Proper Analytic Free Maps

This paper concerns analytic free maps. These maps are free analogs of classical analytic functions in several complex variables, and are defined in terms of non-commuting variables amongst which there are no relations - they are free variables. Analytic free maps include vector-valued polynomials in free (non-commuting) variables and form a canonical class of mappings from one non-commutative domain D in say g variables to another non-commutative domain D' in g' variables. As a natural extension of the usual notion, an analytic free map is proper if it maps the boundary of D into the boundary of D'. Assuming that both domains contain 0, we show that if f:D->D' is a proper analytic free map, and f(0)=0, then f is one-to-one. Moreover, if also g=g', then f is invertible and f^(-1) is also an analytic free map. These conclusions on the map f are the strongest possible without additional assumptions on the domains D and D'.Comment: 17 pages, final version. To appear in the Journal of Functional Analysi

Structural Diversity of the Active N-Terminal Kinase Domain of p90 Ribosomal S6 Kinase 2

The p90 ribosomal protein kinase 2 (RSK2) is a highly expressed Ser/Thr kinase activated by growth factors and is involved in cancer cell proliferation and tumor promoter-induced cell transformation. RSK2 possesses two non-identical kinase domains, and the structure of its N-terminal domain (NTD), which is responsible for phosphorylation of a variety of substrates, is unknown. The crystal structure of the NTD RSK2 was determined at 1.8 Å resolution in complex with AMP-PNP. The N-terminal kinase domain adopted a unique active conformation showing a significant structural diversity of the kinase domain compared to other kinases. The NTD RSK2 possesses a three-stranded βB-sheet inserted in the N-terminal lobe, resulting in displacement of the αC-helix and disruption of the Lys-Glu interaction, classifying the kinase conformation as inactive. The purified protein was phosphorylated at Ser227 in the T-activation loop and exhibited in vitro kinase activity. A key characteristic is the appearance of a new contact between Lys216 (βB-sheet) and the β-phosphate of AMP-PNP. Mutation of this lysine to alanine impaired both NTDs in vitro and full length RSK2 ex vivo activity, emphasizing the importance of this interaction. Even though the N-terminal lobe undergoes structural re-arrangement, it possesses an intact hydrophobic groove formed between the αC-helix, the β4-strand, and the βB-sheet junction, which is occupied by the N-terminal tail. The presence of a unique βB-sheet insert in the N-lobe suggests a different type of activation mechanism for RSK2

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

Studies of a Ring-Cleaving Dioxygenase Illuminate the Role of Cholesterol Metabolism in the Pathogenesis of Mycobacterium tuberculosis

Mycobacterium tuberculosis, the etiological agent of TB, possesses a cholesterol catabolic pathway implicated in pathogenesis. This pathway includes an iron-dependent extradiol dioxygenase, HsaC, that cleaves catechols. Immuno-compromised mice infected with a ΔhsaC mutant of M. tuberculosis H37Rv survived 50% longer than mice infected with the wild-type strain. In guinea pigs, the mutant disseminated more slowly to the spleen, persisted less successfully in the lung, and caused little pathology. These data establish that, while cholesterol metabolism by M. tuberculosis appears to be most important during the chronic stage of infection, it begins much earlier and may contribute to the pathogen's dissemination within the host. Purified HsaC efficiently cleaved the catecholic cholesterol metabolite, DHSA (3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione; kcat/Km = 14.4±0.5 µM−1 s−1), and was inactivated by a halogenated substrate analogue (partition coefficient<50). Remarkably, cholesterol caused loss of viability in the ΔhsaC mutant, consistent with catechol toxicity. Structures of HsaC:DHSA binary complexes at 2.1 Å revealed two catechol-binding modes: bidentate binding to the active site iron, as has been reported in similar enzymes, and, unexpectedly, monodentate binding. The position of the bicyclo-alkanone moiety of DHSA was very similar in the two binding modes, suggesting that this interaction is a determinant in the initial substrate-binding event. These data provide insights into the binding of catechols by extradiol dioxygenases and facilitate inhibitor design

Gamma-Ray Burst observations by the high-energy charged particle detector on board the CSES-01 satellite between 2019 and 2021

In this paper we report the detection of five strong Gamma-Ray Bursts (GRBs) by the High-Energy Particle Detector (HEPD-01) mounted on board the China Seismo-Electromagnetic Satellite (CSES-01), operational since 2018 on a Sun-synchronous polar orbit at a $\sim$ 507 km altitude and 97$^\circ$ inclination. HEPD-01 was designed to detect high-energy electrons in the energy range 3 - 100 MeV, protons in the range 30 - 300 MeV, and light nuclei in the range 30 - 300 MeV/n. Nonetheless, Monte Carlo simulations have shown HEPD-01 is sensitive to gamma-ray photons in the energy range 300 keV - 50 MeV, even if with a moderate effective area above $\sim$ 5 MeV. A dedicated time correlation analysis between GRBs reported in literature and signals from a set of HEPD-01 trigger configuration masks has confirmed the anticipated detector sensitivity to high-energy photons. A comparison between the simultaneous time profiles of HEPD-01 electron fluxes and photons from GRB190114C, GRB190305A, GRB190928A, GRB200826B and GRB211211A has shown a remarkable similarity, in spite of the different energy ranges. The high-energy response, with peak sensitivity at about 2 MeV, and moderate effective area of the detector in the actual flight configuration explain why these five GRBs, characterised by a fluence above $\sim$ 3 $\times$ 10$^{-5}$ erg cm$^{-2}$ in the energy interval 300 keV - 50 MeV, have been detected.Comment: Accepted for publication in The Astrophysical Journal (ApJ

Neutrino Physics with JUNO

The Jiangmen Underground Neutrino Observatory (JUNO), a 20 kton multi-purposeunderground liquid scintillator detector, was proposed with the determinationof the neutrino mass hierarchy as a primary physics goal. It is also capable ofobserving neutrinos from terrestrial and extra-terrestrial sources, includingsupernova burst neutrinos, diffuse supernova neutrino background, geoneutrinos,atmospheric neutrinos, solar neutrinos, as well as exotic searches such asnucleon decays, dark matter, sterile neutrinos, etc. We present the physicsmotivations and the anticipated performance of the JUNO detector for variousproposed measurements. By detecting reactor antineutrinos from two power plantsat 53-km distance, JUNO will determine the neutrino mass hierarchy at a 3-4sigma significance with six years of running. The measurement of antineutrinospectrum will also lead to the precise determination of three out of the sixoscillation parameters to an accuracy of better than 1\%. Neutrino burst from atypical core-collapse supernova at 10 kpc would lead to ~5000inverse-beta-decay events and ~2000 all-flavor neutrino-proton elasticscattering events in JUNO. Detection of DSNB would provide valuable informationon the cosmic star-formation rate and the average core-collapsed neutrinoenergy spectrum. Geo-neutrinos can be detected in JUNO with a rate of ~400events per year, significantly improving the statistics of existing geoneutrinosamples. The JUNO detector is sensitive to several exotic searches, e.g. protondecay via the $p\to K^++\bar\nu$ decay channel. The JUNO detector will providea unique facility to address many outstanding crucial questions in particle andastrophysics. It holds the great potential for further advancing our quest tounderstanding the fundamental properties of neutrinos, one of the buildingblocks of our Universe

A novel bipartite phospholipid-binding module in the neurofibromatosis type 1 protein

Neurofibromatosis type 1 (NF1) is a common tumour predisposition syndrome associated with numerous clinical complications. Mutations in the tumour suppressor gene NF1 are responsible for disease pathogenesis. This gene encodes the 320 kDa protein neurofibromin, the only clearly defined function of which is to act as a Ras-specific GTPase-activating protein (RasGAP). Here we report the structural discovery of a novel module in neurofibromin, composed of a Sec14p homologous segment and a previously undetected pleckstrin homology (PH)-like domain of potentially novel function. We show phospholipid binding by this bipartite module and identify residues that are involved in this activity; we also show that the PH-like domain is not sufficient for lipid binding. The unique architecture of the domain interface points to a model of how the PH-like domain may regulate binding of a ligand by the Sec14 module

Abstract 2680: Nonautoinhibitory properties of the C-terminal helix of the mitogen- and stress-activated protein kinase 1

Abstract Mitogen- and stress-activated protein kinase 1 (MSK1) is a growth factor-stimulated serine/threonine kinase that is important in the regulation of gene transcription and proinflammatory cytokine stimulation. MSK1 is a dual kinase possessing two distinct kinase domains linked by a hydrophobic region. The C-terminal kinase domain (CTD MSK1) is an important regulatory domain activated by ERKs and p38 mitogen-activated protein kinases (MAPKs) in response to various cellular stimuli. The activity of full length MSK1 is controlled by multiple phosphorylation sites and is mediated through stimulation of the C-terminal kinase domain. We have determined the crystal structure of the isolated active CTD MSK1 (residues 414-738) in apo- form and in complex with the non-hydrolyzable ATP analogue AMP-PNP at 2.0 and 2.5 Å resolution, respectively. The structure showed that, despite overall similarity with the p90 ribosomal S6 kinase 2 (RSK2) and the MAPK-activated protein kinase 2 (MK2), the CTD MSK1 is unexpectedly not autoinhibited by the C-terminal αL-helix. The helix does not form hydrogen bonds with a substrate-binding loop and nearby helices and lacks putative “inhibitory” residues responsible for the interaction with the kinase core. CTD MSK1 undergoes active autophosphorylation in vitro as shown by luminescent assay, and mutation of two residues, H712K and F719Y, located on the αL-helix does not convert it to RSK2-like autoinhibitory state. The protein was phosphorylated at Thr581 in the T-activation loop, and a T581A mutant showed significantly impaired autokinase activity. The “full length” C-terminal domain of MSK1 (residues 414-802) possessed weaker autophosphorylation activity compared with the truncated fragment (residues 414-738), which lacks the MAPK-docking site. Overexpression of active truncated CTD MSK1 (residues 414-738) in JB6 cells resulted in neoplastic transformation in response to EGF or TPA stimulation in a manner similar to that induced by the full length MSK1. On the other hand, the “full length” CTD (residues 414-802) suppressed colony formation ex vivo. This results indicate that the extreme C-terminal tail (residues 739-802), which encloses the ERK/p38 docking site, inhibits CTD MSK1 kinase activity. Using surface plasmon resonance (SPR) binding experiments, we showed that the C-terminal end-deleted construct does not interact with ERK1 in vitro, but the “full length” CTD MSK1 binds with ERK1 in a dose-dependent manner with a KD ∼ 70 nM. Similar binding results were obtained for interaction with ERK2 and p38. The SPR data indicate that the αL-helix is not involved in the interaction with MAP kinases. The intrinsic non-autoinhibitory C-terminal αL-helix feature suggests that the CTD has a αL-helix-independent activation mechanism, and the MAPK-docking site may regulate CTD MSK1 activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2680.</jats:p