Sonic Hedgehog Pathway as a Target for Therapy in Angiogenesis-Related Diseases

Hedgehog (Hh) proteins belong to a class of morphogens involved in many biological processes during embryonic development; they are relatively silent during normal adult life although they may be recruited postnatally in response to tissue injury. Three secreted proteins have been identified: Sonic hedgehog (Shh), Desert hedgehog and Indian hedgehog. The interaction of Hh ligand with its receptor Patched-1 triggers the activation of smoothened and initiates transduction events that lead to the regulation of transcriptional factors belonging to the Gli family. Hh pathway orchestrates both coronary development and adult coronary neovascularisation by controlling the expression of multiple proangiogenic genes and anti-apoptotic cytokines. Shh pathway enhances the recruitment of endothelial progenitor cells in addition to the mechanisms described for other Hh and concurs to its myocardial protection. In cerebral ischemia, Hh mimicking molecules has been reported to limit damages caused by vessel occlusion. Besides, Shh carried by microparticles corrects endothelial injury through nitric oxide release. Anomalous activations of Hh pathway are implicated in various types of tumours including medulloblastoma, carcinoma of esophagus, stomach, pancreas and colon. Hh can influence angiogenesis in both positive and negative manner and they may have implication for therapeutic strategies to treat either ischemic or cancer diseases

Higher Dimensional Classical W-Algebras

Classical $W$-algebras in higher dimensions are constructed. This is achieved by generalizing the classical Gel'fand-Dickey brackets to the commutative limit of the ring of classical pseudodifferential operators in arbitrary dimension. These $W$-algebras are the Poisson structures associated with a higher dimensional version of the Khokhlov-Zabolotskaya hierarchy (dispersionless KP-hierarchy). The two dimensional case is worked out explicitly and it is shown that the role of Diff$S(1)$ is taken by the algebra of generators of local diffeomorphisms in two dimensions.Comment: 22 pages, Plain TeX, KUL-TF-92/19, US-FT/6-9

Laboratory animals and respiratory allergies: The prevalence of allergies among laboratory animal workers and the need for prophylaxis

OBJECTIVE: Subjects exposed to laboratory animals are at a heightened risk of developing respiratory and allergic diseases. These diseases can be prevented by simple measures such as the use of personal protective equipment. We report here the primary findings of the Laboratory Animals and Respiratory Allergies Study regarding the prevalence of allergic diseases among laboratory animal workers, the routine use of preventive measures in laboratories and animal facilities, and the need for prevention programs. METHODS: Animal handlers and non-animal handlers from 2 Brazilian universities (University of São Paulo and State University of Campinas) answered specific questionnaires to assess work conditions and symptoms. These subjects also underwent spirometry, a bronchial challenge test with mannitol, and skin prick tests for 11 common allergens and 5 occupational allergens (rat, mouse, guinea pig, hamster, and rabbit). RESULTS: Four hundred fifty-five animal handlers (32±10 years old [mean±SD], 209 men) and 387 non-animal handlers (33±11 years old, 121 men) were evaluated. Sensitization to occupational allergens was higher among animal handlers (16%) than non-animal handlers (3%,

A Benign Ovarian Tumour developing an Endometrial Cancer? Sertoliform Ovarian Cystoadenoma getting together with an Endometrioid Adenocarcinoma

