NMR characterization of angiogenin variants and tRNAAla products impacting aberrant protein oligomerization

Protein oligomerization is key to countless physiological processes, but also to abnormal amyloid conformations implicated in over 25 mortal human diseases. Human Angiogenin (h-ANG), a ribonuclease A family member, produces RNA fragments that regulate ribosome formation, the creation of new blood vessels and stress granule function. Too little h-ANG activity leads to abnormal protein oligomerization, resulting in Amyotrophic Lateral Sclerosis (ALS) or Parkinson's disease. While a score of disease linked h-ANG mutants has been studied by X-ray diffraction, some elude crystallization. There is also a debate regarding the structure that RNA fragments adopt after cleavage by h-ANG. Here, to better understand the beginning of the process that leads to aberrant protein oligomerization, the solution secondary structure and residue-level dynamics of WT h-ANG and two mutants i.e., H13A and R121C, are characterized by multidimensional heteronuclear NMR spectroscopy under near-physiological conditions. All three variants are found to adopt well folded and highly rigid structures in the solution, although the elements of secondary structure are somewhat shorter than those observed in crystallography studies. R121C alters the environment of nearby residues only. By contrast, the mutation H13A affects local residues as well as nearby active site residues K40 and H114. The conformation characterization by CD and 1D 1H NMR spectroscopies of tRNAAla before and after h-ANG cleavage reveals a retention of the duplex structure and little or no G-quadruplex formation

The Auriga Project: the properties and formation mechanisms of disc galaxies across cosmic time

We introduce a suite of 30 cosmological magneto-hydrodynamical zoom simulations of the formation of galaxies in isolated Milky Way mass dark haloes. These were carried out with the moving mesh code arepo, together with a comprehensive model for galaxy formation physics, including active galactic nuclei (AGN) feedback and magnetic fields, which produces realistic galaxy populations in large cosmological simulations. We demonstrate that our simulations reproduce a wide range of present-day observables, in particular, two-component disc-dominated galaxies with appropriate stellar masses, sizes, rotation curves, star formation rates and metallicities. We investigate the driving mechanisms that set present-day disc sizes/scalelengths, and find that they are related to the angular momentum of halo material. We show that the largest discs are produced by quiescent mergers that inspiral into the galaxy and deposit high-angular momentum material into the pre-existing disc, simultaneously increasing the spin of dark matter and gas in the halo. More violent mergers and strong AGN feedback play roles in limiting disc size by destroying pre-existing discs and by suppressing gas accretion on to the outer disc, respectively. The most important factor that leads to compact discs, however, is simply a low angular momentum for the halo. In these cases, AGN feedback plays an important role in limiting central star formation and the formation of a massive bulge

Novel inhibitors of human glucose-6-phosphate dehydrogenase (HsG6PD) affect the activity and stability of the protein

Background: The pentose phosphate pathway (PPP) has received significant attention because of the role of NADPH and R-5-P in the maintenance of cancer cells, which are necessary for the synthesis of fatty acids and contribute to uncontrollable proliferation. The HsG6PD enzyme is the rate-limiting step in the oxidative branch of the PPP, leading to an increase in the expression levels in tumor cells; therefore, the protein has been proposed as a target for the development of new molecules for use in cancer. Methods: Through in vitro studies, we assayed the effects of 55 chemical compounds against recombinant HsG6PD. Here, we present the kinetic characterization of four new HsG6PD inhibitors as well as their functional and structural effects on the protein. Furthermore, molecular docking was performed to determine the interaction of the best hits with HsG6PD. Results: Four compounds, JMM-2, CCM-4, CNZ-3, and CNZ-7, were capable of reducing HsG6PD activity and showed noncompetitive and uncompetitive inhibition. Moreover, experiments using circular dichroism and fluorescence spectroscopy showed that the molecules affect the structure (secondary and tertiary) of the protein as well as its thermal stability. Computational docking analysis revealed that the interaction of the compounds with the protein does not occur at the active site. Conclusions: We identified two new compounds (CNZ-3 and JMM-2) capable of inhibiting HsG6PD that, compared to other previously known HsG6PD inhibitors, showed different mechanisms of inhibition. General significance: Screening of new inhibitors for HsG6PD with a future pharmacological approach for the study and treatment of cancer

Geographical variation in therapy for bloodstream infections due to multidrug-resistant enterobacteriaceae: a post hoc analysis of the INCREMENT study

