Design, synthesis, and characterization of stapled oligosaccharides

Stapling short peptides to lock specific conformations and thereby obtain superior pharmacological properties is well established. However, similar concepts have not been applied to oligosaccharides. Here, we describe the design, synthesis, and characterization of the first stapled oligosaccharides. Automated assembly of β-(1,6)-glucans equipped with two alkenyl side chains was followed by on-resin Grubbs metathesis for efficient ring closure with a variety of cross-linkers of different sizes. Oligosaccharide stapling increases enzymatic stability and cell penetration, therefore opening new opportunities for the use of glycans in medicinal chemistry

HER2/HER3 regulates lactate secretion and expression of lactate receptor mRNA through the MAP3K4 associated protein GIT1

One of the major features of cancer is Otto Warburg's observation that many tumors have increased extracellular acidification compared to healthy tissues. Since Warburg's observation, the importance of extracellular acidification in cancer is now considered a hallmark of cancer. Human MAP3K4 functions upstream of the p38 and JNK mitogen activated protein kinases (MAPKs). Additionally, MAP3K4 is required for cell migration and extracellular acidification of breast cancer cells in response to HER2/HER3 signaling. Here, we demonstrate that GIT1 interacts with MAP3K4 by immunoprecipitation, while cellular lactate production and the capacity of MCF-7 cells for anchorage independent growth in soft agar were dependent on GIT1. Additionally, we show that activation of HER2/HER3 signaling leads to reduced expression of lactate receptor (GPR81) mRNA and that both, GIT1 and MAP3K4, are necessary for constitutive expression of GPR81 mRNA. Our study suggests that targeting downstream proteins in the HER2/HER3-induced extracellular lactate signaling pathway may be a way to inhibit the Warburg Effect to disrupt tumor growth.NIEHS Training grant [ES007091]; Arizona Science Foundation [CAA 0226-08, ES006694, ES012007, ES04940]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity

Malaria is a global health concern and research efforts are ongoing to develop a superior vaccine to RTS,S/AS01. To guide immunogen design, we seek a comprehensive understanding of the protective humoral response against Plasmodium falciparum circumsporozoite protein (PfCSP). In contrast to the well-studied responses to the repeat region and the C-terminus, the antibody response against the N-terminal domain of PfCSP (N-CSP) remains obscure. Here, we characterized the molecular recognition and functional efficacy of the N-CSP-specific monoclonal antibody 5D5. The crystal structure at 1.85 Åresolution revealed that 5D5 binds an α-helical epitope in N-CSP with high affinity through extensive shape and charge complementarity, and the unusual utilization of an N-linked glycan. Nevertheless, functional studies indicated low 5D5 binding to live Pf sporozoites, and lack of sporozoite inhibition in vitro and in mosquitoes. Overall, our data on low recognition and inhibition of sporozoites do not support the inclusion of the 5D5 epitope into the next generation of CSP-based vaccines.Summary Statement The Plasmodium falciparum sporozoite surface protein, PfCSP, is an attractive vaccine target, but the antibody response against the CSP N-terminal domain has remained understudied. Here, to guide immunogen design, Thai et al. provide insights into the binding motif and functional efficacy of the N-terminal domain-specific monoclonal antibody, 5D5

Chemical composition, physicochemical evaluation and sensory analysis of yogurt added with extract of polyphenolic compounds from Quercus crassifolia oak bark

