Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

The molecular structures of the halotelluroxetanes p-MeOC6H4Te(X)[C(=C(H)X′)C(CH2)nO], X=X′=Cl and n=6 (1) and X=Cl, X′=Br and n=5 (4), show similar binuclear aggregates sustained by {· · ·Te–O}2 cores comprising covalent Te–O and secondary Te· · ·O interactions. The resulting C2ClO2(lone-pair) sets define pseudo-octahedral geometries. In each structure, C–X· · ·π(arene) interactions lead to supramolecular layers. Literature studies have shown these and related compounds (i.e. 2: X=X′=Cl and n=5; 3: X=X′=Br and n=5) to inhibit Cathepsins B, K, L and S to varying extents. Molecular docking calculations have been conducted on ligands (i.e. cations derived by removal of the tellurium-bound X atoms) 1′–3′ (note 3′=4′) enabling correlations between affinity for sub-sites and inhibition. The common feature of all docked complexes was the formation of a Te–S covalent bond with cysteine residues, the relative stability of the ligands with an E-configuration and the formation of a C–O· · ·π interaction with the phenyl ring; for 1′ the Te–S covalent bond was weak, a result correlating with its low inhibition profile. At the next level differences are apparent, especially with respect to the interactions formed by the organic-ligand-bound halides. While these atoms do not form specific interactions in Cathepsins B and K, in Cathepsin L, these halides are involved in C–O· · ·X halogen bonds

5-Methyl-2,4-bis­(methyl­sulfan­yl)tricyclo­[6.2.1.02,7]undeca-4,9-diene-3,6-dione1

The structure analysis of the title compound, C14H16O2S2, shows the SMe and H atoms of the bond linking the six-membered rings to be syn and also to be syn to the bridgehead –CH2– group. Each of the five-membered rings adopts an envelope conformation at the bridgehead –CH2– group. The dione-substituted ring adopts a folded conformation about the 1,4-C⋯C vector, with the ketone groups lying to one side. The cyclo­hexene ring adopts a boat conformation

Ultrasonography of the distal limbs in Nellore and Girolando calves 8 to 12 months of age

Submitted by Franciele Moreira ([email protected]) on 2018-01-08T13:43:58Z No. of bitstreams: 2 Artigo - Pryscilla Vanessa Rodrigues Gonçalves - 2014.pdf: 738775 bytes, checksum: 17c42f29f233f408ef568a5c45b1b787 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Approved for entry into archive by Luciana Ferreira ([email protected]) on 2018-01-08T14:49:52Z (GMT) No. of bitstreams: 2 Artigo - Pryscilla Vanessa Rodrigues Gonçalves - 2014.pdf: 738775 bytes, checksum: 17c42f29f233f408ef568a5c45b1b787 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Made available in DSpace on 2018-01-08T14:49:52Z (GMT). No. of bitstreams: 2 Artigo - Pryscilla Vanessa Rodrigues Gonçalves - 2014.pdf: 738775 bytes, checksum: 17c42f29f233f408ef568a5c45b1b787 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2014Background: Ultrasonography can be used anywhere and allows rapid, noninvasive differentiation of soft tissue structures of the musculoskeletal system. The objectives of this study were to describe the ultrasonographic appearance of the structures of the metacarpo-/metatarsophalangeal and the interphalangeal joints, the appearance of the growth plates of the distal metacarpus/metatarsus and of the proximal phalanx and to measure the cross-sectional dimensions of the DDFT and SDFT in Nellore and Girolando calves eight to 12 months of age. Results: In the longitudinal dorsal view the common digital extensor tendon and the digital extensor tendon were depicted as echogenic parallel fiber bundles located directly under the skin. The joint spaces appeared as anechoic interruptions of the hyperechogenic bone surfaces. The normal amount of synovial fluid could not be depicted. The growth plates were seen as anechoic interruptions of the bone surface proximal and distal to the fetlock joint space. In transverse sonograms of the distal palmar/plantar regions, the flexor tendons and branchs of the suspensory ligament were imaged as echogenic structures. The lumen of the digital flexor tendon sheath could not be imaged in these normal cattle. The thin digital distal annular ligament and the reversal of positions of the DDFT and SDFT could be appreciated. No significant differences were found between the cross-sectional measurements of the DDFT and the SDFT from Nellore and Girolando in any age, thoracic/pelvic limbs, right/left sides and lateral/medial digits. Conclusions: The results of this study establish important ultrasonographic reference data of the normal structures of the distal limbs and the normal dimensions of the flexor tendons in Nellore and Girolando calves for use in clinical practice

GATA2 Promotes Hematopoietic Development and Represses Cardiac Differentiation of Human Mesoderm.

