bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple episodes of hematite mineralization indicated by U-Pb dating of iron-ore deposits, Marquette Range, Michigan, USA
Authors: Rasmussen Birger , Zi Jian-Wei , Sheppard Stephen , Krapež Bryan , Muhling Janet R.
Published: June 2016

High-grade hematite ore (so-called “hard ore”) was first mined in the Lake Superior region of North America in A.D. 1848. The development of ore deposit models from the region has strongly influenced research on the origin of this deposit type worldwide. The inability to date high-grade hematite ores has hindered the testing of competing genetic models. In the Marquette Range, northern Michigan (USA), high-grade hematite ore is hosted by the 1.9–1.85 Ga Negaunee Iron Formation and unconformably overlying Goodrich Quartzite. Field relations and new in situ U-Pb geochronology of monazite and xenotime intergrown with hematite from six mines across the Marquette Range, Michigan, indicate that the formation of high-grade hematite ore bodies involved up to three events. The presence of pebbles of hematite ore in basal conglomerate of the Goodrich Quartzite indicates that the first episode of iron-oxide mineralization occurred after deposition and deformation of the Negaunee Iron Formation, but before the ca. 1.85 Ga Sudbury impact. Monazite in iron-ore deposits within the hinges of Penokean-aged folds yields an age of ca. 1.8 Ga, which is interpreted to record a second phase of hematite enrichment. Monazite and xenotime in iron-ore deposits along the limbs of regional folds give ages of ca. 1.77 Ga and are interpreted to record a later episode of hematite upgrading. The ca. 1.8 Ga and ca. 1.77 Ga phosphate ages coincide with the timing of regional tectonic events, suggesting hematite mineralization was coeval with the Penokean orogeny and Yavapai-interval accretion. Our results support the proposal that the formation of high-grade hematite ore bodies is a multistage process linked to discrete orogenic events.
Extending Alaska’s plate boundary: Tectonic tremor generated by Yakutat subduction
Authors: Wech Aaron G.
Published: June 2016

The tectonics of the eastern end of the Alaska-Aleutian subduction zone are complicated by the inclusion of the Yakutat microplate, which is colliding into and subducting beneath continental North America at near-Pacific-plate rates. The interaction among these plates at depth is not well understood, and further east, even less is known about the plate boundary or the source of Wrangell volcanism. The drop-off in Wadati-Benioff zone (WBZ) seismicity could signal the end of the plate boundary, the start of aseismic subduction, or a tear in the downgoing plate. Further compounding the issue is the possible presence of the Wrangell slab, which is faintly outlined by an anemic, eastward-dipping WBZ beneath the Wrangell volcanoes. In this study, I performed a search for tectonic tremor to map slow, plate-boundary slip in south-central Alaska. I identified ∼11,000 tremor epicenters, which continue 85 km east of the inferred Pacific plate edge marked by WBZ seismicity. The tremor zone coincides with the edges of the downgoing Yakutat terrane, and tremors transition from periodic to continuous behavior as they near the aseismic Wrangell slab. I interpret tremor to mark slow, semicontinuous slip occurring at the interface between the Yakutat and North America plates. The slow slip region lengthens the megathrust interface beyond the WBZ and may provide evidence for a connection between the Yakutat slab and the aseismic Wrangell slab.
Control of silicate weathering by interface-coupled dissolution-precipitation processes at the mineral-solution interface
Authors: Ruiz-Agudo Encarnación , King Helen E. , Patiño-López Luis D. , Putnis Christine V. , Geisler Thorsten , Rodriguez-Navarro Carlos , Putnis Andrew
Published: June 2016

The mechanism of surface coating formation (the so-called surface altered layers [SALs] or leached layers) during weathering of silicate minerals is controversial and hinges on understanding the saturation state of the fluid at the dissolving mineral surface. Here we present in-situ data on the evolution of the interfacial fluid composition during dissolution of wollastonite (CaSiO3), obtained using interferometry and micro pH and ion-selective electrodes. Steep concentration gradients develop at the mineral interface as soon as it makes contact with the solution. This interfacial fluid becomes supersaturated with respect to amorphous silica that forms a surface coating, limiting fluid access to the mineral surface and hence affecting the dissolution rate. The thickness of the supersaturated zone and the precipitated layer depends on the relative rates of mass transport and surface reaction in the system; this effect could contribute to the discrepancy between dissolution rates measured in the field and in the laboratory. As well, our results have implications for predictions of silicate weathering rates and hence climate evolution, as different assumptions on dissolution mechanisms affect calculations on CO2 drawdown during weathering and consequent effects on estimates of global mean temperatures.
Microcephalic osteodysplastic primordial dwarfism type 1
Authors: Ferrell Steven , Johnson Aaron , Pearson Waylon
Published: June 2016

Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is an uncommon cause of microcephaly and intrauterine growth retardation in a newborn. Early identifying features include but are not limited to sloping forehead, micrognathia, sparse hair, including of eyebrows and short limbs. Immediate radiological findings may include partial or complete agenesis of the corpus callosum, interhemispheric cyst and shallow acetabula leading to dislocation. Genetic testing displaying a mutation in RNU4ATAC gene is necessary for definitive diagnosis. Early identification is important as MOPD1 is an autosomal recessive condition and could present in subsequent pregnancies. The purpose of this case is to both identify and describe some common physical findings related to MOPD1. We present a case of MOPD1 in a girl born to non-consanguineous parents that was distinct for subglottic stenosis and laryngeal cleft.
Analysis of head impact exposure and brain microstructure response in a season-long application of a jugular vein compression collar: a prospective, neuroimaging investigation in American football
Authors: Myer Gregory D , Yuan Weihong , Barber Foss Kim D , Thomas Staci , Smith David , Leach James , Kiefer Adam W , Dicesare Chris , Adams Janet , Gubanich Paul J , Kitchen Katie , Schneider Daniel K , Braswell Daniel , Krueger Darcy , Altaye Mekibib
Published: June 2016

Background

Historical approaches to protect the brain from outside the skull (eg, helmets and mouthpieces) have been ineffective in reducing internal injury to the brain that arises from energy absorption during sports-related collisions. We aimed to evaluate the effects of a neck collar, which applies gentle bilateral jugular vein compression, resulting in cerebral venous engorgement to reduce head impact energy absorption during collision. Specifically, we investigated the effect of collar wearing during head impact exposure on brain microstructure integrity following a competitive high school American football season.

Methods

A prospective longitudinal controlled trial was employed to evaluate the effects of collar wearing (n=32) relative to controls (CTRL; n=30) during one competitive football season (age: 17.04±0.67 years). Impact exposure was collected using helmet sensors and white matter (WM) integrity was quantified based on diffusion tensor imaging (DTI) serving as the primary outcome.

Results

With similar overall g-forces and total head impact exposure experienced in the two study groups during the season (p>0.05), significant preseason to postseason changes in mean diffusivity, axial diffusivity and radial diffusivity in the WM integrity were noted in the CTRL group (corrected p<0.05) but not in the collar group (p>0.05). The CTRL group demonstrated significantly larger preseason to postseason DTI change in multiple WM regions compared with the collar group (corrected p<0.05).

Discussion

Reduced WM diffusivity alteration was noted in participants wearing a neck collar after a season of competitive football. Collar wearing may have provided a protective effect against brain microstructural changes after repetitive head impacts.

Trial registration number

NCT02696200.
Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study
Authors: Alabas O A , Hall M , Dondo T B , Rutherford M J , Timmis A D , Batin P D , Deanfield J E , Hemingway H , Gale C P
Published: June 2016

Background

The long-term excess risk of death associated with diabetes following acute myocardial infarction is unknown. We determined the excess risk of death associated with diabetes among patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) after adjustment for comorbidity, risk factors and cardiovascular treatments.

Methods

Nationwide population-based cohort (STEMI n=281 259 and NSTEMI n=422 661) using data from the UK acute myocardial infarction registry, MINAP, between 1 January 2003 and 30 June 2013. Age, sex, calendar year and country-specific mortality rates for the populace of England and Wales (n=56.9 million) were matched to cases of STEMI and NSTEMI. Flexible parametric survival models were used to calculate excess mortality rate ratios (EMRR) after multivariable adjustment. This study is registered at ClinicalTrials.gov (NCT02591576).

Results

Over 1.94 million person-years follow-up including 120 568 (17.1%) patients with diabetes, there were 187 875 (26.7%) deaths. Overall, unadjusted (all cause) mortality was higher among patients with than without diabetes (35.8% vs 25.3%). After adjustment for age, sex and year of acute myocardial infarction, diabetes was associated with a 72% and 67% excess risk of death following STEMI (EMRR 1.72, 95% CI 1.66 to 1.79) and NSTEMI (1.67, 1.63 to 1.71). Diabetes remained significantly associated with substantial excess mortality despite cumulative adjustment for comorbidity (EMRR 1.52, 95% CI 1.46 to 1.58 vs 1.45, 1.42 to 1.49), risk factors (1.50, 1.44 to 1.57 vs 1.33, 1.30 to 1.36) and cardiovascular treatments (1.56, 1.49 to 1.63 vs 1.39, 1.36 to 1.43).

Conclusions

At index acute myocardial infarction, diabetes was common and associated with significant long-term excess mortality, over and above the effects of comorbidities, risk factors and cardiovascular treatments.
Novel, single-beat approach for determining both end-systolic pressure–dimension relationship and preload recruitable stroke work
Authors: Inuzuka Ryo , Kass David A , Senzaki Hideaki
Published: June 2016

Objective

The end-systolic pressure–dimension relationship (ESPDR) and the preload recruitable stroke work (PRSW) relationship are load-insensitive measures of contractility, but their clinical application has been limited by the need to record multiple beats over a wide volume range. In this study, we therefore sought to validate a new method to concomitantly determine the ESPDR and the PRSW relationship from a single beat.

Methods

Pressure–dimension loops were recorded in 14 conscious dogs under various haemodynamic and pathological conditions. Multiple-beat PRSW relationship was determined for its slope (Mw) and for a dimension-axis intercept (Dw). The ESPDR represented by the formula, was estimated from a steady-state, single-beat late-systolic pressure–dimension relationship. The single-beat Mwwas determined as an end-systolic pressure when the end-systolic dimension was equal to Dw.

