Crystal structure of the C-terminal domain of DENR

© 2020 The Authors The density regulated protein (DENR) forms a stable heterodimer with malignant T-cell-amplified sequence 1 (MCT-1). DENR-MCT-1 heterodimer then participates in regulation of non-canonical translation initiation and ribosomal recycling. The N-terminal domain of DENR interacts with MCT-1 and carries a classical tetrahedral zinc ion-binding site, which is crucial for the dimerization. DENR-MCT-1 binds the small (40S) ribosomal subunit through interactions between MCT-1 and helix h24 of the 18S rRNA, and through interactions between the C-terminal domain of DENR and helix h44 of the 18S rRNA. This later interaction occurs in the vicinity of the P site that is also the binding site for canonical translation initiation factor eIF1, which plays the key role in initiation codon selection and scanning. Sequence homology modeling and a low-resolution crystal structure of the DENR-MCT-1 complex with the human 40S subunit suggests that the C-terminal domain of DENR and eIF1 adopt a similar fold. Here we present the crystal structure of the C-terminal domain of DENR determined at 1.74 Å resolution, which confirms its resemblance to eIF1 and advances our understanding of the mechanism by which DENR-MCT-1 regulates non-canonical translation initiation and ribosomal recycling

ИНДИВИДУАЛЬНЫЙ ПОДХОД К ПРИМЕНЕНИЮ АНТИТРОМБОЦИТАРНОЙ ТЕРАПИИ. НА ЧТО ОПЕРЕТЬСЯ В РЕШЕНИИ?

Use of antiplatelet therapy in the world indicates real difference in individual drug effect between patients, including the effect on prognosis. Problems of personification of individual approach, concerning antiplatelet therapy, are discussed.Опыт применения антиагрегантной терапии указывает на существенную разницу в реакции больных на антиагреганты, вызывающую различия в выраженности эффекта терапии по влиянию на исходы заболевания. Обсуждены проблемы индивидуального подхода в антиагрегантной терапии

Non-monotonic variation with salt concentration of the second virial coefficient in protein solutions

The osmotic virial coefficient $B_2$ of globular protein solutions is calculated as a function of added salt concentration at fixed pH by computer simulations of the ``primitive model''. The salt and counter-ions as well as a discrete charge pattern on the protein surface are explicitly incorporated. For parameters roughly corresponding to lysozyme, we find that $B_2$ first decreases with added salt concentration up to a threshold concentration, then increases to a maximum, and then decreases again upon further raising the ionic strength. Our studies demonstrate that the existence of a discrete charge pattern on the protein surface profoundly influences the effective interactions and that non-linear Poisson Boltzmann and Derjaguin-Landau-Verwey-Overbeek (DLVO) theory fail for large ionic strength. The observed non-monotonicity of $B_2$ is compared to experiments. Implications for protein crystallization are discussed.Comment: 43 pages, including 17 figure

Hadron Energy Reconstruction for the ATLAS Calorimetry in the Framework of the Non-parametrical Method

This paper discusses hadron energy reconstruction for the ATLAS barrel prototype combined calorimeter (consisting of a lead-liquid argon electromagnetic part and an iron-scintillator hadronic part) in the framework of the non-parametrical method. The non-parametrical method utilizes only the known $e/h$ ratios and the electron calibration constants and does not require the determination of any parameters by a minimization technique. Thus, this technique lends itself to an easy use in a first level trigger. The reconstructed mean values of the hadron energies are within $\pm 1$ of the true values and the fractional energy resolution is $[(58\pm3)/\sqrt{E}+(2.5\pm0.3)$. The value of the $e/h$ ratio obtained for the electromagnetic compartment of the combined calorimeter is $1.74\pm0.04$ and agrees with the prediction that $e/h > 1.7$ for this electromagnetic calorimeter. Results of a study of the longitudinal hadronic shower development are also presented. The data have been taken in the H8 beam line of the CERN SPS using pions of energies from 10 to 300 GeV.Comment: 33 pages, 13 figures, Will be published in NIM

Levilimab clinical efficacy for interleukin-6 receptor inhibition in COVID-19 and its potential for treating cytokine release syndrome of other aetiologies

The COVID-19 mortality is associated with an increase in interleukin-6 (IL-6) levels. Levilimab is an anti–IL-6 receptor antibody with proven clinical efficacy in patients with severe COVID-19.The aim of the study was to assess the association of COVID-19 severity and levilimab effectiveness with IL-6 levels and to explore the potential for using levilimab in other conditions accompanied by cytokine release syndrome.Materials and methods: the subgroup analysis was based on the data of COVID patients with known baseline IL-6 levels from the CORONA clinical study. Subgroups were formed according to baseline IL-6 levels: ≤5 pg/mL (normal) and >5 pg/mL (elevated). The subgroup analysis included descriptive statistics of the patients and time courses of their clinical and laboratory findings (at screening, on the day of investigational product administration, and further until day 14). In order to compare the percentages of patients who had required rescue therapy, the authors used Fisher's exact test.Results: the subgroup analysis included 91 patients (47 from the levilimab group and 44 from the placebo group). At baseline, the authors observed elevated levels of IL-6 in 31/47 (66%) subjects in the levilimab group and 29/44 (48.4%) subjects in the placebo group. The subjects with elevated IL-6 demonstrated more pronounced clinical signs of pneumonia and abnormalities in inflammatory markers. Elevated baseline IL-6 levels were associated with the need for rescue therapy (OR=3.714; 95% CI: 1.317–9.747; p=0.0183); this association was stronger in the placebo group (OR=8.889; 95% CI: 2.098–33.31; p=0.0036). Also, the placebo group showed long-term abnormalities in the clinical and laboratory findings.Conclusions: IL-6 is one of the key elements in the pathogenesis of cytokine release syndrome related to COVID-19 and other conditions. Elevated IL-6 levels are associated with the severity of COVID-19. Inhibition of IL-6 receptors by levilimab leads to clinical improvement in patients with severe COVID-19, suggesting the effectiveness of levilimab in pathogenesis-oriented therapy for cytokine release syndrome of other aetiologies

