1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors

A Subdomain Method for Mapping the Heterogeneous Mechanical Properties of the Human Posterior Sclera

Although strongly correlated with elevated intraocular pressure, primary open-angle glaucoma (POAG) occurs in normotensive eyes. Mechanical properties of the sclera around the optic nerve head (ONH) may play a role in this disparity. The purpose of this study is to present an automated inverse mechanics based approach to determine the distribution of heterogeneous mechanical properties of the human sclera as derived from its surface deformations arising from pressure in fl ation experiments. The scleral shell of a 78 year old European Descent male donor eye was utilized to demonstrate the method; the sclera was coated with a speckle pattern on the outer surface and was subjected to in fl ation pressures of 5, 15, 30, and 45 mmHg. The speckle pattern was imaged at each pressure, and a displacement fi eld was calculated for each pressure step using a previously described sequential digital image correlation(S-DIC) technique. The fiber splay and fiber orientation of the sclera collagen were determined experimentally, and the thickness across the scleral globe was determined using micro CT images. The displacement fi eld from the in fl ation test was used to calculate the strain and also used as an input for inverse mechanics to determine the heterogeneity of material properties. The scleral geometry was divided into subdomains using the first principal strain. The Holzapfel anisotropic material parameters of matrix and fiber stiffness were estimated within each individual subdomain using an inverse mechanics approach by minimizing the sum of the square of the residuals between the computational and experimental displacement fields. The mean and maximum error in displacement across all subdomains were 8.9 +/- 3.0 mu m and 13.2 mu m, respectively. The full pressure-inflation forwardmechanics experiment was done using subdomain-specific mechanical properties on the entire scleral surface. The proposed approach is effective in determining the distribution of heterogeneous mechanical properties of the human sclera in a user-independent manner. Our research group is currently utilizing this approach to better elucidate how scleral stiffness influences those at high risk for POAG.National Eye Institute of the National Institutes of Health (NIH) [R01EY020890, R01FD006582]; University of Pittsburgh Center for Research Computing (CRC); Pittsburgh Supercomputer Center through NSF-XSEDE award [TG-ENG160035]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Lava channel formation during the 2001 eruption on Mount Etna: evidence for mechanical erosion

We report the direct observation of a peculiar lava channel that was formed near the base of a parasitic cone during the 2001 eruption on Mount Etna. Erosive processes by flowing lava are commonly attributed to thermal erosion. However, field evidence strongly suggests that models of thermal erosion cannot explain the formation of this channel. Here, we put forward the idea that the essential erosion mechanism was abrasive wear. By applying a simple model from tribology we demonstrate that the available data agree favorably with our hypothesis. Consequently, we propose that erosional processes resembling the wear phenomena in glacial erosion are possible in a volcanic environment.Comment: accepted for publication in Physical Review Letter

Radar-derived bed roughness characterization of Institute and Möller ice streams, West Antarctica, and comparison with Siple Coast ice streams

Subglacial bed conditions exert a significant control on ice stream behavior and evolution, and can be characterized by determining bed roughness from FFT analysis of radar-imaged basal reflectors. Here we assess bed roughness across Institute and Moller ice streams, West Antarctica, and compare our findings with bed roughness determined across the Siple Coast ice streams. We find that variations in bed roughness are spatially organized, and attribute this to the varying efficacy of subglacial erosion and deposition, with rougher (inland, slow-flowing) regions largely manifesting preglacial topography, and smoother (downstream, fast-flowing) regions evincing significant postglacial modification to the subglacial landscape. The observed similarities between bed roughness characteristics of IIS/MIS and the Siple ice streams suggest that IIS and MIS are largely underlain by wet, poorly consolidated sediments, and may therefore be vulnerable to the types of dynamical instabilities experienced by the Siple ice streams

Formation of Structure in Snowfields: Penitentes, Suncups, and Dirt Cones

Penitentes and suncups are structures formed as snow melts, typically high in the mountains. When the snow is dirty, dirt cones and other structures can form instead. Building on previous field observations and experiments, this work presents a theory of ablation morphologies, and the role of surface dirt in determining the structures formed. The glaciological literature indicates that sunlight, heating from air, and dirt all play a role in the formation of structure on an ablating snow surface. The present work formulates a mathematical model for the formation of ablation morphologies as a function of measurable parameters. The dependence of ablation morphologies on weather conditions and initial dirt thickness are studied, focusing on the initial growth of perturbations away from a flat surface. We derive a single-parameter expression for the melting rate as a function of dirt thickness, which agrees well with a set of measurements by Driedger. An interesting result is the prediction of a dirt-induced travelling instability for a range of parameters.Comment: 28 pages, 13 figure

Textural variations in Neogene pelagic carbonate ooze at DSDP Site 593, southern Tasman Sea, and their paleoceanographic implications

Changes in Neogene sediment texture in pelagic carbonate-rich oozes on the Challenger Plateau, southern Tasman Sea, are used to infer changes in depositional paleocurrent velocities. The most obvious record of textural change is in the mud:sand ratio. Increases in the sand content are inferred to indicate a general up-core trend towards increasing winnowing of sediments resulting from increasing flow velocity of Southern Component Intermediate Water (SCIW), the forerunner of Antarctic Intermediate Water. In particular, the intervals c. 19-14.5 Ma, c. 9.5-8 Ma, and after 5 Ma are suggested to be times of increased SCIW velocity and strong sediment winnowing. Within the mud fraction, the fine silt to coarse clay sizes from 15.6 to 2 µm make the greatest contribution to the sediments and are composed of nannofossil plates. During extreme winnowing events it is the fine silt to very coarse clay material (13-3 µm) within this range that is preferentially removed, suggesting the 10 µm cohesive silt boundary reported for siliciclastic sediments does not apply to calcitic skeletal grains. The winnowed sediment comprises coccolithophore placoliths and spheres, represented by a mode at 4-7 µm. Further support for seafloor winnowing is gained from the presence in Hole 593 of a condensed sedimentary section from c. 18 to 14 Ma where the sand content increases to c. 20% of the bulk sample. Associated with the condensed section is a 6 m thick orange unit representing sediments subjected to particularly oxygen-rich, late early to early middle Miocene SCIW. Together these are inferred to indicate increased SCIW velocity resulting in winnowed sediment associated with faster arrival of oxygen-rich surface water subducted to form SCIW. Glacial development of Antarctica has been recorded from many deep-sea sites, with extreme glacials providing the mechanism to increase watermass flow. Miocene glacial zones Mi1b-Mi6 are identified in an associated oxygen isotope record from Hole 593, and correspond with times of particularly invigorated paleocirculation, bottom winnowing, and sediment textural changes