Medicin

Application of high Power ultrasounds during red wine vinification

[EN] Wine colour is one of the main organoleptic characteristics influencing its quality. It is of special interest in red vinifications due to the economic resources that wineries have to invest for the extraction of the phenolic compounds responsible for wine colour, compounds that are mainly located inside the skin cell vacuoles, where the volatile compounds are also found. The transfer of phenolic compounds from grapes to must during vinification is closely related to the type of grapes and the winemaking technique. During traditional winemaking, grapes are crushed and skin macerated for several days, with pumps overs to facilitate the colour extraction. To increase this extraction, some chemical (maceration enzymes) or physical technologies (thermovinification, cryomaceration, flash-expansion) can be applied. In this work, a new methodology has been tested. This methodology consists in the application of high-power ultrasounds to crushed grapes to increase the extraction of phenolic compounds. Crushed grapes were treated with this non-thermal technology and vinified, with 3, 6 and 8days of skin maceration time, and the results were compared with a control vinification, where crushed grapes were not subjected to any treatment and were skin macerated during 8days. The wine chromatic characteristics (determined spectrophotometrically) and the individual phenolic compounds (anthocyanins and tannins, determined by HPLC) were followed during the maceration period, at the end of alcoholic fermentation and after two months in bottle. Also, the wine volatile compounds were determined by GC-MS. The wines made with ultrasound-treated grapes showed differences with the control wine, especially regarding total phenol content and tannin content. The wines elaborated with sonicated grapes and with only three days of skin maceration time presented similar concentration of anthocyanins and twice the concentration of tannins than control wines elaborated with 8days of skin maceration.This work was funded by the SME Instrument of the Horizon 2020 program from the European Commission.Baustista-Ortin A.B.; Jimenez-Martinez M.D; Jurado, R.; Iniesta, JA.; Terrades-Rocafull, LS.; Andrés Grau, AM.; Gomez-Plaza, E. (2017). Application of high Power ultrasounds during red wine vinification. International Journal of Food Science & Technology. 52(6):1314-1323. https://doi.org/10.1111/ijfs.13411S13141323526De Andrade Neves, N., de Araújo Pantoja, L., & dos Santos, A. S. (2013). Thermovinification of grapes from the Cabernet Sauvignon and Pinot Noir varieties using immobilized yeasts. European Food Research and Technology, 238(1), 79-84. doi:10.1007/s00217-013-2062-2Bautista-Ortín, A. B., Cano-Lechuga, M., Ruiz-García, Y., & Gómez-Plaza, E. (2014). Interactions between grape skin cell wall material and commercial enological tannins. Practical implications. Food Chemistry, 152, 558-565. doi:10.1016/j.foodchem.2013.12.009Bautista-Ortín, A. B., Martínez-Hernández, A., Ruiz-García, Y., Gil-Muñoz, R., & Gómez-Plaza, E. (2016). Anthocyanins influence tannin–cell wall interactions. Food Chemistry, 206, 239-248. doi:10.1016/j.foodchem.2016.03.045Bautista-Ortín, A. B., Fernández-Fernández, J. I., López-Roca, J. M., & Gómez-Plaza, E. (2004). Wine-making of High Coloured Wines: Extended Pomace Contact and Run-off of Juice Prior to Fermentation. Food Science and Technology International, 10(5), 287-295. doi:10.1177/1082013204047565Bautista-Ortin, A. B., Martinez-Cutillas, A., Ros-Garcia, J. M., Lopez-Roca, J. M., & Gomez-Plaza, E. (2005). Improving colour extraction and stability in red wines: the use of maceration enzymes and enological tannins. International Journal of Food Science and Technology, 40(8), 867-878. doi:10.1111/j.1365-2621.2005.01014.xBindon, K. A., Smith, P. A., Holt, H., & Kennedy, J. A. (2010). Interaction between Grape-Derived Proanthocyanidins and Cell Wall Material. 