Current assessment of orthotopic tumor models in animals utilizes survival as the primary therapeutic end point. In vivo bioluminescence imaging (BLI) is a sensitive imaging modality that is rapid ...and accessible, and may comprise an ideal tool for evaluating antineoplastic therapies 1 . Using human tumor cell lines constitutively expressing luciferase, the kinetics of tumor growth and response to therapy have been assessed in intraperitoneal 2, subcutaneous, and intravascular 3 cancer models. However, use of this approach for evaluating orthotopic tumor models has not been demonstrated. In this report, the ability of BLI to noninvasively quantitate the growth and therapeuticinduced cell kill of orthotopic rat brain tumors derived from 9L gliosarcoma cells genetically engineered to stably express firefly luciferase (9LLuc) was investigated. Intracerebral tumor burden was monitored over time by quantitation of photon emission and tumor volume using a cryogenically cooled CCD camera and magnetic resonance imaging (MRI), respectively. There was excellent correlation (r=0.91) between detected photons and tumor volume. A quantitative comparison of tumor cell kill determined from serial MRI volume measurements and BLI photon counts following 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment revealed that both imaging modalities yielded statistically similar cell kill values (P=.951). These results provide direct validation of BLI imaging as a powerful and quantitative tool for the assessment of antineoplastic therapies in living animals.
Detection of a therapeutic response early in the course of cancer treatment, before tumor growth delay or regression, is not currently possible in experimental models or clinical medicine. New ...interim measures of therapeutic response would be particularly useful in the development of cancer chemosensitization gene therapy by facilitating optimization of gene transfer protocols and prodrug dosing schedules. Diffusion MRI is a sensitive technique producing quantitative and noninvasive images of the apparent mobility of water within a tissue. We investigated the utility of diffusion MRI for detecting early changes associated with a refined cytosine deaminase (CD)/5-fluorocytosine (5FC) chemosensitization gene therapy paradigm in orthotopic 9L gliomas stably expressing the recently cloned S. cerevisiae CD gene. Mean tumor diffusion increased 31% within 8 days of initiating 5-FC treatment, preceding tumor growth arrest and regression. Complete regression of the intracranial tumor was observed in four of five treated animals, and recurrent tumor in the remaining animal exhibited water diffusion behavior similar to primary, untreated tumors. These results demonstrate the efficacy of the yCD/5FC strategy for glioma and suggest that increased tumor water diffusion is an indicator of active therapeutic intervention.
The incidence, clinical presentation, pathophysiology, and possible treatment of two rare but clinically meaningful complications of tissue augmentation with Zyderm and Zyplast Collagen Implant are ...described. Abscesses as a manifestation of hypersensitivity to bovine collagen occur rarely (4 in 10,000 cases) and may persist for days to weeks. Periods of remission and exacerbation may occur from 1 month to more than 24 months. Localized tissue necrosis also occurs rarely (9 in 10,000 cases) after implantation and is probably the result of local vascular interruption and not hypersensitivity. The incidence varies greatly between the anatomic sites of implantation; more than half the reported cases involve the glabella. Evidence strongly suggests that the increased vulnerability of the glabellar region is due to its unique vascular distribution.
Subducting slabs provide the main driving force for plate motion and flow in the Earth's mantle, and geodynamic, seismic and geochemical studies offer insight into slab dynamics and ...subduction-induced flow. Most previous geodynamic studies treat subduction zones as either infinite in trench-parallel extent (that is, two-dimensional) or finite in width but fixed in space. Subduction zones and their associated slabs are, however, limited in lateral extent (250-7,400 km) and their three-dimensional geometry evolves over time. Here we show that slab width controls two first-order features of plate tectonics-the curvature of subduction zones and their tendency to retreat backwards with time. Using three-dimensional numerical simulations of free subduction, we show that trench migration rate is inversely related to slab width and depends on proximity to a lateral slab edge. These results are consistent with retreat velocities observed globally, with maximum velocities (6-16 cm yr-1) only observed close to slab edges (<1,200 km), whereas far from edges (>2,000 km) retreat velocities are always slow (<2.0 cm yr-1). Models with narrow slabs (≤1,500 km) retreat fast and develop a curved geometry, concave towards the mantle wedge side. Models with slabs intermediate in width (∼2,000-3,000 km) are sublinear and retreat more slowly. Models with wide slabs (≥4,000 km) are nearly stationary in the centre and develop a convex geometry, whereas trench retreat increases towards concave-shaped edges. Additionally, we identify periods (5-10 Myr) of slow trench advance at the centre of wide slabs. Such wide-slab behaviour may explain mountain building in the central Andes, as being a consequence of its tectonic setting, far from slab edges.