Introduction: A diet high in calories and saturated fats has been associated with health problems that have been increasing worldwide. Therefore, it is required to increase the number of formulated foods that generate well-being to health. Yogurt is a widely consumed food by all sectors of the population and it can be used as a vehicle to incorporate bioactive compounds. The phenolic compounds present in forest residues, such as those from oak bark, can be used and incorporated into yogurt, to increase its benefits as a functional food. Objective: The objective of this study was to develop a multifunctional yogurt enriched with vegetable oil (2.3% w/w) as a source of omega 6 and 3 and adding nanocapsules (24.5% w/w) of an extract of oak bark from Quercus crassifolia, rich in in phenolic compounds and high antioxidant capacity. Methods: Three yogurt formulations were prepared: F1: yogurt was made with non-fat milk, used as a control, F2: yogurt was prepared with non-fat milk and added with vegetable palm oil, and F3: non-fat yogurt was added with vegetable oil and nanoencapsulated oak bark phenolic extract. The yogurts were characterized in their chemical composition, microbiological analysis, and sensory analysis. Results: The multifunctional product F3 and product F2 presented lactic acid bacteria in concentration of 3.01X106 and 4.73x106, respectively, preserving characteristics of probiotic food. Product F3 presented low levels of syneresis (7.34%) and it was significantly different from the control yogurt (9.01%). The viscosity increased from 150 cP in the control yogurt to 341 cP in F3, due to the increase in the concentrations of solids by nanoencapsulating the phenolic. The wall material used for nanoencapsulation was sodium caseinate and mantodextrin. However, this increase in viscosity did not affect the sensory evaluation of the product. There were no significant differences between the control yogurt and the F2 and F3 products. Conclusion: A yogurt added with vegetable oil and nanoencapsulated oak bark phenolic extract was obtained. It was enhanced by the presence of probiotics, bioactive compounds, and essential fatty acids, and then evaluated and accepted by a sensory panel. Nanoencapsulation is a viable alternative to mask the characteristic astringent taste of phenolic compounds because it was not detected by the panelists

Differential transcription profiles inAedes aegyptidetoxification genes after temephos selection

The mosquito Aedes aegypti is the main vector of Dengue and Yellow Fever flaviviruses. The organophosphate insecticide temephos is a larvicide that is used globally to control Ae. aegypti populations; many of which have in turn evolved resistance. Target site alteration in the acetylcholine esterase of this species has not being identified. Instead, we tracked changes in transcription of metabolic detoxification genes using the Ae. aegypti ‘Detox Chip’ microarray during five generations of temephos selection. We selected for temephos resistance in three replicates in each of six collections, five from Mexico, and one from Peru. The response to selection was tracked in terms of lethal concentrations. Uniform upregulation was seen in the epsilon class glutathione-S-transferase (eGST) genes in strains from Mexico prior to laboratory selection, while eGSTs in the Iquitos Peru strain became upregulated after five generations of temephos selection. While expression of many carboxyl/cholinesterase esterase (CCE) genes increased with selection, no single esterase was consistently upregulated and this same pattern was noted in the cytochrome P450 monooxygenase (CYP) genes and in other genes involved in reduction or oxidation of xenobiotics. Bioassays using glutathione-S-transferase (GST), CCE and CYP inhibitors suggest that various CCEs instead of GSTs are the main metabolic mechanism conferring resistance to temephos. We show that temephos-selected strains show no cross resistance to permethrin and that genes associated with temephos selection are largely independent of those selected with permethrin in a previous study

Study of secondary muons detected within the tunnels of the Cholula pyramid

The pyramid of Cholula was built at the beginning of 100 B.C. and during of period of 500 years it was finished, had several new constructions, based on the previous constructions. The primarily material of construction is the adobe. Early in 1931 archaeological excavations began with the intention of exploring the interior of the pyramid, excavations were stopped in 1971, and to date no further excavations have been carried out. This work shows the first measurements of muons, particles that are very penetrating, these are generated by primary cosmic rays that was incoming in the atmosphere and these generates a rain of secondary particles, among them the muons. To measure this kind of particles was implemented a detector system, it is formed by a scintillator plastic coupled to a tube photomultiplier; the signals were acquired by mean of an oscilloscope. The detector was collocated near of the center of the pyramid; the location belongs to the maxima concentration in mass over the detector. Graphs of the charge distribution, maximum amplitude and characteristic rise times of the generated pulses in a plastic scintillator are shown, this is scintillator was synthesized in the materials laboratory of the FCFM-BUAP. In addition the optical characterization of the same was realized

Ballistic Electron Emission Microscopy on CoSi2{}_2/Si(111) interfaces: band structure induced atomic-scale resolution and role of localized surface states

Applying a Keldysh Green`s function method it is shown that hot electrons injected from a STM-tip into a CoSi${}_2$/Si(111) system form a highly focused beam due to the silicide band structure. This explains the atomic resolution obtained in recent Ballistic Electron Emission Microscopy (BEEM) experiments. Localized surface states in the $(2 \times 1)$-reconstruction are found to be responsible for the also reported anticorrugation of the BEEM current. These results clearly demonstrate the importance of bulk and surface band structure effects for a detailed understanding of BEEM data.Comment: 5 pages, RevTex, 4 postscript figures, http://www.icmm.csic.es/Pandres/pedro.ht

