Nonparametric estimation of bivariate failure time associations in the presence of a competing risk

Most research on the study of associations among paired failuretimes has either assumed time invariance or been based on complexmeasures or estimators. Little has accommodated competing risks.This paper targets the conditional cause-specific hazard ratio,henceforth called the cause-specific cross ratio, a recent modificationof the conditional hazard ratio designed to accommodate competingrisks data. Estimation is accomplished by an intuitive, nonparametricmethod that localizes Kendall's tau. Time variance is accommodatedthrough a partitioning of space into ‘bins’ betweenwhich the strength of association may differ. Inferential proceduresare developed, small-sample performance is evaluated, and themethods are applied to the investigation of familial associationin dementia onset.     

秦岭太白红杉群落种间关系的数量分析

应用2×2列联表的Fisher精确检验,研究了太白红杉群落中44种植物 共946个种对 的种间关系.结果有33个种对正关联,12个种对负关联 P<0.05或P<0.01 .另外,用Pearson积矩相关系数和Spearman秩相关系数检验刻划了种对间的数量变化关系.Pearson相关系数显示有31个种对呈显著正协变,5个种对呈显著负协变;Spearman秩相关系数显示有30个种对呈显著正协变,5个种对呈显著负协变,并分别计算出了其相关系数.研究结果表明,太白红杉群落种间关系较为简单,但草本层物种间连接相对较为复杂,灌木层次之.乔木层中,太白红杉和巴山冷杉呈显著的负协变效应.     

Archaeobotanical investigations of an earth oven in Kiribati, Gilbert Islands

This paper is an ethnobotanical study of a 400 year old earth oven discovered on Nikunau, in the southern Gilbert Islands. The anthropological analyses based on almost 2000 identified charcoal specimens show that only a few taxa were used for fuel, primarily monocotyledon endocarp which was waste from food production. In addition, a conventional non-parametric statistical test was evaluated for use as an indicator of similarity between samples. It appears that in an assemblage where the taxonomic range (monocotyledon to dicotyledon) is large, a rank order statistical test is inappropriate due to variation in fragmentation.     

The dual fates of exogenous tau seeds: Lysosomal clearance versus cytoplasmic amplification

Tau assembly movement from the extracellular to intracellular space may underlie transcellular propagation of neurodegenerative tauopathies. This begins with tau binding to cell surface heparan sulfate proteoglycans, which triggers macropinocytosis. Pathological tau assemblies are proposed then to exit the vesicular compartment as “seeds” for replication in the cytoplasm. Tau uptake is highly efficient, but only ∼1 to 10% of cells that endocytose aggregates exhibit seeding. Consequently, we studied fluorescently tagged full-length (FL) tau fibrils added to native U2OS cells or “biosensor” cells expressing FL tau or repeat domain. FL tau fibrils bound tubulin. Seeds triggered its aggregation in multiple locations simultaneously in the cytoplasm, generally independent of visible exogenous aggregates. Most exogenous tau trafficked to the lysosome, but fluorescence imaging revealed a small percentage that steadily accumulated in the cytosol. Intracellular expression of Gal3-mRuby, which binds intravesicular galactosides and forms puncta upon vesicle rupture, revealed no evidence of vesicle damage following tau exposure, and most seeded cells had no evidence of endolysosome rupture. However, live-cell imaging indicated that cells with pre-existing Gal3-positive puncta were seeded at a slightly higher rate than the general population, suggesting a potential predisposing role for vesicle instability. Clearance of tau seeds occurred rapidly in both vesicular and cytosolic fractions. The lysosome/autophagy inhibitor bafilomycin inhibited vesicular clearance, whereas the proteasome inhibitor MG132 inhibited cytosolic clearance. Tau seeds that enter the cell thus have at least two fates: lysosomal clearance that degrades most tau, and entry into the cytosol, where seeds amplify, and are cleared by the proteasome.     