Results

A strong correlation was observed between multiple-beat and single-beat ESPDRs (zero-stress dimension; r=0.98, p<0.0001). The single-beat estimation of Mwcalculated using the wall thickness was strongly correlated with the actual Mw(r=0.93, p<0.0001) and was sensitive enough to detect the change in contractility by dobutamine infusion (p<0.001) and by tachycardia-induced heart failure (p<0.001). Similar results were obtained for Mwestimated without information on wall thickness.

Conclusions

Mwcan be interpreted as an end-systolic pressure when the end-systolic dimension is equal to Dw. By using the non-linear ESPDR, accurate single-beat estimation of the ESPDR and Mwis possible even without information on wall thickness. These results should enhance the applicability of pressure–volume framework to clinical medicine.
Canadian 24-Hour Movement Guidelines for Children and Youth: Exploring the perceptions of stakeholders regarding their acceptability, barriers to uptake, and dissemination
Authors: Faulkner Guy , White Lauren , Riazi Negin , Latimer-Cheung Amy E. , Tremblay Mark S.
Published: June 2016

Engaging stakeholders in the development of guidelines and plans for implementation is vital. The purpose of this study was to examine stakeholders’ (parents, teachers, exercise professionals, paediatricians, and youth) perceptions of the Canadian 24-Hour Movement Behaviour Guidelines for Children and Youth (“Movement Guidelines”). Stakeholders (n = 104) engaged in semi-structured focus groups or interviews to discuss the perceived acceptability of the guidelines, potential barriers to implementation, and preferred methods and messengers of dissemination. A thematic analysis was conducted. Overall, there was consistent support across all stakeholder groups, with the exception of youth participants, for the Movement Guidelines. Stakeholders identified a range of barriers to the uptake of the guidelines including concerns with accurately defining key terms such as “recreational” screen time; everyday challenges such as financial and time constraints; and the possibility of the Movement Guidelines becoming just another source of stress and guilt for already busy and overwhelmed parents. Participants identified a range of recommended methods and messengers for future dissemination. School and medical settings were the most commonly recommended settings through which dissemination efforts should be delivered. Overall, participants representing a range of stakeholder groups were receptive to the new Movement Guidelines and endorsed their value. In complementing the Movement Guidelines, messaging and resources will need to be developed that address common concerns participants had regarding their dissemination and implementation.
Canadian 24-Hour Movement Guidelines for Children and Youth: An Integration of Physical Activity, Sedentary Behaviour, and Sleep
Authors: Tremblay Mark S. , Carson Valerie , Chaput Jean-Philippe , Connor Gorber Sarah , Dinh Thy , Duggan Mary , Faulkner Guy , Gray Casey E. , Gruber Reut , Janson Katherine , Janssen Ian , Katzmarzyk Peter T. , Kho Michelle E. , Latimer-Cheung Amy E. , LeBlanc Claire , Okely Anthony D. , Olds Timothy , Pate Russell R. , Phillips Andrea , Poitras Veronica J. , Rodenburg Sophie , Sampson Margaret , Saunders Travis J. , Stone James A. , Stratton Gareth , Weiss Shelly K. , Zehr Lori
Published: June 2016

Leaders from the Canadian Society for Exercise Physiology convened representatives of national organizations, content experts, methodologists, stakeholders, and end-users who followed rigorous and transparent guideline development procedures to create the Canadian 24-Hour Movement Guidelines for Children and Youth: An Integration of Physical Activity, Sedentary Behaviour, and Sleep. These novel guidelines for children and youth aged 5–17 years respect the natural and intuitive integration of movement behaviours across the whole day (24-h period). The development process was guided by the Appraisal of Guidelines for Research Evaluation (AGREE) II instrument and systematic reviews of evidence informing the guidelines were assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Four systematic reviews (physical activity, sedentary behaviour, sleep, integrated behaviours) examining the relationships between and among movement behaviours and several health indicators were completed and interpreted by expert consensus. Complementary compositional analyses were performed using Canadian Health Measures Survey data to examine the relationships between movement behaviours and health indicators. A stakeholder survey was employed (n = 590) and 28 focus groups/stakeholder interviews (n = 104) were completed to gather feedback on draft guidelines. Following an introductory preamble, the guidelines provide evidence-informed recommendations for a healthy day (24 h), comprising a combination of sleep, sedentary behaviours, light-, moderate-, and vigorous-intensity physical activity. Proactive dissemination, promotion, implementation, and evaluation plans have been prepared in an effort to optimize uptake and activation of the new guidelines. Future research should consider the integrated relationships among movement behaviours, and similar integrated guidelines for other age groups should be developed.
Way-out to the gravitino problem in intersecting D-brane Pati–Salam models
Authors: Addazi Andrea , Khlopov Maxim Yu
Published: June 2016

