A Small Molecule Inhibitor of Signal Peptide Peptidase Inhibits Plasmodium Development in the Liver and Decreases Malaria Severity

The liver stage of Plasmodium's life cycle is the first, obligatory step in malaria infection. Decreasing the hepatic burden of Plasmodium infection decreases the severity of disease and constitutes a promising strategy for malaria prophylaxis. The efficacy of the gamma-secretase and signal peptide peptidase inhibitor LY411,575 in targeting Plasmodium liver stages was evaluated both in human hepatoma cell lines and in mouse primary hepatocytes. LY411,575 was found to prevent Plasmodium's normal development in the liver, with an IC50 of approximately 80 nM, without affecting hepatocyte invasion by the parasite. In vivo results with a rodent model of malaria showed that LY411,575 decreases the parasite load in the liver and increases by 55% the resistance of mice to cerebral malaria, one of the most severe malaria-associated syndromes. Our data show that LY411,575 does not exert its effect via the Notch signaling pathway suggesting that it may interfere with Plasmodium development through an inhibition of the parasite's signal peptide peptidase. We therefore propose that selective signal peptide peptidase inhibitors could be potentially used for preventive treatment of malaria in humans

Performance of two questionnaires to measure treatment adherence in patients with Type-2 Diabetes

<p>Abstract</p> <p>Background</p> <p>Most valid methods to measure treatment adherence require time and resources, and they are not easily applied in highly demanding Primary Health Care Clinics (PHCC). The objective of this study was to determine sensitivity, specificity, predictive values, likelihood ratios, and post-test probabilities of two novel questionnaires as proxy measurements of treatment adherence in Type-2 diabetic patients.</p> <p>Methods</p> <p>Two questionnaires were developed by a group of experts to identify the patient's medical prescription knowledge (knowledge) and their attitudes toward treatment adherence (attitudes) as proxy measurements of adherence. The questionnaires were completed by patients receiving care in PHCC pertaining to the Mexican Institute of Social Security in Aguascalientes (Mexico). Pill count was used as gold standard. Participants were selected randomly, and their oral hypoglycemic prescriptions were studied. The main outcome measures for each questionnaire were sensitivity, specificity, predictive values, likelihood ratios, and post-test probabilities, all as an independent questionnaire test and in a serial analysis.</p> <p>Results</p> <p>Adherence prevalence was 27.0% using pill count. Knowledge questionnaire showed the highest sensitivity (68.1%) and negative predictive value (82.2%), the lowest negative likelihood ratio (0.58) and post-test probability for a negative result (0.16). Serial analysis showed the highest specificity (77.4%) and positive predictive value (40.1%) as well as the highest positive likelihood ratio (1.8) and post-test probability for a positive result (0.39).</p> <p>Conclusion</p> <p>Medical Prescription Knowledge questionnaire showed the best performance as proxy measurement to identify non-adherence in type 2 diabetic patients regarding negative predictive value, negative likelihood ratio, and post-test probability for a negative result. However, Medical Prescription Knowledge questionnaire performance may change in contexts with higher adherence prevalence. Therefore, more research is needed before using this method in other contexts.</p

Is salinity the main ecologic factor that shapes the distribution of two endemic Mediterranean plant species of the genus Gypsophila?

