Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition

CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.Fil: Cherkesova, Tatiana S.. National Academy of Sciences of Belarus. Institute of Bioorganic Chemistry; BielorrusiaFil: Hargrove, Tatiana Y.. Vanderbilt University; Estados UnidosFil: Vanrell, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ges, Igor. Vanderbilt University; Estados UnidosFil: Usanov, Sergey A.. National Academy of Sciences of Belarus. Institute of Bioorganic Chemistry; BielorrusiaFil: Romano, Patricia Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Lepesheva, Galina I.. Vanderbilt University; Estados Unido

Re-conociendo un paisaje. Prospecciones en la Quebrada de Mirigüaca (Antofagasta de la Sierra, Catamarca).

Se presentan los resultados de las prospecciones arqueológicas efectuadas en un sector de la quebrada del río Miriguaca, emplazada en la localidad de Antofagasta de la Sierra, en el NO de la provincia de Catamarca. Durante dichas investigaciones se relevaron una decena de asentamientos de ocupación prehispánica, además de un elevado número de bloques con representaciones rupestres de diferente cronología. En base a la presencia de un conjunto de elementos contextuales que se registraron asociados a los sitios: artefactos líticos, fragmentos cerámicos, representaciones rupestres y rasgos arquitectónicos de cronología conocida; conjuntamente con la obtención de una serie de fechados radiocarbónicos para algunos materiales procedentes de sondeos exploratorios realizados en los sitios, aportamos nueva información ocupacional regional, que involucra un amplio lapso temporal (ca. 3600 a 700 años AP).This paper presents the results of an archaeological research carried out in a sector of the Miriguaca river gorge, situated in Antofagasta de la Sierra, in north west Catamarca. A total of eleven pre-Hispanic settlements were surveyed during this study, along with an important number of rock-art-bearing boulders of diverse chronology. Based on the presence of a number of contextual elements recorded in association with the sites (lithic artifacts, pottery sherds, rock-art and architectural features of known chronology), in addition to a series of radiocarbon dates obtained from a number of test pits conducted there, we introduce new data on the occupation of the region involving a broad time span (ca. 3600-700 BP).Fil: Escola, Patricia Susana. Universidad Nacional de Catamarca. Escuela de Arqueologia; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;Fil: Lopez Campeny, Sara Maria Luisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Conicet -tucumán. Instituto Superior de Estudios Sociales; Argentina;Fil: Martel, Alvaro Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Conicet -tucumán. Instituto Superior de Estudios Sociales; Argentina;Fil: Romano, Andres S.. Universidad Nacional de Tucuman. Facultad de Cs.naturales E Instituto Miguel Lillo. Instituto de Arqueologia y Museo; Argentina;Fil: Hocsman, Salomón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Conicet -tucumán. Instituto Superior de Estudios Sociales; Argentina;Fil: Somonte, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Conicet -tucumán. Instituto Superior de Estudios Sociales; Argentina

Re-Conociendo un espacio. Prospecciones en la Quebrada de Miriguaca (Antofagasta de la Sierra, Catamarca)

Se presentan los resultados de las prospecciones arqueológicas efectuadas en un sector de la quebrada del río Miriguaca, emplazada en la localidad de Antofagasta de la Sierra, en el NO de la provincia de Catamarca. Durante dichas investigaciones se relevaron una decena de asentamientos de ocupación prehispánica, además de un elevado número de bloques con representaciones rupestres de diferente cronología. En base a la presencia de un conjunto de elementos contextuales que se registraron asociados a los sitios: artefactos líticos, fragmentos cerámicos, representaciones rupestres y rasgos arquitectónicos de cronología conocida; conjuntamente con la obtención de una serie de fechados radiocarbónicos para algunos materiales procedentes de sondeos exploratorios realizados en los sitios, aportamos nueva información ocupacional regional, que involucra un amplio lapso temporal (ca. 3600 a 700 años AP).This paper presents the results of an archaeological research carried out in a sector of the Miriguaca river gorge, situated in Antofagasta de la Sierra, in north west Catamarca. A total of eleven pre-Hispanic settlements were surveyed during this study, along with an important number of rock-art-bearing boulders of diverse chronology. Based on the presence of a number of contextual elements recorded in association with the sites (lithic artifacts, pottery sherds, rock-art and architectural features of known chronology), in addition to a series of radiocarbon dates obtained from a number of test pits conducted there, we introduce new data on the occupation of the region involving a broad time span (ca. 3600-700 BP).Fil: Escola, Patricia Susana. Universidad Nacional de Catamarca; ArgentinaFil: Lopez Campeny, Sara Maria Luisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico- Conicet - Tucumán. Instituto Superior de Estudios Sociales; ArgentinaFil: Martel, Alvaro Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico- Conicet - Tucumán. Instituto Superior de Estudios Sociales; ArgentinaFil: Romano, Andrés S..Fil: Hocsman, Salomón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico- Conicet - Tucumán. Instituto Superior de Estudios Sociales; ArgentinaFil: Somonte, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico- Conicet - Tucumán. Instituto Superior de Estudios Sociales; Argentin

Swift Observations of GRB 050603: An afterglow with a steep late time decay slope

