High-Throughput Screening Platform To Identify Inhibitors of Protein Synthesis with Potential for the Treatment of Malaria

Artemisinin-based combination therapies have been crucial in driving down the global burden of malaria, the world’s largest parasitic killer. However, their efficacy is now threatened by the emergence of resistance in Southeast Asia and sub-Saharan Africa. Thus, there is a pressing need to develop new antimalarials with diverse mechanisms of action. One area of Plasmodium metabolism that has recently proven rich in exploitable antimalarial targets is protein synthesis, with a compound targeting elongation factor 2 now in clinical development and inhibitors of several aminoacyl-tRNA synthetases in lead optimization. Given the promise of these components of translation as viable drug targets, we rationalized that an assay containing all functional components of translation would be a valuable tool for antimalarial screening and drug discovery. Here, we report the development and validation of an assay platform that enables specific inhibitors of Plasmodium falciparum translation (PfIVT) to be identified. The primary assay in this platform monitors the translation of a luciferase reporter in a P. falciparum lysate-based expression system. Hits identified in this primary assay are assessed in a counterscreen assay that enables false positives that directly interfere with the luciferase to be triaged. The remaining hit compounds are then assessed in an equivalent human IVT assay. This platform of assays was used to screen MMV’s Pandemic and Pathogen Box libraries, identifying several selective inhibitors of protein synthesis. We believe this new high-throughput screening platform has the potential to greatly expedite the discovery of antimalarials that act via this highly desirable mechanism of action

Historia de la agroecología en México

A mediados del siglo pasado, existían dos tipos de científicos de la agronomía en México. Unos, que veían una agricultura atrasada y que había, ciegamente, que llevar hacia los avances tec- nológicos más modernos. Otros, que salían al campo y exploraban intensivamente los sistemas indígenas y campesinos. El estudiar y dar a conocer la riqueza tanto biológica como humana que albergaban estos sistemas, dio pie a la agroecología en este país. Sobra decir que varios de los pioneros de esa ciencia a nivel mundial, fueron aprendices de sistemas indígenas mexicanos. En este trabajo se hace el esfuerzo por narrar los hitos históricos más importantes en la investigación y la enseñanza de la agroecología en el pasado y en la actualidad; además, hacemos también una reflexión sobre los desafíos que enfrenta esa disciplina

Linking stellar populations to H II regions across nearby galaxies I. Constraining pre-supernova feedback from young clusters in NGC 1672

Context. Stellar feedback is one of the fundamental factors regulating the evolution of galaxies. However, we still do not have access to strong observational constraints on the relative importance of the different feedback mechanisms (e.g. radiation, ionised gas pressure, stellar winds) in driving Ha II region evolution and molecular cloud disruption. To quantify and compare the different feedback mechanisms, the size of an Ha II region is crucial, whereas samples of well-resolved Ha II regions are scarce. Aims. We constrain the relative importance of the various feedback mechanisms from young massive star populations by resolving Ha II regions across the disk of the nearby star-forming galaxy NGC 1672. Methods. We combined measurements of ionised gas nebular lines obtained by PHANGS-MUSE, with high-resolution (PSF FWHM ∼ 0.1 ∼10 pc) imaging from Hubble Space Telescope (HST) in both the narrow-band Hα and broad-band (NUV, U, B, V, I) filters. We identified a sample of 40 isolated, compact Ha II regions in the HST Hα image. We measured the sizes of these Ha II regions, which were previously unresolved in seeing-limited ground-based observations. In addition, we identified the ionisation source(s) for each Ha II region from catalogues produced as part of the PHANGS-HST survey. In doing so, we were able to link young stellar populations with the properties of their surrounding Ha II regions. Results. The HST observations allowed us to resolve all 40 regions, with radii between 5 and 40 pc. The Ha II regions investigated here are mildly dominated by thermal or wind pressure, yet their elevation above the radiation pressure is within the expected uncertainty range. We see that radiation pressure provides a substantially higher contribution to the total pressure than previously found in the literature over similar size scales. In general, we find higher pressures within more compact Ha II regions, which is driven by the inherent size scaling relations of each pressure term, albeit with significant scatter introduced by the variation in the stellar population properties (e.g. luminosity, mass, age, metallicity). Conclusions. For nearby galaxies, the combination of MUSE/VLT observations with stellar population and resolved Hα observations from HST provides a promising approach that could yield the statistics required to map out how the importance of different stellar feedback mechanisms evolve over the lifetime of a Ha II region

Measurement of the production cross section for W-bosons in association with jets in pp collisions at s=7 TeV with the ATLAS detector

This Letter reports on a first measurement of the inclusive W + jets cross section in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC, with the ATLAS detector. Cross sections, in both the electron and muon decay modes of the W-boson, are presented as a function of jet multiplicity and of the transverse momentum of the leading and next-to-leading jets in the event. Measurements are also presented of the ratio of cross sections sigma (W + >= n)/sigma(W + >= n - 1) for inclusive jet multiplicities n = 1-4. The results, based on an integrated luminosity of 1.3 pb(-1), have been corrected for all known detector effects and are quoted in a limited and well-defined range of jet and lepton kinematics. The measured cross sections are compared to particle-level predictions based on perturbative QCD. Next-to-leading order calculations, studied here for n <= 2, are found in good agreement with the data. Leading-order multiparton event generators, normalized to the NNLO total cross section, describe the data well for all measured jet multiplicitie