The final publication is available at Springer via http://dx.doi.org/10.1007/s11104-014-2218-2Aims Responses to salt stress of two Gypsophila species that share territory, but with different ecological optima and distribution ranges, were analysed. G. struthium is a regionally dominant Iberian endemic gypsophyte, whereas G. tomentosa is a narrow endemic reported as halophyte. Theworking hypothesis is that salt tolerance shapes the presence of these species in their specific habitats. Methods Taking a multidisciplinary approach, we assessed the soil characteristics and vegetation structure at the sampling site, seed germination and seedling development, growth and flowering, synthesis of proline and cation accumulation under artificial conditions of increasing salt stress and effect of PEG on germination and seedling development. Results Soil salinity was low at the all sampling points where the two species grow, but moisture was higher in the area of G. tomentosa. Differences were found in the species salt and drought tolerance. The different parameters tested did not show a clear pattern indicating the main role of salt tolerance in plant distribution. Conclusions G. tomentosa cannot be considered a true halophyte as previously reported because it is unable to complete its life cycle under salinity. The presence of G. tomentosa in habitats bordering salt marshes is a strategy to avoid plant competition and extreme water stressSoriano, P.; Moruno Manchón, JF.; Boscaiu Neagu, MT.; Vicente Meana, Ó.; Hurtado, A.; Llinares Palacios, JV.; Estrelles, E. (2014). Is salinity the main ecologic factor that shapes the distribution of two endemic Mediterranean plant species of the genus Gypsophila?. Plant and Soil. 384(1-2):363-379. doi:10.1007/s11104-014-2218-2S3633793841-2Alonso MA (1996) Flora y vegetación del Valle de Villena (Alicante). Instituto de Cultura Juan Gil-Albert, AlicanteAlvarado JJ, Ruiz JM, López-Cantarero I, Molero J, Romero L (2000) Nitrogen metabolism in five plant species characteristic of gypsiferous soils. Plant Physiol 156:612–616Ashraf M, Foolad MR (2007) Roles of glycine betaine and proline in improving plant abiotic stress resistance. Environ Exp Bot 59:206–216Ashraf MY (2009) Salt tolerance mechanisms in some halophytes from Saudi Arabia and Egypt. Res J Agric Biol Sci 5:191–206Bates LS, Waldren RP, Tear LD (1973) Rapid determination of free proline for water-stress studies. Plant Soil 39:205–207Ben-Gal A, Neori-Borochov H, Yermiyahu U, Shani U (2009) Is osmotic potential a more appropriate property than electrical conductivity for evaluating whole plant response to salinity? Environ Exp Bot 65:232–237Biondi E (2011) Phytosociology today: Methodological and conceptual evolution. Plant Biosyst 145:19–29Boscaiu M, Bautista I, Lidón A, Llinares J, Lull C, Donat P, Mayoral O, Vicente O (2013a) Environmental-dependent proline accumulation in plants living on gypsum soils. Acta Physiol Plant 35:2193–2204Boscaiu M, Llul C, Llinares J, Vicente O, Boira H (2013b) Proline as a biochemical marker in relation to the ecology of two halophytic Juncus species. J Plant Ecol 6:177–186Bradford KJ (1990) A water relations analysis of seed germination rates. Plant Physiol 94:840–849Breckle SW (1999) Halophytic and gypsophytic vegetation of the Ebro-Basin at Los Monegros. In: Melic A, Blasco-Zumeta J (eds) Manifiesto científico por Los Monegros, vol 24, Bol. SEA., pp 101–104Brenchley JL, Probert RJ (1998) Seed germination responses to some environmental factors in the sea grass Zoostera capricorni from eastern Australia. Aquat Bot 62:177–188Cañadas EM, Ballesteros M, Valle F, Lorite J (2013) Does gypsum influence seed germination? Turk J Bot 38:141–147Chen Z, Cuin TA, Zhou M et al (2007) Compatible solute accumulation and stress-mitigating effects in barley genotypes contrasting in their salt tolerance. J Exp Bot 58:4245–4255Chutipaijit S, Cha-Um S, Sompornailin K (2009) Differential accumulation of proline and flavonoids in Indica rice varieties against salinity. Pak J Bot 41:2497–2506Cushman JC (2001) Osmoregulation in plants: implications for agriculture. Am Zool 41:758–769Debussche M, Thompson JD (2003) Habitat differentiation between two closely related Mediterranean plant species, the endemic Cyclamen balearicum and the widespread C. repandum. Acta Oecol 24:35–45Eskandari H, Kazemi K (2011) Germination and seedling properties of different wheat cultivars under salinity conditions. Not Sci Biol 3:130–134FAO (2006) Guidelines for soil descriptions, 5th edn. Food and Agricultural Organization of United Nation, RomeFerrandis P, Herranz JM, Copete MA (2005) Caracterización florística y edáfica de las estepas yesosas de Castilla-La Mancha. Invest Agrar Sist Recur For 14:195–216Flowers TJ, Hall JL (1978) Salt tolerance in Suaeda maritima (L.) Dum. The effect of sodium chloride on growth and soluble enzymes in a comparative study with Pisum sativum L. J Exp Bot 23:310–321Flowers TJ, Colmer TD (2008) Salinity tolerance in halophytes. New Phytol 179:945–963Flowers TJ, Hajibagheri MA, Clipson NJW (1986) Halophytes. Q Rev Biol 61:313–335García-Fuentes A, Salazar C, Torres JA, Cano E, Valle F (2001) Review of communities of Lygeum spartum L. in the south-eastern Iberian Peninsula (western Mediterranean). J Arid Environ 48:323–339Géhu JM (2006) Dictionnaire de Sociologie et Synécologie Végétales. J. Cramer, Berlin-Stuttgart, p 899Géhu JM (2011) On the opportunity to celebrate the centenary of modern phytosociology in 2010. Plant Biosyst 145(suppl):4–8Ghassemi F, Jakeman AJ, Nix HA (1995) Salinisation of land and water resources: human causes, extent, management and case studies. Canberra, Australia. CAB International, The Australian National University, WallingfordGrigore MN, Boscaiu M, Vicente O (2011) Assessment of the relevance of osmolyte biosynthesis for salt tolerance of halophytes under natural conditions. Eur J Plant Sci Biotech 5:12–19Grigore MN, Villanueva M, Boscaiu M, Vicente O (2012a) Do halophytes really require salts for their growth and development? An experimental approach mitigation of