12 research outputs found
Economic innovation and sociological analysis : a proposal for a model of entrepreneurship in urban economic development
Activity Enhancement of the Synthetic Syrbactin Proteasome Inhibitor Hybrid and Biological Evaluation in Tumor Cells
Syrbactins belong to a recently emergent class of bacterial
natural
product inhibitors that irreversibly inhibit the proteasome of eukaryotes
by a novel mechanism. The total syntheses of the syrbactin molecules
syringolin A, syringolin B, and glidobactin A have been achieved,
which allowed the preparation of syrbactin-inspired derivatives, such
as the syringolin A–glidobactin A hybrid molecule (SylA–GlbA).
To determine the potency of SylA–GlbA, we employed both in
vitro and cell culture-based proteasome assays that measure the subcatalytic
chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L)
activities. We further studied the inhibitory effects of SylA–GlbA
on tumor cell growth using a panel of multiple myeloma, neuroblastoma,
and ovarian cancer cell lines and showed that SylA–GlbA strongly
blocks the activity of NF-κB. To gain more insights into the
structure–activity relationship, we cocrystallized SylA–GlbA
in complex with the proteasome and determined the X-ray structure.
The electron density map displays covalent binding of the Thr1O<sup>γ</sup> atoms of all active sites to the macrolactam ring of
the ligand via ether bond formation, thus providing insights into
the structure–activity relationship for the improved affinity
of SylA–GlbA for the CT-L activity compared to those of the
natural compounds SylA and GlbA. Our study revealed that the novel
synthetic syrbactin compound represents one of the most potent proteasome
inhibitors analyzed to date and therefore exhibits promising properties
for improved drug development as an anticancer therapeutic
Determination of the Ground Electronic State in Transition Metal Halides: ZrF
The spectroscopy of the ZrF radical, produced by a laser ablation-molecular beam experimental setup, has been investigated for the first time using a two-color two-photon (1 + 1′) REMPI scheme and time-of-flight (TOF) mass spectrometry detection. The region of intense bands 400-470 nm has been studied, based upon the first spectroscopic observations of the isovalent ZrCl radical by Carroll and Daly.(1)The overall spectrum observed is complex. However, simultaneous and individual ion detection of the five naturally occurring isotopologues of ZrF has provided a crucial means of identifying band origins and characterization via the isotopic shift, δ iso, of the numerous vibronic transitions recorded. Hence, five (0-0) transitions, of which only two were free of overlap with other transitions, have been identified. The most intense (0-0) transition at 23113 cm -1 presented an unambiguously characteristic RQP rotational structure. From rotational contour simulations of the observed spectra, the nature of the ground electronic state is found to be unambiguously of 2Δ symmetry, leading to the assignment of this band as (0-0) 2Δ ← X 2Δ at 23113 cm -1. A set of transitions (1-0) 2Δ ← X 2Δ at 22105 cm -1 and (2-0) 2 ← X 2Δ at 22944 cm -1 involving the X 2Δ state has also been identified and analyzed. Furthermore, a second series of transitions with lesser intensity has also been related to the long-lived metastable 4Σ - state: (3-0) 4Π -1/2 ← 4Σ - at 21801 cm -1, (2-0) 4Π -1/2 ← 4Σ - at 21285 cm -1 and (2-0) 4Σ - ← 4Σ - at 23568 cm -1. These spectroscopic assignments are supported by MRCI ab initio calculations, performed using the MOLPRO quantum chemistry package, and show that the low-lying excited states of the ZrF radical are the 4Σ - and 4 states lying at 2383 and 4179 cm -1 respectively above the ground X 2Δ state. The difference in the nature of ground state and ordering of the first electronic states with TiF (X 4)(2-4)and ZrCl,(5)respectively, is examined in terms of the ligand field theory (LFT)(7)applied to diatomic molecules. These results give a precise description of the electronic structure of the low lying electronic states of the ZrF transition metal radical. © 2011 American Chemical Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe
Parallelized Acquisition of Orbitrap and Astral Analyzers Enables High-Throughput Quantitative Analysis
The growing trend toward high-throughput
proteomics demands
rapid
liquid chromatography–mass spectrometry (LC–MS) cycles
that limit the available time to gather the large numbers of MS/MS
fragmentation spectra required for identification. Orbitrap analyzers
scale performance with acquisition time and necessarily sacrifice
sensitivity and resolving power to deliver higher acquisition rates.
