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This paper presents the application of polynomial chaos (PC) to estimating the probability of collision between two spacecraft. Common methods of quantifying this probability for conjunction assessment use either Monte Carlo analyses or include simplifying assumptions to improve tractability. A PC expansion, or PCE, provides a means for approximating the solution to a large set of stochastic ordinary differential equations, which includes orbit propagation. When compared to Monte Carlo methods, non-intrusive, i.e., sampling-based, PCE generation techniques may greatly reduce the number of orbit propagations required to approximate the possibly non-Gaussian, a posteriori probability density function. The presented PC-based method of computing collision probability requires no fundamental simplifying assumptions, and reduces the computation time compared to Monte Carlo. This paper considers two cases where the common conjunction assessment assumptions are no longer valid. The results indeed demonstrate a reduction in computation time when compared to Monte Carlo, and improved accuracy when compared to simplified techniques.

This study investigated the effectiveness of mechanical refining to overcome the biomass recalcitrance barrier. Laboratory scale refining was conducted via PFI mill and valley beater refiners using green liquor and Kraft hardwood pulps. A strong positive correlation was determined between sugar recovery and water retention value. Refining produced significant improvements in enzymatic hydrolysis yield relative to unrefined substrates (e.g., sugar recovery increase from 67% to 90%, for 15% lignin Kraft pulp). A maximum absolute enzymatic hydrolysis improvement with refining was observed at enzymatic hydrolysis conditions that produced intermediate conversion levels. For a 91% target sugar conversion, PFI refining at 4000 revolutions allowed for a 32% reduction in enzyme charge for 15% lignin content hardwood Kraft pulp and 96 h hydrolysis time, compared to the unrefined material.

This paper demonstrates the use of polynomial chaos expansions for the nonlinear, non-Gaussian propagation of orbit state uncertainty. Using linear expansions in tensor products of univariate orthogonal polynomial bases, polynomial chaos expansions approximate the stochastic solution of the ordinary differential equation describing the propagated orbit, and include information on covariance, higher moments, and the spatial density of possible solutions. Results presented in this paper use non-intrusive, i.e., sampling-based, methods in combination with either least-squares regression or pseudospectral collocation to estimate the polynomial chaos expansion coefficients at any future point in time. Such methods allow for the usage of existing orbit propagators. Samples based on sun-synchronous and Molniya orbit scenarios are propagated for up to ten days using two-body and higher-fidelity force models. Tests demonstrate that the presented methods require the propagation of orders of magnitude fewer samples ...

This is a case of a 61 year old woman with chest discomfort and evidence of an inferior, ST-elevation myocardial infarction, who develops persistent cardiogenic shock and respiratory failure after primary percutaneous coronary intervention. We discuss the differential diagnosis for cardiogenic shock after acute myocardial infarction (AMI) including left ventricular failure, right ventricular failure, iatrogenic causes such as over-medication or bleeding complications, and mechanical complications of AMI including ventricular septal rupture (VSR), papillary muscle rupture, and free-wall rupture with cardiac tamponade. We focus on modalities for making the diagnosis including physical exam findings, trans-thoracic echocardiography, left ventriculogram, and right-heart catheterization. Medical as well as surgical management is discussed. Finally, we explore the controversial aspects regarding the evidence for intra-aortic balloon pump use in patients with cardiogenic shock after AMI, the optimal timing of surgical repair for VSR, and percutaneous options for VSR closure.