In vertebrates, GATA2 is a master regulator of hematopoiesis and is expressed throughout embryo development and in adult life. Although the essential role of GATA2 in mouse hematopoiesis is well established, its involvement during early human hematopoietic development is not clear. By combining time-controlled overexpression of GATA2 with genetic knockout experiments, we found that GATA2, at the mesoderm specification stage, promotes the generation of hemogenic endothelial progenitors and their further differentiation to hematopoietic progenitor cells, and negatively regulates cardiac differentiation. Surprisingly, genome-wide transcriptional and chromatin immunoprecipitation analysis showed that GATA2 bound to regulatory regions, and repressed the expression of cardiac development-related genes. Moreover, genes important for hematopoietic differentiation were upregulated by GATA2 in a mostly indirect manner. Collectively, our data reveal a hitherto unrecognized role of GATA2 as a repressor of cardiac fates, and highlight the importance of coordinating the specification and repression of alternative cell fates.Ramón y Cajal Program, Spanish Ministry of Economy, Industry, and Competitiveness, Spanish Cancer Association, FERO, Instituto de Salud Carlos III, European Social Fund, MINECO, PERIS Program of the Generalitat de Catalunya, Obra Social la Caixa-Fundacion Josep Carreras, Spanish Institute of Health Carlos III, Wellcome Trust, MRC, CRUK, NIH-NIDD

Development of a Novel Anti-CD19 Chimeric Antigen Receptor : A Paradigm for an Affordable CAR T Cell Production at Academic Institutions

Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells in vitro, inducing secretion of pro-inflammatory cytokines and CAR T cell proliferation. In vivo, A3B1 CAR T cells are able to fully control disease progression in an NOD.Cg-Prkdc Il2rd/SzJ (NSG) xenograph B-ALL mouse model. Based on the pre-clinical data, we conclude that our CART19 is clearly functional against CD19+ cells, to a level similar to other CAR19s currently being used in the clinic. Concurrently, we describe the implementation of our CAR T cell production system, using lentiviral vector and CliniMACS Prodigy, within a medium-sized academic institution. The results of the validation phase show our system is robust and reproducible, while maintaining a low cost that is affordable for academic institutions. Our model can serve as a paradigm for similar institutions, and it may help to make CAR T cell treatment available to all patients

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

Altres ajuts: Health Canada's Genomics Research and Development Initiative Phase VI (H4080-144541-2014-2019); Obra Social La Caixa-Fundació Josep Carreras and the Generalitat de Catalunya (SGR330); Asociación Española Contra el Cáncer (AECC-CI-2015)Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution. In this article, Díaz de la Guardia and colleagues report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, and IL-10 produced by AML-derived BM-MSCs is an independent prognostic factor negatively impacting on overall survival

Climate seasonality limits leaf carbon assimilation and wood productivity in tropical forests

