The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets

Background The malignant B cells in chronic lymphocytic leukemia receive signals from the bone marrow and lymph node microenvironments which regulate their survival and proliferation. Characterization of these signals and the pathways that propagate them to the interior of the cell is important for the identification of novel potential targets for therapeutic intervention. Design and Methods We compared the gene expression profiles of chronic lymphocytic leukemia B cells purified from bone marrow and peripheral blood to identify genes that are induced by the bone marrow microenvironment. Two of the differentially expressed genes were further studied in cell culture experiments and in an animal model to determine whether they could represent appropriate therapeutic targets in chronic lymphocytic leukemia. Results Functional classification analysis revealed that the majority of differentially expressed genes belong to gene ontology categories related to cell cycle and mitosis. Significantly up-regulated genes in bone marrow-derived tumor cells included important cell cycle regulators, such as Aurora A and B, survivin and CDK6. Down-regulation of Aurora A and B by RNA interference inhibited proliferation of chronic lymphocytic leukemia-derived cell lines and induced low levels of apoptosis. A similar effect was observed with the Aurora kinase inhibitor VX-680 in primary chronic lymphocytic leukemia cells that were induced to proliferate by CpG-oligonucleotides and interleukin-2. Moreover, VX-680 significantly blocked leukemia growth in a mouse model of chronic lymphocytic leukemia. Conclusions Aurora A and B are up-regulated in proliferating chronic lymphocytic leukemia cells and represent potential therapeutic targets in this disease.

Prediction of apparent protein digestibility of ingredients and diets by in vitro pH-stat degree of protein hydrolysis with species-specific enzymes for juvenile Pacific white shrimp Litopenaeus vannamei

Aquafeed production faces global issues related to availability of feed ingredients. Feed manufacturers require greater flexibility in order to develop nutritional and cost-effective formulations that take into account nutrient content and availability of ingredients. The search for appropriate ingredients requires detailed screening of their potential nutritional value and variability at the industrial level. In vitro digestion of feedstuffs by enzymes extracted from the target species has been correlated with apparent protein digestibility (APD) in fish and shrimp species. The present study verified the relationship between APD and in vitro degree of protein hydrolysis (DH) with Litopenaeus vannamei hepatopancreas enzymes in several different ingredients (n = 26): blood meals, casein, corn gluten meal, crab meal, distiller`s dried grains with solubles, feather meal, fish meals, gelatin, krill meals, poultry by-product meal, soybean meals, squid meals and wheat gluten. The relationship between APD and DH was further verified in diets formulated with these ingredients at 30% inclusion into a reference diet. APD was determined in vivo (30.1 +/- 0.5 degrees C, 32.2 +/- 0.4%.) with juvenile L vannamei (9 to 12 g) after placement of test ingredients into a reference diet (35 g kg(-1) CP: 8.03 g kg(-1) lipid; 2.01 kcal g(-1)) with chromic oxide as the inert marker. In vitro DH was assessed in ingredients and diets with standardized hepatopancreas enzymes extracted from pond-reared shrimp. The DH of ingredients was determined under different assay conditions to check for the most suitable in vitro protocol for APD prediction: different batches of enzyme extracts (HPf5 or HPf6), temperatures (25 or 30 degrees C) and enzyme activity (azocasein): crude protein ratios (4 U: 80 mg CP or 4 U: 40 mg CP). DH was not affected by ingredient proximate composition. APD was significantly correlated to DH in regressions considering either ingredients or diets. The relationships between APD and DH of the ingredients could be suitably adjusted to a Rational Function (y = (a + bx)/(1 + cx + dx2), n = 26. Best in vitro APD predictions were obtained at 25 degrees C, 4 U: 80 mg CP both for ingredients (R(2) = 0.86: P = 0.001) and test diets (R(2) = 0.96; P = 0.007). The regression model including all 26 ingredients generated higher prediction residuals (i.e., predicted APD - determined APD) for corn gluten meal, feather meal. poultry by-product meal and krill flour. The remaining test ingredients presented mean prediction residuals of 3.5 points. A model including only ingredients with APD>80% showed higher prediction precision (R(2) = 0.98: P = 0.000004; n = 20) with average residual of 1.8 points. Predictive models including only ingredients from the same origin (e.g., marine-based, R(2) = 0.98; P = 0.033) also displayed low residuals. Since in vitro techniques have been usually validated through regressions against in vivo APD, the DH predictive capacity may depend on the consistency of the in vivo methodology. Regressions between APD and DH suggested a close relationship between peptide bond breakage by hepatopancreas digestive proteases and the apparent nitrogen assimilation in shrimp, and this may be a useful tool to provide rapid nutritional information. (C) 2009 Elsevier B.V. All rights reserved.

