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

Study of the three-dimensional shape and dynamics of coronal loops observed by Hinode/EIS

We study plasma flows along selected coronal loops in NOAA Active Region 10926, observed on 3 December 2006 with Hinode's EUV Imaging Spectrograph (EIS). From the shape of the loops traced on intensity images and the Doppler shifts measured along their length we compute their three-dimensional (3D) shape and plasma flow velocity using a simple geometrical model. This calculation was performed for loops visible in the Fe VIII 185 Ang., Fe X 184 Ang., Fe XII 195 Ang., Fe XIII 202 Ang., and Fe XV 284 Ang. spectral lines. In most cases the flow is unidirectional from one footpoint to the other but there are also cases of draining motions from the top of the loops to their footpoints. Our results indicate that the same loop may show different flow patterns when observed in different spectral lines, suggesting a dynamically complex rather than a monolithic structure. We have also carried out magnetic extrapolations in the linear force-free field approximation using SOHO/MDI magnetograms, aiming toward a first-order identification of extrapolated magnetic field lines corresponding to the reconstructed loops. In all cases, the best-fit extrapolated lines exhibit left-handed twist (alpha < 0), in agreement with the dominant twist of the region.Comment: 17 pages, 6 figure

Targeted Delivery of Immunomodulators to Lymph Nodes

SUMMARY Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node address in molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo

Soft solar X-rays and solar activity

Minor Hα activity, consisting of small brightenings and small, surgelike spikes, was observed to take place above an active center at the solar limb in good time-association with small fluctuations in the soft X-ray background flux, suggesting that even small dynamical events seen optically are associated with coronal heating. The ratio of Hα flux to soft X-ray flux in some of the surges was approximately the same as the ratio already established for flares. The total energy dissipated by the events in a 24-hour period is estimated; it is approximately equivalent to that released by one flare of imp 1 per day.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43719/1/11207_2004_Article_BF00155785.pd

Abstracts from the NIHR INVOLVE Conference 2017

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Failing to Communicate

Short essay