We discuss the gravitino problem in the context of the exotic see-saw mechanism for neutrinos and leptogenesis, UV completed by intersecting D-branes Pati–Salam models. In the exotic see-saw model, supersymmetry is broken at high scales M[Formula: see text] 109 GeV and this seems in contradiction with gravitino bounds from inflation and baryogenesis. However, if gravitino is the lightest stable supersymmetric particle, it will not decay into other SUSY particles, avoiding the gravitino problem and providing a good cold dark matter (CDM). Gravitini are super heavy dark particles and they can be produced by non-adiabatic expansion during inflation. Intriguingly, from bounds on the correct abundance of dark matter (DM), we also constrain the neutrino sector. We set a limit on the exotic instantonic coupling of [Formula: see text] 10[Formula: see text]–10[Formula: see text]. This also sets constrains on the Calabi–Yau compactifications and on the string scale. This model strongly motivates very high energy DM indirect detection of neutrini and photons of 10[Formula: see text]–10[Formula: see text] GeV: gravitini can decay on them in a cosmological time because of soft R-parity breaking effective operators.
Unsteady magnetohydrodynamic flow of a fourth grade fluid caused by an impulsively moving plate in a Darcy porous medium ߞ A group-theoretical analysis
Authors: Carrim A. H. , Aziz Taha , Mahomed F. M. , Khalique Chaudry Masood
Published: June 2016

The effects of non-Newtonian fluids are investigated by means of an appropriate model studying the flow of a fourth grade fluid. The geometry of this model is described by the unsteady unidirectional flow of an incompressible fluid over an infinite flat plate within a porous medium. The fluid is electrically conducting in the presence of a uniform applied magnetic field. The classical Lie symmetry approach is utilized in order to construct group invariant solutions to the governing higher-order nonlinear partial differential equation (PDE). The conditional symmetry approach has also been utilized to solve the governing model. Some new classes of conditional symmetry solutions have been obtained for the model equation in the form of closed-form exponential functions. The invariant solution corresponding to the nontraveling wave type is considered to be the most significant solution for the fluid flow model under investigation since it directly incorporates the physical behavior of the flow model.
Ultralow frequency acoustic bandgap and vibration energy recovery in tetragonal folding beam phononic crystal
Authors: Gao Nansha , Wu Jiu Hui , Yu Lie , Hou Hong
Published: June 2016

This paper investigates ultralow frequency acoustic properties and energy recovery of tetragonal folding beam phononic crystal (TFBPC) and its complementary structure. The dispersion curve relationships, transmission spectra and displacement fields of the eigenmodes are studied with FEA in detail. Compared with the traditional three layer phononic crystal (PC) structure, this structure proposed in this paper not only unfold bandgaps (BGs) in lower frequency range (below 300 Hz), but also has lighter weight because of beam structural cracks. We analyze the relevant physical mechanism behind this phenomenon, and discuss the effects of the tetragonal folding beam geometric parameters on band structure maps. FEM proves that the multi-cell structures with different arrangements have different acoustic BGs when compared with single cell structure. Harmonic frequency response and piezoelectric properties of TFBPC are specifically analyzed. The results confirm that this structure does have the recovery ability for low frequency vibration energy in environment. These conclusions in this paper could be indispensable to PC practical applications such as BG tuning and could be applied in portable devices, wireless sensor, micro-electro mechanical systems which can recycle energy from vibration environment as its own energy supply.
HEAT AND MASS TRANSFER ANALYSIS ON PERISTALTIC FLOW OF PARTICLE–FLUID SUSPENSION WITH SLIP EFFECTS
Authors: BHATTI M. M. , ZEESHAN A.
Published: June 2016

In this paper, the effect of heat and mass transfer on particle–fluid suspension due to peristaltic motion is examined with of slip effects. The governing equations of fluid phase and particulate phase for Casson fluid model with embedded particles are interpreted under the approximation of long wavelength and neglecting the inertial forces. The obtained coupled resulting partial differential equations are solved analytically and an exact form of solutions are conferred. The impact of various sundry parameters are plotted and discussed for velocity, temperature and concentration distribution for both fluid and particle phase. Numerical solution is evaluated for pressure rise along the whole channel. The present analysis reveals various interesting behavior that warrant further analysis on various Newtonian and non-Newtonian fluids. In the present flow problem, the influence of slip represents opposite attitude on the walls of the channel whereas due to the impact of particle volume fractions, the velocity of the fluid diminishes along the whole length of the channel.
Synthesis of ceramic-based porous gradient structures for applications in energy conversion and related fields
Authors: Graule Thomas , Ozog Paulina , Durif Caroline , Wilkens-Heinecke Judit , Kata Dariusz
Published: June 2016

Porous, graded ceramic structures are of high relevance in the field of energy conversion as well as in catalysis, and additionally in filtration technology and in biomedical applications. Among different technologies for the tailored design for such structures we demonstrate here a new environmental friendly UV curing-based concept to prepare laminated structures with pore sizes ranging from a few microns up to 50 microns in diameter and with porosities ranging from 10% up to 75 vol.% porosity.
Debating China’s Energy Security
Authors: Zha Daojiong
Published: June 2016

In China, debates on energy security are diverse and far beyond geopolitical analysis. Findings from the ever-expanding literature indicate two major schools of thought, namely the nationalist and globalist ones, while a pragmatic approach has been prevailing that integrates exploring domestic sources and engaging external actors when needed. The challenges of having to do whatever feasible to meet energy demands and at the same time, pursuing alternatives that reduce its negative impact on human health and environment, have led to growing pluralism in policy advocacy in China. While the two schools of thought on energy security will continue to compete against each other, the argumentative strength of each school shall be conditioned by many factors influencing China’s macro-economic fluctuations in general and energy economies in particular. The Chinese government’s energy policy-making is expected to reflect a dynamic balance between both schools.
Glycan Arrays: From Basic Biochemical Research to Bioanalytical and Biomedical Applications
Authors: Geissner Andreas , Seeberger Peter H.
Published: June 2016

