Structure of the Shroom-Rho Kinase Complex Reveals a Binding Interface with Monomeric Shroom That Regulates Cell Morphology and Stimulates Kinase Activity

Shroom-mediated remodeling of the actomyosin cytoskeleton is a critical driver of cellular shape and tissue morphology that underlies the development of many tissues including the neural tube, eye, intestines, and vasculature. Shroom uses a conserved SD2 domain to direct the subcellular localization of Rho-associated kinase (Rock), which in turn drives changes in the cytoskeleton and cellular morphology through its ability to phosphorylate and activate non-muscle myosin II. Here, we present the structure of the human Shroom-Rock binding module, revealing an unexpected stoichiometry for Shroom in which two Shroom SD2 domains bind independent surfaces on Rock. Mutation of interfacial residues impaired Shroom-Rock binding in vitro and resulted in altered remodeling of the cytoskeleton and loss of Shroom-mediated changes in cellular morphology. Additionally, we provide the first direct evidence that Shroom can function as a Rock activator. These data provide molecular insight into the Shroom-Rock interface and demonstrate that Shroom directly participates in regulating cytoskeletal dynamics, adding to its known role in Rock localization

Comparison of prestellar core elongations and large-scale molecular cloud structures in the Lupus 1 region

Turbulence and magnetic fields are expected to be important for regulating molecular cloud formation and evolution. However, their effects on sub-parsec to 100 parsec scales, leading to the formation of starless cores, are not well understood. We investigate the prestellar core structure morphologies obtained from analysis of the Herschel-SPIRE 350 mum maps of the Lupus I cloud. This distribution is first compared on a statistical basis to the large-scale shape of the main filament. We find the distribution of the elongation position angle of the cores to be consistent with a random distribution, which means no specific orientation of the morphology of the cores is observed with respect to the mean orientation of the large-scale filament in Lupus I, nor relative to a large-scale bent filament model. This distribution is also compared to the mean orientation of the large-scale magnetic fields probed at 350 mum with the Balloon-borne Large Aperture Telescope for Polarimetry during its 2010 campaign. Here again we do not find any correlation between the core morphology distribution and the average orientation of the magnetic fields on parsec scales. Our main conclusion is that the local filament dynamics---including secondary filaments that often run orthogonally to the primary filament---and possibly small-scale variations in the local magnetic field direction, could be the dominant factors for explaining the final orientation of each core

A Spitzer Survey for Dust in Type IIn Supernovae

Recent observations suggest that Type IIn supernovae (SNe IIn) may exhibit late-time (>100 days) infrared (IR) emission from warm dust more than other types of core-collapse SNe. Mid-IR observations, which span the peak of the thermal spectral energy distribution, provide useful constraints on the properties of the dust and, ultimately, the circumstellar environment, explosion mechanism, and progenitor system. Due to the low SN IIn rate (<10% of all core-collapse SNe), few IR observations exist for this subclass. The handful of isolated studies, however, show late-time IR emission from warm dust that, in some cases, extends for five or six years post-discovery. While previous Spitzer/IRAC surveys have searched for dust in SNe, none have targeted the Type IIn subclass. This article presents results from a warm Spitzer/IRAC survey of the positions of all 68 known SNe IIn within a distance of 250 Mpc between 1999 and 2008 that have remained unobserved by Spitzer more than 100 days post-discovery. The detection of late-time emission from ten targets (~15%) nearly doubles the database of existing mid-IR observations of SNe IIn. Although optical spectra show evidence for new dust formation in some cases, the data show that in most cases the likely origin of the mid-IR emission is pre-existing dust, which is continuously heated by optical emission generated by ongoing circumstellar interaction between the forward shock and circumstellar medium. Furthermore, an emerging trend suggests that these SNe decline at ~1000--2000 days post-discovery once the forward shock overruns the dust shell. The mass-loss rates associated with these dust shells are consistent with luminous blue variable (LBV) progenitors.Comment: Accepted for publication to ApJ, 17 pages, 10 figures, 10 table

Structure of a highly conserved domain of rock1 required for shroom-mediated regulation of cell morphology

