Future Path Toward TB Vaccine Development: Boosting BCG or Re-educating by a New Subunit Vaccine

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), kills 5,000 people per day globally. Rapid development and spread of various multi drug-resistant strains of Mtb emphasize that an effective vaccine is still the most cost-effectives and efficient way of controlling and eradicating TB. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, still remains the most widely administered human vaccine, but is inefficient in protecting from pulmonary TB in adults. The protective immunity afforded by BCG is thought to wane with time and considered to last only through adolescent years. Heterologous boosting of BCG-primed immune responses using a subunit vaccine represents a promising vaccination approach to promote strong cellular responses against Mtb. In our earlier studies, we discovered lipopeptides of ESAT-6 antigen with strong potential as a subunit vaccine candidate. Here, we have investigated that potential as a booster to BCG vaccine in both a pre-exposure preventive vaccine and a post-exposure therapeutic vaccine setting. Surprisingly, our results demonstrated that boosting BCG with subunit vaccine shortly before Mtb challenge did not improve the BCG-primed immunity, whereas the subunit vaccine boost after Mtb challenge markedly improved the quantity and quality of effector T cell responses and significantly reduced Mtb load in lungs, liver and spleen in mice. These studies suggest that ESAT-6 lipopeptide-based subunit vaccine was ineffective in overcoming the apparent immunomodulation induced by BCG vaccine in Mtb uninfected mice, but upon infection, the subunit vaccine is effective in re-educating the protective immunity against Mtb infection. These important results have significant implications in the design and investigation of effective vaccine strategies and immunotherapeutic approaches for individuals who have been pre-immunized with BCG vaccine but still get infected with Mtb

GLIDA: GPCR—ligand database for chemical genomics drug discovery—database and tools update

G-protein coupled receptors (GPCRs) represent one of the most important families of drug targets in pharmaceutical development. GLIDA is a public GPCR-related Chemical Genomics database that is primarily focused on the integration of information between GPCRs and their ligands. It provides interaction data between GPCRs and their ligands, along with chemical information on the ligands, as well as biological information regarding GPCRs. These data are connected with each other in a relational database, allowing users in the field of Chemical Genomics research to easily retrieve such information from either biological or chemical starting points. GLIDA includes a variety of similarity search functions for the GPCRs and for their ligands. Thus, GLIDA can provide correlation maps linking the searched homologous GPCRs (or ligands) with their ligands (or GPCRs). By analyzing the correlation patterns between GPCRs and ligands, we can gain more detailed knowledge about their conserved molecular recognition patterns and improve drug design efforts by focusing on inferred candidates for GPCR-specific drugs. This article provides a summary of the GLIDA database and user facilities, and describes recent improvements to database design, data contents, ligand classification programs, similarity search options and graphical interfaces. GLIDA is publicly available at http://pharminfo.pharm.kyoto-u.ac.jp/services/glida/. We hope that it will prove very useful for Chemical Genomics research and GPCR-related drug discovery

Phonons in random alloys: the itinerant coherent-potential approximation

We present the itinerant coherent-potential approximation(ICPA), an analytic, translationally invariant and tractable form of augmented-space-based, multiple-scattering theory in a single-site approximation for harmonic phonons in realistic random binary alloys with mass and force-constant disorder. We provide expressions for quantities needed for comparison with experimental structure factors such as partial and average spectral functions and derive the sum rules associated with them. Numerical results are presented for Ni_{55} Pd_{45} and Ni_{50} Pt_{50} alloys which serve as test cases, the former for weak force-constant disorder and the latter for strong. We present results on dispersion curves and disorder-induced widths. Direct comparisons with the single-site coherent potential approximation(CPA) and experiment are made which provide insight into the physics of force-constant changes in random alloys. The CPA accounts well for the weak force-constant disorder case but fails for strong force-constant disorder where the ICPA succeeds.Comment: 19 pages, 12 eps figures, uses RevTex

British HIV Association guidelines for the management of tuberculosis in adults living with HIV 2019

The overall purpose of these guidelines is to help physicians manage adults with tuberculosis (TB)/human immunodeficiency virus (HIV) co‐infection. Recommendations for the treatment of TB in HIV‐positive adults are similar to those in HIV‐negative adults. Of note, the term “HIV” refers to HIV‐1 throughout these guidelines

Combination therapy with irinotecan and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer

To evaluate the response rate and toxicity of the combination of irinotecan (CPT-11) and cisplatin in a neoadjuvant setting, a phase II study was conducted regarding the regimen of this combination in patients with locally advanced cervical cancer. Eligibility included patients with previously untreated stage Ib2, IIb, or IIIb squamous cell carcinoma with good performance status. CPT-11 (60 mg m−2) was administered intravenously on days 1, 8 and 15, followed by cisplatin (60 mg m−2) given intravenously on day 1. Treatment was repeated every 4 weeks for a total of two or three cycles. Among 23 eligible patients (median age: 59 years), three showed complete response (13%), 15 showed partial response (65%), for an overall response rate of 78% (95% confidence interval 58–90%). Stable disease was observed in four cases (17%) and progressive disease in one (4%). The median time to failure and median survival time have not yet been reached. Of the 52 treatment cycles administered, diarrhoea and grade 3 or 4 neutropenia were observed in 10% and 75% respectively. There were no therapy-related deaths. The combination of CPT-11 with cisplatin is a promising regimen for neoadjuvant chemotherapy in locally advanced cervical cancer. The toxicities of this regimen are well tolerated. © 1999 Cancer Research Campaig