Preservation of Gene Expression Ratios Among Multiple Complex cDNAs After PCR Amplification: Application to Differential Gene Expression Studies

Comparative gene expression studies are often limited by low availability of tissue and poor quality of extractable mRNA. Collective PCR amplification of minute quantities of mRNA has great potential for overcoming these limitations. However, there remains significant concern about the effects of amplification on the absolute and relative abundance of individual mRNAs that could complicate subsequent gene expression studies. To address this problem, we systematically compared the relative abundance of many specific mRNAs from complex cDNA preparations (from tissue and cultured cells) both before and after amplification by PCR. Our results demonstrated that, as expected, the absolute abundance of different mRNAs in a cDNA library is altered in an unpredictable manner by PCR amplification. However, we found that the concentration ratios of specific mRNAs among different cDNA preparations were routinely well conserved after PCR amplification. Thus, for the purpose of comparative expression studies for specific mRNAs in two (or more) complex cDNAs, PCR-amplified cDNA is equally useful as unamplified cDNA. These results provide a rigorous experimental validation and offer a theoretical treatment to support the utility of PCR amplified cDNA for differential gene expression studies. We conclude that the inherent difficulties in performing differential screening studies such as gene chip and array analyses on limited amounts of biological materials can be overcome by a PCR amplification step without compromising data quality. This revised version was published online in July 2006 with corrections to the Cover Date.     

Towards compendia of negative genetic association studies: an example for Alzheimer disease

Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004–April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) β-amyloid (Aβ) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.     

Food security versus biodiversity protection: an example of land-sharing from East Africa

The recent controversial debate on land-sharing versus land-sparing is clearly exemplified in the East African mountains, one of the most diverse biodiversity hotspots on our planet. In these areas, species richness is particularly concentrated in the mountain cloud forests which are surrounded by a sea of dry lowland savannas heavily encroached on by local communities. Sustainable land use practices in the lowlands, however, are necessary to safeguard the natural capital at higher elevations. The interdependence between sustainable land-use and conservation of biodiversity hotspots was underlined during a workshop held in the rural areas of Kenya, East Africa, early spring 2013. It was concluded that close links between livelihoods, natural capital and poverty remains a fundamental challenge in East Africa’s forest conservation efforts.     

Detection of epistatic interactions in association mapping populations: an example from tetraploid potato

Epistatic interactions among loci are expected to contribute substantially to variation of quantitative traits. The objectives of our research were to (i) compare a classical mixed-model approach with a combined mixed-model and analysis of variance approach for detecting epistatic interactions; (ii) examine using computer simulations the statistical power to detect additive-additive, additive-dominance and dominance-dominance epistatic interactions and (iii) detect epistatic interactions between candidate genes for resistance to leaf blight in a set of tetraploid potato clones. Our study was based on the genotypic and phenotypic data of 184 tetraploid potato cultivars as well as computer simulations. The number of significant (α* =1 × 10(-6)) epistatic interactions ranged for the three examined traits from 3 to 32. Our findings suggested that the combined mixed-model and analysis of variance approach leads in comparison with the classical mixed-model approach not to an increased rate of false-positives. The results of the computer simulations suggested that, if molecular markers are available that are in high LD (D'>0.9) with the trait-coding loci, the statistical power to detect epistatic interactions, which explain 5-10% of the phenotypic variance, was of a size that seems promising for their detection.     

Electrochemical studies of arsenite oxidase: an unusual example of a highly cooperative two-electron molybdenum center

Arsenite oxidase from Alcaligenes faecalis, an unusual molybdoenzyme that does not exhibit a Mo(V) EPR signal during oxidative-reductive titrations, has been investigated by protein film voltammetry. A film of the enzyme on a pyrolytic graphite edge electrode produces a sharp two-electron signal associated with reversible reduction of the oxidized Mo(VI) molybdenum center to Mo(IV). That reduction or oxidation of the active site occurs without accumulation of Mo(V) is consistent with the failure to observe a Mo(V) EPR signal for the enzyme under a variety of conditions and is indicative of an obligate two-electron center. The reduction potential for the molybdenum center, 292 mV (vs SHE) at pH 5.9 and 0 degrees C, exhibits a linear pH dependence for pH 5-10, consistent with a two-electron reduction strongly coupled to the uptake of two protons without a pK in this range. This suggests that the oxidized enzyme is best characterized as having an L(2)MoO(2) rather than L(2)MoO(OH) center in the oxidized state and that arsenite oxidase uses a "spectator oxo" effect to facilitate the oxo transfer reaction. The onset of the catalytic wave observed in the presence of substrate correlates well with the Mo(VI/IV) potential, consistent with catalytic electron transport that is limited only by turnover at the active site. The one-electron peaks for the iron-sulfur centers are difficult to observe by protein film voltammetry, but spectrophotometric titrations have been carried out to measure their reduction potentials: at pH 6.0 and 20 degrees C, that of the [3Fe-4S] center is approximately 260 mV and that of the Rieske center is approximately 130 mV.     

