In Silico Design and Selection of New Tetrahydroisoquinoline-Based CD44 Antagonist Candidates

CD44 promotes metastasis, chemoresistance, and stemness in different types of cancer and is a target for the development of new anti-cancer therapies. All CD44 isoforms share a common N-terminal domain that binds to hyaluronic acid (HA). Herein, we used a computational approach to design new potential CD44 antagonists and evaluate their target-binding ability. By analyzing 30 crystal structures of the HA-binding domain (CD44HAbd), we characterized a subdomain that binds to 1,2,3,4-tetrahydroisoquinoline (THQ)-containing compounds and is adjacent to residues essential for HA interaction. By computational combinatorial chemistry (CCC), we designed 168,190 molecules and compared their conformers to a pharmacophore containing the key features of the crystallographic THQ binding mode. Approximately 0.01% of the compounds matched the pharmacophore and were analyzed by computational docking and molecular dynamics (MD). We identified two compounds, Can125 and Can159, that bound to human CD44HAbd (hCD44HAbd) in explicit-solvent MD simulations and therefore may elicit CD44 blockage. These compounds can be easily synthesized by multicomponent reactions for activity testing and their binding mode, reported here, could be helpful in the design of more potent CD44 antagonists

Influence of the calcination temperature on the activity of hydroxyapatite-supported palladium catalyst in the methane oxidation reaction

In the present study, a series of four hydroxyapatite (HAP) supported palladium samples, with a Pd loading close to 0.5 %, obtained through their calcination at 773, 873, 973, or 1073 K has been investigated. These samples have been characterized using a wide battery of complementary techniques. From these studies, it was found that the rise of the calcination temperature induces a progressive dehydroxylation of the support and a structure evolution of the species containing Pd 2+ , from tetrahedral (Td) to square planar geometry (D 4h ). Moreover, this enhances markedly the metal-support interactions. For instance, at the highest temperature (1073 K), Pd particles were found encapsulated by a thin support layer. Consequently, two distinct reducible species have been identified; one of them manifests SMSI. This increase in the Pd-HAP interaction strength seems to (i) expand the HAP lattice, (ii) change the Pd 2+ coordination from Td to D 4h geometry, (iii) promote PdO reduction and (iv) suppress CO chemisorption. These entire properties do compensate the poor textural properties and benefit the efficiency and stability of the Pd active phase in methane oxidation reaction.Ministerio de Economía y Competitividad (CTQ2015-73219-JIN (AEI/FEDER/UE) and CTQ2016-80253-R (AEI/FEDER/UE)) // Basque Government (GIC IT-1297-19) // University of the Basque Country UPV/EHU (PIF15/335

The biology and behavior of the longhorned beetle, Dectes texanus on sunflower and soybean

The biology and behavior of the longhorned beetle Dectes texanus LeConte (Coleoptera: Cerambycidae) was studied on two host plants that suffer economic losses from this pest; sunflower, Helianthus annuus, and soybean, Glycines max. Reciprocal crosses of D. texanus collected from the two plants all produced viable progeny, indicating that conspecific insects attack both crops. Pupae from soybean stalks weighed about 40% less than those from sunflower, and adults fed on soybean lived a mean of 23 days, compared to a mean of 53 days (males) and 76 days (females) for those fed sunflower. A female's larval host plant had no effect on her tendency to ovipuncture plants of either type in a greenhouse trial. A field-tested population collected exclusively from sunflower contained three types of females in similar proportions: those that laid eggs only on sunflower, those that laid only on soybean, and those that laid equally on both host plants. Females in field trials fed more on the plant they had fed on in the laboratory, but soybean-fed females fed more on soybean than did sunflower-fed females. Females fed soybean also made more ovipunctures on soybean plants in field trials than sunflower-fed females, but their responses to sunflower plants were similar. Females displayed higher total ovipositional activity when they encountered sunflower first in the field, and lower total activity when they encountered soybean first. Feeding scores were significantly correlated with ovipunctures and eggs on both plant types. We conclude that sunflower is the preferred host plant, although females will accept soybean when it is the only available food. The results suggest that D. texanus is still in the initial stages of a host range expansion with female host selection behavior demonstrating both genetic influences and phenotypic flexibility. Sunflower represents a nutritionally superior, ancestral host plant and relatively high fitness costs are still associated with utilization of the novel host plant, soybean, costs that may be offset by benefits such as reduced intraspecific competition. These potential benefits and their consequent implications for D. texanus host range evolution are hypothesized and discussed