2. Implications for Vinification. Journal of Agricultural and Food Chemistry, 58(19), 10736-10746. doi:10.1021/jf1022274Busse-Valverde, N., Gómez-Plaza, E., López-Roca, J. M., Gil-Muñoz, R., Fernández-Fernández, J. I., & Bautista-Ortín, A. B. (2010). Effect of Different Enological Practices on Skin and Seed Proanthocyanidins in Three Varietal Wines. Journal of Agricultural and Food Chemistry, 58(21), 11333-11339. doi:10.1021/jf102265cBusse-Valverde, N., Gómez-Plaza, E., López-Roca, J. M., Gil-Muñoz, R., & Bautista-Ortín, A. B. (2011). The Extraction of Anthocyanins and Proanthocyanidins from Grapes to Wine during Fermentative Maceration Is Affected by the Enological Technique. Journal of Agricultural and Food Chemistry, 59(10), 5450-5455. doi:10.1021/jf2002188Cano-López, M., Pardo-Mínguez, F., Schmauch, G., Saucier, C., Teissedre, P.-L., López-Roca, J. M., & Gómez-Plaza, E. (2008). Effect of Micro-oxygenation on Color and Anthocyanin-Related Compounds of Wines with Different Phenolic Contents. Journal of Agricultural and Food Chemistry, 56(14), 5932-5941. doi:10.1021/jf8006147Carrera, C., Ruiz-Rodríguez, A., Palma, M., & Barroso, C. G. (2012). Ultrasound assisted extraction of phenolic compounds from grapes. Analytica Chimica Acta, 732, 100-104. doi:10.1016/j.aca.2011.11.032Castro-López, L. del R., Gómez-Plaza, E., Ortega-Regules, A., Lozada, D., & Bautista-Ortín, A. B. (2016). Role of cell wall deconstructing enzymes in the proanthocyanidin–cell wall adsorption–desorption phenomena. Food Chemistry, 196, 526-532. doi:10.1016/j.foodchem.2015.09.080Da Porto, C., Porretto, E., & Decorti, D. (2013). Comparison of ultrasound-assisted extraction with conventional extraction methods of oil and polyphenols from grape (Vitis vinifera L.) seeds. Ultrasonics Sonochemistry, 20(4), 1076-1080. doi:10.1016/j.ultsonch.2012.12.002Demirdöven, A., & Baysal, T. (2008). The Use of Ultrasound and Combined Technologies in Food Preservation. Food Reviews International, 25(1), 1-11. doi:10.1080/87559120802306157El Darra, N., Grimi, N., Maroun, R. G., Louka, N., & Vorobiev, E. (2012). Pulsed electric field, ultrasound, and thermal pretreatments for better phenolic extraction during red fermentation. European Food Research and Technology, 236(1), 47-56. doi:10.1007/s00217-012-1858-9Gagné, S., Saucier, C., & Gény, L. (2006). Composition and Cellular Localization of Tannins in Cabernet Sauvignon Skins during Growth. Journal of Agricultural and Food Chemistry, 54(25), 9465-9471. doi:10.1021/jf061946gGeffroy, O., Lopez, R., Serrano, E., Dufourcq, T., Gracia-Moreno, E., Cacho, J., & Ferreira, V. (2015). Changes in analytical and volatile compositions of red wines induced by pre-fermentation heat treatment of grapes. Food Chemistry, 187, 243-253. doi:10.1016/j.foodchem.2015.04.105Ghafoor, K. (2009). Optimization of Ultrasound Assisted Extraction of Phenolic Compounds and Antioxidants from Grape Peel through Response Surface Methodology. Journal of the Korean Society for Applied Biological Chemistry, 52(3), 295-300. doi:10.3839/jksabc.2009.052Gómez-Plaza, E., Mestre-Ortuño, L., Ruiz-García, Y., Fernández-Fernández, J. I., & López-Roca, J. M. (2012). Effect of Benzothiadiazole and Methyl Jasmonate on the Volatile Compound Composition of Vitis vinifera L. Monastrell Grapes and Wines. American Journal of Enology and Viticulture, 63(3), 394-401. doi:10.5344/ajev.2012.12011Knorr, D., Zenker, M., Heinz, V., & Lee, D.