CARMENES input catalogue of M dwarfs. I. Low-resolution spectroscopy with CAFOS

Context. CARMENES is a stabilised, high-resolution, double-channel spectrograph at the 3.5 m Calar Alto telescope. It is optimally designed for radial-velocity surveys of M dwarfs with potentially habitable Earth-mass planets. Aims. We prepare a list of the brightest, single M dwarfs in each spectral subtype observable from the northern hemisphere, from which we will select the best planet-hunting targets for CARMENES. Methods. In this first paper on the preparation of our input catalogue, we compiled a large amount of public data and collected low-resolution optical spectroscopy with CAFOS at the 2.2 m Calar Alto telescope for 753 stars. We derived accurate spectral types using a dense grid of standard stars, a double least-squares minimisation technique, and 31 spectral indices previously defined by other authors. Additionally, we quantified surface gravity, metallicity, and chromospheric activity for all the stars in our sample. Results. We calculated spectral types for all 753 stars, of which 305 are new and 448 are revised. We measured pseudo-equivalent widths of Halpha for all the stars in our sample, concluded that chromospheric activity does not affect spectral typing from our indices, and tabulated 49 stars that had been reported to be young stars in open clusters, moving groups, and stellar associations. Of the 753 stars, two are new subdwarf candidates, three are T Tauri stars, 25 are giants, 44 are K dwarfs, and 679 are M dwarfs. Many of the 261 investigated dwarfs in the range M4.0-8.0 V are among the brightest stars known in their spectral subtype. Conclusions. This collection of low-resolution spectroscopic data serves as a candidate target list for the CARMENES survey and can be highly valuable for other radial-velocity surveys of M dwarfs and for studies of cool dwarfs in the solar neighbourhood.Comment: A&A, in pres

QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni.

Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure-activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents

Interobserver agreement in dysplasia grading: toward an enhanced gold standard for clinical pathology trials

Objective: Interobserver agreement in the context of oral epithelial dysplasia (OED) grading has been notoriously unreliable and can impose barriers for developing new molecular markers and diagnostic technologies. This paper aimed to report the details of a 3-stage histopathology review and adjudication process with the goal of achieving a consensus histopathologic diagnosis of each biopsy. Study Design: Two adjacent serial histologic sections of oral lesions from 846 patients were independently scored by 2 different pathologists from a pool of 4. In instances where the original 2 pathologists disagreed, a third, independent adjudicating pathologist conducted a review of both sections. If a majority agreement was not achieved, the third stage involved a face-to-face consensus review. Results: Individual pathologist pair κ values ranged from 0.251 to 0.706 (fair-good) before the 3-stage review process. During the initial review phase, the 2 pathologists agreed on a diagnosis for 69.9% of the cases. After the adjudication review by a third pathologist, an additional 22.8% of cases were given a consensus diagnosis (agreement of 2 out of 3 pathologists). After the face-to-face review, the remaining 7.3% of cases had a consensus diagnosis. Conclusions: The use of the defined protocol resulted in a substantial increase (30%) in diagnostic agreement and has the potential to improve the level of agreement for establishing gold standards for studies based on histopathologic diagnosis

Detection of He I λ10830\lambda10830 \AA{} absorption on HD 189733 b with CARMENES high-resolution transmission spectroscopy

We present three transit observations of HD 189733 b obtained with the high-resolution spectrograph CARMENES at Calar Alto. A strong absorption signal is detected in the near-infrared He I triplet at 10830 \AA{} in all three transits. During mid-transit, the mean absorption level is $0.88\pm0.04$ % measured in a $\pm$10 km s$^{-1}$ range at a net blueshift of $-3.5\pm0.4$ km s$^{-1}$ (10829.84--10830.57 \AA{}). The absorption signal exhibits radial velocities of $+6.5\pm3.1$ km s$^{-1}$ and $-12.6\pm1.0$ km s$^{-1}$ during ingress and egress, respectively; measured in the planetary rest frame. We show that stellar activity related pseudo-signals interfere with the planetary atmospheric absorption signal. They could contribute as much as 80% of the observed signal and might also affect the radial velocity signature, but pseudo-signals are very unlikely to explain the entire signal. The observed line ratio between the two unresolved and the third line of the He I triplet is $2.8\pm0.2$, which strongly deviates from the value expected for an optically thin atmospheres. When interpreted in terms of absorption in the planetary atmosphere, this favors a compact helium atmosphere with an extent of only 0.2 planetary radii and a substantial column density on the order of $4\times 10^{12}$ cm$^{-2}$. The observed radial velocities can be understood either in terms of atmospheric circulation with equatorial superrotation or as a sign of an asymmetric atmospheric component of evaporating material. We detect no clear signature of ongoing evaporation, like pre- or post-transit absorption, which could indicate material beyond the planetary Roche lobe, or radial velocities in excess of the escape velocity. These findings do not contradict planetary evaporation, but only show that the detected helium absorption in HD 189733 b does not trace the atmospheric layers that show pronounced escape signatures.Comment: 13 pages, 12 figures, accepted for publication in A&