Rho-associated coiled coil containing protein kinase (Rho-kinase or Rock) is a well-defined determinant of actin organization and dynamics in most animal cells characterized to date. One of the primary effectors of Rock is non-muscle myosin II. Activation of Rock results in increased contractility of myosin II and subsequent changes in actin architecture and cell morphology. The regulation of Rock is thought to occur via autoinhibition of the kinase domain via intramolecular interactions between the N-terminus and the C-terminus of the kinase. This autoinhibited state can be relieved via proteolytic cleavage, binding of lipids to a Pleckstrin Homology domain near the C-terminus, or binding of GTP-bound RhoA to the central coiled-coil region of Rock. Recent work has identified the Shroom family of proteins as an additional regulator of Rock either at the level of cellular distribution or catalytic activity or both. The Shroom-Rock complex is conserved in most animals and is essential for the formation of the neural tube, eye, and gut in vertebrates. To address the mechanism by which Shroom and Rock interact, we have solved the structure of the coiled-coil region of Rock that binds to Shroom proteins. Consistent with other observations, the Shroom binding domain is a parallel coiled-coil dimer. Using biochemical approaches, we have identified a large patch of residues that contribute to Shrm binding. Their orientation suggests that there may be two independent Shrm binding sites on opposing faces of the coiled-coil region of Rock. Finally, we show that the binding surface is essential for Rock colocalization with Shroom and for Shroom-mediated changes in cell morphology. © 2013 Mohan et al

Altered Trabecular Bone Structure and Delayed Cartilage Degeneration in the Knees of Collagen VI Null Mice

Mutation or loss of collagen VI has been linked to a variety of musculoskeletal abnormalities, particularly muscular dystrophies, tissue ossification and/or fibrosis, and hip osteoarthritis. However, the role of collagen VI in bone and cartilage structure and function in the knee is unknown. In this study, we examined the role of collagen VI in the morphology and physical properties of bone and cartilage in the knee joint of Col6a1−/− mice by micro-computed tomography (microCT), histology, atomic force microscopy (AFM), and scanning microphotolysis (SCAMP). Col6a1−/− mice showed significant differences in trabecular bone structure, with lower bone volume, connectivity density, trabecular number, and trabecular thickness but higher structure model index and trabecular separation compared to Col6a1+/+ mice. Subchondral bone thickness and mineral content increased significantly with age in Col6a1+/+ mice, but not in Col6a1−/− mice. Col6a1−/− mice had lower cartilage degradation scores, but developed early, severe osteophytes compared to Col6a1+/+mice. In both groups, cartilage roughness increased with age, but neither the frictional coefficient nor compressive modulus of the cartilage changed with age or genotype, as measured by AFM. Cartilage diffusivity, measured via SCAMP, varied minimally with age or genotype. The absence of type VI collagen has profound effects on knee joint structure and morphometry, yet minimal influences on the physical properties of the cartilage. Together with previous studies showing accelerated hip osteoarthritis in Col6a1−/− mice, these findings suggest different roles for collagen VI at different sites in the body, consistent with clinical data

State of the California Current 2013-14: El Niño Looming

In 2013, the California current was dominated by strong coastal upwelling and high productivity. Indices of total cumulative upwelling for particular coastal locations reached some of the highest values on record. Chlorophyll a levels were high throughout spring and summer. Catches of upwelling-related fish species were also high. After a moderate drop in upwelling during fall 2013, the California current system underwent a major change in phase. Three major basin-scale indicators, the PDO, the NPGO, and the ENSO-MEI, all changed phase at some point during the winter of 2013/14. The PDO changed to positive values, indicative of warmer waters in the North Pacific; the NPGO to negative values, indicative of lower productivity along the coast; and the MEI to positive values, indicative of an oncoming El Niño. Whereas the majority of the California Current system appears to have transitioned to an El Niño state by August 2014, based on decreases in upwelling and chlorophyll a concentration, and increases in SST, there still remained pockets of moderate upwelling, cold water, and high chlorophyll a biomass at various central coast locations, unlike patterns seen during the more major El Niños (e.g., the 97–98 event). Catches of rockfish, market squid, euphausiids, and juvenile sanddab remained high along the central coast, whereas catches of sardine and anchovy were low throughout the CCS. 2014 appears to be heading towards a moderate El Niño state, with some remaining patchy regions of upwelling-driven productivity along the coast. Superimposed on this pattern, three major regions have experienced possibly non-El Niño-related warming since winter: the Bering Sea, the Gulf of Alaska, and offshore of southern California. It is unclear how this warming may interact with the predicted El Niño, but the result will likely be reduced growth or reproduction for many key fisheries species

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements