The Same As His Faither Did Before Him

https://digitalcommons.library.umaine.edu/mmb-vp/4767/thumbnail.jp

Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor.

Signaling through growth factor receptors controls such diverse cell functions as proliferation, migration, and differentiation. A critical question has been how the activation of these receptors is regulated. Most, if not all, of the known ligands for these receptors are soluble factors. However, as matrix components are highly tissue-specific and change during development and pathology, it has been suggested that select growth factor receptors might be stimulated by binding to matrix components. Herein, we describe a new class of ligand for the epidermal growth factor (EGF) receptor (EGFR) found within the EGF-like repeats of tenascin-C, an antiadhesive matrix component present during organogenesis, development, and wound repair. Select EGF-like repeats of tenascin-C elicited mitogenesis and EGFR autophosphorylation in an EGFR-dependent manner. Micromolar concentrations of EGF-like repeats induced EGFR autophosphorylation and activated extracellular signal-regulated, mitogen-activated protein kinase to levels comparable to those induced by subsaturating levels of known EGFR ligands. EGFR-dependent adhesion was noted when the ligands were tethered to inert beads, simulating the physiologically relevant presentation of tenascin-C as hexabrachion, and suggesting an increase in avidity similar to that seen for integrin ligands upon surface binding. Specific binding to EGFR was further established by immunofluorescence detection of EGF-like repeats bound to cells and cross-linking of EGFR with the repeats. Both of these interactions were abolished upon competition by EGF and enhanced by dimerization of the EGF-like repeat. Such low affinity behavior would be expected for a matrix-tethered ligand; i.e., a ligand which acts from the matrix, presented continuously to cell surface EGF receptors, because it can neither diffuse away nor be internalized and degraded. These data identify a new class of insoluble growth factor ligands and a novel mode of activation for growth factor receptors

How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse

Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model

Management of the Post-Shuttle Extravehicular Mobility Unit (EMU) Water Circuits

The EMU incorporates two separate water circuits for the rejection of metabolic heat from the astronaut and the cooling of electrical components. The first (the Transport Water Loop) circulates in a semi-closed-loop manner and absorbs heat into a Liquid Coolant and Ventilation Garment (LCVG) warn by the astronaut. The second (the Feed Water Loop) provides water to a cooling device (Sublimator) with a porous plate, and that water subsequently sublimates to space vacuum. The cooling effect from the sublimation of this water translates to a cooling of the LCVG water that circulates through the Sublimator. Efforts are underway to streamline the use of a water processing kit (ALCLR) that is being used to periodically clean and disinfect the Transport Loop Water. Those efforts include a fine tuning of the duty cycle based on a review of prior performance data as well as an assessment of a fixed installation of this kit into the EMU backpack or within on-orbit EMU interface hardware. Furthermore, testing is being conducted to ensure compatibility between the International Space Station (ISS) Water Processor Assembly (WPA) effluent and the EMU Sublimator as a prelude to using the WPA effluent as influent to the EMU Feed Water loop. This work is undertaken to reduce the crew-time and logistics burdens for the EMU, while ensuring the long-term health of the EMU water circuits for a post-Shuttle 6-year service life

Laserprobe 40Ar/39Ar dating of strain fringes: Mid-Cretaceous synconvergent orogen-parallel extension in the interior of the Sevier orogen

