Trace Element Composition of Stream Sediments an Integrating Factor for Water Quality

Bottom sediments, suspended sediments, and water were sampled along 130 miles of the Buffalo River in northern Arkansas. The water and acid extracts of the suspended sediments and the minus 95 mesh fraction of the bottom sediments were analyzed by atomic absorption spectrometry. All samples were analyzed for Na, K, Mg, Ca, Zn, Cd, Cu, Pb, Fe, Co, Cr, Ni, and Mn. Selected bottom samples also were analyzed by As, Hg, and Zr. Zr was determined by x-ray fluorescence. Li and Sr were determined for selected water and suspended sediment samples. There is a general decrease downstream in Fe, Cu, Cr, Ni, Mn, Pb, K, and Na in the bottom sediments as the drainage area increases in carbonate rock and decreases in shale. The elements Mg, Ca, Zn, and Cd increase in bottom sediments downstream. The values for these elements in the water, especially the major elements, also correspond closely with the geology of the region. Tributaries are sites of abrupt rise and fall of metal values, within a few miles, from background to anomalously high values to background, especially tributaries draining Zn and Pb mineralized areas. The bottom sediments are mainly quartz and chert grains. These grains apparently are coated with hydrous iron oxide which acts as a sorbent for many of the elements and is a dominant transport mechanism for acid extractable Co, Cr, Ni, Cu, Mn, and K. Other acid extractable metals, particularly Mg, Ca, Zn, Cd, and Pb, are mostly in clastic grains. Graphic representation of the Langmuir equation for Mn is consistent with adsorption of Mn by iron in both bottom sediments and suspended sediments. On the basis of the volume of water collected, all the elements except Fe are more concentrated in the water than in the suspended sediments. Fe concentration of the suspended sediments increases with increasing flow because the suspended load is increased. The Mn/Fe ratio of the suspended sediments is approximately equal to or greater than that of the bottom sediments. The Mn/Fe ratio of suspended sediments relative to that of the bottom sediments increases downstream, possibly because of an autocatalytic effect of Mn precipitation. The relationship between sediment and water concentrations is not clear from the data because of the restricted concentration ranges for some elements in the suspended sediment and water. The sediment from the Buffalo River can be used to estimate grossly the concentration of elements in the water

Postglacial (Holocene) ostracodes from Lake Erie

26 p., 8 fig., 4 pl.http://paleo.ku.edu/contributions.htm

On the Distribution of a Second Class Particle in the Asymmetric Simple Exclusion Process

We give an exact expression for the distribution of the position X(t) of a single second class particle in the asymmetric simple exclusion process (ASEP) where initially the second class particle is located at the origin and the first class particles occupy the sites {1,2,...}

A modifier of Huntington's disease onset at the MLH1 locus

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on 32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3’end of MLH1 and the 5’end of the neighboring LRRFIP2, and marked by an isoleucinevaline missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets

Haplotype-based stratification of Huntington's disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome-wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject-derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD

Haplotype-based stratification of Huntington's disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome-wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject-derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD

Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12

PURPOSE: For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS: We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS: For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). CONCLUSION: For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life

Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease

SummaryAs a Mendelian neurodegenerative disorder, the genetic risk of Huntington’s disease (HD) is conferred entirely by an HTT CAG repeat expansion whose length is the primary determinant of the rate of pathogenesis leading to disease onset. To investigate the pathogenic process that precedes disease, we used genome-wide association (GWA) analysis to identify loci harboring genetic variations that alter the age at neurological onset of HD. A chromosome 15 locus displays two independent effects that accelerate or delay onset by 6.1 years and 1.4 years, respectively, whereas a chromosome 8 locus hastens onset by 1.6 years. Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD. Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders.PaperCli

Time Out of Joint: Hamlet and the Pure Form of Time

The aim of this paper is to explore why Deleuze takes up Hamlet’s claim that ‘time is out of joint’. In the first part of this paper, I explore this claim by looking at how Deleuze relates it to Plato’s Timaeus and its conception of the relationship between movement and time. Once we have seen how time functions when it is ‘in joint’, I explore what it would mean for time to no longer be understood in terms of an underlying rational structure. The claim can be understood as about a relationship between time and action. In the second part of this paper, I want to relate this new understanding of time to Hamlet itself, in order to see how temporality operates within the play. I will conclude by relating these two different conceptions of time out of joint to one another through Nietzsche’s Eternal Return