A major branch of glycobiology and glycan-focused biomedicine studies the interaction between carbohydrates and other biopolymers, most importantly, glycan-binding proteins. Today, this research into glycan-biopolymer interaction is unthinkable without glycan arrays, tools that enable high-throughput analysis of carbohydrate interaction partners. Glycan arrays offer many applications in basic biochemical research, for example, defining the specificity of glycosyltransferases and lectins such as immune receptors. Biomedical applications include the characterization and surveillance of influenza strains, identification of biomarkers for cancer and infection, and profiling of immune responses to vaccines. Here, we review major applications of glycan arrays both in basic and applied research. Given the dynamic nature of this rapidly developing field, we focus on recent findings.
Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases
Authors: Liepelt Anke , Tacke Frank
Published: June 2016

The chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is constitutively expressed in healthy liver. However, its expression increases following acute or chronic liver injury. Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and malignant hepatocytes are important sources of SDF-1/CXCL12 in liver diseases. CXCL12 is able to activate two chemokine receptors with different downstream signaling pathways, CXCR4 and CXCR7. CXCR7 expression is relevant on LSEC, while HSC, mesenchymal stem cells, and tumor cells mainly respond via CXCR4. Here, we summarize recent developments in the field of liver diseases involving this chemokine and its receptors. SDF-1-dependent signaling contributes to modulating acute liver injury and subsequent tissue regeneration. By activating HSC and recruiting mesenchymal cells from bone marrow, CXCL12 can promote liver fibrosis progression, while CXCL12-CXCR7 interactions endorse proregenerative responses in chronic injury. Moreover, the SDF-1 pathway is linked to development of hepatocellular carcinoma (HCC) by promoting tumor growth, angiogenesis, and HCC metastasis. High hepatic CXCR4 expression has been suggested as a biomarker indicating poor prognosis of HCC patients. Tumor-infiltrating myeloid-derived suppressor cells (MDSC) also express CXCR4 and migrate toward CXCL12. Thus CXCL12 inhibition might not only directly block HCC growth but also modulate the tumor microenvironment (angiogenesis, MDSC), thereby sensitizing HCC patients to conventional or emerging novel cancer therapies (e.g., sorafenib, regorafenib, nivolumab, pembrolizumab). We herein summarize the current knowledge on the complex interplay between CXCL12 and CXCR4/CXCR7 in liver diseases and discuss approaches on the therapeutic targeting of these axes in hepatitis, fibrosis, and liver cancer.
PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells
Authors: Nasri Imen , Bonnet Delphine , Zwarycz Bailey , d'Aldebert Emilie , Khou Sokchea , Mezghani-Jarraya Raoudha , Quaranta Muriel , Rolland Corinne , Bonnart Chrystelle , Mas Emmanuel , Ferrand Audrey , Cenac Nicolas , Magness Scott , Van Landeghem Laurianne , Vergnolle Nathalie , Racaud-Sultan Claire
Published: June 2016

Protease-activated receptors PAR1 and PAR2 play an important role in the control of epithelial cell proliferation and migration. However, the survival of normal and tumor intestinal stem/progenitor cells promoted by proinflammatory mediators may be critical in oncogenesis. The glycogen synthase kinase-3β (GSK3β) pathway is overactivated in colon cancer cells and promotes their survival and drug resistance. We thus aimed to determine PAR1 and PAR2 effects on normal and tumor intestinal stem/progenitor cells and whether they involved GSK3β. First, PAR1 and PAR2 were identified in colon stem/progenitor cells by immunofluorescence. In three-dimensional cultures of murine crypt units or single tumor Caco-2 cells, PAR2 activation decreased numbers and size of normal or cancerous spheroids, and PAR2-deficient spheroids showed increased proliferation, indicating that PAR2 represses proliferation. PAR2-stimulated normal cells were more resistant to stress (serum starvation or spheroid passaging), suggesting prosurvival effects of PAR2. Accordingly, active caspase-3 was strongly increased in PAR2-deficient normal spheroids. PAR2 but not PAR1 triggered GSK3β activation through serine-9 dephosphorylation in normal and tumor cells. The PAR2-triggered GSK3β activation implicates an arrestin/PP2A/GSK3β complex that is dependent on the Rho kinase activity. Loss of PAR2 was associated with high levels of GSK3β nonactive form, strengthening the role of PAR2 in GSK3β activation. GSK3 pharmacological inhibition impaired the survival of PAR2-stimulated spheroids and serum-starved cells. Altogether our data identify PAR2/GSK3β as a novel pathway that plays a critical role in the regulation of stem/progenitor cell survival and proliferation in normal colon crypts and colon cancer.
Aortic pulse pressure homeostasis emerges from physiological adaptation of systemic arteries to local mechanical stresses
Authors: Nguyen Phuc H. , Tuzun Egemen , Quick Christopher M.
Published: June 2016