The Cryo-EM Structure of a Complete 30S Translation Initiation Complex from Escherichia coli

Formation of the 30S initiation complex (30S IC) is an important checkpoint in regulation of gene expression. The selection of mRNA, correct start codon, and the initiator fMet-tRNAfMet requires the presence of three initiation factors (IF1, IF2, IF3) of which IF3 and IF1 control the fidelity of the process, while IF2 recruits fMet-tRNAfMet. Here we present a cryo-EM reconstruction of the complete 30S IC, containing mRNA, fMet-tRNAfMet, IF1, IF2, and IF3. In the 30S IC, IF2 contacts IF1, the 30S subunit shoulder, and the CCA end of fMet-tRNAfMet, which occupies a novel P/I position (P/I1). The N-terminal domain of IF3 contacts the tRNA, whereas the C-terminal domain is bound to the platform of the 30S subunit. Binding of initiation factors and fMet-tRNAfMet induces a rotation of the head relative to the body of the 30S subunit, which is likely to prevail through 50S subunit joining until GTP hydrolysis and dissociation of IF2 take place. The structure provides insights into the mechanism of mRNA selection during translation initiation

Status of ART-XC/SRG Instrument

Spectrum Roentgen Gamma (SRG) is an X-ray astrophysical observatory, developed by Russia in collaboration with Germany. The mission will be launched in March 2016 from Baikonur, by a Zenit rocket with a Fregat booster and placed in a 6-month-period halo orbit around L2. The scientific payload consists of two independent telescopes - a soft-x-ray survey instrument, eROSITA, being provided by Germany and a medium-x-ray-energy survey instrument ART-XC being developed by Russia. ART-XC will consist of seven independent, but co-aligned, telescope modules. The NASA Marshall Space Flight Center (MSFC) is fabricating the flight mirror modules for the ART-XC/SRG. Each mirror module will be aligned with a focal plane CdTe double-sided strip detectors which will operate over the energy range of 6-30 keV, with an angular resolution of less than 1, a field of view of approximately 34 and an expected energy resolution of about 10 percent at 14 keV

The ART-XC telescope on board the SRG observatory

ART-XC (Astronomical Roentgen Telescope - X-ray Concentrator) is the hard X-ray instrument with grazing incidence imaging optics on board the Spektr-Roentgen-Gamma (SRG) observatory. The SRG observatory is the flagship astrophysical mission of the Russian Federal Space Program, which was successively launched into orbit around the second Lagrangian point (L2) of the Earth-Sun system with a Proton rocket from the Baikonur cosmodrome on 13 July 2019. The ART-XC telescope will provide the first ever true imaging all-sky survey performed with grazing incidence optics in the 4-30 keV energy band and will obtain the deepest and sharpest map of the sky in the energy range of 4-12 keV. Observations performed during the early calibration and performance verification phase as well as during the on-going all-sky survey that started on 12 Dec. 2019 have demonstrated that the in-flight characteristics of the ART-XC telescope are very close to expectations based on the results of ground calibrations. Upon completion of its 4-year all-sky survey, ART-XC is expected to detect ~5000 sources (~3000 active galactic nuclei, including heavily obscured ones, several hundred clusters of galaxies, ~1000 cataclysmic variables and other Galactic sources), and to provide a high-quality map of the Galactic background emission in the 4-12 keV energy band. ART-XC is also well suited for discovering transient X-ray sources. In this paper, we describe the telescope, results of its ground calibrations, major aspects of the mission, the in-flight performance of ART-XC and first scientific results.Comment: 19 pages, 30 figures, accepted for publication in Astronomy and Astrophysic

Response of the ATLAS tile calorimeter prototype to muons

A study of high energy muons traversing the ATLAS hadron Tile calorimeter in the barrel region in the energy range between 10 and 300~GeV is presented. Both test beam experimental data and Monte Carlo simulations are given and show good agreement. The Tile calorimeter capability of detecting isolated muons over the above energy range is demonstrated. A signal to background ratio of about 10 is expected for the nominal LHC luminosity ($10^{34} cm^{-2} sec^{-1}$). The photoelectron statistics effect in the muon shape response is shown. The e/mip ratio is found to be $0.81 \pm 0.03$; the e/$\mu$ ratio is in the range 0.91 - 0.97. The energy loss of a muon in the calorimeter, dominated by the energy lost in the absorber, can be correlated to the energy loss in the active material. This correlation allows one to correct on an event by event basis the muon energy loss in the calorimeter and therefore reduce the low energy tails in the muon momentum distribution