We developed a new mass spectrometer that combines a mass-resolving
quadrupole, the Orbitrap, and the novel Asymmetric Track Lossless
(Astral) analyzer. The new hybrid instrument enables faster acquisition
of high-resolution accurate mass (HRAM) MS/MS spectra compared with
state-of-the-art mass spectrometers. Accordingly, new proteomics methods
were developed that leverage the strengths of each HRAM analyzer,
whereby the Orbitrap analyzer performs full scans with a high dynamic
range and resolution, synchronized with the Astral analyzer’s
acquisition of fast and sensitive HRAM MS/MS scans. Substantial improvements
are demonstrated over previous methods using current state-of-the-art
mass spectrometer
Considerations of Environmentally Relevant Test Conditions for Improved Evaluation of Ecological Hazards of Engineered Nanomaterials
Engineered
nanomaterials (ENMs) are increasingly entering the environment
with uncertain consequences including potential ecological effects.
Various research communities view differently whether ecotoxicological
testing of ENMs should be conducted using environmentally relevant
concentrationswhere observing outcomes is difficultversus
higher ENM doses, where responses are observable. What exposure conditions
are typically used in assessing ENM hazards to populations? What conditions
are used to test ecosystem-scale hazards? What is known regarding
actual ENMs in the environment, via measurements or modeling simulations?
How should exposure conditions, ENM transformation, dose, and body
burden be used in interpreting biological and computational findings
for assessing risks? These questions were addressed in the context
of this critical review. As a result, three main recommendations emerged.
First, researchers should improve ecotoxicology of ENMs by choosing
test end points, duration, and study conditionsincluding ENM
test concentrationsthat align with realistic exposure scenarios.
Second, testing should proceed via tiers with iterative feedback that
informs experiments at other levels of biological organization. Finally,
environmental realism in ENM hazard assessments should involve greater
coordination among ENM quantitative analysts, exposure modelers, and
ecotoxicologists, across government, industry, and academia
Energy Resolution of the Barrel of the CMS Electromagnetic Calorimeter
The energy resolution of the barrel part of the CMS Electromagnetic Calorimeter has been studied using electrons of 20 to 250 GeV in a test beam. The incident electron's energy was reconstructed by summing the energy measured in arrays of 3x3 or 5x5 channels. There was no significant amount of correlated noise observed within these arrays. For electrons incident at the centre of the studied 3x3 arrays of crystals, the mean stochastic term was measured to be 2.8% and the mean constant term to be 0.3%. The amount of the incident electron's energy which is contained within the array depends on its position of incidence. The variation of the containment with position is corrected for using the distribution of the measured energy within the array. For uniform illumination of a crystal with 120 GeV electrons a resolution of 0.5% was achieved. The energy resolution meets the design goal for the detector
Results of the first performance tests of the CMS electromagnetic calorimeter
CMS ECALPerformance tests of some aspects of the CMS ECAL were carried out on modules of the "barrel" sub-system in 2002 and 2003. A brief test with high energy electron beams was made in late 2003 to validate prototypes of the new Very Front End electronics. The final versions of the monitoring and cooling systems, and of the high and low voltage regulation were used in these tests. The results are consistent with the performance targets including those for noise and overall energy resolution, required to fulfil the physics programme of CMS at the LHC
Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study
Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1–3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1–60 years) and 39.1 kg (9.2–108.9 kg), respectively. About 63% of patients aged 2–60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale–Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients
Early stage litter decomposition across biomes
[Departement_IRSTEA]Territoires [TR1_IRSTEA]SEDYVINInternational audienceThrough litter decomposition enormous amounts of carbon is emitted to the atmosphere. Numerous large-scale decomposition experiments have been conducted focusing on this fundamental soil process in order to understand the controls on the terrestrial carbon transfer to the atmosphere. However, previous studies were mostly based on site-specific litter and methodologies, adding major uncertainty to syntheses, comparisons and meta-analyses across different experiments and sites. In the TeaComposition initiative, the potential litter decomposition is investigated by using standardized substrates (Rooibos and Green tea) for comparison of litter mass loss at 336 sites (ranging fro
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Search for supersymmetry in hadronic final states with missing transverse energy using the variables αT and b-quark multiplicity in pp collisions at √s = 8 TeV
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Previous issue date: 2013-09-01
An inclusive search for supersymmetric processes that produce final states with jets and missing transverse energy is performed in pp collisions at a centre-of-mass energy of 8 TeV. The data sample corresponds to an integrated luminosity of 11.7 fb-1 collected by the CMS experiment at the LHC. In this search, a dimensionless kinematic variable, αT, is used to discriminate between events with genuine and misreconstructed missing transverse energy. The search is based on an examination of the number of reconstructed jets per event, the scalar sum of transverse energies of these jets, and the number of these jets identified as originating from bottom quarks. No significant excess of events over the standard model expectation is found. Exclusion limits are set in the parameter space of simplified models, with a special emphasis on both compressed-spectrum scenarios and direct or gluino-induced production of third-generation squarks. For the case of gluino-mediated squark production, gluino masses up to 950-1125 GeV are excluded depending on the assumed model. For the direct pair-production of squarks, masses up to 450 GeV are excluded for a single light first- or second-generation squark, increasing to 600 GeV for bottom squarks. © 2013 CERN for the benefit of the CMS collaboration.
