CKS1 expression in melanocytic nevi and melanoma

Cyclin-dependent kinase subunit 1 (Cks1) regulates the degradation of p27, an important G1-S inhibitor, which is up regulated by MAPK pathway activation. In this study, we sought to determine whether Cks1 expression is increased in melanocytic tumors and correlates with outcome and/or other clinicopathologic prognostic markers. Cks1 expression was assessed by immunohistochemistry in 298 melanocytic lesions. The frequency and intensity of cytoplasmic and nuclear expression was scored as a labeling index and correlated with clinico-pathological data. Nuclear Cks1 protein was found in 63% of melanocytic nevi, 89% primary and 90% metastatic melanomas with mean labeling index of 7 ± 16, 19 ± 20, and 30 ± 29, respectively. While cytoplasmic Cks1 was found in 41% of melanocytic nevi, 84% primary and 95% metastatic melanomas with mean labeling index of 18 ± 34, 35 ± 34, and 52 ± 34, accordingly. Histologic stepwise model of tumor progression, defined as progression from benign nevi to primary melanomas, to melanoma metastases, revealed a significant increase in nuclear and cytoplasmic Cks1 expression with tumor progression. Nuclear and cytoplasmic Cks1 expression correlated with the presence of ulceration, increased mitotic rate, Breslow depth, Clark level, tumor infiltrating lymphocytes and gender. However, other well-known prognostic factors (age, anatomic site, and regression) did not correlate with any type of Cks1 expression. Similarly, increasing nuclear expression of Cks1 significantly correlated with worse overall survival. Thus, Cks1 expression appears to play a role in the progression of melanoma, where high levels of expression are associated with poor outcome. Cytoplasmic expression of Cks1 might represent high turnover of protein via the ubiquination/proteosome pathway. © Brozyna et al

Pre- and post- prandial appetite hormone levels in normal weight and severely obese women

<p>Abstract</p> <p>Background</p> <p>Appetite is affected by many factors including the hormones leptin, ghrelin and adiponectin. Ghrelin stimulates hunger, leptin promotes satiety, and adiponectin affects insulin response. This study was designed to test whether the pre- and postprandial response of key appetite hormones differs in normal weight (NW) and severely obese (SO) women.</p> <p>Methods</p> <p>Twenty three women ages 25–50 were recruited for this study including 10 NW (BMI = 23.1 ± 1.3 kg/m²) and 13 SO (BMI = 44.5 ± 7.1 kg/m²). The study was conducted in a hospital-based clinical research centre. Following a 12-hour fast, participants had a baseline blood draw, consumed a moderately high carbohydrate meal (60% carbohydrate, 20% protein, 20% fat) based on body weight. Postprandially, participants had six blood samples drawn at 0, 15, 30, 60, 90, and 120 minutes. Primary measures included pre- and post-prandial total ghrelin, leptin, adiponectin and insulin. A repeated measures general linear model was used to evaluate the hormone changes by group and time (significance p ≤ 0.05).</p> <p>Results</p> <p>There were significant differences between the NW and the SO for all hormones in the preprandial fasting state. The postprandial responses between the SO versus NW revealed: higher leptin (p < 0.0001), lower adiponectin (p = 0.04), trend for lower ghrelin (p = 0.06) and insulin was not different (p = 0.26). Postprandial responses over time between the SO versus NW: higher leptin (p < 0.001), lower ghrelin and adiponectin (p = 0.004, p = 0.015, respectively), and trend for higher insulin (p = 0.06).</p> <p>Conclusion</p> <p>This study indicates that significant differences in both pre- and selected post- prandial levels of leptin, ghrelin, adiponectin and insulin exist between NW and SO women. Improving our understanding of the biochemical mechanisms accounting for these differences in appetite hormones among individuals with varying body size and adiposity should aid in the development of future therapies to prevent and treat obesity.</p

Astrocyte-Specific Overexpression of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons and Reduces Behavioral Deficits following Traumatic Brain Injury in Mice