We aimed to describe regional differences in therapy for bloodstream infection (BSI) caused by extended-spectrum ?-lactamase-producing Enterobacteriaceae (ESBL-E) or carbapenemase-producing Enterobacteriaceae (CPE). 1,482 patients in 12 countries were included from an observational study of BSI caused by ESBL-E or CPE. Multivariate logistic regression was used to calculate adjusted odds ratios (aORs) for the influence of country of recruitment on empirical use of ?-lactam/?-lactamase inhibitors (BLBLI) or carbapenems, targeted use of BLBLI for ESBL-E and use of targeted combination therapy for CPE. The use of BLBLI for empirical therapy was least likely in sites from Israel (aOR 0.34, 95% CI 0.14-0.81), Greece (aOR 0.49, 95% CI 0.26-0.94) and Canada (aOR 0.31, 95% CI 0.11-0.88) but more likely in Italy (aOR 1.58, 95% CI 1.11-2.2) and Turkey (aOR 2.09, 95% CI 1.14-3.81), compared to Spain as a reference. Empirical carbapenems were more likely to be used in sites from Taiwan (aOR 1.73, 95% CI 1.03-2.92) and USA (aOR 1.89; 95% CI 1.05-3.39), and less likely in Italy (aOR 0.44, 95% CI 0.28-0.69) and Canada (aOR 0.10, 95% CI 0.01-0.74). Targeted BLBLI for ESBL-E was more likely in sites from Italy. Treatment at sites within Israel, Taiwan, Turkey and Brazil was associated with less combination therapy for CPE. Although this study does not provide precise data on the relative prevalence of ESBL-E or CPE, significant variation in therapy exists across countries even after adjustment for patient factors. A better understanding of what influences therapeutic choices for these infections will aid antimicrobial stewardship efforts.PH is supported by an Australian Postgraduate Award from the University of Queensland. The study was funded by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III - co-financed by European Development Regional Fund "A way to achieve Europe" ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). BGG, JRB, APH and YC also received funds from the COMBACTE-CARE project (grant agreement 115620), Innovative Medicines Initiative (IMI), the European Union's Seventh Framework Programme (FP7/2007-2013) and in-kind contributions from EFPIA companies

Relationships between Parental Education and Overweight with Childhood Overweight and Physical Activity in 9-11 Year Old Children: Results from a 12-Country Study

Background: Globally, the high prevalence of overweight and low levels of physical activity among children has serious implications for morbidity and premature mortality in adulthood. Various parental factors are associated with childhood overweight and physical activity. The objective of this paper was to investigate relationships between parental education or overweight, and (i) child overweight, (ii) child physical activity, and (iii) explore household coexistence of overweight, in a large international sample. Methods: Data were collected from 4752 children (9-11 years) as part of the International Study of Childhood Obesity, Lifestyle and the Environment in 12 countries around the world. Physical activity of participating children was assessed by accelerometry, and body weight directly measured. Questionnaires were used to collect parents' education level, weight, and height. Results: Maternal and paternal overweight were positively associated with child overweight. Higher household coexistence of parent-child overweight was observed among overweight children compared to the total sample. There was a positive relationship between maternal education and child overweight in Colombia 1.90 (1.23-2.94) [odds ratio (confidence interval)] and Kenya 4.80 (2.21-10.43), and a negative relationship between paternal education and child overweight in Brazil 0.55 (0.33-0.92) and the USA 0.54 (0.33-0.88). Maternal education was negatively associated with children meeting physical activity guidelines in Colombia 0.53 (0.33-0.85), Kenya 0.35 (0.19-0.63), and Portugal 0.54 (0.31-0.96). Conclusions: Results are aligned with previous studies showing positive associations between parental and child overweight in all countries, and positive relationships between parental education and child overweight or negative associations between parental education and child physical activity in lower economic status countries. Relationships between maternal and paternal education and child weight status and physical activity appear to be related to the developmental stage of different countries. Given these varied relationships, it is crucial to further explore familial factors when investigating child overweight and physical activity

First Sagittarius A* Event Horizon Telescope Results. I. The Shadow of the Supermassive Black Hole in the Center of the Milky Way

We present the first Event Horizon Telescope (EHT) observations of Sagittarius A* (Sgr A*), the Galactic center source associated with a supermassive black hole. These observations were conducted in 2017 using a global interferometric array of eight telescopes operating at a wavelength of λ = 1.3 mm. The EHT data resolve a compact emission region with intrahour variability. A variety of imaging and modeling analyses all support an image that is dominated by a bright, thick ring with a diameter of 51.8 \ub1 2.3 μas (68% credible interval). The ring has modest azimuthal brightness asymmetry and a comparatively dim interior. Using a large suite of numerical simulations, we demonstrate that the EHT images of Sgr A* are consistent with the expected appearance of a Kerr black hole with mass ∼4 7 106 M☉, which is inferred to exist at this location based on previous infrared observations of individual stellar orbits, as well as maser proper-motion studies. Our model comparisons disfavor scenarios where the black hole is viewed at high inclination (i > 50\ub0), as well as nonspinning black holes and those with retrograde accretion disks. Our results provide direct evidence for the presence of a supermassive black hole at the center of the Milky Way, and for the first time we connect the predictions from dynamical measurements of stellar orbits on scales of 103-105 gravitational radii to event-horizon-scale images and variability. Furthermore, a comparison with the EHT results for the supermassive black hole M87* shows consistency with the predictions of general relativity spanning over three orders of magnitude in central mass