We report the results of Swift observations of the Gamma Ray Burst GRB 050603. With a V magnitude V=18.2 about 10 hours after the burst the optical afterglow was the brightest so far detected by Swift and one of the brightest optical afterglows ever seen. The Burst Alert Telescope (BAT) light curves show three fast-rise-exponential-decay spikes with $T_{90}$=12s and a fluence of 7.6$\times 10^{-6}$ ergs cm$^{-2}$ in the 15-150 keV band. With an $E_{\rm \gamma, iso} = 1.26 \times 10^{54}$ ergs it was also one of the most energetic bursts of all times. The Swift spacecraft began observing of the afterglow with the narrow-field instruments about 10 hours after the detection of the burst. The burst was bright enough to be detected by the Swift UV/Optical telescope (UVOT) for almost 3 days and by the X-ray Telescope (XRT) for a week after the burst. The X-ray light curve shows a rapidly fading afterglow with a decay index $\alpha$=1.76$^{+0.15}_{-0.07}$. The X-ray energy spectral index was $\beta_{\rm X}$=0.71\plm0.10 with the column density in agreement with the Galactic value. The spectral analysis does not show an obvious change in the X-ray spectral slope over time. The optical UVOT light curve decays with a slope of $\alpha$=1.8\plm0.2. The steepness and the similarity of the optical and X-ray decay rates suggest that the afterglow was observed after the jet break. We estimate a jet opening angle of about 1-2$^{\circ}$Comment: 14 pages, accepted for publication in Ap

Evidence of pseudoprogression in patients treated with PD1/ PDL1 antibodies across tumor types

Background: PD(L)1 antibodies (anti-PD(L)-1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti-PD(L)-1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti-PD(L)-1. Methods: All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti-PD(L)-1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. Results: A total of 169 patients treated with anti-PD(L)-1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non-small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT-scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). Conclusions: A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune-related response evaluations may require further attention

Comparative Innate and Adaptive Immune Responses in Atlantic Bottlenose Dolphins (Tursiops truncatus) With Viral, Bacterial, and Fungal Infections

Free-ranging Atlantic bottlenose dolphins (n = 360) from two southeastern U.S. estuarine sites were given comprehensive health examinations between 2003 and 2015 as part of a multi-disciplinary research project focused on individual and population health. The study sites (and sample sizes) included the Indian River Lagoon (IRL), Florida, USA (n = 246) and Charleston harbor and associated rivers (CHS), South Carolina, USA (n = 114). Results of a suite of clinicoimmunopathologic tests revealed that both populations have a high prevalence of infectious and neoplastic disease and a variety of abnormalities of their innate and adaptive immune systems. Subclinical infections with cetacean morbillivirus and Chlamydiaceae were detected serologically. Clinical evidence of orogenital papillomatosis was supported by the detection of a new strain of dolphin papillomavirus and herpesvirus by molecular pathology. Dolphins with cutaneous lobomycosis/lacaziasis were subsequently shown to be infected with a novel, uncultivated strain of Paracoccidioides brasiliensis, now established as the etiologic agent of this enigmatic disease in dolphins. In this review, innate and adaptive immunologic responses are compared between healthy dolphins and those with clinical and/or immunopathologic evidence of infection with these specific viral, bacterial, and fungal pathogens. A wide range of immunologic host responses was associated with each pathogen, reflecting the dynamic and complex interplay between the innate, humoral, and cell-mediated immune systems in the dolphin. Collectively, these studies document the comparative innate and adaptive immune responses to various types of infectious diseases in free-ranging Atlantic bottlenose dolphins. Evaluation of the type, pattern, and degree of immunologic response to these pathogens provides novel insight on disease immunopathogenesis in this species and as a comparative model. Importantly, the data suggest that in some cases infection may be associated with subclinical immunopathologic perturbations that could impact overall individual and population health

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Identifying priorities in methodological research using ICD-9-CM and ICD-10 administrative data: report from an international consortium

BACKGROUND: Health administrative data are frequently used for health services and population health research. Comparative research using these data has been facilitated by the use of a standard system for coding diagnoses, the International Classification of Diseases (ICD). Research using the data must deal with data quality and validity limitations which arise because the data are not created for research purposes. This paper presents a list of high-priority methodological areas for researchers using health administrative data. METHODS: A group of researchers and users of health administrative data from Canada, the United States, Switzerland, Australia, China and the United Kingdom came together in June 2005 in Banff, Canada to discuss and identify high-priority methodological research areas. The generation of ideas for research focussed not only on matters relating to the use of administrative data in health services and population health research, but also on the challenges created in transitioning from ICD-9 to ICD-10. After the brain-storming session, voting took place to rank-order the suggested projects. Participants were asked to rate the importance of each project from 1 (low priority) to 10 (high priority). Average ranks were computed to prioritise the projects. RESULTS: Thirteen potential areas of research were identified, some of which represented preparatory work rather than research per se. The three most highly ranked priorities were the documentation of data fields in each country's hospital administrative data (average score 8.4), the translation of patient safety indicators from ICD-9 to ICD-10 (average score 8.0), and the development and validation of algorithms to verify the logic and internal consistency of coding in hospital abstract data (average score 7.0). CONCLUSION: The group discussions resulted in a list of expert views on critical international priorities for future methodological research relating to health administrative data. The consortium's members welcome contacts from investigators involved in research using health administrative data, especially in cross-jurisdictional collaborative studies or in studies that illustrate the application of ICD-10