On the three-finger protein domain fold and CD59-like proteins in Schistosoma mansoni

Background: It is believed that schistosomes evade complement-mediated killing by expressing regulatory proteins on their surface. Recently, six homologues of human CD59, an important inhibitor of the complement system membrane attack complex, were identified in the schistosome genome. Therefore, it is important to investigate whether these molecules could act as CD59-like complement inhibitors in schistosomes as part of an immune evasion strategy. Methodology/Principal Findings: Herein, we describe the molecular characterization of seven putative SmCD59-like genes and attempt to address the putative biological function of two isoforms. Superimposition analysis of the 3D structure of hCD59 and schistosome sequences revealed that they contain the three-fingered protein domain (TFPD). However, the conserved amino acid residues involved in complement recognition in mammals could not be identified. Real-time RT-PCR and Western blot analysis determined that most of these genes are up-regulated in the transition from free-living cercaria to adult worm stage. Immunolocalization experiments and tegument preparations confirm that at least some of the SmCD59-like proteins are surface-localized; however, significant expression was also detected in internal tissues of adult worms. Finally, the involvement of two SmCD59 proteins in complement inhibition was evaluated by three different approaches: (i) a hemolytic assay using recombinant soluble forms expressed in Pichia pastoris and E. coli; (ii) complement-resistance of CHO cells expressing the respective membrane-anchored proteins; and (iii) the complement killing of schistosomula after gene suppression by RNAi. Our data indicated that these proteins are not involved in the regulation of complement activation. Conclusions: Our results suggest that this group of proteins belongs to the TFPD superfamily. Their expression is associated to intra-host stages, present in the tegument surface, and also in intra-parasite tissues. Three distinct approaches using SmCD59 proteins to inhibit complement strongly suggested that these proteins are not complement inhibitors and their function in schistosomes remains to be determined.Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, Grant Number:04/12872-3)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Institute of Health, National Institute of Allergy and Infectious Diseases (NIH-NIAID), Grant AI-095893NIH-NIAID Grant AI-056273FAPESP 00/11624-

New proposal of silver diamine fluoride use in arresting approximal caries: study protocol for a randomized controlled trial

Abstract\ud \ud Background\ud Approximal surfaces are a challenge to caries lesions control. Silver diamine fluoride (SDF) is a simple,low-cost and promisor intervention for arresting caries lesions, but it has never been tested on approximal surfaces. Our aim is to evaluate the efficacy and cost-efficacy of SDF in arresting initial lesions compared to resin infiltration and exclusively flossing (control group). Our second aim is to assess discomfort and satisfaction regarding interventions.\ud \ud \ud Methods/design\ud This is a randomized clinical trial, double-blinded, placebo-controlled study. Children/adolescents presenting at least one approximal initial caries lesion in primary molars/permanent premolars and molars will be included. Surfaces with advanced dentine lesions identified by radiography and participants who refuse to participate or present negative behaviors will be excluded. A minimum sample size of 504 surfaces will be required for each subgroup. Individuals will be randomly allocated in three groups of interventions: SDF, resin infiltration, and control group. Depending on the allocation, the patients will receive the active treatment and respective placebo therapies. All patients will be oriented to daily flossing the included surfaces. Our primary outcome will be caries progression by clinical and radiographic examinations. Appointments will be timed and costs of materials will be considered to calculate cost-efficacy. Patient discomfort will be assessed after interventions. Parent and patient satisfaction with the treatment will be collected after treatment and in the last follow-up visit. Individuals will be assessed at 1 and 3 months after treatment to evaluate dental biofilm and at 6, 12, and 24 months to assess caries progression by visual examination and/or radiography. Multilevel analyses will be used to verify if the type of treatment influenced on the tested outcomes. Costs will be compared and analyses of cost-efficacy will be performed. Poisson analysis will test the association between intervention and reported discomfort and satisfaction.\ud \ud \ud Discussion\ud Our hypothesis is that SDF is the most cost-efficacious option from all tested interventions. If our hypothesis is confirmed, the use of SDF in private and public contexts could represent an easier and effective option in the treatment of enamel approximal caries in children/adolescents.\ud \ud \ud Trial registration\ud ClinicalTrials.gov (\ud NCT01477385\ud \ud ), Initial release: 11/16/2011: last update: 06/02/2014.Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP (Protocols 2012/50716-0 and 2014/00271-7)CNPQCape

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence.

Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and affects over 200 million people worldwide. The control and treatment of this neglected tropical disease is based on a single drug, praziquantel, which raises concerns about the development of drug resistance. This, and the lack of efficacy of praziquantel against juvenile worms, highlights the urgency for new antischistosomal therapies. In this review we focus on innovative approaches to the identification of antischistosomal drug candidates, including the use of automated assays, fragment-based screening, computer-aided and artificial intelligence-based computational methods. We highlight the current developments that may contribute to optimizing research outputs and lead to more effective drugs for this highly prevalent disease, in a more cost-effective drug discovery endeavor