Outcomes Associated With Microalbuminuria: Effect Modificatin By Chronic Kidney Disease.

OBJECTIVES: To compare association of microalbuminuria with outcomes in patients with different comorbidities. BACKGROUND: The risk of adverse outcomes associated with proteinuria has been found to be linearly decreasing with even low-normal levels of microalbuminuria. It is unclear if comorbid conditions change these associations. METHODS: We examined the association of urine microalbumin-creatinine ratio (UACR) with mortality and the slopes of estimated glomerular filtration rate (eGFR) in a nationally representative cohort of 298,875 US veterans. Associations of UACR with all-cause mortality overall and in subgroups of patients with and without diabetes, hypertension, cardiovascular disease, congestive heart failure and advanced CKD were examined in Cox models, and with the slopes of eGFR in linear and logistic regression models. RESULTS: Very low levels of UACR were linearly associated with decreased mortality and less progression of CKD overall: adjusted mortality hazard ratio and estimated glomerular filtration rate slope (95%CI) associated with UACR =200, compared to <5 mcg/mg were 1.53 (1.38-1.69, p<0.001) and -1.59 (-1.83, -1.35, p<0.001). Similar linearity was present in all examined subgroups, except in patients with CKD in whom a U-shaped association was present and in whom a UACR of 10-19 was associated with the best outcomes. CONCLUSIONS: The association of UACR with mortality and with progressive CKD is modified in patients with CKD, who experience higher mortality and worse progression of CKD with the lowest levels of UACR. Proteinuria-lowering interventions in patients with advanced CKD should be implemented cautiously, considering the potential for adverse outcomes

The search for the ideal biocatalyst

While the use of enzymes as biocatalysts to assist in the industrial manufacture of fine chemicals and pharmaceuticals has enormous potential, application is frequently limited by evolution-led catalyst traits. The advent of designer biocatalysts, produced by informed selection and mutation through recombinant DNA technology, enables production of process-compatible enzymes. However, to fully realize the potential of designer enzymes in industrial applications, it will be necessary to tailor catalyst properties so that they are optimal not only for a given reaction but also in the context of the industrial process in which the enzyme is applied

A Generic Program for Multistate Protein Design

Some protein design tasks cannot be modeled by the traditional single state design strategy of finding a sequence that is optimal for a single fixed backbone. Such cases require multistate design, where a single sequence is threaded onto multiple backbones (states) and evaluated for its strengths and weaknesses on each backbone. For example, to design a protein that can switch between two specific conformations, it is necessary to to find a sequence that is compatible with both backbone conformations. We present in this paper a generic implementation of multistate design that is suited for a wide range of protein design tasks and demonstrate in silico its capabilities at two design tasks: one of redesigning an obligate homodimer into an obligate heterodimer such that the new monomers would not homodimerize, and one of redesigning a promiscuous interface to bind to only a single partner and to no longer bind the rest of its partners. Both tasks contained negative design in that multistate design was asked to find sequences that would produce high energies for several of the states being modeled. Success at negative design was assessed by computationally redocking the undesired protein-pair interactions; we found that multistate design's accuracy improved as the diversity of conformations for the undesired protein-pair interactions increased. The paper concludes with a discussion of the pitfalls of negative design, which has proven considerably more challenging than positive design