Subduction of oceanic lithosphere occurs through two modes: subducting plate motion and trench migration. Using a global subduction zone data set and three-dimensional numerical subduction models, we ...show that slab width (W) controls these modes and the partitioning of subduction between them. Subducting plate velocity scales with W²/³, whereas trench velocity scales with 1/W. These findings explain the Cenozoic slowdown of the Farallon plate and the decrease in subduction partitioning by its decreasing slab width. The change from Sevier-Laramide orogenesis to Basin and Range extension in North America is also explained by slab width; shortening occurred during wide-slab subduction and overriding-plate-driven trench retreat, whereas extension occurred during intermediate to narrow-slab subduction and slab-driven trench retreat.
Previous models of subduction (both analogue and numerical) have observed a number of distinct styles of subduction, each with particular subduction motions (partitioned between slab rollback and ...forward plate advance) and associated slab morphologies. We use 3-D numerical models to investigate subduction dynamics by varying the strength of slabs as well as the buoyancy, and propose a new classification based on these parameters. The slab strength is specified both through the ratio of viscosities between the subducting plate and upper mantle (
η
plate/
η
um) as well as the plate thickness,
h
plate. Only a very restrictive range of plates (“strong” plates with smaller buoyancy) tend to favor modes of subduction which are exclusively advancing. Plates which have greater negative buoyancy will eventually transition into a retreating style. We find that the flexural strength and the buoyancy determine the subduction style (as distinguished by a characteristic slab morphology), and control several subduction characteristics including the partitioning between slab rollback and plate advance, the trench curvature, and the slab's radius of curvature. Plates that are 80–100
km thick with
η
plate/
η
um
~
100–300 are classified here as “weak” and are the only plates to exhibit slab geometry with several recumbent folds atop the more viscous lower mantle. This regime of weak plates with their associated slab morphologies (predominant folding) is argued to be most similar to slabs on Earth based on the presence of folded slab piles in Earth's upper mantle (as interpreted from seismic tomography).
We present extensive optical photometric and spectroscopic observations, from 4 to 482 days after explosion, of the Type II-plateau (II-P) supernova (SN) 2017eaw in NGC 6946. SN 2017eaw is a normal ...SN II-P intermediate in properties between, for example, SN 1999em and SN 2012aw and the more luminous SN 2004et, also in NGC 6946. We have determined that the extinction to SN 2017eaw is primarily due to the Galactic foreground and that the SN site metallicity is likely subsolar. We have also independently confirmed a tip-of-the-red-giant-branch (TRGB) distance to NGC 6946 of 7.73 0.78 Mpc. The distances to the SN that we have also estimated via both the standardized candle method and expanding photosphere method corroborate the TRGB distance. We confirm the SN progenitor identity in pre-explosion archival Hubble Space Telescope (HST) and Spitzer Space Telescope images, via imaging of the SN through our HST Target of Opportunity program. Detailed modeling of the progenitor's spectral energy distribution indicates that the star was a dusty, luminous red supergiant consistent with an initial mass of ∼15 M .
