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Conjugation with polyethylene glycol (PEG) is a strategy for improving the pharmaceutical properties of therapeutic proteins. In nonclinical studies of PEGylated compounds, microscopic tissue vacuolation is often observed, characterized ultrastructurally in this report by lysosomal distension. Although PEGylation-associated vacuolation appears to be of limited toxicologic concern when alternative therapies are limited, the risk-benefit considerations may be impacted by uncertainty about reversibility, lack of methods for monitoring PEG accumulation in vivo without biopsy, and the variability in tissues affected depending on species studied. We demonstrate the use of magnetic resonance spectroscopy (MRS) to measure PEG concentrations at multiple time points in vivo in the kidney with comparison to PEG concentrations ex vivo in body fluids and tissue extracts using nuclear magnetic resonance (NMR) spectroscopy. Furthermore, we demonstrate the use of these techniques to study distribution and elimination of PEG in a dog model of PEGylation-associated vacuolation. This report suggests that MRS could be further investigated as a feasible imaging-based method for monitoring PEG accumulation in a clinical setting in conjunction with NMR quantitation of PEG in plasma and urine. [ABSTRACT FROM AUTHOR]

Focuses on the structural features of Vibrio cholerae O139 Bengal strain. Nuclear magnetic resonance frequency (NMR) spectra; Chemical shifts; Remarks on structural polysaccharide; Effect of transposon insertion.

Polar codes, as the coding scheme for the control channel in fifth-generation mobile communication technology (5G), have attracted widespread attention since their proposal. As a mainstream decoding algorithm for polar codes, the successive cancellation list (SCL) decoder usually improves the error correction performance by increasing the list size, but this method suffers from the problems of high decoding complexity. To address this problem, this paper proposes a layered-search bit-flipping (LS-SCLF) decoding algorithm based on SCL decoding. Firstly, a new flip-bit metric is proposed, which derives a formula to approximate the probability of an error occurring in an information bit. This formula introduces a perturbation parameter to improve the calculation accuracy. Secondly, a compromise scheme for determining the perturbation parameter is proposed. The scheme uses Monte Carlo simulation to determine an optimized parameter for the precise positioning of the first erroneous decoded bit under different decoding conditions. Finally, a layered search strategy is adopted to sequentially search the erroneous decoded bits from the low order to high order, which can correct up to multiple bits at the same time. Simulation results show that the proposed algorithm achieves improved error correction performance with a slight increase in decoding complexity compared to the generalized SCL-Flip (GSCLF) decoding algorithm. This algorithm also achieves a good balance between the error correction performance and decoding complexity. [ABSTRACT FROM AUTHOR]

Examines the structure of capsular polysaccharide from Vibrio vulnificus bacterium in strain 6353. Derivation of proton homonuclear coupling constants; Differences in the detailed structure of the polysaccharide; Composition of sugar residues.

Mutations in either the mitochondrial or nuclear genomes can give rise to respiratory chain disease (RCD), a large class of devastating metabolic disorders. Their clinical management is challenging, in part because we lack facile and accurate biomarkers to aid in diagnosis and in the monitoring of disease progression. Here we introduce a sequential strategy that combines biochemical analysis of spent media from cell culture with analysis of patient plasma to identify disease biomarkers. First, we applied global metabolic profiling to spotlight 32 metabolites whose uptake or secretion kinetics were altered by chemical inhibition of the respiratory chain in cultured muscle . These metabolites span a wide range of pathways and include lactate and alanine, which are used clinically as biomarkers of RCD. We next measured the cell culture-defined metabolites in human plasma to discover that creatine is reproducibly elevated in two independent cohorts of RCD patients, exceeding lactate and alanine in magnitude of elevation and statistical significance. In cell culture extracellular creatine was inversely related to the intracellular phosphocreatine:creatine ratio suggesting that the elevation of plasma creatine in RCD patients signals a low energetic state of tissues using the phosphocreatine shuttle. Our study identifies plasma creatine as a potential biomarker of human mitochondrial dysfunction that could be clinically useful. More generally, we illustrate how spent media from cellular models of disease may provide a window into the biochemical derangements in human plasma, an approach that could, in principle, be extended to a range of complex diseases. [ABSTRACT FROM AUTHOR]

Bile acid binding to sevelamer HCl. Background. Clinical studies have shown sevelamer HCl (Renagel®) to be effective for the reduction of serum phosphate in hemodialysis patients. These studies also consistently have demonstrated a significant reduction of low-density lipoprotein (LDL) cholesterol following treatment with sevelamer. Methods. Equilibrium binding of bile acids and oleic acid was determined by incubating sevelamer with ligand containing buffer. Aliquots of the solution were filtered and the free ligand concentrations quantitated by high-pressure liquid chromatography (HPLC). Flow kinetics were determined using a cylindrical flow cell containing trapped sevelamer. Bile acid and oleic acid were pumped through the stirred cell in a manner designed to mimic the in vivo situation. Binding was monitored by HPLC. Results. Sevelamer binds bile acids cooperatively and with high capacity. At low binding densities, the presence of the more hydrophobic bile acids enhances the binding of the less hydrophobic bile acids, and the presence of oleic acid enhances the binding of all bile acids. At saturating oleic acid concentrations, the bile acid binding capacity of sevelamer is reduced by only a factor of two. Moreover, the presence of oleic acid dramatically diminishes the release rate of bile acids from sevelamer. Conclusions. The favorable bile acid binding characteristics of sevelamer provide a compelling explanation for its ability to lower LDL cholesterol in hemodialysis patients and in healthy volunteers. [ABSTRACT FROM AUTHOR]