Crystal-field effects in Er3+- and Yb3+-doped hexagonal NaYF4 nanoparticles

COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSince the up-conversion phenomenon in rare-earths (REs) doped NaYF4 is strongly affected by the crystal electric field (CF), determining the CF parameters, wave functions, and scheme of the energy levels of the RE J multiplets could be crucial to improve and tune the up-conversion efficiency. In this work, the temperature and magnetic field dependent magnetization of NaY1-x[Er(Yb)](x)F-4 hexagonal nanoparticles (NPs) is reported. The data were best fit using the appropriated CF Hamiltonian for the J = 15/2 (J = 7/2) ground state multiplet of Er3+ (Yb3+) ions. The B-2(0), B-4(0), B-6(0), and B-6(6) CF parameters were considered in the Hamiltonian for RE ions located at the hexagonal C-3h point symmetry site of the NaYF4 host lattice. These results allowed us to predict an overall CF splitting of similar to 214 (similar to 356 K) for Er3+ (Yb3+) and the wave functions and their energy levels for the J = 15/2 (J = 7/2) ground state multiplet which are in good agreement with the low temperature electron spin resonance experiments. Besides, our measurements allowed us to calculate all the excited CF J multiplets that yield to a good estimation of the up-conversion light emission linewidth. The nonlinear optical light emission of the studied NaY1-x[Er(Yb)](x)F-4 hexagonal NPs was also compared with the most efficient up-conversion codoped NaY1-x-yErxYbyF4 hexagonal NPs.961617COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informaçãoSem informação2011/19924-22012/04870-72012/05903-62015/23882-4This work was supported and performed under the auspices of the Brazilian agencies CAPES, CNPq, and FAPESP through Grants No. 2011/19924-2, No. 2012/04870-7, No. 2012/05903-6, and No. 2015/23882-4. The SEM data were acquired in the LNNano at the Centro Nacional de Pesquisa em Energia e Materiais (CNPEM) in Campinas-SP, Brazil. D.J.G. acknowledges support from FONCyT (PICT 2012-1069)

Crystal-field effects in Er 3 + - and Yb 3 + -doped hexagonal NaYF 4 nanoparticles

Since the up-conversion phenomenon in rare-earths (REs) doped NaYF4 is strongly affected by the crystal electric field (CF), determining the CF parameters, wave functions, and scheme of the energy levels of the RE J multiplets could be crucial to improve and tune the up-conversion efficiency. In this work, the temperature and magnetic field dependent magnetization of NaY1−x[Er(Yb)]xF4 hexagonal nanoparticles (NPs) is reported. The data were best fit using the appropriated CF Hamiltonian for the J=15/2(J=7/2) ground state multiplet of Er3+(Yb3+) ions. The B02, B04, B06, and B66 CF parameters were considered in the Hamiltonian for RE ions located at the hexagonal C3h point symmetry site of the NaYF4 host lattice. These results allowed us to predict an overall CF splitting of ∼214 (∼356 ) for Er3+(Yb3+) and the wave functions and their energy levels for the J=15/2 (J=7/2) ground state multiplet which are in good agreement with the low temperature electron spin resonance experiments. Besides, our measurements allowed us to calculate all the excited CF J multiplets that yield to a good estimation of the up-conversion light emission linewidth. The nonlinear optical light emission of the studied NaY1−x[Er(Yb)]xF4 hexagonal NPs was also compared with the most efficient up-conversion codoped NaY1−x−yErxY by F4 hexagonal NPs.Fil: García Flores, A. F.. Universidade Federal do ABC; BrasilFil: Matias, J.S.. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; ArgentinaFil: Garcia, D. J.. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; ArgentinaFil: Martínez, E. D.. Instituto de Física “Gleb Wataghin”, Unicamp; BrasilFil: Cornaglia de la Cruz, Pablo Sebastian. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; ArgentinaFil: Lesseux, G.G.. Instituto de Física “Gleb Wataghin”, Unicamp; BrasilFil: Ribeiro, R. A.. Universidade Federal do ABC; BrasilFil: Urbano, R. R.. Instituto de Física “Gleb Wataghin”, Unicamp; BrasilFil: Rettori, C.. Instituto de Física “Gleb Wataghin”, Unicamp; Brasil. Universidade Federal do ABC; Brasi