X-ray structure of the mature ectodomain of phogrin

Phogrin/IA-2β and ICA512/IA-2 are two paralogs receptor-type protein-tyrosine phosphatases (RPTP) that localize in secretory granules of various neuroendocrine cells. In pancreatic islet β-cells, they participate in the regulation of insulin secretion, ensuring proper granulogenesis, and β-cell proliferation. The role of their cytoplasmic tail has been partially unveiled, while that of their luminal region remains unclear. To advance the understanding of its structure-function relationship, the X-ray structure of the mature ectodomain of phogrin (ME phogrin) at pH 7.4 and 4.6 has been solved at 1.95- and 2.01-Å resolution, respectively. Similarly to the ME of ICA512, ME phogrin adopts a ferredoxin-like fold: a sheet of four antiparallel β-strands packed against two α-helices. Sequence conservation among vertebrates, plants and insects suggests that the structural similarity extends to all the receptor family. Crystallized ME phogrin is monomeric, in agreement with solution studies but in striking contrast with the behavior of homodimeric ME ICA512. The structural details that may cause the quaternary structure differences are analyzed. The results provide a basis for building models of the overall orientation and oligomerization state of the receptor in biological membranes

Circundatin H, a new inhibitor of mitochondrial NADH oxidase from Aspergillus ochraceus

[EN] Circumdatin H (1), a new alkaloid from the culture broth of Aspergillus ochraceus, has been isolated, together with a known circumdatin, circumdatin E (2) and other known compounds: flavacol (3) and stephacidin A (4). The structure of 1 was established on the basis of chemical and spectral evidence. All of these alkaloids showed biological activity as inhibitors of the mammalian mitochondrial respiratory chain.López-Gresa, MP.; Gonzalez Más, MC.; Primo, J.; Moya, P.; Romero, V.; Estornell, E. (2005). Circundatin H, a new inhibitor of mitochondrial NADH oxidase from Aspergillus ochraceus. The Journal of Antibiotics. 58:416-419. http://hdl.handle.net/10251/134335S4164195

Protein-Protein Interactions in Crystals of the Human Receptor-Type Protein Tyrosine Phosphatase ICA512 Ectodomain

ICA512 (or IA-2) is a transmembrane protein-tyrosine phosphatase located in secretory granules of neuroendocrine cells. Initially, it was identified as one of the main antigens of autoimmune diabetes. Later, it was found that during insulin secretion, the cytoplasmic domain of ICA512 is cleaved and relocated to the nucleus, where it stimulates the transcription of the insulin gene. The role of the other parts of the receptor in insulin secretion is yet to be unveiled. The structures of the intracellular pseudocatalytic and mature extracellular domains are known, but the transmembrane domain and several intracellular and extracellular parts of the receptor are poorly characterized. Moreover the overall structure of the receptor remains to be established. We started to address this issue studying by X-ray crystallography the structure of the mature ectodomain of ICA512 (ME ICA512) and variants thereof. The variants and crystallization conditions were chosen with the purpose of exploring putative association interfaces, metal binding sites and all other structural details that might help, in subsequent works, to build a model of the entire receptor. Several structural features were clarified and three main different association modes of ME ICA512 were identified. The results provide essential pieces of information for the design of new experiments aimed to assess the structure in vivo

A precision medicine test predicts clinical response after idarubicin and cytarabine induction therapy in AML patients

Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients and has prognostic impact. Our purpose is to determine the correlation between the observed CR/CRi rate after idarubicin (IDA) and cytarabine (CYT) 3 + 7 induction and the leukemic chemosensitivity measured by an ex vivo test of drug activity. Bone marrow samples from adult patients with newly diagnosed AML were included in this study. Whole bone marrow samples were incubated for 48 h in well plates containing IDA, CYT, or their combination. Pharmacological response parameters were estimated using population pharmacodynamic models. Patients attaining a CR/CRi with up to two induction cycles of 3 + 7 were classified as responders and the remaining as resistant. A total of 123 patients fulfilled the inclusion criteria and were evaluable for correlation analyses. The strongest clinical predictors were the area under the curve of the concentration response curves of CYT and IDA. The overall accuracy achieved using MaxSpSe criteria to define positivity was 81%, predicting better responder (93%) than non-responder patients (60%). The ex vivo test provides better yet similar information than cytogenetics, but can be provided before treatment representing a valuable in-time addition. After validation in an external cohort, this novel ex vivo test could be useful to select AML patients for 3 + 7 regimen vs. alternative schedules

DNA multigene characterization of Fasciola hepatica and Lymnaea neotropica and its fascioliasis transmission capacity in Uruguay, with historical correlation, human report review and infection risk analysis

Fascioliasis is a highly pathogenic zoonotic disease emerging in recent decades, in part due to the effects of climate and global changes. South America is the continent presenting more numerous human fascioliasis endemic areas and the highest Fasciola hepatica infection prevalences and intensities known in humans. These serious public health scenarios appear mainly linked to altitude areas in Andean countries, whereas lowland areas of non-Andean countries, such as Uruguay, only show sporadic human cases or outbreaks. To understand this difference, we characterized F. hepatica from cattle and horses and lymnaeids of Uruguay by sequencing of ribosomal DNA ITS-2 and ITS-1 spacers and mitochondrial DNA cox1, nad1 and 16S genes. Results indicate that vectors belong to Lymnaea neotropica instead of to Lymnaea viator, as always reported from Uruguay. Our correlation of fasciolid and lymnaeid haplotypes with historical data on the introduction and spread of livestock species into Uruguay allow to understand the molecular diversity detected. We study the life cycle and transmission features of F. hepatica by L. neotropica of Uruguay under standardized experimental conditions to enable a comparison with the transmission capacity of F. hepatica by Galba truncatula at very high altitude in Bolivia. Results demonstrate that although L. neotropica is a highly efficient vector in the lowlands, its transmission capacity is markedly lower than that of G. truncatula in the highlands. On this baseline, we review the human fascioliasis cases reported in Uruguay and analyze the present and future risk of human infection in front of future climate change estimations