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice

TOI-2257 b: A highly eccentric long-period sub-Neptune transiting a nearby M dwarf

N.S., R.W. and B.-O.D. acknowledge support from the Swiss National Science Foundation (PP00P2-163967 and PP00P2-190080). M.N.G. acknowledges support from MIT's Kavli Institute as a Juan Carlos Torres Fellow and from the European Space Agency (ESA) as an ESA Research Fellow. A.A.B., B.S.S.and I.A.S. acknowledge the support of the Ministry of Science and Higher Education of the Russian Federation under the grant 075-15-2020-780 (N13.1902.21.0039). L.D. is an F.R.S.-FNRS Postdoctoral Researcher. B.V.R. thanks the Heising-Simons Foundation for support. This publication benefits from the support of the French Community of Belgium in the context of the FRIA Doctoral Grant awarded to M.T. and E.J. acknowledges DGAPA for his postdoctoral fellowship. Y.G.M.C. acknowledges support from UNAM-DGAPA PAPIIT BG-101321. D.D. acknowledges support from the TESS Guest Investigator Program grant 80NSSC19K1727 and NASA Exoplanet Research Program grant 18-2XRP18_2-0136. We acknowledge support from the Centre for Space and Habitability (CSH) of the University of Bern. Part of this work received support from the National Centre for Competence in Research PlanetS, supported by the Swiss National Science Foundation (SNSF). Funding for the TESS mission is provided by NASA's Science Mission Directorate. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. This research has made use of the Exoplanet Follow-up Observation Program website, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. This paper includes data collected by the TESS mission that are publicly available from the Mikulski Archive for Space Telescopes (MAST). This work is based upon observations carried out at the Observatorio Astronomico Nacional on the Sierra de San Pedro Martir (OAN-SPM), Baja California, Mexico. We warmly thank the entire technical staff of the Observatorio Astronomico Nacional at San Pedro Martir in Mexico for their unfailing support to SAINT-EX operations, namely: E. Cadena, T. Calvario, E. Colorado, F. Diaz, A. Franco, B. Garcia, C. Guerrero, G. Guisa, F. Guillen, A. Landa, L. Figueroa, B. Hernandez, J. Herrera, E. Lopez, E. Lugo, B. Martinez, G. Melgoza, F. Montalvo, J.M. Nunez, J.L. Ochoa, I. Plauchu, F. Quiroz, H. Riesgo, H. Serrano, T. Verdugo, I. Zavala. The research leading to these results has received funding from the European Research Council (ERC) under the FP/2007-2013 ERC grant agreement nffi 336480, and under the European Union's Horizon 2020 research and innovation programme (grants agreements nffi 679030 and 803193/BEBOP); from an Actions de Recherche Concertee (ARC) grant, financed by the Wallonia-Brussels Federation, from the Balzan Prize Foundation, from the BEL-SPO/BRAIN2.0 research program (PORTAL project), from the Science and Technology Facilities Council (STFC; grant nffi ST/S00193X/1), and from F.R.S-FNRS (Research Project ID T010920F). This work was also partially supported by a grant from the Simons Foundation (PI: Queloz, grant number 327127), as well as by the MERAC foundation (PI: Triaud). PI: Gillon is F.R.S.-FNRS Senior Research Associate. TRAPPIST is funded by the Belgian Fund for Scientific Research (Fond National de la Recherche Scientifique, FNRS) under the grant PDR T.0120.21, with the participation of the Swiss National Science Fundation (SNF). M.G. and E.J. are F.R.S.-FNRS Senior Research Associate. This work makes use of observations from the LCOGT network. Part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP). M.S.I.P. is funded by NSF. Some of the observations in the paper made use of the High-Resolution Imaging instrument(s) `Alopeke (and/or Zorro). `Alopeke (and/or Zorro) was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. Data were reduced using a software pipeline originally written by Elliott Horch and Mark Everett. `Alopeke (and/or Zorro) was mounted on the Gemini North (and/or South) telescope of the international Gemini Observatory, a program of NSF's OIR Lab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation, on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigacion y Desarrollo (Chile), Ministerio de Ciencia, Tecnologia e Innovacion (Argentina), Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). This research has made use of the NASA Exoplanet Archive, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. This research made use of exoplanet (Foreman-Mackey et al. 2021a,b) and its dependencies (Agol et al. 2020; Kumar et al. 2019; Astropy Collaboration 2013, 2018; Kipping 2013; Luger et al. 2019; Salvatier et al. 2016; Theano Development Team 2016). Additional use of software packages AstroImageJ (Collins et al. 2017) and TAPIR (Jensen 2013).Context. Thanks to the relative ease of finding and characterizing small planets around M-dwarf stars, these objects have become cornerstones in the field of exoplanet studies. The current paucity of planets in long-period orbits around M dwarfs makes such objects particularly compelling as they provide clues about the formation and evolution of these systems. Aims. In this study we present the discovery of TOI-2257 b (TIC 198485881), a long-period (35 d) sub-Neptune orbiting an M3 star at 57.8 pc. Its transit depth is about 0.4%, large enough to be detected with medium-size, ground-based telescopes. The long transit duration suggests the planet is in a highly eccentric orbit (e similar to 0.5), which would make it the most eccentric planet known to be transiting an M-dwarf star. Methods. We combined TESS and ground-based data obtained with the 1.0-meter SAINT-EX, 0.60-meter TRAPPIST-North, and 1.2-meter FLWO telescopes to find a planetary size of 2.2 R-circle plus and an orbital period of 35.19 days. In addition, we make use of archival data, high-resolution imaging, and vetting packages to support our planetary interpretation. Results. With its long period and high eccentricity, TOI-2257 b falls into a novel slice of parameter space. Despite the planet's low equilibrium temperature (similar to 256 K), its host star's small size (R-* = 0.311 +/- 0.015) and relative infrared brightness (K-mag = 10.7) make it a suitable candidate for atmospheric exploration via transmission spectroscopy.Swiss National Science Foundation (SNSF)European Commission PP00P2-163967 PP00P2-190080MIT's Kavli InstituteEuropean Space Agency European CommissionMinistry of Science and Higher Education of the Russian Federation 075-15-2020-780 (N13.1902.21.0039)Heising-Simons FoundationFrench Community of BelgiumDGAPAPrograma de Apoyo a Proyectos de Investigacion e Innovacion Tecnologica (PAPIIT) Universidad Nacional Autonoma de Mexico BG-101321TESS Guest Investigator Program 80NSSC19K1727NASA Exoplanet Research Program 18-2XRP18_2-0136Centre for Space and Habitability (CSH) of the University of BernSwiss National Science Foundation (SNSF)European Research Council (ERC) 336480Actions de Recherche Concertee (ARC) grant - Wallonia-Brussels FederationUK Research & Innovation (UKRI)Science & Technology Facilities Council (STFC)Science and Technology Development Fund (STDF) ST/S00193X/1Fonds de la Recherche Scientifique - FNRS T010920FSimons Foundation 327127MERAC foundationFonds de la Recherche Scientifique - FNRS PDR T.0120.21Swiss National Science Foundation (SNSF)National Science Foundation (NSF)NASA Exoplanet Exploration Program NASA's Science Mission DirectorateEuropean Research Council (ERC) 679030 803193/BEBOPBalzan Prize Foundation BEL-SPO/BRAIN2.0 research program (PORTAL project

