Identification of Specific Inhibitors of Trypanosoma cruzi Malic Enzyme Isoforms by Target-Based HTS.

Trypanosoma cruzi is the causative agent of Chagas disease. The lack of an efficient and safe treatment supports the research into novel metabolic targets, with the malic enzyme (ME) representing one such potential candidate. T. cruzi expresses a cytosolic (TcMEc) and a mitochondrial (TcMEm) ME isoform, with these activities functioning to generate NADPH, a key source of reducing equivalents that drives a range of anabolic and protective processes. To identify specific inhibitors that target TcMEs, two independent high-throughput screening strategies using a diversity library containing 30,000 compounds were employed. IC50 values of 262 molecules were determined for both TcMEs, as well as for three human ME isoforms, with the inhibitors clustered into six groups according to their chemical similarity. The most potent hits belonged to a sulfonamide group that specifically target TcMEc. Moreover, several selected inhibitors of both TcMEs showed a trypanocidal effect against the replicative forms of T. cruzi. The chemical diversity observed among those compounds that inhibit TcMEs activity emphasizes the druggability of these enzymes, with a sulfonamide-based subset of compounds readily able to block TcMEc function at a low nanomolar range.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Sao Paulo Research Foundation (FAPESP) (process numbers 2013/03983-5, 2012/23682-7, and 2015/03336-5)

The sharpest view on the high-mass star-forming region S255IR. Near-InfraRed Adaptive Optics Imaging on the Outbursting Source NIRS3

Massive stars have an impact on their surroundings from early in their formation until the end of their lives. However, very little is known about their formation. Episodic accretion may play a crucial role, but observations of these events have only been reported towards a handful of massive protostars. We aim to investigate the outburst event from the high-mass star-forming region S255IR where recently the protostar NIRS3 underwent an accretion outburst. We follow the evolution of this source both in photometry and morphology of its surroundings. Methods: We perform near-infrared adaptive optics observations on the S255IR central region using the Large Binocular Telescope in the K$_{\rm s}$ broad-band and the H$_2$ and Br$\gamma$ narrow-band filters with an angular resolution of \sim0\farcs06, close to the diffraction limit. We discover a new near-infrared knot north-east from NIRS3 that we interpret as a jet knot that was ejected during the last accretion outburst and observed in the radio regime as part of a follow-up after the outburst. We measure a mean tangential velocity for this knot of $450\pm50\,\mathrm{km\,s^{-1}}$. We analyse the continuum-subtracted images from H$_2$ which traces jet shocked emission, and Br$\gamma$ which traces scattered light from a combination of accretion activity and UV radiation from the central massive protostar. We observe a significant decrease in flux at the location of NIRS3, with K=13.48\,mag being the absolute minimum in the historic series. Our observations strongly suggest a scenario where the episodic accretion is followed by an episodic ejection response in the near-infrared, as it was seen in the earlier radio follow-up. The 30 years of $\sim2\,\mu{\rm m}$ photometry suggests that NIRS3 might have undergone another outburst in the late 1980s, being the first massive protostar with such evidence observed in the near-infrared.Comment: Accepted for publication in Astronomy and Astrophysics. 10 pages, 8 figure

NIR jets from a clustered region of massive star formation: Morphology and composition in the IRAS 18264-1152 region

Context. Massive stars play crucial roles in determining the physical and chemical evolution of galaxies. However, they form deeply embedded in their parental clouds, making it challenging to directly observe these stars and their immediate environments. It is known that accretion and ejection processes are intrinsically related, thus observing the massive protostellar outflows can provide crucial information about the processes governing massive star formation very close to the central engine. Aims. We aim to probe the IRAS 18264-1152 (also known as G19.88-0.53) high-mass star-forming complex in the near infrared (NIR) through its molecular hydrogen (H2) jets to analyse the morphology and composition of the line emitting regions and to compare with other outflow tracers. Methods. We observed the H2 NIR jets via K-band (1.9 2.5 μm) observations obtained with the integral field units VLT/SINFONI and VLT/KMOS. VLT/SINFONI provides the highest NIR angular resolution achieved so far for the central region of IRAS 18264-1152 (∼0.2). We compared the geometry of the NIR outflows with that of the associated molecular outflow, probed by CO (2-1) emission mapped with the Submillimeter Array. Results. We identify nine point sources in the SINFONI and KMOS fields of view. Four of these display a rising continuum in the K-band and are Brγ emitters, revealing that they are young, potentially jet-driving sources. The spectro-imaging analysis focusses on the H2 jets, for which we derived visual extinction, temperature, column density, area, and mass. The intensity, velocity, and excitation maps based on H2 emission strongly support the existence of a protostellar cluster in this region, with at least two (and up to four) different large-scale outflows, found through the NIR and radio observations. We compare our results with those found in the literature and find good agreement in the outflow morphology. This multi-wavelength comparison also allows us to derive a stellar density of ∼4000 stars pc-3. Conclusions. Our study reveals the presence of several outflows driven by young sources from a forming cluster of young, massive stars, demonstrating the utility of such NIR observations for characterising massive star-forming regions. Moreover, the derived stellar number density together with the geometry of the outflows suggest that stars can form in a relatively ordered manner in this cluster