The seasonal climate drivers of the carbon cycle in tropical forests remain poorly known, although these forests account for more carbon assimilation and storage than any other terrestrial ecosystem. Based on a unique combination of seasonal pan-tropical data sets from 89 experimental sites (68 include aboveground wood productivity measurements and 35 litter productivity measurements), their associated canopy photosynthetic capacity (enhanced vegetation index, EVI) and climate, we ask how carbon assimilation and aboveground allocation are related to climate seasonality in tropical forests and how they interact in the seasonal carbon cycle. We found that canopy photosynthetic capacity seasonality responds positively to precipitation when rainfall is < 2000ĝ€-mmĝ€-yrĝ'1 (water-limited forests) and to radiation otherwise (light-limited forests). On the other hand, independent of climate limitations, wood productivity and litterfall are driven by seasonal variation in precipitation and evapotranspiration, respectively. Consequently, light-limited forests present an asynchronism between canopy photosynthetic capacity and wood productivity. First-order control by precipitation likely indicates a decrease in tropical forest productivity in a drier climate in water-limited forest, and in current light-limited forest with future rainfall < 2000ĝ€-mmĝ€-yrĝ'1. Author(s) 2016.Fil: Wagner, Fabien H.. Instituto Nacional de Pesquisas Espaciais; BrasilFil: Hérault, Bruno. Ecologie Des Forets de Guyane; BrasilFil: Bonal, Damien. Institut National de la Recherche Agronomique; FranciaFil: Stahl, Clment. Universiteit Antwerp; BélgicaFil: Anderson, Liana O.. National Center For Monitoring And Early Warning Of Natural Disasters; BrasilFil: Baker, Timothy R.. University Of Leeds; Reino UnidoFil: Sebastian Becker, Gabriel. Universidad de Hohenheim; AlemaniaFil: Beeckman, Hans. Royal Museum For Central Africa; BélgicaFil: Boanerges Souza, Danilo. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Cesar Botosso, Paulo. Ministerio da Agricultura Pecuaria e Abastecimento de Brasil. Empresa Brasileira de Pesquisa Agropecuaria; BrasilFil: Bowman, David M. J. S.. University of Tasmania; AustraliaFil: Bräuning, Achim. Universitat Erlangen-Nuremberg; AlemaniaFil: Brede, Benjamin. Wageningen University And Research Centre; Países BajosFil: Irving Brown, Foster. Universidade Federal Do Acre; BrasilFil: Julio Camarero, Jesus. Instituto Boliviano de Investigacion Forestal Bolivia; BoliviaFil: Camargo, Plnio Barbosa. Universidade de Sao Paulo; BrasilFil: Cardoso, Fernanda C.G.. Universidade Federal do Paraná; BrasilFil: Carvalho, Fabrcio Alvim. Universidade Federal de Juiz de Fora; BrasilFil: Castro, Wendeson. Universidade Federal Do Acre; BrasilFil: Koloski Chagas, Rubens. Universidade de Sao Paulo; BrasilFil: Chave, Jrome. Centre National de la Recherche Scientifique; FranciaFil: Chidumayo, Emmanuel N.. University Of Zambia; ZambiaFil: Clark, Deborah A.. University Of Missouri-st. Louis; Estados UnidosFil: Regina Capellotto Costa, Flavia. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Couralet, Camille. Royal Museum For Central Africa; BélgicaFil: Henrique Da Silva Mauricio, Paulo. Universidade Federal Do Acre; BrasilFil: Dalitz, Helmut. Universidad de Hohenheim; AlemaniaFil: Resende De Castro, Vinicius. Universidade Federal de Vicosa; BrasilFil: Milani, Jaanan Eloisa De Freitas. Universidade Federal do Paraná; BrasilFil: Roig Junent, Fidel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla | Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla | Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla; Argentin

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (bodymass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

Common Limitations of Image Processing Metrics:A Picture Story

While the importance of automatic image analysis is continuously increasing, recent meta-research revealed major flaws with respect to algorithm validation. Performance metrics are particularly key for meaningful, objective, and transparent performance assessment and validation of the used automatic algorithms, but relatively little attention has been given to the practical pitfalls when using specific metrics for a given image analysis task. These are typically related to (1) the disregard of inherent metric properties, such as the behaviour in the presence of class imbalance or small target structures, (2) the disregard of inherent data set properties, such as the non-independence of the test cases, and (3) the disregard of the actual biomedical domain interest that the metrics should reflect. This living dynamically document has the purpose to illustrate important limitations of performance metrics commonly applied in the field of image analysis. In this context, it focuses on biomedical image analysis problems that can be phrased as image-level classification, semantic segmentation, instance segmentation, or object detection task. The current version is based on a Delphi process on metrics conducted by an international consortium of image analysis experts from more than 60 institutions worldwide.Comment: This is a dynamic paper on limitations of commonly used metrics. The current version discusses metrics for image-level classification, semantic segmentation, object detection and instance segmentation. For missing use cases, comments or questions, please contact [email protected] or [email protected]. Substantial contributions to this document will be acknowledged with a co-authorshi