Commonly upregulated in human cancers, the scaffolding protein NEDD9/HEF1 is a known regulator of mesenchymal migration and cancer cell plasticity. However, the functional role of NEDD9 as a regulator of different migration/invasion modes in the context of breast cancer metastasis is currently unknown. Here, it is reported that NEDD9 is necessary for both mesenchymal and amoeboid individual cell migration/invasion in triple-negative breast cancer (TNBC). NEDD9 deficiency results in acquisition of the amoeboid morphology, but severely limits all types of cell motility. Mechanistically, NEDD9 promotes mesenchymal migration via VAV2-dependent Rac1 activation, and depletion of VAV2 impairs the ability of NEDD9 to activate Rac1. In addition, NEDD9 supports a mesenchymal phenotype through stimulating polymerization of actin via promoting CTTN phosphorylation in an AURKA-dependent manner. Interestingly, an increase in RhoA activity in NEDD9-depleted cells does not facilitate a switch to functional amoeboid motility, indicating a role of NEDD9 in the regulation of downstream RhoA signaling effectors. Simultaneous depletion of NEDD9 or inhibition of AURKA in combination with inhibition of the amoeboid driver ROCK results in an additional decrease in cancer cell migration/invasion. Finally, we confirmed that a dual targeting strategy is a viable and efficient therapeutic approach to hinder the metastasis of breast cancer in xenograft models, showcasing the important need for further clinical evaluation of this regimen to impede the spread of disease and improve patient survival. Implications: This study provides new insight into the therapeutic benefit of combining NEDD9 depletion with ROCK inhibition to reduce tumor cell dissemination and discovers a new regulatory role of NEDD9 in the modulation of VAV2-dependent activation of Rac1 and actin polymerization. Mol Cancer Res; 15(6); 670–82. ©2017 AACR.

The mesopredator release hypothesis (MRH) has been suggested as a reason why many mammalian generalist mesopredators flourish and become abundant. However, the MRH has only been examined in a limited number of field studies. Some studies have argued that coyotes (Canis latrans) act as top predators in fragmented forest systems and coyote presence has a positive effect on song bird diversity and abundance by controlling mesopredator abundance. We integrated camera trap data and occupancy modeling to determine the factors that affect coyote detection probability and habitat use in a fragmented suburban landscape in central Missouri. We then examined the influence of coyote presence and other habitat variables on mesopredator detection probability and habitat use in the same system. Coyote detection was negatively related to increasing forest cover, whereas red fox (Vulpes vulpes) detection was positively related to increasing urbanization. Coyote occurrence models suggested little habitat selection...

Evolution of reactive oxygen species (ROS), generated during the patho-physiological stress of nervous tissue, has been implicated in the etiology of several progressive human neurological disorders including Alzheimer’s disease (AD) and amylotrophic lateral sclerosis (ALS). In this brief communication we used mixed isomers of 5-(and-6)-carboxy-2′,7′-dichlorofluorescein diacetate (carboxy-DCFDA; C25H14Cl2O9; MW 529.3), a novel fluorescent indicator, to assess ROS generation within human neuronal-glial (HNG) cells in primary co-culture. We introduced pathological stress using the sulfates of 12 environmentally-, industrially- and agriculturally-relevant divalent and trivalent metals including Al, Cd, Cu, Fe, Hg, Ga, Mg, Mn, Ni, Pb, Sn and Zn. In this experimental test system, of all the metal sulfates analyzed, aluminum sulfate showed by far the greatest ability to induce intracellular ROS. These studies indicate the utility of using isomeric mixtures of carboxy-H2DCFDA diacetates as novel and highly sensitive, long-lasting, cell-permeant, fluorescein-based tracers for quantifying ROS generation in intact, metabolizing human brain cells, and in analyzing the potential epigenetic contribution of different metal sulfates to ROS-generation and ROS-mediated neurological dysfunction.

AimTo assess plasma zinc and copper concentration in individuals with autism and correlate these levels with symptom severity.Subjects and MethodsPlasma from 102 autistic individuals, and 18 neurotypical controls, were tested for plasma zinc and copper using inductively-coupled plasma-mass spectrometry. Copper and zinc levels and Cu/Zn were analyzed for possible correlation with severity of 19 symptoms.ResultsAutistic individuals had elevated plasma levels of copper and Cu/Zn and lower, but not significantly lower, plasma Zn compared to neurotypical controls. There was a correlation between Cu/Zn and expressive language, receptive language, focus attention, hyperactivity, fine motor skills, gross motor skills and Tip Toeing. There was a negative correlation between plasma zinc concentration and hyperactivity, and fine motor skills severity.DiscussionThese results suggest an association between plasma Cu/Zn and severity of symptoms associated with autism.

The cubed-sphere model provides rapid evaluation of the gravity field for more efficient orbit propagation. This paper characterizes the improved computational efficiency of sequential orbit determination, specifically the extended and unscented Kalman filters, when using this new model instead of the common spherical harmonic model. To use the new gravity model with the extended Kalman filter, capabilities to represent the Jacobian of the gravity acceleration are added to numerically integrate the state transition matrix. Filter tests consider improvements for several simulated satellite scenarios with several combinations of measurements provided for estimation. Since cubed-sphere models of higher degree require only a slight change in computation time, orbit propagation and determination systems may now use this model to improve fidelity without any significant change in cost. Using the cubed-sphere model reduces the computational burden of the orbit determination process, with larger benefits found for high-degree filter models. Differences in the estimated trajectories when using the disparate gravity models remain several orders of magnitude less than the absolute filter error for the cases examined.

