Description: Background: Multiple solutes are retained in uremia, but it is currently unclear which solutes are toxic. Small studies suggest that protein-bound solutes, such as p-cresol sulfate and indoxyl sulfate and intracellular solutes, such as methylamine (MMA) and dimethylamine (DMA), may be toxic. Our objective was to test whether elevated levels of these solutes were associated with mortality. Methods: We conducted a prospective cohort study in 521 U.S. incident hemodialysis patients to evaluate associations between these solutes and all-cause and cardiovascular mortality. P-cresol sulfate, indoxyl sulfate, MMA and DMA levels were measured from frozen plasma samples obtained 2 to 6 months after initiation of dialysis. Mortality data was available through 2004 using the National Death Index. Results: Elevated (greater than the population median) p-cresol sulfate, MMA or DMA levels were not associated with all-cause or cardiovascular mortality. Elevated indoxyl sulfate levels were associated with all-cause mortality but not cardiovascular mortality (hazard ratio 1.30 (95% confidence interval 1.01, 1.69) p-value 0.043). Conclusions: In this cohort of 521 incident hemodialysis patients, only elevated indoxyl sulfate levels were associated with all-cause mortality. Further research is needed to identify causes of the toxicity of uremia to provide better care for patients with kidney disease.

Description: Background: The identification of the loci and specific alleles underlying variation in quantitative traits is an important goal for evolutionary biologists and breeders. Despite major advancements in genomics technology, moving from QTL to causal alleles remains a major challenge in genetics research. Near-isogenic lines are the ideal raw material for QTL validation, refinement of QTL location and, ultimately, gene discovery. Results: In this study, a population of 75 Arabidopsis thaliana near-isogenic lines was developed from an existing recombinant inbred line (RIL) population derived from a cross between physiologically divergent accessions Kas-1 and Tsu-1. First, a novel algorithm was developed to utilize genome-wide marker data in selecting RILs fully isogenic to Kas-1 for a single chromosome. Seven such RILs were used in 2 generations of crossing to Tsu-1 to create BC1 seed. BC1 plants were genotyped with SSR markers so that lines could be selected that carried Kas-1 introgressions, resulting in a population carrying chromosomal introgressions spanning the genome. BC1 lines were genotyped with 48 genome-wide SSRs to identify lines with a targeted Kas-1 introgression and the fewest genomic introgressions elsewhere. 75 such lines were selected and genotyped at an additional 41 SNP loci and another 930 tags using 2b-RAD genotyping by sequencing. The final population carried an average of 1.35 homozygous and 2.49 heterozygous introgressions per line with average introgression sizes of 5.32 and 5.16 Mb, respectively. In a simple case study, we demonstrate the advantage of maintaining heterozygotes in our library whereby fine-mapping efforts are conducted simply by self-pollination. Crossovers in the heterozygous interval during this single selfing generation break the introgression into smaller, homozygous fragments (sub-NILs). Additionally, we utilize a homozygous NIL for validation of a QTL underlying stomatal conductance, a low heritability trait. Conclusions: The present results introduce a new and valuable resource to the Brassicaceae research community that enables rapid fine-mapping of candidate loci in parallel with QTL validation. These attributes along with dense marker coverage and genome-wide chromosomal introgressions make this population an ideal starting point for discovery of genes underlying important complex traits of agricultural and ecological significance.

Description: Environmental Science & Technology DOI: 10.1021/es401609n

Description: The t(8;21) chromosomal translocation activates aberrant expression of the AML1-ETO (AE) fusion protein and is commonly associated with core binding factor acute myeloid leukaemia (CBF AML). Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t(8;21) CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms. Initially, AE expression modified the lineage potential of haematopoietic stem cells (HSCs), resulting in the selective expansion of the myeloid compartment at the expense of normal erythro- and lymphopoiesis. This lineage skewing was followed by a second substantial rewiring of transcriptional networks occurring in the trajectory to manifest leukaemia. We also find that both HSC and lineage-restricted granulocyte macrophage progenitors (GMPs) acquired leukaemic stem cell (LSC) potential being capable of initiating and maintaining the disease. Finally, our data demonstrate that long-term expression of AE induces an indolent myeloproliferative disease (MPD)-like myeloid leukaemia phenotype with complete penetrance and that acute inactivation of AE function is a potential novel therapeutic option. This novel model system of AML1-ETO driven acute myeloid leukaemia addresses the concept of ‘oncogene addiction’. Better understanding of AML1-ETO need to maintain leukemia and rewire the transcriptome may help to design future therapies.

Description: Modeling sub-canopy elevation is an important step in the processing of waveform lidar data to measure three dimensional forest structure. Here, we present a methodology based on high resolution discrete-return lidar (DRL) to correct the ground elevation derived from large-footprint Laser Vegetation Imaging Sensor (LVIS) and to improve measurement of forest structure. We use data acquired over Barro Colorado Island, Panama by LVIS large-footprint lidar (LFL) in 1998 and DRL in 2009. The study found an average vertical difference of 28.7 cm between 98,040 LVIS last-return points and the discrete-return lidar ground surface across the island. The majority (82.3%) of all LVIS points matched discrete return elevations to 2 m or less. Using a multi-step process, the LVIS last-return data is filtered using an iterative approach, expanding window filter to identify outlier points which are not part of the ground surface, as well as applying vertical corrections based on terrain slope within the individual LVIS footprints. The results of the experiment demonstrate that LFL ground surfaces can be effectively filtered using methods adapted from discrete-return lidar point filtering, reducing the average vertical error by 15 cm and reducing the variance in LVIS last-return data by 70 cm. The filters also reduced the largest vertical estimations caused by sensor saturation in the upper reaches of the forest canopy by 14.35 m, which improve forest canopy structure measurement by increasing accuracy in the sub-canopy digital elevation model.

Description: Background: Solely in Europoe, Salmonella Typhimurium causes more than 100,000 infections per year.Improved detection of livestock colonised with S. Typhimurium is necessary to preventfoodborne diseases. Currently, commercially available ELISA assays are based on a mixtureof O-antigens (LPS) or total cell lysate of Salmonella and are hampered by cross-reaction.The identification of novel immunogenic proteins would be useful to develop ELISA baseddiagnostic assays with a higher specificity. Results: A phage display library of the entire Salmonella Typhimurium genome was constructed and47 immunogenic oligopeptides were identified using a pool of convalescent sera from pigsinfected with Salmonella Typhimurium. The corresponding complete genes of seven of theidentified oligopeptids were cloned. Five of them were produced in E. coli. The immunogeniccharacter of these antigens was validated with sera from pigs infeced with S. Tyhimurium andcontrol sera from non-infected animals. Finally, human antibody fragments (scFv) againstthese five antigens were selected using antibody phage display and characterised. Conclusion: In this work, we identified novel immunogenic proteins of Salmonella Typhimurium andgenerated antibody fragments against these antigens completely based on phage display. Fiveimmunogenic proteins were validated using a panel of positive and negative sera forprospective applications in diagnostics of Salmonela Typhimurium.

Description: The Authors Reply: Kidney International 82, 1033 (November (1) 2012). doi:10.1038/ki.2012.291 Authors: Timothy W Meyer & Thomas H Hostetter