Aortic pulse pressure arises from the interaction of the heart, the systemic arterial system, and peripheral microcirculations. The complex interaction between hemodynamics and arterial remodeling precludes the ability to experimentally ascribe changes in aortic pulse pressure to particular adaptive responses. Therefore, the purpose of the present work was to use a human systemic arterial system model to test the hypothesis that pulse pressure homeostasis can emerge from physiological adaptation of systemic arteries to local mechanical stresses. First, we assumed a systemic arterial system that had a realistic topology consisting of 121 arterial segments. Then the relationships of pulsatile blood pressures and flows in arterial segments were characterized by standard pulse transmission equations. Finally, each arterial segment was assumed to remodel to local stresses following three simple rules: 1) increases in endothelial shear stress increases radius, 2) increases in wall circumferential stress increases wall thickness, and 3) increases in wall circumferential stress decreases wall stiffness. Simulation of adaptation by iteratively calculating pulsatile hemodynamics, mechanical stresses, and vascular remodeling led to a general behavior in response to mechanical perturbations: initial increases in pulse pressure led to increased arterial compliances, and decreases in pulse pressure led to decreased compliances. Consequently, vascular adaptation returned pulse pressures back toward baseline conditions. This behavior manifested when modeling physiological adaptive responses to changes in cardiac output, changes in peripheral resistances, and changes in local arterial radii. The present work, thus, revealed that pulse pressure homeostasis emerges from physiological adaptation of systemic arteries to local mechanical stresses.
Distinct contributions of explicit and implicit memory processes to weight prediction when lifting objects and judging their weights: an aging study
Authors: Trewartha Kevin M. , Flanagan J. Randall
Published: June 2016

Weight predictions used to scale lifting forces adapt quickly when repeatedly lifting unusually weighted objects and are readily updated by explicit information provided about weight. In contrast, weight predictions used when making perceptual judgments about weight are more resistant to change and are largely unaffected by explicit information about weight. These observations suggest that distinct memory systems underlie weight prediction when lifting objects and judging their weights. Here we examined whether these weight predictions differ in their reliance on declarative and nondeclarative memory resources by comparing the adaptability of these predictions in older adults, who exhibit relatively impaired declarative memory processes, to those in younger adults. In the size condition, we measured lift forces as participants repeatedly lifted a pair of size-weight inverted objects in alternation. To assess weight judgments, we measured the size-weight illusion every 10 lifts. The material condition was similar, except that we used material-weight inverted objects and measured the material-weight illusion. The strengths of these illusions prior to lifting, and the attenuation of the illusions that arise when lifting inverted objects, were similar for both groups. The magnitude of the change in the illusions was positively correlated with implicit memory performance in both groups, suggesting that predictions used when judging weight rely on nondeclarative memory resources. Updating of lifting forces also did not differ between groups. However, within the older group the success with which lifting forces were updated was positively correlated with working memory performance, suggesting that weight predictions used when lifting rely on declarative memory resources.
The Determination of Feasible Control Variables for Geoengineering and Weather Modification Based on the Theory of Sensitivity in Dynamical Systems
Authors: Soldatenko Sergei A. , Yusupov Rafael M.
Published: June 2016

Geophysical cybernetics allows for exploring weather and climate modification (geoengineering) as an optimal control problem in which the Earth’s climate system is considered as a control system and the role of controller is given to human operators. In mathematical models used in climate studies control actions that manipulate the weather and climate can be expressed via variations in model parameters that act as controls. In this paper, we propose the “instability-sensitivity” approach that allows for determining feasible control variables in geoengineering. The method is based on the sensitivity analysis of mathematical models that describe various types of natural instability phenomena. The applicability of this technique is illustrated by a model of atmospheric baroclinic instability since this physical mechanism plays a significant role in the general circulation of the atmosphere and, consequently, in climate formation. The growth rate of baroclinic unstable waves is taken as an indicator of control manipulations. The information obtained via calculated sensitivity coefficients is very beneficial for assessing the physical feasibility of methods of control of the large-scale atmospheric dynamics and for designing optimal control systems for climatic processes. It also provides insight into potential future changes in baroclinic waves, as a result of a changing climate.
Influence of Cultivar on the Postharvest Hardening of Trifoliate Yam (Dioscorea dumetorum) Tubers
Authors: Siadjeu Christian , Akdowa Panyoo Emmanuel , Mahbou Somo Toukam Gabriel , Bell Joseph Martin , Nono Benoit , Medoua Gabriel Nama
Published: June 2016