Biogeochemistry of an Amazonian podzol-ferralsol soil system with white kaolin

The podzol-ferralsol soil systems, which cover great areas of Amazonia and other equatorial regions, are frequently associated with kaolin deposits and store and export large amounts of carbon. Although natural organic matter (NOM) plays a key role in their dynamics, little is known about their biogeochemistry. In order to assess the specific role of dissolved organic matter (DOM) on NOM storage in deep horizons and to determine possible relationships between kaolin formation and DOM properties, we studied the groundwater composition of a typical podzol-ferralsol soil catena from the Alto Rio Negro region, Brazil. Groundwater was sampled using tension-free lysimeters placed according to soil morphology. DOC, E-H, p(H), and dissolved Si, Al3+, Fe2+, and Fe3+ were analyzed for all samples and values are given in a database. Quantification of other dissolved ions, small carboxylic acids and SUVA(254) index and acid-base microtitration was achieved on selected samples. Part of the DOM produced by the hydromorphic podzols is directly exported to the blackwater streams; another part percolates at greater depth, and more than 90% of it adsorbs in the Bh-Bhs horizons, allowing carbon storage at depth. Humic substances are preferentially adsorbed with regard to small carboxylic compounds. With regard to kaolin genesis, kaolinite precipitation is favored by Al release from NOM mineralization within the Bh-Bhs and kaolin bleaching is ensured by iron reduction due to acidity and relatively low E-H. Fe2+ mobility can be related to small E-H variations and enhanced by the significant concentration of small carboxylic acids. The long-term result of these processes is the thickening of the kaolin, and it can be inferred that kaolin is likely to occur where active, giant podzols are close to a slope gradient sufficient enough to lower the deep water table.

The Integration of the Glutamatergic and the White Matter Hypotheses of Schizophrenia's Etiology

Background: schizophrenia's endophenotipic profile is not only generally complex, but often varies from case to case. The perspective of trying to define specific anatomic correlates of the syndrome has led to disappointing results. In that context, neurophysiologic hypotheses (e. g. glutamatergic hypothesis) and connectivity hypotheses became prominent. Nevertheless, despite their commitment to the principle of denying 'localist' views and approaching the syndrome's endophenotype from a whole brain perspective, efforts to integrate both have not flourished at this moment in time. Objectives: This paper aims to introduce a new etiological model that integrates the glutamatergic and the WM (WM) hypotheses of schizophrenia's etiology. This model proposes to serve as a framework in order to relate to patterns of brain abnormalities from the onset of the syndrome to stages of advanced chronification. Highlights: Neurotransmitter abnormalities forego noticeable WM abnormalities. The former, chiefly represented by NMDAR hypo-function and associated molecular cascades, is related to the first signs of cell loss. This process is both directly and indirectly integrated to the underpinning of WM structural abnormalities; not only is the excess of glutamate toxic to the WM, but its disruption is associated to the expression of known genetic risk factors (e. g., NRG-1). A second level of the model develops the idea that abnormal neurotransmission within specific neural populations ('motifs') impair particular cognitive abilities, while subsequent WM structural abnormalities impair the integration of brain functions and multimodality. As a result of this two-stage dynamic, the affected individual progresses from experiencing specific cognitive and psychological deficits, to a condition of cognitive and existential fragmentation, linked to hardly reversible decreases in psychosocial functioning.

An in vitro comparison of subjective image quality of panoramic views acquired via 2D or 3D imaging

Objectives: The objective of this study is to compare subjective image quality and diagnostic validity of cone-beam CT (CBCT) panoramic reformatting with digital panoramic radiographs. Materials and methods: Four dry human skulls and two formalin-fixed human heads were scanned using nine different CBCTs, one multi-slice CT (MSCT) and one standard digital panoramic device. Panoramic views were generated from CBCTs in four slice thicknesses. Seven observers scored image quality and visibility of 14 anatomical structures. Four observers repeated the observation after 4 weeks. Results: Digital panoramic radiographs showed significantly better visualization of anatomical structures except for the condyle. Statistical analysis of image quality showed that the 3D imaging modalities (CBCTs and MSCT) were 7.3 times more likely to receive poor scores than the 2D modality. Yet, image quality from NewTom VGi® and 3D Accuitomo 170® was almost equivalent to that of digital panoramic radiographs with respective odds ratio estimates of 1.2 and 1.6 at 95% Wald confidence limits. A substantial overall agreement amongst observers was found. Intra-observer agreement was moderate to substantial. Conclusions: While 2D-panoramic images are significantly better for subjective diagnosis, 2/3 of the 3D-reformatted panoramic images are moderate or good for diagnostic purposes. Clinical relevance: Panoramic reformattings from particular CBCTs are comparable to digital panoramic images concerning the overall image quality and visualization of anatomical structures. This clinically implies that a 3D-derived panoramic view can be generated for diagnosis with a recommended 20-mm slice thickness, if CBCT data is a priori available for other purposes.