A novel and divergent role of granzyme a and B in resistance to helminth infection.

Granzyme (gzm) A and B, proteases of NK cells and T killer cells, mediate cell death, but also cleave extracellular matrices, inactivate intracellular pathogens, and induce cytokines. Moreover, macrophages, Th2 cells, regulatory T cells, mast cells, and B cells can express gzms. We recently reported gzm induction in human filarial infection. In this study, we show that in rodent filarial infection with Litomosoides sigmodontis, worm loads were significantly reduced in gzmA×B and gzmB knockout mice during the whole course of infection, but enhanced only early in gzmA knockout compared with wild-type mice. GzmA/B deficiency was associated with a defense-promoting Th2 cytokine and Ab shift, enhanced early inflammatory gene expression, and a trend of reduced alternatively activated macrophage induction, whereas gzmA deficiency was linked with reduced inflammation and a trend toward increased alternatively activated macrophages. This suggests a novel and divergent role for gzms in helminth infection, with gzmA contributing to resistance and gzmB promoting susceptibility.

Transcription factors link mouse WAP-T mammary tumors with human breast cancer.

Mouse models are important tools to decipher the molecular mechanisms of mammary carcinogenesis and to mimic the respective human disease. Despite sharing common phenotypic and genetic features, the proper translation of murine models to human breast cancer remains a challenging task. In a previous study we showed that in the SV40 transgenic WAP-T mice an active Met-pathway and epithelial-mesenchymal characteristics distinguish low- and high-grade mammary carcinoma. To assign these murine tumors to corresponding human tumors we here incorporated the analysis of expression of transcription factor (TF) coding genes and show that thereby a more accurate interspecies translation can be achieved. We describe a novel cross-species translation procedure and demonstrate that expression of unsupervised selected TFs, such as ELF5, HOXA5 and TFCP2L1, can clearly distinguish between the human molecular breast cancer subtypes-or as, for example, expression of TFAP2B between yet unclassified subgroups. By integrating different levels of information like histology, gene set enrichment, expression of differentiation markers and TFs we conclude that tumors in WAP-T mice exhibit similarities to both, human basal-like and non-basal-like subtypes. We furthermore suggest that the low- and high-grade WAP-T tumor phenotypes might arise from distinct cells of tumor origin. Our results underscore the importance of TFs as common cross-species denominators in the regulatory networks underlying mammary carcinogenesis.

Keisarileikkaus : gynekologian ja obstetriikan historiaa Helsingin yliopiston kirjastossa

Hindrik Strandberg

Executive Order, July 15, 1953

Otto Weber is appointed to Colonel on Staff of the Commander-in-Chief

A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.

BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118.

Mineralização da palhada e crescimento de raízes de cana-de-açúcar relacionados com a adubação nitrogenada de plantio

O experimento foi realizado em canavial comercial, com a variedade SP81 3250, na Usina São Martinho (Pradópolis-SP), em Latossolo Vermelho-Escuro de textura argilosa, com o objetivo de avaliar a mineralização da palha de cana-de-açúcar e sua composição após um ciclo de desenvolvimento da cultura. Foi utilizado um delineamento experimental de blocos completos casualizados, com quatro repetições. Sacos de telas que continham palha marcada em 15N (1,07 % de átomos de 15N), em quantidades equivalentes a 9 t ha-1 de matéria seca, foram colocados entre as fileiras de cana-planta, em todos os tratamentos (0, 40, 80 e 120 kg ha-1 de N). Após 14 meses (de junho 2005 a agosto 2006), foram retirados os sacos para a quantificação do material seco remanescente e para determinações de N, de isótopos de 15N e do teor de C, por espectrometria de massas. A decomposição da palhada nos sacos foi maior nos tratamentos adubados com N e o balanço de massa subestimou a liberação do N da palha em comparação com os dados obtidos com a técnica isotópica. Após 14 meses, verificou-se que 37 a 65 % da matéria seca do material da palhada remanescente sobre o solo eram compostos por restos de raízes da cana cultivada durante esse período, pela contaminação por solo e por microrganismos que se desenvolveram na palhada, indicando que os processos ocorridos durante a decomposição da palhada são mais dinâmicos do que os avaliados pelo balanço de massas.