The influence of cultivar on the postharvest hardening ofDioscorea dumetorumtubers was assessed. 32 cultivars ofD. dumetorumtubers were planted in April 2014, harvested at physiological maturity, and stored under prevailing tropical ambient conditions (19–28°C, 60–85% RH) for 0, 5, 14, 21, and 28 days. Samples were evaluated for cooked hardness. Results showed that one cultivar, Ibo sweet 3, was not affected by the hardening phenomenon. The remaining 31 were all subject to the hardening phenomenon at different degree. Cooked hardness increased more rapidly in cultivars with many roots on the tuber surface compared to cultivars with few roots on the tuber surface. When both the characteristics flesh colour and number of roots on tuber surface were associated, cooked hardness in cultivars with yellow flesh and many roots increased more rapidly than in cultivars with white flesh and many roots, whereas cooked hardness in cultivars with yellow flesh and few roots increased more slowly than in cultivars with white flesh and few roots. Accessions collected in high altitude increased more rapidly compared to accessions collected in low altitude. The cultivar Ibo sweet 3 identified in this study could provide important information for breeding program ofD. dumetorumagainst postharvest hardening phenomenon.
Obstructive Sleep Apnea and Hypertension in Adolescents: Effect on Neurobehavioral and Cognitive Functioning
Authors: Madaeva Irina , Berdina Olga , Polyakov Vladimir , Kolesnikov Sergey
Published: June 2016

Background. There are limited published data in regard to the relationship between obstructive sleep apnea (OSA) and hypertension and neurobehavioral and mental status in adolescence. The aim of our study was to evaluate neurobehavioral patterns and cognitive functions in adolescents with hypertension according to absence or presence of OSA.Methods. This was a retrospective cohort study completed at the Scientific Center for Family Health and Human Reproduction Problems. Participants included adolescents aged 14–17 years and referred for 24-hour ambulance blood pressure monitoring (ABPM) and polysomnographic (PSG) studies between 2007 and 2009, inclusive.Results. 18 hypertensive OSA (the 1st group) and 20 hypertensive non-OSA adolescents (the 2nd group) were included in the study. Significant changes of neurobehavioral functioning in OSA patients were shown. Cognitive abilities also were impaired. Verbal and visual memory indexes and attention index were 2.1 and 2.2 times lower, accordingly, in the 1st group than in the 2nd group (P<0.05). Speech index was significantly 2.8 times lower in OSA patients than in non-OSA patients (P<0.05). In hypertensive OSA adolescents more significant Spearman correlations between classic sleep parameters and cognitive measures were found compared to patients without OSA.Conclusions. These results suggest that OSA is closely associated with neurobehavioral and cognitive functioning in hypertensive adolescents.
Probabilistic Path and Data Capacity Based Handover Decision for Hierarchical Macro- and Femtocell Networks
Authors: Lee Jae-Wook , Yoo Sang-Jo
Published: June 2016

Femtocells are considered a technology to improve performance of a network by increasing network coverage and communication capacity at a relatively low cost. However, if there are a lot of femtocells in a macrocell, the number of handovers greatly increases, and unnecessary handovers can occur from the mobile station temporarily passing through a femtocell. In this paper, we propose a method that probabilistically estimates the path in a femtocell and makes a handover decision based on the available data capacity of a mobile station on the estimated path. Simulation results show that the proposed method effectively reduces the number of unnecessary handovers while improving the data rate and capacity.
Analytical Investigation of Magnetohydrodynamic Flow over a Nonlinear Porous Stretching Sheet
Authors: Mabood Fazle , Pochai Nopparat
Published: June 2016

We investigated the magnetohydrodynamic (MHD) boundary layer flow over a nonlinear porous stretching sheet with the help of semianalytical method known as optimal homotopy asymptotic method (OHAM). The effects of different parameters on fluid flow are investigated and discussed. The obtained results are compared with numerical Runge-Kutta-Fehlberg fourth-fifth-order method. It is found that the OHAM solution agrees well with numerical as well as published data for different assigned values of parameters; this thus indicates the feasibility of the proposed method (OHAM).
Combined DSEK and Transconjunctival Pars Plana Vitrectomy
Authors: Sane Mona , Shaikh Naazli , Shaikh Saad
Published: June 2016

We report here three patients who underwent combined Descemet’s stripping with endothelial keratoplasty and transconjunctival pars plana vitrectomy for bullous keratopathy and posterior segment pathology. A surgical technique and case histories are described. Anatomic and visual outcomes of combined Descemet’s stripping with endothelial keratoplasty and vitrectomy were excellent. Our experience provides technical guidelines and limitations. The combined minimally invasive techniques allow for rapid anatomical recovery and return of function and visual acuity in a single sitting.
Sorafenib and Quinacrine Target Anti-Apoptotic Protein MCL1: A Poor Prognostic Marker in Anaplastic Thyroid Cancer (ATC)
Authors: Abdulghani Junaid , Gokare Prashanth , Gallant Jean-Nicolas , Dicker David , Whitcomb Tiffany , Cooper Timothy , Liao Jiangang , Derr Jonathan , Liu Jing , Goldenberg David , Finnberg Niklas K. , El-Deiry Wafik S.
Published: June 2016

Purpose and Experimental Design: Anaplastic thyroid cancer (ATC) comprises approximately 2% of all thyroid cancers, and its median survival rate remains poor. It is responsible for more than one third of thyroid cancer–related deaths. ATC is frequently resistant to conventional therapy, and NFκB signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the antimalaria drug quinacrine known to target NFκB signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFκB-p65/RELA and its target MCL1 was demonstrated in ATC by meta-data gene set enrichment analysis and IHC. We assessed the responses of a panel of human ATC cell lines to quinacrine and sorafenib in vitro and in vivo.