Direct and inverse spectral transform for the relativistic Toda lattice and the connection with Laurent orthogonal polynomials

We introduce a spectral transform for the finite relativistic Toda lattice (RTL) in generalized form. In the nonrelativistic case, Moser constructed a spectral transform from the spectral theory of symmetric Jacobi matrices. Here we use a non-symmetric generalized eigenvalue problem for a pair of bidiagonal matrices (L,M) to define the spectral transform for the RTL. The inverse spectral transform is described in terms of a terminating T-fraction. The generalized eigenvalues are constants of motion and the auxiliary spectral data have explicit time evolution. Using the connection with the theory of Laurent orthogonal polynomials, we study the long-time behaviour of the RTL. As in the case of the Toda lattice the matrix entries have asymptotic limits. We show that L tends to an upper Hessenberg matrix with the generalized eigenvalues sorted on the diagonal, while M tends to the identity matrix.Comment: 24 pages, 9 figure

SOXS: a wide band spectrograph to follow up transients

SOXS (Son Of X-Shooter) will be a spectrograph for the ESO NTT telescope capable to cover the optical and NIR bands, based on the heritage of the X-Shooter at the ESO-VLT. SOXS will be built and run by an international consortium, carrying out rapid and longer term Target of Opportunity requests on a variety of astronomical objects. SOXS will observe all kind of transient and variable sources from different surveys. These will be a mixture of fast alerts (e.g. gamma-ray bursts, gravitational waves, neutrino events), mid-term alerts (e.g. supernovae, X-ray transients), fixed time events (e.g. close-by passage of minor bodies). While the focus is on transients and variables, still there is a wide range of other astrophysical targets and science topics that will benefit from SOXS. The design foresees a spectrograph with a Resolution-Slit product ~ 4500, capable of simultaneously observing over the entire band the complete spectral range from the U- to the H-band. The limiting magnitude of R~20 (1 hr at S/N~10) is suited to study transients identified from on-going imaging surveys. Light imaging capabilities in the optical band (grizy) are also envisaged to allow for multi-band photometry of the faintest transients. This paper outlines the status of the project, now in Final Design Phase.Comment: 12 pages, 14 figures, to be published in SPIE Proceedings 1070

A detector system for 'absolute' measurements of fission cross sections at n_TOF in the energy range below 200 MeV

A new measurement of the $^{235}$U(n,f) cross section was performed at the neutron time-of-flight facility n_TOF at CERN. The experiment focused on neutron energies from 20 MeV to several hundred MeV, and was normalized to neutron scattering on hydrogen. This is a measurement first of its kind at this facility, in an energy range that was until now not often explored, so the detector development phase was crucial for its success. Two detectors are presented, a parallel plate fission chamber (PPFC) and a recoil proton telescope (RPT), both dedicated to perform measurements in the incident neutron energy range from 30 MeV to 200 MeV. The experiment was designed to minimize statistical uncertainties in the allocated run time. Several efforts were made to ensure that the systematic effects were understood and under control. The results show that the detectors are suited for measurements at n_TOF above 30 MeV, and indicate the path for possible future lines of development.Comment: Added acknowledgement to Euratom fundin

High-accuracy determination of the neutron flux in the new experimental area n_TOF-EAR2 at CERN

A new high flux experimental area has recently become operational at the n_TOF facility at CERN. This new measuring station, n_TOF-EAR2, is placed at the end of a vertical beam line at a distance of approximately 20m from the spallation target. The characterization of the neutron beam, in terms of flux, spatial profile and resolution function, is of crucial importance for the feasibility study and data analysis of all measurements to be performed in the new area. In this paper, the measurement of the neutron flux, performed with different solid-state and gaseous detection systems, and using three neutron-converting reactions considered standard in different energy regions is reported. The results of the various measurements have been combined, yielding an evaluated neutron energy distribution in a wide energy range, from 2meV to 100MeV, with an accuracy ranging from 2%, at low energy, to 6% in the high-energy region. In addition, an absolute normalization of the n_TOF-EAR2 neutron flux has been obtained by means of an activation measurement performed with 197Au foils in the beam.Peer reviewe

Growth of Long Range Forward-Backward Multiplicity Correlations with Centrality in Au+Au Collisions at sNN\sqrt{s_{NN}} = 200 GeV

Forward-backward multiplicity correlation strengths have been measured with the STAR detector for Au+Au and $\textit{p+p}$ collisions at $\sqrt{s_{NN}}$ = 200 GeV. Strong short and long range correlations (LRC) are seen in central Au+Au collisions. The magnitude of these correlations decrease with decreasing centrality until only short range correlations are observed in peripheral Au+Au collisions. Both the Dual Parton Model (DPM) and the Color Glass Condensate (CGC) predict the existence of the long range correlations. In the DPM the fluctuation in the number of elementary (parton) inelastic collisions produces the LRC. In the CGC longitudinal color flux tubes generate the LRC. The data is in qualitative agreement with the predictions from the DPM and indicates the presence of multiple parton interactions.Comment: 6 pages, 3 figures The abstract has been slightly modifie