A new model, dubbed the MRQSphere, provides a multiresolution representation of the gravity field designed for its estimation. The multiresolution representation uses an approximation via Gaussians of the solution of the Laplace’s equation in the exterior of a sphere. Also, instead of the spherical harmonics, variations in the angular variables are modeled by a set of functions constructed using quadratures for the sphere invariant under the icosahedral group. When combined, these tools specify the spatial resolution of the gravity field as a function of altitude and required accuracy. We define this model, and apply it to representing and estimating the gravity field of the asteroid 433 Eros. We verified that a MRQSphere model derived directly from the true spherical harmonics gravity model satisfies the user defined precision. We also use the MRQSphere model to estimate the gravity field of Eros for a simulated satellite mission, yielding a solution with accuracy only limited by measurement errors and their spatial distribution.

4,4'-Methylenedianiline (DAPM) is an aromatic diamine used directly in the production of polyurethane foams and epoxy resins, or as a precursor to MDI in the manufacture of some polyurethanes. In our prior experiments, we showed that chronic, intermittent treatment of female rats with DAPM resulted in vascular medial hyperplasia of pulmonary arteries. In addition, treatment of vascular smooth muscle cells (VSMC) in culture with DAPM increased the rates of proliferation in a manner that was inhibited by co-treatment with N-acetylcysteine but was not associated with oxidative stress. We thus hypothesized that NAC treatment inhibited DAPM toxicity by competing for binding reactive intermediates formed through DAPM metabolism. Because the peroxidase enzyme cyclooxygenase is constitutively expressed in VSMC, and because cyclooxygenase is known to metabolize similar aromatic amines to electrophilic intermediates, we further hypothesized that DAPM-induced VSMC proliferation was dependent upon COX-1/2-mediated bioactivation. To test this hypothesis, we treated VSMC with DAPM and measured cell proliferation, COX-2 expression, COX-1/2 activity, and levels of covalent binding. DAPM treatment resulted in a dose-dependent increase in proliferation that was abolished by co-treatment with the COX-2-selective inhibitor celecoxib. In addition, DAPM exposure increased the rates of proliferation in VSMC isolated from wild-type but not COX-2 (-/-) mice. Paradoxically, treatment with DAPM reduced the cellular production of PGE(2) and PGF(2α), but dose-dependently increased the COX-2 protein levels. Covalent binding of [(14)C]-DAPM to VSMC biomolecules was greater in wild-type than in COX-2 (-/-) cells. However, covalent binding of [(14)C]-DAPM was not altered by co-treatment with a nonselective inhibitor of cytochromes P450. These studies thus suggest that DAPM-induced VSMC proliferation may be due to bioactivation of DAPM, perhaps through the action of cyclooxygenase. The data furthermore suggest that DAPM's mechanism of action may possibly involve inhibition or suicide inactivation of COX-2. In addition, because we observed an increase in DAPM-induced VSMC proliferation in cells isolated from female compared to male rats, further studies into the potential interplay between DAPM, the estrogen receptor, and COX-2 seem warranted.

The MitraClip is an US Food and Drug Administration-approved device for inoperable patients with severe degenerative mitral regurgitation (MR) and is under investigation for use in patients with severe functional MR. Simultaneously grasping both leaflets of the mitral valve can be technically challenging, however, in patients with a restricted posterior leaflet. We present one such case in which a pigtail catheter, placed retrograde into the left ventricle, was able to push the ventricular surface of the posterior leaflet into closer approximation with the anterior leaflet, and facilitate successful clip placement. We provide this report in hopes that it will provide a useful strategy for interventionalists faced with this challenging situation.

12020Background: Despite remarkable upfront response to ALK tyrosine kinase inhibitors (TKIs) in ALK+ lung cancer, acquired resistance eventually develops. Molecular mechanisms of the initial emerg...