Traumatic brain injury (TBI) survivors often suffer from long-lasting cognitive impairment that stems from hippocampal injury. Systemic administration of insulin-like growth factor-1 (IGF-1), a polypeptide growth factor known to play vital roles in neuronal survival, has been shown to attenuate posttraumatic cognitive and motor dysfunction. However, its neuroprotective effects in TBI have not been examined. To this end, moderate or severe contusion brain injury was induced in mice with conditional (postnatal) overexpression of IGF-1 using the controlled cortical impact (CCI) injury model. CCI brain injury produces robust reactive astrocytosis in regions of neuronal damage such as the hippocampus. We exploited this regional astrocytosis by linking expression of hIGF-1 to the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, effectively targeting IGF-1 delivery to vulnerable neurons. Following brain injury, IGF-1Tg mice exhibited a progressive increase in hippocampal IGF-1 levels which was coupled with enhanced hippocampal reactive astrocytosis and significantly greater GFAP levels relative to WT mice. IGF-1 overexpression stimulated Akt phosphorylation and reduced acute (1 and 3d) hippocampal neurodegeneration, culminating in greater neuron survival at 10d after CCI injury. Hippocampal neuroprotection achieved by IGF-1 overexpression was accompanied by improved motor and cognitive function in brain-injured mice. These data provide strong support for the therapeutic efficacy of increased brain levels of IGF-1 in the setting of TBI

Towards an Aero-Propulso-Servo-Elasticity Analysis of a Commercial Supersonic Transport

This paper covers the development of an aero-propulso-servo-elastic (APSE) model using computational fluid dynamics (CFD) and linear structural deformations. The APSE model provides the integration of the following two previously developed nonlinear dynamic simulations: a variable cycle turbofan engine and an elastic supersonic commercial transport vehicle. The primary focus of this study is to provide a means to include relevant dynamics of a turbomachinery propulsion system into the aeroelastic studies conducted during a vehicle design, which have historically neglected propulsion effects. A high fidelity CFD tool is used here for the integration platform. The elastic vehicle neglecting the propulsion system serves as a comparison of traditional approaches to the APSE results. An overview of the methodology is presented for integrating the propulsion system and elastic vehicle. Static aeroelastic analysis comparisons between the traditional and developed APSE models for a wing tip detection indicate that the propulsion system impact on the vehicle elastic response could increase the detection by approximately ten percent

Rapid early Holocene deglaciation of the Laurentide ice sheet

Author Posting. © Nature Publishing Group, 2008. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Geoscience 1 (2008): 620-624, doi:10.1038/ngeo285.The early Holocene deglaciation of the Laurentide Ice Sheet (LIS) is the most recent and best constrained disappearance of a large Northern Hemisphere ice sheet. Its demise is a natural experiment for assessing rates of ice sheet decay and attendant contributions to sea level rise. Here we demonstrate with terrestrial and marine records that the final LIS demise occurred in two stages of rapid melting from ~9.0- 8.5 and 7.6-6.8 kyr BP with the LIS contributing ~1.3 and 0.7 cm yr-1 to sea level rise, respectively. Simulations using a fully coupled atmosphere-ocean general circulation model suggest that increased ablation from enhanced early Holocene boreal summer insolation may have been the predominant cause of the LIS contributions to sea level rise. Although the boreal summer surface radiative forcing of early Holocene LIS retreat is twice that of projections for 2100 C.E. greenhouse gas radiative forcing, the associated summer surface air temperature increase is the same. The geologic evidence for rapid LIS retreat under a comparable forcing provides a prehistoric precedent for a possible large negative mass balance response of the Greenland Ice Sheet by the end of the coming century.This research was funded by National Science Foundation grants ATM-05-01351 & ATM-05-01241 to D.W.O. & G.A.S., start-up funds from the University of Wisconsin-Madison and a Woods Hole Oceanographic Institution Postdoctoral Scholarship to A.E.C., and the Woods Hole Oceanographic Institution's Ocean and Climate Change Institute (D.W.O. & R.E.C.)

Glueball production in radiative J/psi, Upsilon decays

Using a bound-state model of weakly bound gluons for glueballs made of two gluons and a natural generalization of the perturbative QCD formalism for exclusive hadronic processes, we present results for glueball production in radiative J/psi, Upsilon decays into several possible glueball states, including L \not= 0 ones. We perform a detailed phenomenological analysis, presenting results for the more favored experimental candidates and for decay angular distributions.Comment: RevTeX4, 26 pages, 11 eps figure

Models of the SL9 Impacts II. Radiative-hydrodynamic Modeling of the Plume Splashback