A super-Earth and a mini-Neptune near the 2:1 MMR straddling the radius valley around the nearby mid-M dwarf TOI-2096

Context. Several planetary formation models have been proposed to explain the observed abundance and variety of compositions of super-Earths and mini-Neptunes. In this context, multitransiting systems orbiting low-mass stars whose planets are close to the radius valley are benchmark systems, which help to elucidate which formation model dominates.Aims. We report the discovery, validation, and initial characterization of one such system, TOI-2096 (TIC 142748283), a two-planet system composed of a super-Earth and a mini-Neptune hosted by a mid-type M dwarf located 48 pc away.Methods. We characterized the host star by combining optical spectra, analyzing its broadband spectral energy distribution, and using evolutionary models for low-mass stars. Then, we derived the planetary properties by modeling the photometric data from TESS and ground-based facilities. In addition, we used archival data, high-resolution imaging, and statistical validation to support our planetary interpretation.Results. We found that the stellar properties of TOI-2096 correspond to a dwarf star of spectral type M4±0.5. It harbors a super-Earth (R = 1.24 ± 0.07 R⊕) and a mini-Neptune (R = 1.90 ± 0.09 R⊕) in likely slightly eccentric orbits with orbital periods of 3.12 d and 6.39 d, respectively. These orbital periods are close to the first-order 2:1 mean-motion resonance (MMR), a configuration that may lead to measurable transit timing variations (TTVs). We computed the expected TTVs amplitude for each planet and found that they might be measurable with high-precision photometry delivering mid-transit times with accuracies of ≲2 min. Moreover, we conclude that measuring the planetary masses via radial velocities (RVs) could also be possible. Lastly, we found that these planets are among the best in their class to conduct atmospheric studies using the NIRSpec/Prism onboard the James Webb Space Telescope (JWST).Conclusions. The properties of this system make it a suitable candidate for further studies, particularly for mass determination using RVs and/or TTVs, decreasing the scarcity of systems that can be used to test planetary formation models around low-mass stars

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]