Aproveitamento pela cana-de-açúcar da adubação nitrogenada de plantio

O balanço de 15N de fontes nitrogenadas no sistema solo-planta tem sido de muita valia em estudos das transformações do N em diferentes agroecossistemas. No agrossistema da cana-de-açúcar, nas condições brasileiras, a resposta à adubação nitrogenada de cana-planta ainda é questão não totalmente esclarecida e a utilização de fertilizantes nitrogenados marcados com 15N pode auxiliar no entendimento dessa lacuna. Com o objetivo de avaliar o aproveitamento do N da uréia pela cana-de-açúcar no ciclo agrícola de cana-planta, realizaram-se dois experimentos em área comercial de cana-de-açúcar, com o cultivar SP81-3250. Esses experimentos foram feitos de fevereiro de 2005 a julho de 2006. O delineamento experimental foi o de blocos ao acaso, sendo os tratamentos constituídos de três doses de N: 40, 80 e 120 kg ha-1, na forma de uréia, e uma testemunha sem fertilização nitrogenada. No centro das parcelas com doses de N-uréia, foram instaladas microparcelas que receberam o fertilizante marcado com 15N. A recuperação de 15N-uréia pela cana-planta (planta toda) foi na média dos experimentos de 30, 30 e 21 %, respectivamente, para as doses de 40, 80 e 120 kg ha-1 de N. A menor recuperação do N-uréia nas maiores doses, especialmente na de 120 kg ha-1, deveu-se às perdas de N do sistema solo-planta. O aproveitamento do N da uréia (15N) representou em média 11,7 % do N total acumulado na planta toda. A distribuição do N proveniente do fertilizante nas diversas partes da planta não variou com a dose de N, sendo em média de 50 % nos colmos, 22 % nas folhas secas, 20 % nos ponteiros e 8 % nas raízes.

Root system distribution of sugar cane as related to nitrogen fertilization, evaluated by two methods: monolith and probes

Few studies on sugar cane have evaluated the root system of the crop, in spite of its importance. This is mainly due to the difficulty of evaluation and high variability of results. The objective of this study was to develop an evaluation method of the cane root system by means of probes so as to evaluate the mass, distribution and metabolically active roots related to N fertilization at planting. For this purpose, an experiment was conducted in an Arenic Kandiustults with medium texture in Jaboticabal/SP, in a randomized block design with four replications and four treatments: control (without N) and 40, 80 and 120 kg ha-1 of N applied in the form of urea in the planting furrow of the cane variety SP81 3250. One week before harvest, a urea-15N solution was applied at the cane stalk base to detect active metabolism in the root system. Trenches of 1.5 m length and 0.6 m depth were opened between two sugar cane rows for root sampling by two methods: monoliths (0.3, 0.2 and 0.15 m wide, deep and long respectively) taken from the trench wall and by probe (internal diameter 0.055 m). For each method, 15 samples per plot were collected. The roots were separated from the soil in a sieve (2 mm mesh), oven-dried (at 65 ºC) and the dry matter was measured. Root sampling by probes resulted in root mass that did not differ from the evaluation in monoliths, indicating that this evaluation method may be used for sugar cane root mass, although neither the root distribution in the soil profile nor the rhizome mass were efficiently evaluated, due to the small sample volume. Nitrogen fertilization at planting did not result in a greater root accumulation in the sugar cane plant, but caused changes in the distribution of the root system in the soil. The absence of N fertilization led to a better root distribution in the soil profile, with 50, 34 and 16 % in the 0-0.2, 0.2-0.4 and 0.4-0.6 m layers, respectively; in the fertilized treatments the roots were concentrated in the surface layer, with on average 70, 17 and 13 % for the same layers. The metabolically active roots were concentrated in the center of the cane stool, amounting to 40 % of the total root mass, regardless of N fertilization (application of 120 kg ha-1 N or without N).

Utilization of Boron (10B) derived from fertilizer by sugar cane

The response to B in agricultural systems of sugar cane is still an unexplored issue; B application has however recently been widely publicized and used with a certain degree of frequency. The use of 10B-labeled fertilizers may further contribute to clarify this practice. With the objective of evaluating sugar cane use of B (10B) derived from fertilizer (boric acid), an experiment was conducted under field conditions in the 2005/2006 growing season. The experiment consisted of the installation of microplots (2 x 1.5 m) where 4 kg ha-1 B (boric acid with 85.95 % in 10B atoms) dissolved in water was applied 90 days after planting (May 2005). The solution was applied to the soil on both sides of the plant row at a distance of 20 cm. After harvest (June 2006) the B content and 10B abundance in % atoms in all parts of the sugar cane plants (stalks, dry leaves, tips and roots) were determined. Results showed that the total B accumulated was 471 g ha-1 in the entire plant (35 % in the stalks, 22 % in the dry leaves, 9 % in the tips and 34 % in the roots). The sugar cane plants used on average 14 % of the total accumulated B in the above-ground part (44 g ha-1) and 11 % in the roots (19 g ha-1), totaling 13 % in the entire plant (63 g ha-1). The recovery of 10B-fertilizer by sugar cane plants was low, around 2 % of the total applied amount.