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km2 resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e. offset) between in situ soil temperature measurements, based on time series from over 1200 1-km2 pixels (summarized from 8519 unique temperature sensors) across all the world\u27s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (−0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Label-free graphene oxide-based surface plasmon resonance immunosensor for the quantification of Galectin-3, a novel cardiac biomarker

We report the first optical biosensor for the novel and important cardiac biomarker, galectin-3 (Gal3), using the anti-Gal3 antibody as a biorecognition element and surface plasmon resonance (SPR) for transducing the bioaffinity event. The immunosensing platform was built at a thiolated Au surface modified by self-assembling four bilayers of poly(diallyldimethylammonium chloride) and graphene oxide (GO), followed by the covalent attachment of 3-aminephenylboronic acid (3ABA). The importance of GO, both as the anchoring point of the antibody and as a field enhancer for improving the biosensor sensitivity, was critically discussed. The advantages of using 3ABA to orientate the anti-Gal3 antibody through the selective link to the Fc region were also demonstrated. The new platform represents an interesting alternative for the label-free biosensing of Gal3 in the whole range of clinically relevant concentrations (linear range between 10.0 and 50.0 ng mL-1, detection limit of 2.0 ng mL-1) with successful application for Gal3 biosensing in enriched human serum samples.Fil: Primo, Emiliano Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; ArgentinaFil: Kogan, Marcelo Javier. Universidad de Chile; ChileFil: Verdejo, Hugo E.. Universidad de Chile; Chile. Pontificia Universidad Catolica de Chile. Facultad de Ciencias Biológicas; ChileFil: Bollo, Soledad. Pontificia Universidad Católica de Chile; ChileFil: Rubianes, María Dolores. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Rivas, Gustavo Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentin

El recreo zona de encuentro en la Educación Infantil, Educación Primaria y Educación Secundaria

Incluye anexo con cuestionarios de evaluación, materiales elaborados y fotosSe continúa con el proyecto del curso anterior donde se trata de enraizar al centro en la localidad de manera que los alumnos conozcan, identifiquen y disfruten los recursos del municipio. Los objetivos son valorar la diversidad de culturas, creencias e ideologías como fuente de enriquecimiento para todas las personas; dar la posibilidad de conocer juegos, bailes y costumbres relacionadas con la localidad, la comunidad o Europa; y adecuar la oferta educativa a las necesidades del alumnado. El trabajo se planifiva en talleres de artesanía, Medio Ambiente y Relaciones y Comunicación; en salidas ecológicas a Toledo o al Museo de Ciencias Naturales; y en actividades y jornadas como la Semana de la Paz, Semana del Libro y participación en competiciones deportivas, culturales y concursos de la localidad. Las actividades son elaboración de crónicas de visitas, periódico y guiones radiofónicos; representación teatral, cuentacuentos, danzas y música folclórica; ilustración de libros y creación de escenarios para las Jornadas; elaboración del huerto, semillero y vivero; taller de reciclado; y concursos sobre el euro. Los padres colaboran en la decoración y pintura de la zona infantil, en los talleres y las jornadas. Se evalúa la participación, motivación, implicación del profesor y resolución de conflictos y dificultades encontradas.Madrid (Comunidad Autónoma). Consejería de EducaciónMadridMadrid (Comunidad Autónoma). Subdirección General de Formación del Profesorado. CRIF Las Acacias; General Ricardos 179 - 28025 Madrid; Tel. + 34915250893ES

Reflection in Action: A Key to Developing Competences for the Teaching of Science Reflection in Action: A Key to Developing Competences for the Teaching of Science

Abstract Motivated by the widespread concern over the quality of science education in Mexican elementary schools, the Faculty of Biology at the Benemérita Universidad Autónoma de Puebla (BUAP, or the Autonomous University of Puebla) held a teacher training workshop in collaboration with the Ministry of Education. The purpose was to promote the participants' reflective action in order to reflect on their experience as teachers and design and evaluate new teaching strategies for the development of scientific thought in their students. An analysis of government programs and national and international assessments was carried out in order to detect critical situations. Both subjects that involve more learning challenges and those activities taken from the official textbooks that enable the development of scientific skills were chosen. The educational strategy was developed from a critical position on the expository models and guided discovery. Teachers assume the role of students, reflecting on their learning and teaching and, eventually, rebuilding this learning situation with their students, with the process based on the following: ATINER CONFERENCE PAPER SERIES No: EDU2014-0931 7 a) previous ideas; b) flipped classroom; c) joint action; d) reflection-in-action; and, e) formative assessment. The formative assessment comprised a portfolio which included a scientific dictionary, daily research and projects undertaken with students. An analysis of the portfolio enables researchers to establish how teachers structure their thinking and incorporate new concepts and teaching strategies. The objective of this research was to identify and analyse the concepts and ideas related to the nature of science, scientific concepts, and teaching and learn about science developed by a group of teachers during a training course for the teaching of sciences skills. In conclusion, the workshop promoted a conceptual change related to the topics and subjects addressed in the classroom: ideas (both the teachers' and the students') related to learning about science; the evaluation of teaching; the development of creative and critical thinking; and, the development of scientific tools. Overall the teachers enjoyed the course and reoriented their approach to working in the classroom