salt stress-induced inhibition of Plantago crassifolia reproductive development by supplemental calcium or magnesium. Not Sci Biol 4:23–29Grigore MN, Boscaiu M, Llinares J, Vicente O (2012b) Mitigation of salt stressed-induced Inhibition of Plantago crassifolia reproductive development by supplemental calcium or magnesium. Not Bot Horti Agrobo 40:58–66Hare PD, Cress WA (1997) Metabolic implications of stress-induced proline accumulation in plants. Plant Growth Regul 21:79–102Ishikawa SI, Kachi N (2000) Differential salt tolerance of two Artemisia species growing in contrasting coastal habitats. Ecol Res 15:241–247Kebreab E, Murdoch AJ (1999) Modelling the effects of water stress and temperature on germination rate of Orobanche aegyptiaca seeds. J Exp Bot 50:655–664Khan MA (2002) Halophyte seed germination: Success and Pitfalls. In: Hegazi AM, El-Shaer HM, El-Demerdashe S et al (eds) International symposium on optimum resource utilization in salt affected ecosystems in arid and semi arid regions. Desert Research Centre, Cairo, pp 346–358Khan MA, Gul B, Weber DJ (2000) Germination responses of Salicornia rubra to temperature and salinity. J Arid Environ 45:207–214Khan A, Rayner GD (2003) Robustness to non-normality of common tests for the many-sample location problem. J Appl Math Decis Sci 7:187–206Lidón A, Boscaiu M, Collado F, Vicente O (2009) Soil requirements of three salt tolerant, endemic species from south-east Spain. Not Bot Horti Agrobo 37:64–70López González G (1990) Gypsohila L. In: Castroviejo S, Laínz M, López G et al (eds) Flora Ibérica 2. Real Jardín Botánico, Madrid, pp 408–415Lutts S, Kinet JM, Bouharmont J (1996) Effects of salt stress on growth, mineral nutrition and proline accumulation in relation to osmotic adjustment in rice (Oryza sativa L.) cultivars differing in salinity resistance. Plant Growth Regul 19:207–218Madidi S, Baroudi B, Ameur FB (2004) Effects of salinity on germination and early growth of barley (Hordeum vulgare L.) cultivars. Int J Agric Biol 6:767–770Marchal FM, Lendínez ML, Salazar C, Torres JA (2008) Aportaciones al conocimiento de la vegetación gispsícola en el occidente de la provincia de Granada (sur de España). Lazaroa 29:95–100Médail F, Verlaque R (1997) Ecological characteristics and rarity of endemic plants from southern France and Corsica: implications for biodiversity conservation. Biol Conserv 80:269–281Meyer SE (1986) The ecology of gypsophile endemism in the Eastern Mojave desert. Ecology 67:1303–1313Moruno F, Soriano P, Oscar V, Boscaiu M, Estrelles E (2011) Opportunistic germination behaviour of Gypsophila (Caryophyllaceae) in two priority habitats from semi-arid Mediterranean steppes. Not Bot Horti Agrobo 9:18–23Mota JF, Sánchez Gómez P, Merlo Calvente ME, Catalán Rodríguez P, Laguna Lumbreras E, de la Cruz RM, Navarro Reyes FB, Marchal Gallardo F, Bartolomé Esteban C, Martínez Labarga JM, Sainz Ollero H, Valle Tendero F, Serra Laliga L, Martínez Hernández F, Garrido Becerra JA, Pérez García FJ (2009) Aproximación a la checklist de los gipsófitos ibéricos. An Biol 31:71–80Mota JF, Sola AJ, Jiménez-Sánchez ML, Pérez-García F, Merlo ME (2004) Gypsicolous flora, conservation and restoration of quarries in the southeast of the Iberian Peninsula. Biodivers Conserv 13:1797–1808Munns R (2002) Comparative physiology of salt and water stress. Plant Cell Environ 25:239–250Palacio S, Escudero A, Montserrat-Martí G, Maestro M, Milla R, Albert M (2007) Plants living on gypsum: beyond the specialist model. Ann Bot 99:333–343Peinado M, Martínez-Parras JM (1982) Sobre la posición fitosociológica de Gypsophila tomentosa L. Lazaroa 4:129–140Pueyo Y, Alados CL, Maestro M, Komac B (2007) Gypsophile vegetation patterns under a range of soil properties induced by topographical position. Plant Ecol 189:301–311Rasband WS (1997–2012) ImageJ. U S National Institutes of Health. http://rsb.info.nih.gov/ij/ , Bethesda, MarylandRivas-Martínez S (2005) Notions on dynamic-catenal phytosociology as a basis of landscape science. Plant Biosyst 139:135–144Rivas-Martínez S, Rivas-Saenz S (1996–2009) Worldwide bioclimatic classification system, Phytosociological Research Center, Spain. http://www.globalbioclimatics.org . Accessed 1 July 2013Rivas-Martínez S, Fernández-González F, Loidi J, Lousã M, Penas A (2001) Syntaxonomical checklist of vascular plant communities of Spain and Portugal to association level. Itinera Geobot 14:5–341Salmerón-Sánchez E, Martínez-Nieto MI, Martínez-Hernández F, Garrido-Becerra JA, Mendoza-Fernández AJ, Gil de Carrasco C, Ramos-Miras JJ, Lozano R, Merlo ME, Mota JF (2014) Ecology, genetic diversity and phylogeography of the Iberian endemic plant Jurinea pinnata (Lag.) DC. (Compositae) on two special edaphic substrates: dolomite and gypsum. Plant Soil 374:233–250Saradhi P, Alia P, Arora S, Prasad KV (1995) Proline accumulates in plants exposed to UV radiation and protects them against UV induced peroxidation. Biochem Biophys Res Commun 209:1–5Sekmen AH, Turkan I, Tanyolac ZO, Ozfidan C, Dinc A (2012) Different antioxidant defense responses to salt stress during germination and vegetative stages of endemic halophyte Gypsophila oblanceolata Bark. Environ Exp Bot 77:63–76Tipirdamaz R, Gagneul D, Duhaze C, Ainouche A, Monnier C, Ozkum D, Larher F (2006) Clustering of halophytes from an inland salt marsh in Turkey according to their ability to accumulate sodium and nitrogenous osmolytes. Environ Exp Bot 57:139–153Ungar IA (1996) Effect of salinity on seed germination, growth, and ion accumulation of Atriplex patula (Chenopodiaceae). Am J Bot 83:604–607USDA-ARS (2008) Research databases. Bibliography on salt tolerance. George E. Brown, Jr. Salinity Lab. US Dep. Agric., Agric. Res. Serv. Riverside, CA. http://www.ars.usda.gov/Services/docs.htm?docid=8908USSL Staff (1954) Diagnosis and improvement of saline and alkali soils. US Department of Agriculture Handbook no. 60, 160 ppVicente O, Boscaiu M, Naranjo M, Estrelles E, Bellés JM, Soriano P (2004) Responses to salt stress in the halophyte Plantago crassifolia (Plantaginaceae). J Arid Environ 58:463–48