Effect of correcting outcome data for case mix: an example from stroke medicine.

OBJECTIVE--To show the influence of variations in case mix on clinical outcome indicators for patients admitted to hospital with acute stroke. DESIGN--"Before and after" cohort study, with prospective, consecutive identification of patients and prospective follow up; multiple logistic regression analyses to correct for case mix variations. SETTING--University teaching hospital. SUBJECTS--216 patients with stroke identified before the introduction of an organised stroke service, and 252 patients with stroke identified after its introduction. MAIN OUTCOME MEASURES--Case fatality at 30 days and 12 months; for survivors at 12 months, proportions of patients who were independent (according to the Oxford handicap scale) and of those living at home. RESULTS--Crude outcome data suggested that patients in the cohort identified after the introduction of the stroke service were significantly more likely to be alive, independent, and living at home than patients managed before the stroke service. After adjustment for age and sex these "improvements" were less impressive but still significant. After adjustment for many other possible prognostic indicators, however, the differences between the two groups for all four outcomes were non-significant, suggesting that the "improvements" may have been entirely due to differences in case mix between the two cohorts, rather than the new stroke service. CONCLUSIONS--Variations in case mix have a crucial influence on the interpretation of outcome data, and this is particularly important in non-randomised comparative studies. Such studies, comparing performance within and between different provider units, are likely to become increasingly common in the new reformed NHS. To allow meaningful interpretation, these studies must try to correct for case mix.     

Equilibrium binding of myristoyllysophosphatidylcholine to bovine myelin basic protein: an example of ligand-mediated acceptor association

The interaction of myristoyllysophosphatidylcholine with bovine myelin basic protein at pH 7.4 and 4.5, I = 0.48, has been investigated by a recycling partition equilibrium technique with Bio-Gel P-2 as the gel phase. Important points to emerge from this direct binding study are that it is a monomeric (not micellar) amphiphile that binds to myelin basic protein, that the amphiphile binds preferentially to the monomeric form of myelin basic protein, that this binding to monomer is highly cooperative, that the similarity of binding behavior in the two environments tested is consistent with the dominance of a hydrophobic contribution to the protein-amphiphile interaction, and that the self-association of myelin basic protein in the presence of phospholipid [Smith, R. (1982) Biochemistry 21, 2697-2701] must reflect the aggregation of a protein-amphiphile complex(es) coupled with concomitant release of some lipid. These findings are then related to earlier nuclear magnetic resonance and circular dichroism studies in which the results were interpreted on the basis that myelin basic protein bound preferentially to micellar phospholipid.     

Positive selection versus demography: evolutionary inferences based on an unusual haplotype structure in Drosophila simulans

Coalescent simulations were used to investigate the possible role of population subdivision and history in shaping nucleotide variation in a recombining 88-kb genomic fragment of Drosophila simulans displaying an unusual large-scale haplotype structure. The multilocus analysis, based on summary statistics using specific demographic null models under recombination, indicates that the observed levels of linkage disequilibrium differed significantly from the values expected under different bottleneck and population admixture scenarios. These results indicate that demography alone may not account for the observed pattern of variation and support the previous claim that the data are better described by a model in which an adaptive mutation has not yet gone to fixation.     

Morphological and cytochemical analysis of an unusual nucleus-pyrenoid association in a unicellular red alga

Summary Protrusions of the nucleus that extend into the pyrenoid of the unicellular red algaRhodella maculata have been characterised morphologically and cytochemically. Serial reconstructions indicate that cells frequently have two tubular nuclear protrusions that are up to 1.2 m long. Cytochemical analyses were undertaken to investigate the nucleic acid content of the protrusions. DNA was not detected in the nuclear protrusions, though clear labelling was seen in all other DNA-containing zones (viz. the main nuclear compartment, the chloroplast and the mitochondria). High concentrations of RNA were observed in the nuclear protrusion. In situ hybridization experiments indicate that ribosomal RNAs are not a major component of the protrusion RNA. Possible roles of the protrusion and its RNA content are discussed.Abbreviations DNA deoxyribonucleic acid - RNA ribonucleic acid - rRNA ribosomal RNA     

Structural Characterization of Tau in Fuzzy Tau:Tubulin Complexes

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