Results: We detected increased expression of NFκB-p65/RELA and MCL1 in the nucleus of a subset of ATC compared with non-neoplastic thyroid. ATC cells were found to respond with additive/synergistic tumor cell killing to the combination of sorafenib plus quinacrine in vitro, and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC cells as compared with mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and quinacrine is well tolerated in mice. At the molecular level, quinacrine and sorafenib inhibited expression of prosurvival MCL1, pSTAT3, and dampened NFκB signaling.

Conclusions: The combination of quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus quinacrine can be conducted in ATC patients. Clin Cancer Res; 22(24); 6192–203. ©2016 AACR.
PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo
Authors: Niessner Heike , Schmitz Jennifer , Tabatabai Ghazaleh , Schmid Andreas M. , Calaminus Carsten , Sinnberg Tobias , Weide Benjamin , Eigentler Thomas K. , Garbe Claus , Schittek Birgit , Quintanilla-Fend Leticia , Bender Benjamin , Mai Marion , Praetorius Christian , Beissert Stefan , Schackert Gabriele , Muders Michael H. , Meinhardt Matthias , Baretton Gustavo B. , Dummer Reinhard , Flaherty Keith , Pichler Bernd J. , Kulms Dagmar , Westphal Dana , Meier Friedegund
Published: June 2016

Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for “brain-specific” therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases.

Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib.

Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. Clin Cancer Res; 22(23); 5818–28. ©2016 AACR.
Delta One T Cells for Immunotherapy of Chronic Lymphocytic Leukemia: Clinical-Grade Expansion/Differentiation and Preclinical Proof of Concept
Authors: Almeida Afonso R. , Correia Daniel V. , Fernandes-Platzgummer Ana , da Silva Cláudia L. , da Silva Maria Gomes , Anjos Diogo Remechido , Silva-Santos Bruno
Published: June 2016

Purpose: The Vδ1+ subset of γδ T lymphocytes is a promising candidate for cancer immunotherapy, but the lack of suitable expansion/differentiation methods has precluded therapeutic application. We set out to develop and test (preclinically) a Vδ1+ T-cell–based protocol that is good manufacturing practice compatible and devoid of feeder cells for prompt clinical translation.

Experimental design: We tested multiple combinations of clinical-grade agonist antibodies and cytokines for their capacity to expand and differentiate (more than 2–3 weeks) Vδ1+ T cells from the peripheral blood of healthy donors and patients with chronic lymphocytic leukemia (CLL). We characterized the phenotype and functional potential of the final cellular product, termed Delta One T (DOT) cells, in vitro and in vivo (xenograft models of CLL).

Results: We describe a very robust two-step protocol for the selective expansion (up to 2,000-fold in large clinical-grade cell culture bags) and differentiation of cytotoxic Vδ1+ (DOT) cells. These expressed the natural cytotoxicity receptors, NKp30 and NKp44, which synergized with the T-cell receptor to mediate leukemia cell targeting in vitro. When transferred in vivo, DOT cells infiltrated tumors and peripheral organs, and persisted until the end of the analysis without showing signs of loss of function; indeed, DOT cells proliferated and produced abundant IFNγ and TNFα, but importantly no IL17, in vivo. Critically, DOT cells were capable of inhibiting tumor growth and preventing dissemination in xenograft models of CLL.

Conclusions: We provide a clinical-grade method and the preclinical proof of principle for application of a new cellular product, DOT cells, in adoptive immunotherapy of CLL. Clin Cancer Res; 22(23); 5795–804. ©2016 AACR.
External validation of the IMPROVE Bleeding Risk Assessment Model in medical patients
Authors: Rosenberg David J. , Press Anne , Fishbein Joanna , Lesser Martin , McCullagh Lauren , McGinn Thomas , Spyropoulos Alex C.
Published: June 2016

The IMPROVE Bleed Risk Assessment Model (RAM) remains the only bleed RAM in hospitalised medical patients using 11 clinical and laboratory factors. The aim of our study was to externally validate the IMPROVE Bleed RAM. A retrospective chart review was conducted between October 1, 2012 and July 31, 2014. We applied the point scoring system to compute risk scores for each patient in the validation sample. We then dichotomised the patients into those with a score <7 (low risk) vs ≥ 7 (high risk), as outlined in the original study, and compared the rates of any bleed, non-major bleed, and major bleed. Among the 12,082 subjects, there was an overall 2.6 % rate of any bleed within 14 days of admission. There was a 2.12 % rate of any bleed in those patients with a score of < 7 and a 4.68 % rate in those with a score ≥ 7 [Odds Ratio (OR) 2.3 (95 % CI=1.8–2.9), p<0.0001]. MB rates were 1.5 % in the patients with a score of < 7 and 3.2 % in the patients with a score of ≥ 7, [OR 2.2 (95 % CI=1.6–2.9), p<0.0001]. The ROC curve was 0.63 for the validation sample. This study represents the largest externally validated Bleed RAM in a hospitalised medically ill patient population. A cut-off point score of 7 or above was able to identify a high-risk patient group for MB and any bleed. The IMPROVE Bleed RAM has the potential to allow for more tailored approaches to thromboprophylaxis in medically ill hospitalised patients.

Supplementary Material to this article is available online at www.thrombosis-online.com.