Dendritic Cells and Hepatocytes Use Distinct Pathways to Process Protective Antigen from Plasmodium in vivo

Malaria-protective CD8+ T cells specific for the circumsporozoite (CS) protein are primed by dendritic cells (DCs) after sporozoite injection by infected mosquitoes. The primed cells then eliminate parasite liver stages after recognizing the CS epitopes presented by hepatocytes. To define the in vivo processing of CS by DCs and hepatocytes, we generated parasites carrying a mutant CS protein containing the H-2Kb epitope SIINFEKL, and evaluated the T cell response using transgenic and mutant mice. We determined that in both DCs and hepatocytes CS epitopes must reach the cytosol and use the TAP transporters to access the ER. Furthermore, we used endosomal mutant (3d) and cytochrome c treated mice to address the role of cross-presentation in the priming and effector phases of the T cell response. We determined that in DCs, CS is cross-presented via endosomes while, conversely, in hepatocytes protein must be secreted directly into the cytosol. This suggests that the main targets of protective CD8+ T cells are parasite proteins exported to the hepatocyte cytosol. Surprisingly, however, secretion of the CS protein into hepatocytes was not dependent upon parasite-export (Pexel/VTS) motifs in this protein. Together, these results indicate that the presentation of epitopes to CD8+ T cells follows distinct pathways in DCs when the immune response is induced and in hepatocytes during the effector phase

