected DES dwarf galaxy satellites of the Milky Way with H.E.S.S.
No full textDwarf spheroidal galaxy satellites of the Milky Way are prime targets for indirect detection of dark matter with gamma rays due to their proximity, high dark matter content, and absence of nonthermal emission processes. Recently, the Dark Energy Survey (DES) revealed the existence of new ultrafaint dwarf spheroidal galaxies in the southern-hemisphere sky, therefore ideally located for ground-based observations with the imaging atmospheric Cherenkov telescope array H.E.S.S. We present a search for very-high-energy (E≳100 GeV) gamma-ray emission using H.E.S.S. observations carried out recently towards Reticulum II, Tucana II, Tucana III, Tucana IV, and Grus II satellites. No significant very-high-energy gamma-ray excess is found from the observations on any individual object nor in the combined analysis of all the datasets. Using the most recent modeling of the dark matter distribution in the dwarf galaxy halo, we compute for the first time on DES satellites individual and combined constraints from Cherenkov telescope observations on the annihilation cross section of dark matter particles in the form of Weakly Interacting Massive Particles. The combined 95% C.L. observed upper limits reach ⟨σv⟩≃ in the channel and in the channels for a dark matter mass of 1.5 TeV. The H.E.S.S. constraints well complement the results from Fermi-LAT, HAWC, MAGIC, and VERITAS and are currently the most stringent in the channels in the multi-GeV/multi-TeV mass range