Computation of Solar Radiative Fluxes by 1D and 3D Methods Using Cloudy Atmospheres Inferred from A-train Satellite Data

The main point of this study was to use realistic representations of cloudy atmospheres to assess errors in solar flux estimates associated with 1D radiative transfer models. A scene construction algorithm, developed for the EarthCARE satellite mission, was applied to CloudSat, CALIPSO, and MODIS satellite data thus producing 3D cloudy atmospheres measuring 60 km wide by 13,000 km long at 1 km grid-spacing. Broadband solar fluxes and radiances for each (1 km)2 column where then produced by a Monte Carlo photon transfer model run in both full 3D and independent column approximation mode (i.e., a 1D model)

Haplotype Estimation from Fuzzy Genotypes Using Penalized Likelihood

The Composite Link Model is a generalization of the generalized linear model in which expected values of observed counts are constructed as a sum of generalized linear components. When combined with penalized likelihood, it provides a powerful and elegant way to estimate haplotype probabilities from observed genotypes. Uncertain (“fuzzy”) genotypes, like those resulting from AFLP scores, can be handled by adding an extra layer to the model. We describe the model and the estimation algorithm. We apply it to a data set of accurate human single nucleotide polymorphism (SNP) and to a data set of fuzzy tomato AFLP scores

Haplotype-based quantitative trait mapping using a clustering algorithm

BACKGROUND: With the availability of large-scale, high-density single-nucleotide polymorphism (SNP) markers, substantial effort has been made in identifying disease-causing genes using linkage disequilibrium (LD) mapping by haplotype analysis of unrelated individuals. In addition to complex diseases, many continuously distributed quantitative traits are of primary clinical and health significance. However the development of association mapping methods using unrelated individuals for quantitative traits has received relatively less attention. RESULTS: We recently developed an association mapping method for complex diseases by mining the sharing of haplotype segments (i.e., phased genotype pairs) in affected individuals that are rarely present in normal individuals. In this paper, we extend our previous work to address the problem of quantitative trait mapping from unrelated individuals. The method is non-parametric in nature, and statistical significance can be obtained by a permutation test. It can also be incorporated into the one-way ANCOVA (analysis of covariance) framework so that other factors and covariates can be easily incorporated. The effectiveness of the approach is demonstrated by extensive experimental studies using both simulated and real data sets. The results show that our haplotype-based approach is more robust than two statistical methods based on single markers: a single SNP association test (SSA) and the Mann-Whitney U-test (MWU). The algorithm has been incorporated into our existing software package called HapMiner, which is available from our website at . CONCLUSION: For QTL (quantitative trait loci) fine mapping, to identify QTNs (quantitative trait nucleotides) with realistic effects (the contribution of each QTN less than 10% of total variance of the trait), large samples sizes (≥ 500) are needed for all the methods. The overall performance of HapMiner is better than that of the other two methods. Its effectiveness further depends on other factors such as recombination rates and the density of typed SNPs. Haplotype-based methods might provide higher power than methods based on a single SNP when using tag SNPs selected from a small number of samples or some other sources (such as HapMap data). Rank-based statistics usually have much lower power, as shown in our study

Factive Scientific Understanding Without Accurate Representation

This paper analyzes two ways idealized biological models produce factive scientific understanding. I then argue that models can provide factive scientific understanding of a phenomenon without providing an accurate representation of the (difference-making) features of their real-world target system(s). My analysis of these cases also suggests that the debate over scientific realism needs to investigate the factive scientific understanding produced by scientists’ use of idealized models rather than the accuracy of scientific models themselves

Cytotoxicity of rhein, the active metabolite of sennoside laxatives, is reduced by multidrug resistance-associated protein 1

Anthranoid laxatives, belonging to the anthraquinones as do anthracyclines, possibly increase colorectal cancer risk. Anthracyclines interfere with topoisomerase II, intercalate DNA and are substrates for P-glycoprotein and multidrug resistance-associated protein 1. P-glycoprotein and multidrug resistance-associated protein 1 protect colonic epithelial cells against xenobiotics. The aim of this study was to analyse the interference of anthranoids with these natural defence mechanisms and the direct cytotoxicity of anthranoids in cancer cell lines expressing these mechanisms in varying combinations. A cytotoxicity profile of rhein, aloe emodin and danthron was established in related cell lines exhibiting different levels of topoisomerases, multidrug resistance-associated protein 1 and P-glycoprotein. Interaction of rhein with multidrug resistance-associated protein 1 was studied by carboxy fluorescein efflux and direct cytotoxicity by apoptosis induction. Rhein was less cytotoxic in the multidrug resistance-associated protein 1 overexpressing GLC4/ADR cell line compared to GLC4. Multidrug resistance-associated protein 1 inhibition with MK571 increased rhein cytotoxicity. Carboxy fluorescein efflux was blocked by rhein. No P-glycoprotein dependent rhein efflux was observed, nor was topoisomerase II responsible for reduced toxicity. Rhein induced apoptosis but did not intercalate DNA. Aloe emodin and danthron were no substrates for MDR mechanisms. Rhein is a substrate for multidrug resistance-associated protein 1 and induces apoptosis. It could therefore render the colonic epithelium sensitive to cytotoxic agents, apart from being toxic in itself