Dietary inflammatory index and inflammatory biomarkers in adolescents from LabMed physical activity study

Background/objectives The dietary inflammatory index (DII) is a tool to measure the diet’s inflammatory potential and has been used with adults to predict low-grade inflammation. The present study aims to assess whether this dietary score predicts low-grade inflammation in adolescents. Subjects/methods The sample comprises 329 adolescents (55.9% girls), aged 12–18 years, from LabMed Physical Activity Study. DII score was calculated based on a food-frequency questionnaire and categorized into tertiles. We collected blood samples to determine the follow inflammatory biomarkers: C-reactive protein (CRP), interleukin-6 (IL-6), complement component 3 (C3), and 4 (C4). In addition we calculated an overall inflammatory biomarker score. Odds ratios (OR) and 95% confidence intervals (95%CI) were computed from binary logistic regression models. Results DII score, comparing first with third tertile, was positively associated with IL-6 in crude model (OR = 1.88, 95% CI:1.09–3.24, ptrend = 0.011) and in fully adjusted (for biological and lifestyle variables) (OR = 3.38, 95%CI:1.24–9.20, ptrend = 0.023). Also, DII score was positively associated with C4, when fully adjusted (OR = 3.12, 95%CI:1.21–8.10, ptrend = 0.016). DII score was negatively associated with C3 in crude model, comparing first with second but not with third tertile, and no significant associations in fully adjusted model were observed, although a trend was found (OR = 1.71, 95% CI:0.63–4.66, ptrend = 0.044). No significant associations were observed between DII score and CRP. However, DII score was positively associated with the overall inflammatory biomarker score, when fully adjusted (OR = 5.61, 95% CI:2.00–15.78, ptrend = 0.002). Conclusions DII score can be useful to assess the diet’s inflammatory potential and its association with low-grade inflammation in adolescents.The authors gratefully acknowledged the participation of all adolescents and their parents, teachers and schools of the LabMed and Physical Activity Study, the cooperation of volunteer’s, the Department of Hygiene and Epidemiology (University of Porto) for the conversion food frequency questionnaire data into nutrients, and the Research Centre in Physical Activity, Health and Leisure (University of Porto) for the sponsoring the LabMed and Physical Activity Study.info:eu-repo/semantics/publishedVersio

Dietary factors associated with metabolic syndrome in Brazilian adults

<p>Abstract</p> <p>Background</p> <p>Metabolic Syndrome (MS) is defined as the association of numerous factors that increase cardiovascular risk and diet is one of the main factors related to increase the MS in the population. This study aimed to evaluate the association of diet on the presence of MS in an adult population sample.</p> <p>Methodology</p> <p>305 adults were clinically screened to participate in a lifestyle modification program. Anthropometric assessments included waist circumference (WC), body fat and calculated BMI (kg/m²) and muscle-mass index (MMI kg/m²). Dietary intake was estimated by 24 h dietary recall. Fasting blood was used for biochemical analysis. MS was diagnosed using NCEP-ATPIII (2001) criteria with adaptation for glucose (≥ 100 mg/dL). Logistic regression (Odds ratio) was performed in order to determine the odds ratio for developing MS according to dietary intake.</p> <p>Results</p> <p>An adequate intake of fruits, OR = 0.52 (CI:0.28-0.98), and an intake of more than 8 different items in the diet (variety), OR = 0.31 (CI:0.12-0.79) showed to be a protective factor against a diagnosis of MS. Saturated fat intake greater than 10% of total caloric value represented a risk for MS diagnosis, OR = 2.0 (1.04-3.84).</p> <p>Conclusion</p> <p>Regarding the dietary aspect, a risk factor for MS was higher intake of saturated fat, and protective factors were high diet variety and adequate fruit intake.</p