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State Key Laboratory of Nuclear Physics and Technology Peking University, Beijing
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Technical University of Split, Split
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Institute Rudjer Boskovic, Zagreb
University of Cyprus, Nicosia
Charles University, Prague
Academy of Scientific Research and Technology of the Arab Republic of Egypt Egyptian Network of High Energy Physics, Cairo
National Institute of Chemical Physics and Biophysics, Tallinn
Department of Physics University of Helsinki, Helsinki
Helsinki Institute of Physics, Helsinki
Lappeenranta University of Technology, Lappeenranta
DSM/IRFU CEA/Saclay, Gif-sur-Yvette
Laboratoire Leprince-Ringuet, Ecole Polytechnique IN2P3-CNRS, Palaiseau
Institut Pluridisciplinaire Hubert Curien, Universite de Strasbourg, Universite de Haute Alsace Mulh CNRS/IN2P3, Strasbourg
CNRS-IN2P3, Institut de Physique Nucléaire de Lyon Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne
Institute of High Energy Physics and Informatization Tbilisi State University, Tbilisi
I. Physikalisches Institut RWTH Aachen University, Aachen
III. Physikalisches Institut A RWTH Aachen University, Aachen
III. Physikalisches Institut B RWTH Aachen University, Aachen
Deutsches Elektronen-Synchrotron, Hamburg
University of Hamburg, Hamburg
Institut für Experimentelle Kernphysik, Karlsruhe
Institute of Nuclear and Particle Physics (INPP) NCSR Demokritos, Aghia Paraskevi
University of Athens, Athens
University of Ioánnina, Ioánnina
KFKI Research Institute for Particle and Nuclear Physics, Budapest
Institute of Nuclear Research ATOMKI, Debrecen
University of Debrecen, Debrecen
Panjab University, Chandigarh
University of Delhi, Delhi
Saha Institute of Nuclear Physics, Kolkata
Bhabha Atomic Research Centre, Mumbai
Tata Institute of Fundamental Research - EHEP, Mumbai
Tata Institute of Fundamental Research - HECR, Mumbai
Institute for Research in Fundamental Sciences (IPM), Tehran
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Università di Napoli 'Federico II', Napoli
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Kangwon National University, Chunchon
Kyungpook National University, Daegu
Institute for Universe and Elementary Particles Chonnam National University, Kwangju
Korea University, Seoul
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Universidad Autónoma de San Luis Potosí, San Luis Potosí
University of Auckland, Auckland
University of Canterbury, Christchurch
National Centre for Physics Quaid-I-Azam University, Islamabad
National Centre for Nuclear Research, Swierk
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Laboratório de Instrumentação e Física Experimental de Partículas, Lisboa
Joint Institute for Nuclear Research, Dubna
Petersburg Nuclear Physics Institute, Gatchina (St. Petersburg)
Institute for Nuclear Research, Moscow
Institute for Theoretical and Experimental Physics, Moscow
P.N. Lebedev Physical Institute, Moscow
Skobeltsyn Institute of Nuclear Physics Lomonosov Moscow State University, Moscow
State Research Center of Russian Federation Institute for High Energy Physics, Protvino
Faculty of Physics and Vinca Institute of Nuclear Sciences University of Belgrade, Belgrade
Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Madrid
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Instituto de Física de Cantabria (IFCA) CSIC-Universidad de Cantabria, Santander
European Organization for Nuclear Research CERN, Geneva
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Institute for Particle Physics ETH Zurich, Zurich
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National Central University, Chung-Li
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Cukurova University, Adana
Physics Department Middle East Technical University, Ankara
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