Since the advent of plate tectonics different global reference frames have been used to describe the motion of plates and trenches. The difference in plate motion and trench migration between ...different reference frames can be substantial (up to 4 cm/yr). This study presents an overview of trench migration velocities for all the mature and incipient subduction zones on Earth as calculated in eight different global reference frames. Calculations show that, irrespective of the reference frame: (1) trench retreat always dominates over trench advance, with 62–78% of the 244 trench segments retreating; (2) the mean and median trench velocity are always positive (retreating) and within the range 1.3–1.5 cm/yr and 0.9–1.3 cm/yr, respectively; (3) rapid trench retreat is only observed close to lateral slab edges (<
1500 km); and (4) trench retreat is always slow far from slab edges (>
2000 km). These calculations are predicted by geodynamic models with a varying slab width, in which plate motion, trench motion and mantle flow result from subduction of dense slabs, suggesting that trench motion is indeed primarily driven by slab buoyancy forces and that proximity to a lateral slab edge exerts a dominant control on the trench migration velocity. Despite these four general conclusions, significant differences in velocities between such reference frames remain. It is therefore important to determine which reference frame most likely describes the true absolute velocities to get an understanding of the forces driving plate tectonics and mantle convection. It is here proposed that, based on fluid dynamic considerations and predictions from geodynamic modelling, the best candidate is the one, which optimises the number of trench segments that retreat, minimizes the trench–perpendicular trench migration velocity (
v
T⊥) in the centre of wide (>
4000 km) subduction zones, maximizes the number of retreating trench segments located within 2000 km of the closest lateral slab edge, minimizes the average of the absolute of the trench–perpendicular trench migration velocity (|
v
T⊥|) for all subduction zones on Earth, and minimizes the global upper mantle toroidal volume flux (
ϕ
To) that results from trench migration and associated lateral slab migration (i.e. slab rollback or slab roll-forward). Calculations show that these conditions are best met in one particular Indo-Atlantic hotspot reference frame, where 75% of the subduction zones retreat,
v
T⊥ in the centre of wide subduction zones ranges between −
3.5 and 1.8 cm/yr, 83% of the trench segments located within 2000 km of the closest lateral slab edge retreat, the average of |
v
T⊥| is 2.1 cm/yr, and
ϕ
To
=
456 km
3/yr (lower limit) and 539 km
3/yr (upper limit). Inclusion of all the incipient subduction zones on Earth results in slightly greater fluxes of 465 km
3/yr (lower limit) and 569 km
3/yr (upper limit). It is also found that this reference frame is close to minimizing the total sub-lithospheric upper mantle volume flux (
ϕ
K) associated with motion of continental keels located below the major cratons. It is stressed, however, that
ϕ
K is an order of magnitude smaller than
ϕ
To, and thus of subordinate importance. In conclusion, the Indo-Atlantic hotspot reference frame appears preferable for calculating plate velocities and plate boundary velocities.
Although most organisms thermoregulate behaviorally, biologists still cannot easily predict whether mobile animals will thermoregulate in natural environments. Current models fail because they ignore ...how the spatial distribution of thermal resources constrains thermoregulatory performance over space and time. To overcome this limitation, we modeled the spatially explicit movements of animals constrained by access to thermal resources. Our models predict that ectotherms thermoregulate more accurately when thermal resources are dispersed throughout space than when these resources are clumped. This prediction was supported by thermoregulatory behaviors of lizards in outdoor arenas with known distributions of environmental temperatures. Further, simulations showed how the spatial structure of the landscape qualitatively affects responses of animals to climate. Biologists will need spatially explicit models to predict impacts of climate change on local scales.
Subduction of tectonic plates limited in lateral extent and with a free‐trailing tail, i.e., “free subduction,” is modeled in a three‐dimensional (3‐D) geometry. The models use a nonlinear ...viscoplastic rheology for the subducting plate and exhibit a wide range of behaviors depending on such plate characteristics as strength, width, and thickness. We investigate the time evolution of this progressive rollback subduction, measure the accompanying return flow in the upper mantle, and quantify the plate kinematics. Due to the 3‐D geometry, flow is allowed to accompany slab rollback around the lateral edges of the slab (the toroidal component), as opposed to 2‐D geometry, where material is forced to flow underneath the slab tip (the poloidal component). A simple force balance is provided which relates the speed of backward trench migration to the resistive forces of generating flow and weakening the plate. Our results indicate most of the gravitational energy of the system (i.e., the negative buoyancy of the subducting slab) is converted into a toroidal flow (∼69%), a much smaller amount goes into weakening the plate (∼18%), and the remaining amount goes into driving flow parallel to displacement of the slab (∼13%). For the trench widths (W) we investigate (≤1500 km), a maximum trench retreat rate occurs for trenches 600 km wide, which is attributed to the interaction between a plate of finite width and the induced flow (which has a lengthscale in the horizontal direction). These numerical results quantitatively agree with comparable 3‐D laboratory experiments using analogue models with a purely viscous plate material (Schellart, 2004a, 2004b), including correlations between increasing retreat rate with increasing plate thickness, trench width for maximum retreat rate (500 km), and estimated amount of slab buoyancy used to drive rollback‐induced flow (∼70%). Several implications for plate tectonics on Earth result from these models such as rollback subduction providing a physical mechanism for ephemeral slab graveyards situated above the more viscous lower mantle (and endothermic phase transition) prior to a flushing event into the lower mantle (mantle avalanche).
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