[1] UV and CO2 laser-probe 40Ar/39Ar in situ analyses of phlogopite and muscovite in fibrous strain fringes from greenschist-facies metamorphic rocks document mica growth ages at temperatures lower than their closure temperatures, and therefore directly date deformation. The new dates resolve the age of the earliest ductile fabric recorded in the Raft River–Albion–Grouse Creek metamorphic core complex of Utah and Idaho. Phlogopite was dated in quartz-calcite-phlogopite strain fringes around pyrite in Pennsylvanian-Permian rocks from the Grouse Creek Mountains (Utah) using both the UV and CO2 laser probe; muscovite was dated in quartz-muscovite strain fringes around pyrite in deformed Jurassic sills from the Black Pine Mountains (Idaho) using the CO2 laser probe. Phlogopite 40Ar/39Ar ages for individual strain fringes (Grouse Creek Mountains) range from 92 Ma to 110 Ma, with the most reliable ages ranging from 101 Ma to 110 Ma (mean age, 105.0 ± 5.8 Ma). Muscovite 40Ar/39Ar ages for individual strain fringes (Black Pine Mountains) range from 97 Ma to 112 Ma (mean age, 104.7 ± 5.8 Ma). Strain fringes are associated with a subhorizontal foliation and a generally N-trending elongation lineation exhibiting components of top-to-the-north simple shear and coaxial strain accommodating N-S extension and subvertical shortening. Midcrustal northward flow at 105 (±6) Ma within the interior of the Sevier orogen, coeval with east-directed shortening in the foreland and with plate convergence, records orogen-parallel synconvergent extension. We favor gravitational relaxation of structural culminations resulting from focused crustal shortening as a driving mechanism for orogen-parallel flow

A quantitative assessment of the amount of prion diverted to category 1 materials and wastewater during processing

In this article the development and parameterization of a quantitative assessment is described that estimates the amount of TSE infectivity that is present in a whole animal carcass (bovine spongiform encephalopathy [BSE] for cattle and classical/atypical scrapie for sheep and lambs) and the amounts that subsequently fall to the floor during processing at facilities that handle specified risk material (SRM). BSE in cattle was found to contain the most oral doses, with a mean of 9864 BO ID50s (310, 38840) in a whole carcass compared to a mean of 1851 OO ID50s (600, 4070) and 614 OO ID50s (155, 1509) for a sheep infected with classical and atypical scrapie, respectively. Lambs contained the least infectivity with a mean of 251 OO ID50s (83, 548) for classical scrapie and 1 OO ID50s (0.2, 2) for atypical scrapie. The highest amounts of infectivity falling to the floor and entering the drains from slaughtering a whole carcass at SRM facilities were found to be from cattle infected with BSE at rendering and large incineration facilities with 7.4 BO ID50s (0.1, 29), intermediate plants and small incinerators with a mean of 4.5 BO ID50s (0.1, 18), and collection centers, 3.6 BO ID50s (0.1, 14). The lowest amounts entering drains are from lambs infected with classical and atypical scrapie at intermediate plants and atypical scrapie at collection centers with a mean of 3 × 10−7 OO ID50s (2 × 10−8, 1 × 10−6) per carcass. The results of this model provide key inputs for the model in the companion paper published here

Isolation of YAC Clones From the Pericentromeric Region of Chromosome 10 and Development of New Genetic Markers Linked to the Multiple Endocrine Neoplasia Type 2A Gene

Genetic linkage mapping and contig assembly using yeast artificial chromosome (YAC) technology form the basis of our strategy to clone and define the genomic structure of the pericentromeric region of chromosome 10 containing the multiple endocrine neoplasia type 2A gene. Thus far YAC walks have been initiated from five chromosome 10 pericentromeric loci including RBP3, D10S94, RET, D10Z1, and FNRB. Long range pulsed-field gel electrophoresis maps are constructed from the YACs isolated to define clone overlaps and to identify putative CpG islands. Bidirectional YAC walks are continued by rescreening the YAC library with sequence-tagged site assays developed from endclones. Several new restriction fragment length polymorphisms and simple sequence repeat polymorphism markers have been identified from the YAC clones. In particular, two highly informative (CA)n dinucleotide repeat markers, sTCL-1 from proximal chromosome 10p (16 alleles, PIC = 0.68) and sJRH-1 from the RBP3 locus (18 alleles. PIC = 0.88), provide useful reagents for a polymerase chain reaction-based predictive genetic test that can be performed rapidly from small amounts of DNA