Drug and Alcohol Rehabilitation: The First Structure of Polarity Suppression Protein, Psu From Enterobacteria Phage P4, Reveals a Novel Fold and a Knotted Dimer.

The first structure of Polarity Suppression protein, Psu from Enterobacteria phage P4, reveals a novel fold and a knotted dimer.

Filed under: Drug and Alcohol Rehabilitation

J Biol Chem. 2012 Nov 12;
Banerjee R, Nath S, Ranjan A, Khamrui S, Pani B, Sen R, Sen U

Psu is a capsid decoration protein of bacteriophage P4 and acts as an antiterminator of Rho-dependent transcription termination in bacteria. So far, no structures have been reported for the Psu protein or its homologues. Here we report the first structure of Psu solved by Hg-SAD method, which reveals that Psu exists as a knotted homodimer and is first of its kind in nature. Each monomer of Psu attains a novel fold around a tight coiled-coil motif. CD spectroscopy and the structure of an engineered disulphide-bridged Psu derivative reveal that the protein folds reversibly and re-assembles by itself into the knotted dimeric conformation without the requirement of any chaperone. This structure would help to explain the functional properties of the protein and can be used as a template to design a minimal peptide fragment that can be used as a drug against Rho dependent transcription termination in bacteria.
HubMed – drug


Assembly of subtype 1 influenza neuraminidase is driven by both the transmembrane and head domains.

Filed under: Drug and Alcohol Rehabilitation

J Biol Chem. 2012 Nov 13;
da Silva DV, Nordholm J, Madjo U, Pfeiffer A, Daniels R

Neuraminidase (NA) is one of the two major influenza surface antigens and the main influenza drug target. Although NA has been well-characterized and thought to function as a tetramer, the role of the transmembrane domain (TMD) in promoting proper NA assembly has not been systematically studied. Here, we demonstrate that in the absence of the TMD, NA is synthesized and transported in a predominantly inactive state. Substantial activity was rescued by progressive truncations of the stalk domain suggesting the TMD contributes to NA maturation by tethering the stalk to the membrane. To analyze how the TMD supports NA assembly, the TMD was examined by itself. The NA TMD formed a homo-tetramer and efficiently trafficked to the plasma membrane indicating the TMD and enzymatic head domain drive assembly together through matching oligomeric states. In support of this, an unrelated strong oligomeric TMD rescued almost full NA activity, whereas the weak oligomeric mutant of this TMD restored only half of wild type activity. These data illustrate that a large soluble domain can force assembly with a poorly compatible TMD, however optimal assembly requires coordinated oligomerization between the TMD and the soluble domain.
HubMed – drug


Resource Use and Cost Implications of Switching Among Warfarin Formulations in Atrial Fibrillation Patients (December).

Filed under: Drug and Alcohol Rehabilitation

Ann Pharmacother. 2012 Nov 13;
Kwong WJ, Kamat S, Fang C

BACKGROUND:Despite the uncertainty surrounding the safety of switching warfarin formulations, limited data exist on the resource use and costs associated with this switching pattern.OBJECTIVE:To evaluate health care resource use and costs associated with switching warfarin formulations among patients with atrial fibrillation (AF) in a managed care organization.METHODS:Patients diagnosed with AF (ICD-9 427.31) between July 2004 and August 2008 and who received warfarin therapy were identified in the HealthCore Integrated Research Database and categorized into 3 groups: users of generic warfarin formulations from a single drug manufacturer (generic-only group), users of branded warfarin formulations only (brand-only group), and patients who used generic and branded warfarin therapy interchangeably or who may have used generic drugs from 1 or more manufacturers (generic/brand switching group). Patients were followed 12 months or longer after their index warfarin prescription date to compare all-cause resource use and costs using multivariable regression analysis.RESULTS:The analysis included 12,908 patients: 71.82% were in the generic-only group, 9.61% were in the brand-only group, and 18.57% were in the generic/brand switching group. Patients in the generic/brand switching group were more likely to be hospitalized (relative risk [RR] = 1.43, p < 0.0001) or to use emergency department services (RR = 1.20, p < 0.01), compared to the brand-only users. Hospitalizations were more likely (RR = 1.26, p < 0.001) to occur among generic-only users versus brand-only users. Adjusted mean pharmacy costs per member per month were lower in the generic/brand switching group compared to the brand-only group ($ 257 vs $ 273, p = 0.038), but inpatient costs were higher ($ 1250 vs $ 972, p < 0.001), resulting in higher ($ 2125 vs $ 1847, p < 0.001) total costs. Generic-only users had lower pharmacy costs compared to brand-only users ($ 246 vs $ 273, p < 0.001), but total health care costs trended to be higher in the generic-only group ($ 1957 vs $ 1847, p = 0.053).CONCLUSIONS:The use of both generic and branded formulations of warfarin interchangeably, or the use of generics from more than 1 manufacturer, was associated with increased use of all-cause health care resources and total costs in patients with AF. HubMed – drug


Bioinspired multivalent DNA network for capture and release of cells.

Filed under: Drug and Alcohol Rehabilitation

Proc Natl Acad Sci U S A. 2012 Nov 12;
Zhao W, Cui CH, Bose S, Guo D, Shen C, Wong WP, Halvorsen K, Farokhzad OC, Teo GS, Phillips JA, Dorfman DM, Karnik R, Karp JM

Capture and isolation of flowing cells and particulates from body fluids has enormous implications in diagnosis, monitoring, and drug testing, yet monovalent adhesion molecules used for this purpose result in inefficient cell capture and difficulty in retrieving the captured cells. Inspired by marine creatures that present long tentacles containing multiple adhesive domains to effectively capture flowing food particulates, we developed a platform approach to capture and isolate cells using a 3D DNA network comprising repeating adhesive aptamer domains that extend over tens of micrometers into the solution. The DNA network was synthesized from a microfluidic surface by rolling circle amplification where critical parameters, including DNA graft density, length, and sequence, could readily be tailored. Using an aptamer that binds to protein tyrosine kinase-7 (PTK7) that is overexpressed on many human cancer cells, we demonstrate that the 3D DNA network significantly enhances the capture efficiency of lymphoblast CCRF-CEM cells over monovalent aptamers and antibodies, yet maintains a high purity of the captured cells. When incorporated in a herringbone microfluidic device, the 3D DNA network not only possessed significantly higher capture efficiency than monovalent aptamers and antibodies, but also outperformed previously reported cell-capture microfluidic devices at high flow rates. This work suggests that 3D DNA networks may have broad implications for detection and isolation of cells and other bioparticles.
HubMed – drug


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