12018Background: ALK tyrosine kinase inhibitors (TKIs) yield a significant tumor response in advanced ALK+ non-small cell lung cancer (NSCLC), that is often rapid and remarkable. Nonetheless, acqui...

The cubed-sphere gravitational model is a modification of a base model, e.g., the spherical harmonic model, to allow for the fast evaluation of acceleration. The model consists of concentric spheres, each mapped to the surface of a cube and combined with an appropriate interpolation scheme. The paper presents a brief description of the cubed-sphere model and a comparison of it with the spherical harmonic model. The model was configured to achieve a desired accuracy so that dynamical tests, e.g., evaluation of the integration constant, closely approximate that of the spherical harmonic model. The new model closely approximates the spherical harmonic model, with propagated orbits deviating by a fraction of a millimeter at or above feasible Earth-centered altitudes.

This study examined the influence of relationship-specific dimensions of social support (i.e., support, depth, conflict) on nocturnal blood pressure (BP) dipping and mental health (i.e., satisfaction with life, stress, and depression) among 303 normotensive and un-medicated hypertensive males and females ages 20-68. Results revealed that support was associated with better, and conflict with poorer, mental health; however, neither was associated with BP dipping. In contrast, relationship depth was associated with greater life satisfaction and greater systolic and diastolic BP dipping, and the effect on dipping was independent of sleep quality, age, hypertensive status, marital status, and level of perceived network support. Relationship conflict was moderated by marital status and gender. Low conflict for females, or with one's spouse, is associated with greater nocturnal diastolic BP dipping. Overall, this study found an association between close relationships and BP dipping, thus identifying one virtually unexplored mechanism by which close relationships may have a protective influence on health.

Moderate to severe aortic regurgitation after transcatheter aortic valve replacement is associated with worse outcomes. The impact of mild aortic regurgitation has been less clear, possibly because of the broad categories that have been used in clinical trials, but holds increasing importance in the study of next-generation devices in low- and intermediate-risk cohorts. A more granular scheme, which is common in clinical practice and proposed for future trials, may add prognostic value.We evaluated all patients undergoing transfemoral transcatheter aortic valve replacement at the Cleveland Clinic from 2006 to 2012. The degree of aortic regurgitation after transcatheter aortic valve replacement was reported from the echocardiography database based on a clinical, transthoracic echocardiogram performed within 30 days of the procedure. Aortic regurgitation was finely discriminated on the basis of a multiwindow, multiparametric, integrative approach using our usual clinical scale: none, trivial to 1+, 1+, 1 to 2+, 2+, 2 to 3+, 3+, 3 to 4+, or 4+.There were 237 patients included in the analysis. By controlling for age, gender, Society of Thoracic Surgeons score, baseline ejection fraction, and aortic regurgitation before transcatheter aortic valve replacement, there was a significant increase in mortality for each half grade of aortic regurgitation compared with the complete absence of aortic regurgitation after transcatheter aortic valve replacement. The unit hazard ratio for each 1+ increase in aortic regurgitation after transcatheter aortic valve replacement was 2.26 (95% confidence interval, 1.48-3.43; P .001) considering aortic regurgitation as a continuous variable. Other clinical variables did not significantly affect mortality.Even mild aortic regurgitation after transcatheter aortic valve replacement is associated with worse long-term mortality. There may be prognostic value in reporting milder categories of aortic regurgitation with more granular gradations.

Most approximations for stochastic differential equations with high-dimensional, non-Gaussian inputs suffer from a rapid (e.g., exponential) increase of computational cost, an issue known as the curse of dimensionality. In astrodynamics, this results in reduced accuracy when propagating an orbit-state probability density function. This paper considers the application of separated representations for orbit uncertainty propagation, where future states are expanded into a sum of products of univariate functions of initial states and other uncertain parameters. An accurate generation of separated representation requires a number of state samples that is linear in the dimension of input uncertainties. The computation cost of a separated representation scales linearly with respect to the sample count, thereby improving tractability when compared to methods that suffer from the curse of dimensionality. In addition to detailed discussions on their construction and use in sensitivity analysis, this paper presents results for three test cases of an Earth orbiting satellite. The first two cases demonstrate that approximation via separated representations produces a tractable solution for propagating the Cartesian orbit-state uncertainty with up to 20 uncertain inputs. The third case, which instead uses Equinoctial elements, reexamines a scenario presented in the literature and employs the proposed method for sensitivity analysis to more thoroughly characterize the relative effects of uncertain inputs on the propagated state.