We model the plume "splashback" phase of the SL9 collisions with Jupiter using the ZEUS-3D hydrodynamic code. We modified the Zeus code to include gray radiative transport, and we present validation tests. We couple the infalling mass and momentum fluxes of SL9 plume material (from paper I) to a jovian atmospheric model. A strong and complex shock structure results. The modeled shock temperatures agree well with observations, and the structure and evolution of the modeled shocks account for the appearance of high excitation molecular line emission after the peak of the continuum light curve. The splashback region cools by radial expansion as well as by radiation. The morphology of our synthetic continuum light curves agree with observations over a broad wavelength range (0.9 to 12 microns). A feature of our ballistic plume is a shell of mass at the highest velocities, which we term the "vanguard". Portions of the vanguard ejected on shallow trajectories produce a lateral shock front, whose initial expansion accounts for the "third precursors" seen in the 2-micron light curves of the larger impacts, and for hot methane emission at early times. Continued propagation of this lateral shock approximately reproduces the radii, propagation speed, and centroid positions of the large rings observed at 3-4 microns by McGregor et al. The portion of the vanguard ejected closer to the vertical falls back with high z-component velocities just after maximum light, producing CO emission and the "flare" seen at 0.9 microns. The model also produces secondary maxima ("bounces") whose amplitudes and periods are in agreement with observations.Comment: 13 pages, 9 figures (figs 3 and 4 in color), accepted for Ap.J. latex, version including full figures at: http://oobleck.tn.cornell.edu/jh/ast/papers/slplume2-20.ps.g

Models of the SL9 Impacts I. Ballistic Monte-Carlo Plume

We model the Comet Shoemaker-Levy 9 - Jupiter impact plumes to calculate synthetic plume views, atmospheric infall fluxes, and debris patterns. Our plume is a swarm of ballistic particles with one of several mass-velocity distributions (MVD). The swarm is ejected instantaneously and uniformly into a cone from its apex. Upon falling to the ejection altitude, particles slide with horizontal deceleration following one of several schemes. The model ignores hydrodynamic and Coriolis effects. We adjust plume tilt, opening angle, and minimum velocity, and choose MVD and sliding schemes, to create impact patterns that match observations. Our best match uses the power-law MVD from the numerical impact model of Zahnle and Mac Low, with velocity cutoffs at 4.5 and 11.8 km/sec, cone opening angle of 75 degrees, cone tilt of 30 degrees from vertical, and a sliding constant deceleration of 1.74 m/sec^2. A mathematically-derived feature of Zahnle and Mac Low's published cumulative MVD is a thin shell of mass at the maximum velocity, corresponding to the former atmospheric shock front. This vanguard contains 22% of the mass and 45% of the energy of the plume, and accounts for several previously-unexplained observations, including the large, expanding ring seen at 3.2 microns by McGregor et al. and the ``third precursors'' and ``flare'' seen near 300 and 1000 sec, respectively, in the infrared lightcurves. We present synthetic views of the plumes in flight and after landing and derive infall fluxes of mass, energy, and vertical momentum as a function of time and position on the surface. These fluxes initialize a radiative-hydrodynamic atmosphere model (Paper II of this series) that calculates the thermal and dynamical response of the atmosphere and produces synthetic lightcurves.Comment: Accepted by ApJ. 15 pages, 12 figures, LaTeX/AASTeX. Fig. 10 (p. 12) is color. Version with full-resolution figures available at http://oobleck.tn.cornell.edu/jh/ast/papers/slplume1-20.ps.g

Dementia and cognitive impairment in French-speaking Sub-Saharan Africa: a comprehensive review on moving out of the shadows of neglect

Dementia is a global public health problem with increasing prevalence and incidence worldwide. The African continent is expected to bear the biggest brunt of the burden of dementia by 2050 because of the rapid demographic changes, including rapid population growth, an increase in life expectancy, and ageing. However, French-speaking Sub-Saharan African (FS-SSA) countries are underrepresented in research on dementia in Africa. While the reasons are diverse and complex, linguistic and cultural barriers to research, disproportionately affect these countries and may be significant factors. Any efforts, therefore, to redress the burden of dementia in Africa must consider the specific demographic, cultural, and linguistic characteristics of FS-SSA countries. This scoping review explores the current state of knowledge in dementia and cognitive impairment in Sub-Saharan Africa, highlighting research gaps and specific patterns unique to FS-SSA Africa. We identify pathways for research to bridge the knowledge gaps on dementia in FS-SSA as part of the global endeavor to tackle dementia worldwide