Discovery of Small-Molecule Modulators of the Sonic Hedgehog Pathway

The Hedgehog signaling pathway is involved in the development of multicellular organisms and, when deregulated, can contribute to certain cancers, among other diseases. The molecular characterization of the pathway, which has been enabled by small-molecule probes targeting its components, remains incomplete. Here, we report the discovery of two potent, small-molecule inhibitors of the Sonic Hedgehog (Shh) pathway, BRD50837 and BRD9526. Both compounds exhibit stereochemistry-based structure–activity relationships, a feature suggestive of a specific and selective interaction of the compounds with as-yet-unknown cellular target(s) and made possible by the strategy used to synthesize them as members of a stereochemically and skeletally diverse screening collection. The mechanism-of-action of these compounds in some ways shares similarities to that of cyclopamine, a commonly used pathway inhibitor. Yet, in other ways their mechanism-of-action is strikingly distinct. We hope that these novel compounds will be useful probes of this complex signaling pathway

The Bailey chain and mock theta functions

Standard applications of the Bailey chain preserve mixed mock modularity but not mock modularity. After illustrating this with some examples, we show how to use a change of base in Bailey pairs due to Bressoud, Ismail and Stanton to explicitly construct families of q-hypergeometric multisums which are mock theta functions. We also prove identities involving some of these multisums and certain classical mock theta functions.Comment: 17 pages, to appear in Advances in Mathematic

Evolution of a Canada Basin ice-ocean boundary layer and mixed layer across a developing thermodynamically forced marginal ice zone

A comprehensive set of autonomous, ice-ocean measurements were collected across the Canada Basin to study the summer evolution of the ice-ocean boundary layer (IOBL) and ocean mixed layer (OML). Evaluation of local heat and freshwater balances and associated turbulent forcing reveals that melt ponds (MPs) strongly influence the summer IOBL-OML evolution. Areal expansion of MPs in mid-June start the upper ocean evolution resulting in significant increases to ocean absorbed radiative flux (19 W m−2 in this study). Buoyancy provided by MP drainage shoals and freshens the IOBL resulting in a 39 MJ m−2 increase in heat storage in just 19 days (52% of the summer total). Following MP drainage, a near-surface fresh layer deepens through shear-forced mixing to form the summer mixed layer (sML). In late summer, basal melt increases due to stronger turbulent mixing in the thin sML and the expansion of open water areas due in part to wind-forced divergence of the sea ice. Thermal heterogeneities in the marginal ice zone (MIZ) upper ocean led to large ocean-to-ice heat fluxes (100–200 W m−2) and enhanced basal ice melt (3–6 cm d−1), well away from the ice edge. Calculation of the upper ocean heat budget shows that local radiative heat input accounted for at least 89% of the observed latent heat losses and heat storage (partitioned 0.77/0.23). These results suggest that the extensive area of deteriorating sea ice observed away from the ice edge during the 2014 season, termed the “thermodynamically forced MIZ,” was driven primarily by local shortwave radiative forcing

Expression levels of glycoprotein O (gO) vary between strains of human cytomegalovirus, influencing the assembly of gH/gL complexes and virion infectivity

Tropism of human cytomegalovirus (HCMV) is influenced by the envelope glycoprotein complexes gH/gL/gO and gH/gL/UL128-131. During virion assembly, gO and the UL128-131 proteins compete for binding to gH/gL in the ER. This assembly process clearly differs among strains since Merlin (ME) virions contain abundant gH/gL/UL128-131 and little gH/gL/gO, whereas TR contains much higher levels of total gH/gL, mostly in the form of gH/gL/gO, but much less gH/gL/UL128-131 than ME. Remaining questions include 1) what are the mechanisms behind these assembly differences, and 2) do differences reflect in vitro culture adaptations or natural genetic variations? Since the UL74(gO) ORF differs by 25% of amino acids between TR and ME, we analyzed recombinant viruses in which the UL74(gO) ORF was swapped. TR virions were >40-fold more infectious than ME. Transcriptional repression of UL128-131 enhanced infectivity of ME to the level of TR, despite still far lower levels of gH/gL/gO. Swapping the UL74(gO) ORF had no effect on either TR or ME. A quantitative immunoprecipitation approach revealed that gH/gL expression was within 4-fold between TR and ME, but gO expression was 20-fold less by ME, and suggested differences in mRNA transcription, translation or rapid ER-associated degradation of gO. Trans-complementation of gO expression during ME replication gave 6-fold enhancement of infectivity beyond the 40-fold effect of UL128-131 repression alone. Overall, strain variations in assembly of gH/gL complexes result from differences in expression of gO and UL128-131, and selective advantages for reduced UL128-131 expression during fibroblast propagation are much stronger than for higher gO expression

Emerging Technologies and Approaches for In Situ, Autonomous Observing in the Arctic