The role of the family physician in managing knee pain is expanding as recent literature supports nonsurgical management for many patients. Effective treatment depends on the etiology of knee pain. Oral analgesics-most commonly nonsteroidal anti-inflammatory drugs and acetaminophen-are used initially in combination with physical therapy to manage the most typical causes of chronic knee pain. The American Academy of Orthopaedic Surgeons recommends against glucosamine/chondroitin supplementation for osteoarthritis. In patients who are not candidates for surgery, opioid analgesics should be used only if conservative pharmacotherapy is ineffective. Exercise-based therapy is the foundation for treating knee osteoarthritis and patellofemoral pain syndrome. Weight loss should be encouraged for all patients with osteoarthritis and a body mass index greater than 25 kg per m2. Aside from stabilizing traumatic knee ligament and tendon tears, the effectiveness of knee braces for chronic knee pain is uncertain, and the use of braces should not replace physical therapy. Foot orthoses can be helpful for anterior knee pain. Corticosteroid injections are effective for short-term pain relief in patients with osteoarthritis. The benefit of hyaluronic acid injections is controversial, and recommendations vary; recent systematic reviews do not support a clinically significant benefit. Small studies suggest that regenerative injections can improve pain and function in patients with chronic knee tendinopathies and osteoarthritis.

Cardiac amyloidosis is an under recognized and underdiagnosed heart failure etiology characterized by protein misfolding, myocardial deposition, and restrictive cardiomyopathy. Cardiac involvement in elderly patients most commonly results from the transthyretin protein (ATTR) and carries a poor

Mechanical refining is widely used in the pulp and paper industry to enhance the end-use properties of products by creating external fibrillation and internal delamination. This technology can be directly applied to biochemical conversion processes. By implementing mechanical refining technology, biomass recalcitrance to enzyme hydrolysis can be overcome and carbohydrate conversion can be enhanced with commercially attractive levels of enzymes. In addition, chemical and thermal pretreatment severity can be reduced to achieve the same level of carbohydrate conversion, which reduces pretreatment cost and results in lower concentrations of inhibitors. Refining is versatile and a commercially proven technology that can be operated at process flows of ∼ 1500 dry tons per day of biomass. This paper reviews the utilization of mechanical refining in the pulp and paper industry and summarizes the recent development in applications for biochemical conversion, which potentially make an overall biorefinery process more economically viable.

This paper will review recent research results focused on the effect of realistic asteroid shapes on the linear momentum delivered to an asteroid during a mitigation attempt. We use simple models for the effect of kinetic impactors and convolve these with a realistic asteroid shape model. For the asteroid shape we use a radar-derived shape model for the asteroid Golevka that captures global topography. For a given impact site we use realistic error distributions and determine how variable the delivered linear and angular momentum impulse is. We find strongly non-Gaussian deviations in delivered momentum, indicating that it may be difficult to achieve a desired level of precision in a deflection attempt.

Moderate to severe aortic regurgitation (AR) after trans-catheter aortic valve replacement (TAVR) is associated with worse outcomes. The impact of mild AR remains controversial. We evaluated all patients undergoing TF-TAVR at our institution from 2006-2012 (Edwards SAPIEN Valve System, 9000TFX).

One of the key classical pathological features of Alzheimer's disease (AD) is the progressive accumulation of amyloid beta (Aβ42) peptides and their coalescence into highly insoluble senile plaque cores. A major factor driving Aβ42 peptide accumulation is the inability of brain cells to effectively clear excessive amounts of Aβ42 via phagocytosis. The trans-membrane spanning, sensor-receptor known as the "triggering receptor expressed in myeloid cells 2" (TREM2; chr6p21) is essential in the sensing, recognition, phagocytosis and clearance of noxious cellular debris from brain cells, including neurotoxic Aβ42 peptides. Recently, mutations in the TREM2 gene have been associated with amyloidogenesis in neurodegenerative diseases including AD. In this report, we provide evidence that aluminum-sulfate, when incubated with microglial cells, induces the up-regulation of an NF-кB-sensitive micro RNA-34a (miRNA-34a; chr1p36) that is known to target the TREM2 mRNA 3'-untranslated region (3'-UTR), significantly down-regulating TREM2 expression. The aluminum-induced up-regulation of miRNA-34a and down-regulation of TREM2 expression were effectively quenched using the natural phenolic compound and NF-kB inhibitor CAPE [2-phenylethyl-(2E)-3-(3,4-dihydroxyphenyl) acrylate; caffeic-acid phenethyl ester]. These results suggest, for the first time, that an epigenetic mechanism involving an aluminum-triggered, NF-kB-sensitive, miRNA-34a-mediated down-regulation of TREM2 expression may impair phagocytic responses that ultimately contribute to Aβ42 peptide accumulation, aggregation, amyloidogenesis and inflammatory degeneration in the brain.