Susceptibility of biological stages of the horn fly, Haematobia irritans, to entomopathogenic fungi (Hyphomycetes)

The susceptibility of the egg, pupa, and adult of Haematobia irritans (L.) (Diptera: Muscidae) to isolates of the fungi Metarhizium anisopliae (Metsch.) Sor., Beauveria bassiana (Bals.) Vuill., and Paecilomyces fumosoroseus (Wize) Brown and Smith, was evaluated under laboratory conditions. Groups of 20 eggs than 4 h old, pupae less than 48h old and adults were sprayed with a conidial suspension of each isolate. Eggs, pupae and adults of horn fly were susceptible to these entomopathogenic fungi. For treated eggs, the isolates Ma3, Ma 15, Ma25, Pfr1, and Pfr8 reduced adult emergence to 3.8% to 6.3% in comparison with the control (72%). The mortality of pupae infected by the isolates Ma2, Ma25, and Pfr10 ranged between 50% and 71.3%. Mortality of adults after treatment with the isolates Ma6, Ma 10, Ma 14, Ma 15, Pfr 1, Pfr 9, Pfr 10, Pfr 11, and Pfr12 were higher than 90%. The isolate Ma6 produced the lowest LC(50) against adult horn flies (8.08 &times 10(2)conidia/ml). These findings supported the hypotheses that isolates of M. anisopliae, and P. fumosoroseus are pathogenic against the different biological stages of horn flies by reducing adult emergence when applied on groups of eggs and pupae, and producing mortality when applied to adults

Coalescent-based species delimitation in the sand lizards of the Liolaemus wiegmannii complex (Squamata: Liolaemidae)

Coalescent-based algorithms coupled with the access to genome-wide data have become powerful tools forassessing questions on recent or rapid diversification, as well as delineating species boundaries in the absence of reciprocal monophyly. In southern South America, the diversification of Liolaemus lizards during the Pleistocene is well documented and has been attributed to the climatic changes that characterized this recent period of time. Past climatic changes had harsh effects at extreme latitudes, including Patagonia, but habitat changes at intermediate latitudes of South America have also been recorded, including expansion of sand fields over northern Patagonia and Pampas). In this work, we apply a coalescent-based approach to study the diversification of the Liolaemus wiegmannii species complex, a morphologically conservative clade that inhabits sandy soils across northwest and south-central Argentina, and the south shores of Uruguay. Using four standard sequence markers (mitochondrial DNA and three nuclear loci) along with ddRADseq data we inferred species limits and a time calibrated species tree for the L. wiegmannii complex in order to evaluate the influence of Quaternary sand expansion/retraction cycles on diversification. We also evaluated the evolutionary independence of the recently described L. gardeli and inferred its phylogenetic position relative to L. wiegmannii. We find strong evidence for six allopatric candidate species within L. wiegmannii, which diversified during the Pleistocene. The Great Patagonian Glaciation (∼1 million years before present) likely split the species complex into two main groups: one composed of lineages associated with sub-Andean sedimentary formations, and the other mostly related to sand fields in the Pampas and northern Patagonia. We hypothesize that early speciation within L. wiegmannii was influenced by the expansion of sand dunes throughout central Argentina and Pampas. Finally, L. gardeli is supported as a distinct lineage nested within the L. wiegmannii complex.Fil: Villamil, Joaquín. Universidad de la República. Facultad de Ciencias; UruguayFil: Avila, Luciano Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; ArgentinaFil: Morando, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; ArgentinaFil: Sites, Jack W.. University Brigham Young; Estados UnidosFil: Leaché, Adam D.. University of Washington; Estados UnidosFil: Maneyro, Raúl. Universidad de la República. Facultad de Ciencias; UruguayFil: Camargo Bentaberry, Arley. Universidad de la República; Urugua

Effect of the harvest date, calcium and other chemicals on the quality and storability of ‘Golden Smoothie’ apples