Understanding and predicting Arctic change and its impacts on global climate requires broad, sustained observations of the atmosphere-ice-ocean system, yet technological and logistical challenges severely restrict the temporal and spatial scope of observing efforts. Satellite remote sensing provides unprecedented, pan-Arctic measurements of the surface, but complementary in situ observations are required to complete the picture. Over the past few decades, a diverse range of autonomous platforms have been developed to make broad, sustained observations of the ice-free ocean, often with near-real-time data delivery. Though these technologies are well suited to the difficult environmental conditions and remote logistics that complicate Arctic observing, they face a suite of additional challenges, such as limited access to satellite services that make geolocation and communication possible. This paper reviews new platform and sensor developments, adaptations of mature technologies, and approaches for their use, placed within the framework of Arctic Ocean observing needs

Winter-to-summer transition of Arctic sea ice breakup and floe size distribution in the Beaufort Sea

Breakup of the near-continuous winter sea ice into discrete summer ice floes is an important transition that dictates the evolution and fate of the marginal ice zone (MIZ) of the Arctic Ocean. During the winter of 2014, more than 50 autonomous drifting buoys were deployed in four separate clusters on the sea ice in the Beaufort Sea, as part of the Office of Naval Research MIZ program. These systems measured the ocean-ice-atmosphere properties at their location whilst the sea ice parameters in the surrounding area of these buoy clusters were continuously monitored by satellite TerraSAR-X Synthetic Aperture Radar. This approach provided a unique Lagrangian view of the winter-to-summer transition of sea ice breakup and floe size distribution at each cluster between March and August. The results show the critical timings of a) temporary breakup of winter sea ice coinciding with strong wind events and b) spring breakup (during surface melt, melt ponding and drainage) leading to distinctive summer ice floes. Importantly our results suggest that summer sea ice floe distribution is potentially affected by the state of winter sea ice, including the composition and fracturing (caused by deformation events) of winter sea ice, and that substantial mid-summer breakup of sea ice floes is likely linked to the timing of thermodynamic melt of sea ice in the area. As the rate of deformation and thermodynamic melt of sea ice has been increasing in the MIZ in the Beaufort Sea, our results suggest that these elevated factors would promote faster and more enhanced breakup of sea ice, leading to a higher melt rate of sea ice and thus a more rapid advance of the summer MIZ

Emerging Technologies and Approaches for In Situ, Autonomous Observing in the Arctic

Understanding and predicting Arctic change and its impacts on global climate requires broad, sustained observations of the atmosphere-ice-ocean system, yet technological and logistical challenges severely restrict the temporal and spatial scope of observing efforts. Satellite remote sensing provides unprecedented, pan-Arctic measurements of the surface, but complementary in situ observations are required to complete the picture. Over the past few decades, a diverse range of autonomous platforms have been developed to make broad, sustained observations of the ice-free ocean, often with near-real-time data delivery. Though these technologies are well suited to the difficult environmental conditions and remote logistics that complicate Arctic observing, they face a suite of additional challenges, such as limited access to satellite services that make geolocation and communication possible. This paper reviews new platform and sensor developments, adaptations of mature technologies, and approaches for their use, placed within the framework of Arctic Ocean observing needs

Ice and ocean velocity in the Arctic marginal ice zone: Ice roughness and momentum transfer

The interplay between sea ice concentration, sea ice roughness, ocean stratification, and momentum transfer to the ice and ocean is subject to seasonal and decadal variations that are crucial to understanding the present and future air-ice-ocean system in the Arctic. In this study, continuous observations in the Canada Basin from March through December 2014 were used to investigate spatial differences and temporal changes in under-ice roughness and momentum transfer as the ice cover evolved seasonally. Observations of wind, ice, and ocean properties from four clusters of drifting instrument systems were complemented by direct drill-hole measurements and instrumented overhead flights by NASA operation IceBridge in March, as well as satellite remote sensing imagery about the instrument clusters. Spatially, directly estimated ice-ocean drag coefficients varied by a factor of three with rougher ice associated with smaller multi-year ice floe sizes embedded within the first-year-ice/multi-year-ice conglomerate. Temporal differences in the ice-ocean drag coefficient of 20–30% were observed prior to the mixed layer shoaling in summer and were associated with ice concentrations falling below 100%. The ice-ocean drag coefficient parameterization was found to be invalid in September with low ice concentrations and small ice floe sizes. Maximum momentum transfer to the ice occurred for moderate ice concentrations, and transfer to the ocean for the lowest ice concentrations and shallowest stratification. Wind work and ocean work on the ice were the dominant terms in the kinetic energy budget of the ice throughout the melt season, consistent with free drift conditions. Overall, ice topography, ice concentration, and the shallow summer mixed layer all influenced mixed layer currents and the transfer of momentum within the air-ice-ocean system. The observed changes in momentum transfer show that care must be taken to determine appropriate parameterizations of momentum transfer, and imply that the future Arctic system could become increasingly seasonal