Ethnic Related Selection for an ADH Class I Variant within East Asia

The alcohol dehydrogenases (ADH) are widely studied enzymes and the evolution of the mammalian gene cluster encoding these enzymes is also well studied. Previous studies have shown that the ADH1B*47His allele at one of the seven genes in humans is associated with a decrease in the risk of alcoholism and the core molecular region with this allele has been selected for in some East Asian populations. As the frequency of ADH1B*47His is highest in East Asia, and very low in most of the rest of the world, we have undertaken more detailed investigation in this geographic region.Here we report new data on 30 SNPs in the ADH7 and Class I ADH region in samples of 24 populations from China and Laos. These populations cover a wide geographic region and diverse ethnicities. Combined with our previously published East Asian data for these SNPs in 8 populations, we have typed populations from all of the 6 major linguistic phyla (Altaic including Korean-Japanese and inland Altaic, Sino-Tibetan, Hmong-Mien, Austro-Asiatic, Daic, and Austronesian). The ADH1B genotyping data are strongly related to ethnicity. Only some eastern ethnic phyla or subphyla (Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian) have a high frequency of ADH1B*47His. ADH1B haplotype data clustered the populations into linguistic subphyla, and divided the subphyla into eastern and western parts. In the Hmong-Mien and Altaic populations, the extended haplotype homozygosity (EHH) and relative EHH (REHH) tests for the ADH1B core were consistent with selection for the haplotype with derived SNP alleles. In the other ethnic phyla, the core showed only a weak signal of selection at best.The selection distribution is more significantly correlated with the frequency of the derived ADH1B regulatory region polymorphism than the derived amino-acid altering allele ADH1B*47His. Thus, the real focus of selection may be the regulatory region. The obvious ethnicity-related distributions of ADH1B diversities suggest the existence of some culture-related selective forces that have acted on the ADH1B region

Energetic Selection of Topology in Ferredoxins

Models of early protein evolution posit the existence of short peptides that bound metals and ions and served as transporters, membranes or catalysts. The Cys-X-X-Cys-X-X-Cys heptapeptide located within bacterial ferredoxins, enclosing an Fe4S4 metal center, is an attractive candidate for such an early peptide. Ferredoxins are ancient proteins and the simple α+β fold is found alone or as a domain in larger proteins throughout all three kingdoms of life. Previous analyses of the heptapeptide conformation in experimentally determined ferredoxin structures revealed a pervasive right-handed topology, despite the fact that the Fe4S4 cluster is achiral. Conformational enumeration of a model CGGCGGC heptapeptide bound to a cubane iron-sulfur cluster indicates both left-handed and right-handed folds could exist and have comparable stabilities. However, only the natural ferredoxin topology provides a significant network of backbone-to-cluster hydrogen bonds that would stabilize the metal-peptide complex. The optimal peptide configuration (alternating αL,αR) is that of an α-sheet, providing an additional mechanism where oligomerization could stabilize the peptide and facilitate iron-sulfur cluster binding

Assembly, organization, and function of the COPII coat

A full mechanistic understanding of how secretory cargo proteins are exported from the endoplasmic reticulum for passage through the early secretory pathway is essential for us to comprehend how cells are organized, maintain compartment identity, as well as how they selectively secrete proteins and other macromolecules to the extracellular space. This process depends on the function of a multi-subunit complex, the COPII coat. Here we describe progress towards a full mechanistic understanding of COPII coat function, including the latest findings in this area. Much of our understanding of how COPII functions and is regulated comes from studies of yeast genetics, biochemical reconstitution and single cell microscopy. New developments arising from clinical cases and model organism biology and genetics enable us to gain far greater insight in to the role of membrane traffic in the context of a whole organism as well as during embryogenesis and development. A significant outcome of such a full understanding is to reveal how the machinery and processes of membrane trafficking through the early secretory pathway fail in disease states