Oxidation of sulfur by microorganisms is a topic of interest for a number of researchers worldwide. Literature reports indicate that several different pathways for sulfur oxidation may be present within a single organism. In order to discriminate between activities within these pathways, methods must be available which allow discrimination between specific sulfur oxidizing activities. We describe herein a general method of increasing contrast of ferricyanide reducing zymograms and simultaneously fixing gels for storage.

The majority of cancer-related deaths (90%) are happened due to metastasis from the primary tumor site to distant organs. MLN8237 is a small, highly selective molecule inhibitor of Aurora A kinase (AURKA), which results in disruption of the mitotic spindle, chromosome segregation collapse, and inhibition of cell proliferation. Numerous studies have showed that levels of AURKA are elevated in many types of cancer, including breast cancer. Our previous studies indicated that MLN8237 is extremely potent against pulmonary metastasis, but not the primary tumor in orthotropic xenograft model. To further enhance MLN8237 based regiment, its combination with other therapeutic compounds can be used. As a potential partner we chose eribulin - fully synthetic macrocyclic analogue of the marine natural product halichondrin B. Eribulin belong to the class of non-taxane microtubule destabilizing molecules, currently used in clinic to treat taxol resistant metastatic breast cancer. In present study we have investigated the effect of MLN8237 and eribulin against breast cancer in vivo and in vitro. The results showed that combination of drugs possess a synergistic effect on both primary tumor and metastases, through inducing cytotoxic autophagy and apoptosis. This data clearly indicate great potential behind the MLN8237 based therapies and introduce a new hope for the eradication of metastatic breast cancer. Citation Format: Elena N. Pugacheva, Varvara Kozyreva, Anna Kiseleva, Ryan Ice, Brandon Jones, Yuriy Loskutov. Combination of eribulin and AURKA inhibitor prevents metastatic colonization and eradicates established metastases in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1084. doi:10.1158/1538-7445.AM2017-1084

Background: Computed tomography angiography (CTA) is used to predict the size and orientation of transcatheter aortic valve replacement (TAVR) devices in the annulus. We previously showed that the annular plane does not predict the orientation of the valve after deployment. We hypothesized that a

Background: The impact of Coronary artery disease (CAD) on the outcome after Transcatheter Aortic Valve Replacement (TAVR) is not understood well. Finding an optimum revascularization strategy for the TAVR patients who have concomitant CAD is also an ongoing debate. We sought to evaluate the

Background: The Medtronic CoreValve, a self-expanding (SE) valve is comprised of trileaflet porcine pericardial tissue sutured into a nitinol frame, as opposed to the balloon-expandable (BE) Edwards SAPIEN 3, a trileaflet bovine pericardial valve mounted in a cobalt chromium stent. We sought to

The dissemination of tumor cells relies on efficient cell adhesion and migration, which in turn depends upon endocytic trafficking of integrins. In the current work, it was found that depletion of the prometastatic protein, NEDD9, in breast cancer cells results in a significant decrease in individual cell migration due to impaired trafficking of ligand-bound integrins. NEDD9 deficiency does not affect the expression or internalization of integrins but heightens caveolae-dependent trafficking of ligand-bound integrins to early endosomes. Increase in mobility of ligand-bound integrins is concomitant with an increase in tyrosine phosphorylation of caveolin-1 (CAV1) and volume of CAV1-vesicles. NEDD9 directly binds to CAV1 and colocalizes within CAV1 vesicles. In the absence of NEDD9, the trafficking of ligand-bound integrins from early to late endosomes is impaired, resulting in a significant decrease in degradation of ligand–integrin complexes and an increase in recycling of ligand-bound integrins from early endosomes back to the plasma membrane without ligand disengagement, thus leading to low adhesion and migration. Reexpression of NEDD9 or decrease in the amount of active, tyrosine 14 phosphorylated (Tyr14) CAV1 in NEDD9-depleted cells rescues the integrin trafficking deficiency and restores cellular adhesion and migration capacity. Collectively, these findings indicate that NEDD9 orchestrates trafficking of ligand-bound integrins through the attenuation of CAV1 activity. Implications: This study provides valuable new insight into the potential therapeutic benefit of NEDD9 depletion to reduce dissemination of tumor cells and discovers a new regulatory role of NEDD9 in promoting migration through modulation of CAV1-dependent trafficking of integrins. Mol Cancer Res; 13(3); 423–38. ©2014 AACR.

