Separating the Effects of Hemodialysis Dose and Nutrition: In Search of the Optimal Dialysis Dose

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73859/1/j.1525-139X.1999.90218.x.pd

How Will the Results of the HEMO Study Impact Dialysis Practice?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71984/1/j.1525-139X.2003.03003_3.x.pd

A Sequential Stratification Method for Estimating the Effect of a Time-Dependent Experimental Treatment in Observational Studies

Survival analysis is often used to compare experimental and conventional treatments. In observational studies, the therapy may change during follow-up and such crossovers can be summarized by time-dependent covariates. Given the ever-increasing donor organ shortage, higher-risk kidneys from expanded criterion donors (ECD) are being transplanted. Transplant candidates can choose whether to accept an ECD organ (experimental therapy), or to remain on dialysis and wait for a possible non-ECD transplant later (conventional therapy). A three-group time-dependent analysis of such data involves estimating parameters corresponding to two time-dependent indicator covariates representing ECD transplant and non-ECD transplant, each compared to remaining on dialysis on the waitlist. However, the ECD hazard ratio estimated by this time-dependent analysis fails to account for the fact that patients who forego an ECD transplant are not destined to remain on dialysis forever, but could subsequently receive a non-ECD transplant. We propose a novel method of estimating the survival benefit of ECD transplantation relative to conventional therapy (waitlist with possible subsequent non-ECD transplant). Compared to the time-dependent analysis, the proposed method more accurately characterizes the data structure and yields a more direct estimate of the relative outcome with an ECD transplant.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66010/1/j.1541-0420.2006.00527.x.pd

Intracellular localization and interaction of mRNA binding proteins as detected by FRET

<p>Abstract</p> <p>Background</p> <p>A number of RNA binding proteins (BPs) bind to A+U rich elements (AREs), commonly present within 3'UTRs of highly regulated RNAs. Individual RNA-BPs proteins can modulate RNA stability, RNA localization, and/or translational efficiency. Although biochemical studies have demonstrated selectivity of ARE-BPs for individual RNAs, less certain is the <it>in vivo </it>composition of RNA-BP multiprotein complexes and how their composition is affected by signaling events and intracellular localization. Using FRET, we previously demonstrated that two ARE-BPs, HuR and AUF1, form stable homomeric and heteromeric associations in the nucleus and cytoplasm. In the current study, we use immuno-FRET of endogenous proteins to examine the intracellular localization and interactions of HuR and AUF1 as well as KSRP, TIA-1, and Hedls. These results were compared to those obtained with their exogenously expressed, fluorescently labeled counterparts.</p> <p>Results</p> <p>All ARE-BPs examined were found to colocalize and to form stable associations with selected other RNA-BPs in one or more cellular locations variably including the nucleus, cytoplasm (in general), or in stress granules or P bodies. Interestingly, FRET based interaction of the translational suppressor, TIA-1, and the decapping protein, Hedls, was found to occur at the interface of stress granules and P bodies, dynamic sites of intracellular RNA storage and/or turnover. To explore the physical interactions of RNA-BPs with ARE containing RNAs, <it>in vitro </it>transcribed Cy3-labeled RNA was transfected into cells. Interestingly, Cy3-RNA was found to coalesce in P body like punctate structures and, by FRET, was found to interact with the RNA decapping proteins, Hedls and Dcp1.</p> <p>Conclusions</p> <p>Biochemical methodologies, such as co-immunoprecipitation, and cell biological approaches such as standard confocal microscopy are useful in demonstrating the possibility of proteins and/or proteins and RNAs interacting. However, as demonstrated herein, colocalization of proteins and proteins and RNA is not always indicative of interaction. To this point, using FRET and immuno-FRET, we have demonstrated that RNA-BPs can visually colocalize without producing a FRET signal. In contrast, proteins that appear to be delimited to one or another intracellular compartment can be shown to interact when those compartments are juxtaposed.</p

Ensemble perturbation smoother for optimizing tidal boundary conditions by assimilation of High-Frequency radar surface currents - application to the German Bight

High-Frequency (HF) radars measure the ocean surface currents at various spatial and temporal scales. These include tidal currents, wind-driven circulation, density-driven circulation and Stokes drift. Sequential assimilation methods updating the model state have been proven successful to correct the density-driven currents by assimilation of observations such as sea surface height, sea surface temperature and in-situ profiles. However, the situation is different for tides in coastal models since these are not generated within the domain, but are rather propagated inside the domain through the boundary conditions. For improving the modeled tidal variability it is therefore not sufficient to update the model state via data assimilation without updating the boundary conditions. The optimization of boundary conditions to match observations inside the domain is traditionally achieved through variational assimilation methods. In this work we present an ensemble smoother to improve the tidal boundary values so that the model represents more closely the observed currents. To create an ensemble of dynamically realistic boundary conditions, a cost function is formulated which is directly related to the probability of each boundary condition perturbation. This cost function ensures that the boundary condition perturbations are spatially smooth and that the structure of the perturbations satisfies approximately the harmonic linearized shallow water equations. Based on those perturbations an ensemble simulation is carried out using the full three-dimensional General Estuarine Ocean Model (GETM). Optimized boundary values are obtained by assimilating all observations using the co-variances of the ensemble simulation

A Probabilistic proof of the breakdown of Besov regularity in LL-shaped domains

{We provide a probabilistic approach in order to investigate the smoothness of the solution to the Poisson and Dirichlet problems in $L$-shaped domains. In particular, we obtain (probabilistic) integral representations for the solution. We also recover Grisvard's classic result on the angle-dependent breakdown of the regularity of the solution measured in a Besov scale

Streptococcus pyogenes polymyxin B-resistant mutants display enhanced exportal integrity

The ExPortal protein secretion organelle in Streptococcus pyogenes is an anionic phospholipid-containing membrane microdomain enriched in Sec translocons and postsecretion protein biogenesis factors. Polymyxin B binds to and disrupts ExPortal integrity, resulting in defective secretion of several toxins. To gain insight into factors that influence ExPortal organization, a genetic screen was conducted to select for spontaneous polymyxin B-resistant mutants displaying enhanced ExPortal integrity. Whole-genome resequencing of 25 resistant mutants revealed from one to four mutations per mutant genome clustered primarily within a core set of 10 gene groups. Construction of mutants with individual deletions or insertions demonstrated that 7 core genes confer resistance and enhanced ExPortal integrity through loss of function, while 3 were likely due to gain of function and/or combinatorial effects. Core resistance genes include a transcriptional regulator of lipid biosynthesis, several genes involved in nutrient acquisition, and a variety of genes involved in stress responses. Two members of the latter class also function as novel regulators of the secreted SpeB cysteine protease. Analysis of the most frequently isolated mutation, a single nucleotide deletion in a track of 9 consecutive adenine residues in pstS, encoding a component of a high-affinity P(i) transporter, suggests that this sequence functions as a molecular switch to facilitate stress adaptation. Together, these data suggest the existence of a membrane stress response that promotes enhanced ExPortal integrity and resistance to cationic antimicrobial peptides