Trigger and Aperture of the Surface Detector Array of the Pierre Auger Observatory

The surface detector array of the Pierre Auger Observatory consists of 1600 water-Cherenkov detectors, for the study of extensive air showers (EAS) generated by ultra-high-energy cosmic rays. We describe the trigger hierarchy, from the identification of candidate showers at the level of a single detector, amongst a large background (mainly random single cosmic ray muons), up to the selection of real events and the rejection of random coincidences. Such trigger makes the surface detector array fully efficient for the detection of EAS with energy above $3\times 10^{18}$ eV, for all zenith angles between 0$^\circ$ and 60$^\circ$, independently of the position of the impact point and of the mass of the primary particle. In these range of energies and angles, the exposure of the surface array can be determined purely on the basis of the geometrical acceptance.Comment: 29 pages, 12 figure

Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption

Objective: Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research. Design: Children previously randomized to continuous (continuous ART, n=41) vs. planned treatment interruption (PTI, n=47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6-16 years old) or Wechsler Adult Intelligence Scale ( 6517 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann-Whitney U test, respectively. Scores indicating clinical concern were compared (<7 for neurocognition and <70 for QoL tests). Results: Characteristics were similar between arms with a median age of 12.6 years, CD4 + of 830 cells/\u3bcl and HIV RNA of 1.7 log 10 copies/ml. The median cumulative ART exposure was 9.6 in continuous ART vs. 7.7 years in PTI (P=0.02). PTI children had a median of 12 months off ART and had resumed ART for 25.2 months at time of first assessment. Neurocognitive scores were similar between arms for all tests. Physical and psychological QoL scores were no different. About 40% had low neurocognitive and QoL scores indicating clinical concern. Conclusion: No differences in information processing speed, sustained attention, short-term memory and QoL functioning were observed between children previously randomized to continuous ART vs. PTI in the PENTA 11 trial

Combined measurements of Higgs boson couplings in proton- proton collisions at v s=13TeV

Combined measurements of the production and decay rates of the Higgs boson, as well as its couplings to vector bosons and fermions, are presented. The analysis uses the LHC proton-proton collision data set recorded with the CMS detector in 2016 at fb-1. The combination is based on analyses targeting the five main Higgs boson production mechanisms (gluon fusion, vector boson fusion, and associated production with a W or Z boson, or a top quark-antiquark pair) and the following decay modes: H, ZZ, WW, , bb, and . Searches for invisible Higgs boson decays are also considered. The best-fit ratio of the signal yield to the standard model expectation is measured to be =1.17 +/- 0.10, assuming a Higgs boson mass of 125.09. Additional results are given for various assumptions on the scaling behavior of the production and decay modes, including generic parametrizations based on ratios of cross sections and branching fractions or couplings. The results are compatible with the standard model predictions in all parametrizations considered. In addition, constraints are placed on various two Higgs doublet models.Peer reviewe

Production of pions, kaons and protons in pp collisions at s=900\sqrt{s}=900 GeV with ALICE at the LHC

The production of $\pi^+$, $\pi^-$, $K^+$, $K^-$, p, and pbar at mid-rapidity has been measured in proton-proton collisions at $\sqrt{s} = 900$ GeV with the ALICE detector. Particle identification is performed using the specific energy loss in the inner tracking silicon detector and the time projection chamber. In addition, time-of-flight information is used to identify hadrons at higher momenta. Finally, the distinctive kink topology of the weak decay of charged kaons is used for an alternative measurement of the kaon transverse momentum ($p_{\rm T}$) spectra. Since these various particle identification tools give the best separation capabilities over different momentum ranges, the results are combined to extract spectra from $p_{\rm T}$ = 100 MeV/$c$ to 2.5 GeV/$c$. The measured spectra are further compared with QCD-inspired models which yield a poor description. The total yields and the mean $p_{\rm T}$ are compared with previous measurements, and the trends as a function of collision energy are discussed.Comment: 24 pages, 18 captioned figures, 5 tables, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/388