The MitraClip is an US Food and Drug Administration-approved device for inoperable patients with severe degenerative mitral regurgitation (MR) and is under investigation for use in patients with severe functional MR. Simultaneously grasping both leaflets of the mitral valve can be technically challenging, however, in patients with a restricted posterior leaflet. We present one such case in which a pigtail catheter, placed retrograde into the left ventricle, was able to push the ventricular surface of the posterior leaflet into closer approximation with the anterior leaflet, and facilitate successful clip placement. We provide this report in hopes that it will provide a useful strategy for interventionalists faced with this challenging situation.

The cardinalized probability hypothesis density (CPHD) multi-target filter allows for the state estimation of known and previously unknown objects in challenging observation environments. To identify new objects, the CPHD requires a birth model to define the density of potential new targets in the single-target space. This paper presents an observation-based birth model using the constrained admissible region that identifies previously unknown space objects and instantiates a Gaussian mixture representation of the new target density. The Gaussian mixture formulation of the CPHD then refines the state estimate of the new target while simultaneously tracking known targets. Two variations of a simulation test demonstrate the efficacy of the method for the tracking of objects in the near-geosynchronous region using groundand space-based optical sensors. The first test case shows the filter’s performance for dense clutter and a priori knowledge of the new target’s presence. The second variation demonstrates the filter’s ability to track known and unknown objects with no a priori knowledge of the new target and a reduced clutter density. This latter case demonstrates that the CPHD with the new birth model correctly identifies potential new targets, discards false detections, and maintains custody of the previously known objects in the multi-target state.

Camera traps are commonly used for mammal surveys and many recent studies have published variable trap success rates. All published reports have focused survey efforts in protected areas or large contiguous forests, but we used camera traps in a highly altered suburban landscape. We selected 22 camera trap sites in Warrensburg and Lee’s Summit, Missouri and surveyed for a total of 308 trapnights (TN) of effort. Procyon lotor (raccoon) had the highest trap success (38.96/100 TN), followed by: Didelphis virginiana (Virginia opossum, 37.34/100 TN); Odocoileus virginianus (white tailed deer, 27.92/100 TN); Sciurus niger and S. carolinensis (fox and gray squirrel, 19.48/100 TN); Vulpes vulpes (red fox, 8.77/100 TN); Canis latrans (coyote, 7.79/100 TN); Sylvilagus floridanus (cottontail rabbit, 3.90/100 TN); Urocyon cinereoargenteus (gray fox, 2.92/100 TN); Lynx rufus (bobcat, 1.95/100 TN); and Mephitis mephitis (striped skunk, 1.62/100 TN). These results are higher than any other published findings. We used 1-3 kg of deer meat as bait at each camera station and we believe this increased our trap success of mesopredators (Cove et al., 2012) versus studies that used no bait. However, our trap success for deer, squirrels, and rabbits were also higher than those published and these species were not attracted to bait. We hypothesize that the increased trap success in our study reflects (1) a true state of increased mesopredator abundance due to increased human-derived resources in the suburbs, and (2) concentrated activity of mammals in small fragmented forest patches versus the expansive forest tracts in other studies.

The purpose of this review is to outline the most common objections about robotic coronary artery bypass graft (CABG), often expressed by cardiac surgeons, cardiologists, and administrators who have little direct knowledge of the procedure. The summarized objections include the high intraoperative costs of robotic versus traditional CABG, a prolonged and difficult learning curve for members of the surgical team, and concerns about compromising graft patency with this technique. Arguments for continued procedure development in robotically assisted CABG are provided.