-U. (2004). Applications and potential of ultrasonics in food processing. Trends in Food Science & Technology, 15(5), 261-266. doi:10.1016/j.tifs.2003.12.001Labarbe, B., Cheynier, V., Brossaud, F., Souquet, J.-M., & Moutounet, M. (1999). Quantitative Fractionation of Grape Proanthocyanidins According to Their Degree of Polymerization. Journal of Agricultural and Food Chemistry, 47(7), 2719-2723. doi:10.1021/jf990029qMorel-Salmi, C., Souquet, J.-M., Bes, M., & Cheynier, V. (2006). Effect of Flash Release Treatment on Phenolic Extraction and Wine Composition. Journal of Agricultural and Food Chemistry, 54(12), 4270-4276. doi:10.1021/jf053153kPetropulos, V. I., Bogeva, E., Stafilov, T., Stefova, M., Siegmund, B., Pabi, N., & Lankmayr, E. (2014). Study of the influence of maceration time and oenological practices on the aroma profile of Vranec wines. Food Chemistry, 165, 506-514. doi:10.1016/j.foodchem.2014.05.144Rapp, A. (1988). Wine Aroma Substances from Gas Chromatographic Analysis. Modern Methods of Plant Analysis, 29-66. doi:10.1007/978-3-642-83340-3_3Romero-Cascales, I., Fernández-Fernández, J. I., López-Roca, J. M., & Gómez-Plaza, E. (2005). The maceration process during winemaking extraction of anthocyanins from grape skins into wine. European Food Research and Technology, 221(1-2), 163-167. doi:10.1007/s00217-005-1144-1Romero-Cascales, I., Fernández-Fernández, J. I., Ros-García, J. M., López-Roca, J. M., & Gómez-Plaza, E. (2008). Characterisation of the main enzymatic activities present in six commercial macerating enzymes and their effects on extracting colour during winemaking of Monastrell grapes. International Journal of Food Science & Technology, 43(7), 1295-1305. doi:10.1111/j.1365-2621.2007.01608.xRomero-Cascales, I., Ros-García, J. M., López-Roca, J. M., & Gómez-Plaza, E. (2012). The effect of a commercial pectolytic enzyme on grape skin cell wall degradation and colour evolution during the maceration process. Food Chemistry, 130(3), 626-631. doi:10.1016/j.foodchem.2011.07.091Souquet, J.-M., Cheynier, V., Brossaud, F., & Moutounet, M. (1996). Polymeric proanthocyanidins from grape skins. Phytochemistry, 43(2), 509-512. doi:10.1016/0031-9422(96)00301-9Tao, Y., Zhang, Z., & Sun, D.-W. (2014). Kinetic modeling of ultrasound-assisted extraction of phenolic compounds from grape marc: Influence of acoustic energy density and temperature. Ultrasonics Sonochemistry, 21(4), 1461-1469. doi:10.1016/j.ultsonch.2014.01.029Tiwari, B. K., Patras, A., Brunton, N., Cullen, P. J., & O’Donnell, C. P. (2010). Effect of ultrasound processing on anthocyanins and color of red grape juice. Ultrasonics Sonochemistry, 17(3), 598-604. doi:10.1016/j.ultsonch.2009.10.009Zhang, Q.-A., Shen, Y., Fan, X., Martín, J. F. G., Wang, X., & Song, Y. (2015). Free radical generation induced by ultrasound in red wine and model wine: An EPR spin-trapping study. Ultrasonics Sonochemistry, 27, 96-101. doi:10.1016/j.ultsonch.2015.05.003Zhang, Q.-A., Shen, Y., Fan, X.-H., & García Martín, J. F. (2015). Preliminary study of the effect of ultrasound on physicochemical properties of red wine. CyTA - Journal of Food, 14(1), 55-64. doi:10.1080/19476337.2015.104503

Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels

CONTEXT: Appetite-related hormones may play an important role in weight regain after obesity therapy. OBJECTIVE: Our objective was to investigate the potential involvement of ghrelin, leptin, and insulin plasma levels in weight regain after a therapeutic hypocaloric diet. DESIGN: A group of obese/overweight volunteers (49 women and 55 men; 35 ± 7 yr; 30.7 ± 2.4 kg/m(2)) followed an 8-wk hypocaloric diet (-30% energy expenditure) and were evaluated again 32 wk after treatment. Body weight as well as plasma fasting ghrelin, leptin, and insulin concentrations were measured at three points (wk 0, 8, and 32). RESULTS: After the 8-wk hypocaloric diet, the average weight loss was -5.0 ± 2.2% (P < 0.001). Plasma leptin and insulin concentrations decreased significantly, whereas ghrelin levels did not markedly change. In the group regaining more than 10% of the weight loss, leptin levels were higher (P < 0.01), whereas ghrelin levels were lower (P < 0.05). No differences were observed in insulin levels. Weight regain at wk 32 was negatively correlated with ghrelin and positively associated with leptin levels at baseline (wk 0) and endpoint (wk 8). These outcomes showed a gender-specific influence, being statistically significant among men for ghrelin and between women for leptin. Moreover, a decrease in ghrelin after an 8-wk hypocaloric diet was related to an increased risk for weight regain (odds ratio = 3.109; P = 0.008) whereas a greater reduction in leptin (odds ratio = 0.141; P = 0.001) was related to weight-loss maintenance. CONCLUSIONS: Subjects with higher plasma leptin and lower ghrelin levels at baseline could be more prone to regain lost weight, and hormones levels could be proposed as biomarkers for predicting obesity-treatment outcomes

Transport and Noise Properties of sub-100-nm Planar Nb Josephson Junctions with Metallic Hf-Ti Barriers for nano-SQUID Applications

We analyze electric transport and noise properties at 4.2 K of self-shunted superconductor-normal metal-superconductor (SNS) sandwich-type Josephson junctions, comprising Nb as the superconductor and Hf-Ti as the normal conducting material, with lateral dimensions down to approximately 80 nm. The junctions are fabricated with an optimized multilayer Nb technology based on nanopatterning by electron-beam lithography and chemical-mechanical polishing. The dependence of transport properties on the junction geometry (lateral size and barrier thickness d(Hf-Ti)) is studied, yielding a characteristic voltage V-c up to approximately 100 mu V for the smallest d(Hf-Ti) = 17 nm. The observed small hysteresis in the current-voltage curves of devices with high V-c and large size can be attributed to self-heating of the junctions and fitted with an extended version of the resistively shunted junction model. Measurements of voltage noise of single junctions are consistent with the model including self-heating effects. The potential of our technology for further miniaturization of nanoscale superconducting quantum interference devices and for the improvement of their performance is discussed

The role of disulfide bond replacements in analogues of the Tarantula toxin ProTx-II and their effects on inhibition of the voltage-gated sodium ion channel Nav1.7

Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate

ASYMMETRIC LEAVES2-LIKE1gene a member of the AS2/LOB family, controls proximal-distal patterning in Arabidopsis petals

The formation and the development of the floral organs require an intercalate expression of organ-specific genes. At the same time, meristem-specific genes are repressed to complete the differentiation of the organs in the floral whorls. In an Arabidopsis activation tagging population, a mutant affected in inflorescence architecture was identified. This gain-of-function mutant, designateddownwards siliques1 (dsl1-D), has shorter internodes and the lateral organs such as flowers are bending downwards, similar to the loss-of-function brevipedicellus (bp) mutant. The affected gene in dsl1-D appeared to be ASYMMETRIC LEAVES2-LIKE1 (ASL1)/LATERAL ORGAN BOUNDARIESdomain gene 36 (LBD36), which is a member of the ASYMMETRIC LEAVES2 (AS2)/LATERAL ORGAN BOUNDARIES (LOB) domain gene family. Analysis of the loss-of-function mutant asl1/lbd36 did not show morphological aberration. Double mutant analysis of asl1/lbd36 together with as2, the ASL1/LBD36 closest homologue, demonstrates that these two members of the AS2/LOB family act partially redundant to control cell fate determination in Arabidopsis petals. Moreover, molecular analysis revealed that overexpression of ASL1/LBD36 leads to repression of the homeobox gene BP, which supports the model that an antagonistic relationship between ASL/LBD and homeobox members is required for the differentiation of lateral organ