Bmp4 Is Essential for the Formation of the Vestibular Apparatus that Detects Angular Head Movements

Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-β), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification

Structure-activity relationship of 4-azaindole-2-piperidine derivatives as agents against Trypanosoma cruzi

The structure-activity relationship of a 4-Azaindole-2-piperidine compound selected from GlaxoSmithKline's recently disclosed open-resource "Chagas box" and possessing moderate activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, is presented. Despite considerable medicinal chemistry efforts, a suitably potent and metabolically stable compound could not be identified to advance the series into in vivo studies. This research should be of interest to those in the area of neglected diseases and in particular anti-kinetoplastid drug discovery301FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2015/19495-5; 2015/50655-9; 2013/07600-3We would like to thank FAPESP (Grant Nos 2015/19495-5, 2015/50655-9 and 2013/07600-3) as well as DNDi for funding; UNICAMP NMR and technical staff for assistance; The Thomson Mass Spectrometry Lab at UNICAMP for use of HRMS equipment; the High-Throughput ADME team at AbbVie for ADME testing; and additional thanks to Sir Simon Campbell, Dr. Dale Kempf (AbbVie), and Dr. Michael Schrimpf (AbbVie) for helpful discussions. DNDi is grateful to its donors, public and private, who have provided funding for all DNDi activities since its inception in 2003. A full list of DNDi’s donors can be found at http://www.dndi.org/donors/donors

Hydrolysis and dispersion properties of aqueous Y2Si2O7 suspensions

Eukaryotic cytosolic ACBPs (acyl-CoA-binding proteins) bind acyl-CoA esters and maintain a cytosolic acyl-CoA pool, but the thermodynamics of their protein-lipid interactions and physiological relevance in plants are not well understood. Arabidopsis has three cytosolic ACBPs which have been identified as AtACBP4, AtACBP5 and AtACBP6, and microarray data indicated that all of them are expressed in seeds; AtACBP4 is expressed in early embryogenesis, whereas AtACBP5 is expressed later. ITC (isothermal titration calorimetry) in combination with transgenic Arabidopsis lines were used to investigate the roles of these three ACBPs from Arabidopsis thaliana. The dissociation constants, stoichiometry and enthalpy change of AtACBP interactions with various acyl-CoA esters were determined using ITC. Strong binding of recombinant (r) AtACBP6 with long-chain acyl-CoA (C16-to C18-CoA) esters was observed with dissociation constants in the nanomolar range. However, the affinity of rAtACBP4 and rAtACBP5 to these acyl-CoA esters was much weaker (dissociation constants in the micromolar range), suggesting that they interact with acyl-CoA esters differently from rAtACBP6. When transgenic Arabidopsis expressing AtACBP6pro::GUS was generated, strong GUS (beta-glucuronidase) expression in cotyledonary-staged embryos and seedlings prompted us to measure the acyl-CoA contents of the acbp6 mutant. This mutant accumulated higher levels of C18:1-CoA and C18:1- and C18:2-CoAs in cotyledonary-staged embryos and seedlings, respectively, in comparison with the wild type. The acbp4acbp5acbp6 mutant showed the lightest seed weight and highest sensitivity to abscisic acid during germination, suggesting their physiological functions in seeds.Article Number: e00165</p

Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents

A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound 29. Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series

On a multivariate Markov chain model for credit risk measurement

In this paper, we use credibility theory to estimate credit transition matrices in a multivariate Markov chain model for credit rating. A transition matrix is estimated by a linear combination of the prior estimate of the transition matrix and the empirical transition matrix. These estimates can be easily computed by solving a set of linear programming (LP) problems. The estimation procedure can be implemented easily on Excel spreadsheets without requiring much computational effort and time. The number of parameters is O(s2m2), where s is the dimension of the categorical time series for credit ratings and m is the number of possible credit ratings for a security. Numerical evaluations of credit risk measures based on our model are presented.Correlated credit migrations, Linear programming, Transition matrices, Credibility theory,

Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives

Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1–9 displayed good potency (EC50 T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32–64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.Fil: Slafer, Brian W.. Universidade Estadual de Campinas; BrasilFil: Dessoy, Marco A.. Universidade Estadual de Campinas; BrasilFil: de Oliveira, Ramon G.. Universidade Estadual de Campinas; BrasilFil: Mollo, María Cruz. Universidade Estadual de Campinas; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lee, Eun. Universidade Estadual de Campinas; BrasilFil: Matheeussen, An. Universidade Estadual de Campinas; BrasilFil: Maes, Louis. Universidade Estadual de Campinas; BrasilFil: Caljon, Guy. Universiteit Antwerp; BélgicaFil: Ferreira, Leonardo L. G.. Universidade de Sao Paulo; BrasilFil: Krogh, Renata. Universidade de Sao Paulo; BrasilFil: Andricopulo, Adriano D.. Universidade de Sao Paulo; BrasilFil: Cruz, Luiza R.. No especifíca;Fil: Mowbray, Charles E.. No especifíca;Fil: Kratz, Jadel M.. No especifíca;Fil: Dias, Luiz C.. Universidade Estadual de Campinas; Brasi