Differentiating between pericardial constriction and restrictive myocardial disease can be extremely difficult, and the cardiac catheterization laboratory provides a number of powerful ways in which pericardial disease can be evaluated, or in which a suspected diagnosis can be confirmed. In fact, all cath lab operators should be well versed in the interpretation of invasive hemodynamic data. While a comprehensive constriction study involves several measurements that are made using simultaneous (duel-transducer) left and right heart catheters, it is equally important to be alert to the signs and symptoms of acute pericardial disease, which may be noticed during other, routine cath lab procedures. Cardiac tamponade can rarely but rapidly develop during different procedures in the catheterization laboratory like coronary artery perforation during a percutaneous intervention (PCI), right ventricular injury during a myocardial biopsy or pacing wire insertion, or an injury during transseptal catheterization or electrophysiology procedures like ablation or lead extraction. Failure to quickly make a diagnosis may potentially delay otherwise life saving interventions. Thus, this section will focus on the normal hemodynamic relationships of the heart and pericardium, the steps required to perform a dedicated study to differentiate pericardial constriction from restrictive myocardial disease, and the hemodynamic findings of acute cardiac tamponade.

Genetic deficits and loss of function for the triggering receptor expressed in myeloid cells 2 (TREM2; encoded at chr6p21.1), a transmembrane spanning stimulatory receptor of the immunoglobulin/lectin-like gene superfamily, have been associated with deficiencies in phagocytosis and the innate immune system in Alzheimer's disease. In this study, we provide evidence that TREM2 is downregulated in samples of sporadic Alzheimer hippocampal CA1 compared with age-matched controls. A nuclear factor-кB (NF-кB)-sensitive miRNA-34a (encoded at chr1p36.22), upregulated in Alzheimer's disease, was found to target the 299 nucleotide human TREM2 mRNA 3'-untranslated region (3'-UTR) and downregulate the expression of a TREM2-3'-UTR reporter vector. A stabilized anti-miRNA-34a (AM-34a) quenched this pathogenic response. The results suggest that an epigenetic mechanism involving an NF-кB-mediated, miRNA-34a-regulated downregulation of TREM2 expression may shape innate immune and phagocytic responses that contribute to inflammatory neurodegeneration.

This document describes the work performed as part of the Ananke simulation development. The Ananke simulation tool development is a larger project to provide end-to-end space object simulation and characterization to demonstrate the feasibility of such methods. This document describes the orbit propagation tool, CO-TurboProp, used in the Ananke tool. The document describes the addition of higher-fidelity models in CO-TurboProp and validation of the new tools. The description provided here includes the mathematical background and description of the models implemented, as well as a definition of the software interface for the larger Ananke tool. Comparisons of the software with semi-analytic techniques and other available high-fidelity propagation tools are also presented, and all tools met all required and expected accuracies.

Having close social relationships and being married specifically have been reliably associated with health benefits including lower morbidity and mortality.The purpose of this study was to examine the influence of marital status, relationship quality, and network support on measures of psychological and cardiovascular health.We examined ambulatory blood pressure (ABP) among 204 married and 99 single males and females (N = 303).We found that both marital status and marital quality were important. Married individuals had greater satisfaction with life (SWL) and blood pressure dipping than single individuals. High marital quality was associated with lower ABP, lower stress, less depression, and higher SWL. Importantly, contrasting those who are unmarried with those in low-quality marriages, we find that single individuals had lower ABP-suggesting that single individuals fare better than their unhappily married counterparts. Likewise, having a supportive network did not moderate (i.e., buffer) the effects of being single or unhappily married.Findings indicate being married per se is not universally beneficial, rather, the satisfaction and support associated with such a relationship is important. However, marriage may be distinctive, as evidence further suggests that support from one's network does not compensate for the effect of being single. These results highlight the complexities in understanding the influence of social relationships on long-term health, and they may help clarify the physiological pathways by which such associations exist.

Accelerated apoptosis of erythroid progenitors in beta-thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin-inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu-erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with beta+-thalassemia had relatively low levels of endogenous EPO (145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one beta 0-globin mutation had higher baseline HbF levels (60%) and EPO levels (160 mU/mL), and three-fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin-inducing short-chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of beta-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of beta-thalassemia.