Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo

An Overview of the Semi-Span Super-Sonic Transport (S4T) Wind-Tunnel Model Program

A summary of computational and experimental aeroelastic (AE) and aeroservoelastic (ASE) results for the Semi-Span Super-Sonic Transport (S4T) wind-tunnel model is presented. A broad range of analyses and multiple AE and ASE wind-tunnel tests of the S4T wind-tunnel model have been performed in support of the ASE element in the Supersonics Program, part of the NASA Fundamental Aeronautics Program. This paper is intended to be an overview of multiple papers that comprise a special S4T technical session. Along those lines, a brief description of the design and hardware of the S4T wind-tunnel model will be presented. Computational results presented include linear and nonlinear aeroelastic analyses, and rapid aeroelastic analyses using CFD-based reduced-order models (ROMs). A brief survey of some of the experimental results from two open-loop and two closed-loop wind-tunnel tests performed at the NASA Langley Transonic Dynamics Tunnel (TDT) will be presented as well

Cytomegalovirus and polyomavirus BK posttransplant

Virus replication and progression to disease in transplant patients is determined by patient-, graft- and virus-specific factors. This complex interaction is modulated by the net state of immunosuppression and its impact on virus-specific cellular immunity. Due to the increasing potency of immunosuppressive regimens, graft rejections have decreased, but susceptibility to infections has increased. Therefore, cytomegalovirus (CMV) remains the most important viral pathogen posttransplant despite availability of effective antiviral drugs and validated strategies for prophylactic, preemptive and therapeutic intervention. CMV replication can affect almost every organ system, with frequent recurrences and increasing rates of antiviral resistance. Together with indirect long-term effects, CMV significantly reduces graft and patient survival after solid organ and hematopoietic stem cell transplantation. The human polyomavirus called BK virus (BKV), on the other hand, only recently surfaced as pathogen with organ tropism largely limited to the reno-urinary tract, manifesting as polyomavirus-associated nephropathy in kidney transplant and hemorrhagic cystitis in hematopoetic stem cell transplant patients. No licensed anti-polyoma viral drugs are available, and treatment relies mainly on improving immune functions to regain control over BKV replication. In this review, we discuss diagnostic and therapeutic aspects of CMV and BKV replication and disease posttransplantatio

Biophysical Characterization of Fluorotyrosine Probes Site-Specifically Incorporated into Enzymes:

Fluorinated tyrosines (F[subscript n]Y's, n = 2 and 3) have been site-specifically incorporated into E. coli class Ia ribonucleotide reductase (RNR) using the recently evolved M. jannaschii Y-tRNA synthetase/tRNA pair. Class Ia RNRs require four redox active Y's, a stable Y radical (Y·) in the β subunit (position 122 in E. coli), and three transiently oxidized Y's (356 in β and 731 and 730 in α) to initiate the radical-dependent nucleotide reduction process. F[subscript n]Y (3,5; 2,3; 2,3,5; and 2,3,6) incorporation in place of Y₁₂₂-β and the X-ray structures of each resulting β with a diferric cluster are reported and compared with wt-β2 crystallized under the same conditions. The essential diferric-F[subscript n]Y· cofactor is self-assembled from apo F[subscript n]Y-β2, Fe ²⁺, and O₂ to produce ∼1 Y·/β2 and ∼3 Fe ³⁺ /β2. The F[subscript n]Y· are stable and active in nucleotide reduction with activities that vary from 5% to 85% that of wt-β2. Each F[subscript n] Y·-β2 has been characterized by 9 and 130 GHz electron paramagnetic resonance and high-field electron nuclear double resonance spectroscopies. The hyperfine interactions associated with the 19 F nucleus provide unique signatures of each F[subscript n]Y· that are readily distinguishable from unlabeled Y·'s. The variability of the abiotic F[subscript n]Y pK a 's (6.4 to 7.8) and reduction potentials (-30 to +130 mV relative to Y at pH 7.5) provide probes of enzymatic reactions proposed to involve Y·'s in catalysis and to investigate the importance and identity of hopping Y·'s within redox active proteins proposed to protect them from uncoupled radical chemistry.National Institutes of Health (U.S.) (Grant GM29595)National Science Foundation (U.S.) (Grant 0645960

Explorations into the Psyche of Dwarves

An attempt to explain the characters of the roles played by, and the major reasons for the creation of, Dwarves as presented in Tolkien’s three major works of fiction concerning Middle-earth. The argument is heavily biased in favour of Dwarves’ indispensability