PHANGS-JWST First Results: A Combined HST and JWST Analysis of the Nuclear Star Cluster in NGC 628

We combine archival Hubble Space Telescope and new James Webb Space Telescope imaging data covering the ultraviolet to mid-infrared regime to morphologically analyze the nuclear star cluster (NSC) of NGC 628, a grand-design spiral galaxy. The cluster is located in a 200 pc × 400 pc cavity lacking both dust and gas. We find roughly constant values for the effective radius (r eff ∼ 5 pc) and ellipticity (ε ∼ 0.05), while the Sérsic index (n) and position angle (PA) drop from n ∼ 3 to ∼2 and PA ∼ 130° to 90°, respectively. In the mid-infrared, r eff ∼ 12 pc, ε ∼ 0.4, and n ∼ 1-1.5, with the same PA ∼ 90°. The NSC has a stellar mass of log 10 ( M ⋆ nsc / M ⊙ ) = 7.06 ± 0.31 , as derived through B − V, confirmed when using multiwavelength data, and in agreement with the literature value. Fitting the spectral energy distribution (SED), excluding the mid-infrared data, yields a main stellar population age of (8 ± 3) Gyr with a metallicity of Z = 0.012 ± 0.006. There is no indication of any significant star formation over the last few gigayears. Whether gas and dust were dynamically kept out or evacuated from the central cavity remains unclear. The best fit suggests an excess of flux in the mid-infrared bands, with further indications that the center of the mid-infrared structure is displaced with respect to the optical center of the NSC. We discuss five potential scenarios, none of them fully explaining both the observed photometry and structure

X-ray Crystallographic Structure of an Artificial β-Sheet Dimer

This paper describes the X-ray crystallographic structure of a designed cyclic beta-sheet peptide that forms a well-defined hydrogen-bonded dimer that mimics beta-sheet dimers formed by proteins. The 54-membered ring macrocyclic peptide (1a) contains molecular template and turn units that induce beta-sheet structure in a heptapeptide strand that forms the dimerization interface. The X-ray crystallographic structure reveals the structures of the two "Hao" amino acids that help template the beta-sheet structure and the two delta-linked ornithine turn units that link the Hao-containing template to the heptapeptide beta-strand. The Hao amino acids adopt a conformation that resembles a tripeptide in a beta-strand conformation, with one edge of the Hao unit presenting an alternating array of hydrogen-bond donor and acceptor groups in the same pattern as that of a tripeptide beta-strand. The delta-linked ornithines adopt a conformation that resembles a hydrogen-bonded beta-turn, in which the ornithine takes the place of the i+1 and i+2 residues. The dimers formed by macrocyclic beta-sheet 1a resemble the dimers of many proteins, such as defensin HNP-3, the lambda-Cro repressor, interleukin 8, and the ribonuclease H domain of HIV-1 reverse transcriptase. The dimers of 1a self-assemble in the solid state into a barrel-shaped trimer of dimers in which the three dimers are arranged in a triangular fashion. Molecular modeling in which one of the three dimers is removed and the remaining two dimers are aligned face-to-face provides a model of the dimers of dimers of closely related macrocyclic beta-sheet peptides that were observed in solution

The PHANGS-JWST Treasury Survey: Star Formation, Feedback, and Dust Physics at High Angular Resolution in Nearby GalaxieS

The PHANGS collaboration has been building a reference data set for the multiscale, multiphase study of star formation and the interstellar medium (ISM) in nearby galaxies. With the successful launch and commissioning of JWST, we can now obtain high-resolution infrared imaging to probe the youngest stellar populations and dust emission on the scales of star clusters and molecular clouds (∼5-50 pc). In Cycle 1, PHANGS is conducting an eight-band imaging survey from 2 to 21 μm of 19 nearby spiral galaxies. Optical integral field spectroscopy, CO(2-1) mapping, and UV-optical imaging for all 19 galaxies have been obtained through large programs with ALMA, VLT-MUSE, and Hubble. PHANGS-JWST enables a full inventory of star formation, accurate measurement of the mass and age of star clusters, identification of the youngest embedded stellar populations, and characterization of the physical state of small dust grains. When combined with Hubble catalogs of ∼10,000 star clusters, MUSE spectroscopic mapping of ∼20,000 H ii regions, and ∼12,000 ALMA-identified molecular clouds, it becomes possible to measure the timescales and efficiencies of the earliest phases of star formation and feedback, build an empirical model of the dependence of small dust grain properties on local ISM conditions, and test our understanding of how dust-reprocessed starlight traces star formation activity, all across a diversity of galactic environments. Here we describe the PHANGS-JWST Treasury survey, present the remarkable imaging obtained in the first few months of science operations, and provide context for the initial results presented in the first series of PHANGS-JWST publications