Apples cultivated in Mexico generally are smaller and softer than those produced in other geographical latitudes considered as optimal for apple production. The aim of this evaluation was determine the effect of applications with calcium, nitrogen, potassium, magnesium, sulfur and naphthaleneacetic acid (NAA), as well as the harvest date on the quality of apple fruits. ‘Golden Smoothie’ apple trees were treated foliarly with CaCl2 with and without NAA, and with a mixture of N, K, Mg and S or gypsum applied to soil for two years. Apples were harvested at 141 (regular harvest date), 161 (mid-late harvest) and 171 days (late harvest) after full bloom (DAFB) and evaluated for quality at harvest time and during their storage at 0°C for up to 179 days. Foliar applications of CaCl2 significantly increased the calcium content in fruit and leaves, but fruit quality, including firmness, was not influenced. Fertilization of soil with the mixture of nutrients, including CaSO4, did not influence the fruit quality. Lately harvested fruit was 14.9% heavier but 17.1% softer than fruit picked at the commercial harvest date. Delaying of fruit harvest reduced about 43 d the storability of fruit. Based in these results, the relative softness of apples grown in Mexico is not related with its calcium content, hence unlikely to be overcome with the application of this mineral. Even in the control fruits, both seasons, the stored fruits do not show some physiological disorder as bitter pit.  Objective: Apples cultivated in Mexico generally are smaller and softer than those produced in other geographical latitudes considered as optimal for apple production. The aim of this evaluation was determine the effect of applications with calcium, nitrogen, potassium, magnesium, sulfur and naphthaleneacetic acid (NAA), as well as the harvest date on the quality of apple fruits. Methodology ‘Golden Smoothie’ apple trees were treated foliarly with CaCl2 with and without NAA, and with a mixture of N, K, Mg and S or gypsum applied to soil for two years. Apples were harvested at 141 (regular harvest date), 161 (mid-late harvest) and 171 days (late harvest) after full bloom (DAFB) and evaluated for quality at harvest time and during their storage at 0°C for up to 179 days. Results: Foliar applications of CaCl2 significantly increased the calcium content in fruit and leaves, but fruit quality, including firmness, was not influenced. Fertilization of soil with the mixture of nutrients, including CaSO4, did not influence the fruit quality. Lately harvested fruit was 14.9% heavier but 17.1% softer than fruit picked at the commercial harvest date. Delaying of fruit harvest reduced about 43 d the storability of fruit. Based in these results, the relative softness of apples grown in Mexico is not related with its calcium content, hence unlikely to be overcome with the application of this mineral. Conclusions: Even in the control fruits, both seasons, the stored fruits do not show some physiological disorder as bitter pi

Critical pathways for the management of preeclampsia and severe preeclampsia in institutionalised health care settings

BACKGROUND: Preeclampsia is a complex disease in which several providers should interact continuously and in a coordinated manner to provide proper health care. However, standardizing criteria to treat patients with preeclampsia is problematical and severe flaws have been observed in the management of the disease. This paper describes a set of critical pathways (CPs) designed to provide uniform criteria for clinical decision-making at different levels of care of pregnant patients with preeclampsia or severe preeclampsia. METHODS: Clinicians and researchers from different countries participated in the construction of the CPs. The CPs were developed using the following steps: a) Definition of the conceptual framework; b) Identification of potential users: primary care physicians and maternal and child health nurses in ambulatory settings; ob/gyn and intensive care physicians in secondary and tertiary care levels. c) Structural development. RESULTS: The CPs address the following care processes: 1. Screening for preeclampsia, risk assessment and classification according to the level of risk. 2. Management of preeclampsia at primary care clinics. 3. Evaluation and management of preeclampsia at secondary and tertiary care hospitals: 4. Criteria for clinical decision-making between conservative management and expedited delivery of patients with severe preeclampsia. CONCLUSION: Since preeclampsia continues to be one of the primary causes of maternal deaths and morbidity worldwide, the expected impact of these CPs is the contribution to improving health care quality in both developed and developing countries. The CPs are designed to be applied in a complex health care system, where different physicians and health providers at different levels of care should interact continuously and in a coordinated manner to provide care to all preeclamptic women. Although the CPs were developed using evidence-based criteria, they could require careful evaluation and remodelling according to each system's demands. Additionally, the CPs need to be tested in large-scale, multi-level studies in order to thoroughly examine and evaluate their efficacy and effectiveness

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE