264 research outputs found
Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis
open24siSelenoproteins are rare proteins among all kingdoms of life containing the 21st amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the substitution of selenium for sulfur. Yet the actual advantage of selenolate- versus thiolate-based catalysis has remained enigmatic, as most of the known selenoproteins also exist as cysteine-containing homologs. Here, we demonstrate that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis. Yet the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX4, thereby preventing fatal epileptic seizures. Mechanistically, selenocysteine utilization by GPX4 confers exquisite resistance to irreversible overoxidation as cells expressing a cysteine variant are highly sensitive toward peroxide-induced ferroptosis. Remarkably, concomitant deletion of all selenoproteins in Gpx4cys/cys cells revealed that selenoproteins are dispensable for cell viability provided partial GPX4 activity is retained. Conclusively, 200 years after its discovery, a specific and indispensable role for selenium is provided.openIngold, Irina; Berndt, Carsten; Schmitt, Sabine; Doll, Sebastian; Poschmann, Gereon; Buday, Katalin; Roveri, Antonella; Peng, Xiaoxiao; Porto Freitas, Florencio; Seibt, Tobias; Mehr, Lisa; Aichler, Michaela; Walch, Axel; Lamp, Daniel; Jastroch, Martin; Miyamoto, Sayuri; Wurst, Wolfgang; Ursini, Fulvio; Arnér, Elias S J; Fradejas-Villar, Noelia; Schweizer, Ulrich; Zischka, Hans; Friedmann Angeli, José Pedro; Conrad, MarcusIngold, Irina; Berndt, Carsten; Schmitt, Sabine; Doll, Sebastian; Poschmann, Gereon; Buday, Katalin; Roveri, Antonella; Peng, Xiaoxiao; Porto Freitas, Florencio; Seibt, Tobias; Mehr, Lisa; Aichler, Michaela; Walch, Axel; Lamp, Daniel; Jastroch, Martin; Miyamoto, Sayuri; Wurst, Wolfgang; Ursini, Fulvio; Arnér, Elias S J; Fradejas-Villar, Noelia; Schweizer, Ulrich; Zischka, Hans; Friedmann Angeli, José Pedro; Conrad, Marcu
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
Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma
Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted
therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is
fundamental for cell survival and contributes to different oncogenic signaling pathways.
Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several
cancer types. We have examined the expression of HSP90 in different adrenal tumors
and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC.
Methods: Immunohistochemical expression of HSP90 isoforms was investigated in
different adrenocortical tumors and associated with clinical features. Additionally, a
panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib,
and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested
on various ACC cell lines.
Results: Within adrenocortical tumors, ACC samples exhibited the highest expression
of HSP90β. Within a cohort of ACC patients, HSP90β expression levels were inversely
correlated with recurrence-free and overall survival. In functional assays, among five
different compounds tested luminespib and ganetespib induced a significant decrease
in cell viability in single as well as in combined treatments with compounds of the
clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of
cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation
of the ERK1/2—and AKT—pathways by luminespib and ganetespib treatment.
Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and
promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic
efficacy toward ACC
Physical Processes in Star Formation
© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s11214-020-00693-8.Star formation is a complex multi-scale phenomenon that is of significant importance for astrophysics in general. Stars and star formation are key pillars in observational astronomy from local star forming regions in the Milky Way up to high-redshift galaxies. From a theoretical perspective, star formation and feedback processes (radiation, winds, and supernovae) play a pivotal role in advancing our understanding of the physical processes at work, both individually and of their interactions. In this review we will give an overview of the main processes that are important for the understanding of star formation. We start with an observationally motivated view on star formation from a global perspective and outline the general paradigm of the life-cycle of molecular clouds, in which star formation is the key process to close the cycle. After that we focus on the thermal and chemical aspects in star forming regions, discuss turbulence and magnetic fields as well as gravitational forces. Finally, we review the most important stellar feedback mechanisms.Peer reviewedFinal Accepted Versio
Measurement of event-shape observables in Z→ℓ+ℓ− events in pp collisions at √ s=7 TeV with the ATLAS detector at the LHC
Event-shape observables measured using charged particles in inclusive
-boson events are presented, using the electron and muon decay modes of the
bosons. The measurements are based on an integrated luminosity of of proton--proton collisions recorded by the ATLAS detector at the
LHC at a centre-of-mass energy TeV. Charged-particle
distributions, excluding the lepton--antilepton pair from the -boson decay,
are measured in different ranges of transverse momentum of the boson.
Distributions include multiplicity, scalar sum of transverse momenta, beam
thrust, transverse thrust, spherocity, and -parameter, which are
in particular sensitive to properties of the underlying event at small values
of the -boson transverse momentum. The Sherpa event generator shows larger
deviations from the measured observables than Pythia8 and Herwig7. Typically,
all three Monte Carlo generators provide predictions that are in better
agreement with the data at high -boson transverse momenta than at low
-boson transverse momenta and for the observables that are less sensitive to
the number of charged particles in the event.Comment: 36 pages plus author list + cover page (54 pages total), 14 figures,
4 tables, submitted to EPJC, All figures including auxiliary figures are
available at
http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2014-0
Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for investigating .
Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for investigating the distribution of proteins and small molecules within biological systems through the in situ analysis of tissue sections. MALDI-IMS can determine the distribution of hundreds of unknown compounds in a single measurement and enables the acquisition of cellular expression profiles while maintaining the cellular and molecular integrity. In recent years, a great many advances in the practice of imaging mass spectrometry have taken place, making the technique more sensitive, robust, and ultimately useful. In this review, we focus on the current state of the art of MALDI-IMS, describe basic technological developments for MALDI-IMS of animal and human tissues, and discuss some recent applications in basic research and in clinical settings
<em>In situ</em> drug and metabolite analyzes in biological and clinical research by MALDI MS imaging.
In recent years the analysis in mass spectrometry imaging has been expanded to detect a wide variety of low molecular weight compounds (LMWC), including exogenous and endogenous compounds. The high sensitivity and selectivity of MS imaging combined with visualization of molecular spatial distribution in tissue making it to a valuable platform in targeted drug and untargeted metabolomic analyzes in biological and clinical research. Here, we review the current and potential applications of MALDI MS imaging in these areas. The aim of advancing MALDI MS imaging in the field of LMWC is to support clinical applications by understanding drug and drug-metabolite distribution, investigating toxicity and discover new biomarkers
MALDI Imaging mass spectrometry: Current frontiers and perspectives in pathology research and practice.
MALDI Imaging mass spectrometry has entered the field of tissue-based research by providing unique advantages for analyzing tissue specimen in an unprecedented detail. A broad spectrum of analytes ranging from proteins, peptides, protein modification over small molecules, drugs and their metabolites as well as pharmaceutical components, endogenous cell metabolites, lipids, and other analytes are made accessible by this in situ technique in tissue. Some of them were even not accessible in tissues within the histological context before. Thereby, the great advantage of MALDI Imaging is the correlation of molecular information with traditional histology by keeping the spatial localization information of the analytes after mass spectrometric measurement. This method is label-free and allows multiplex analysis of hundreds to thousands of molecules in the very same tissue section simultaneously. Imaging mass spectrometry brings a new quality of molecular data and links the expert discipline of pathology and deep molecular mass spectrometric analysis to tissue-based research. This review will focus on state-of-the-art of MALDI Imaging mass spectrometry, its recent applications by analyzing tissue specimen and the contributions in understanding the biology of disease as well as its perspectives for pathology research and practice
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