bluuebunny/crossref_metadata_2025 huggingface dataset:
Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi‐targeted kinase inhibitors in pimasertib‐resistant human lung and colorectal cancer cells
Authors: Martinelli Erika , Troiani Teresa , D'Aiuto Elena , Morgillo Floriana , Vitagliano Donata , Capasso Anna , Costantino Sarah , Ciuffreda Loreta Pia , Merolla Francesco , Vecchione Loredana , De Vriendt Veerle , Tejpar Sabine , Nappi Anna , Sforza Vincenzo , Martini Giulia , Berrino Liberato , De Palma Raffaele , Ciardiello Fortunato
Published: April 2013

The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti‐cancer therapies. The in vitro and in vivo anti‐tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi‐targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib‐sensitive (IC50 for cell growth inhibition of 0.001 µM) or pimasertib‐resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up‐regulated in pimasertib‐resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK‐ and AKT‐dependent signaling pathways in pimasertib‐resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition.
Lipoproteins are an important bacterial component responsible for bone destruction through the induction of osteoclast differentiation and activation
Authors: Kim Jiseon , Yang Jihyun , Park Ok-Jin , Kang Seok-Seong , Kim Woo-Shin , Kurokawa Kenji , Yun Cheol-Heui , Kim Hong-Hee , Lee Bok Luel , Han Seung Hyun
Published: April 2013

Bacterial infection can cause inflammatory bone diseases accompanied by the bone destruction resulting from excess generation of osteoclasts. Although lipoproteins are one of the major immunostimulating components of bacteria, little is known about their effects on bone metabolism. In this study, we investigated the role of lipoproteins in bacteria-induced bone destruction using Staphylococcus aureus wild type, its lipoprotein-deficient mutant, and synthetic lipopeptides Pam2CSK4 and Pam3CSK4 known to mimic bacterial lipoproteins. Formaldehyde-inactivated S. aureus or the synthetic lipopeptides induced severe bone loss in the femurs of mice after intraperitoneal administration and in a calvarial bone implantation model, whereas the lipoprotein-deficient S. aureus did not show such effects. Mechanism studies further identified three action mechanisms for the lipopeptide-induced osteoclast differentiation and bone resorption via (i) enhancement of osteoclast differentiation through Toll-like receptor 2 and MyD88-dependent signaling pathways; (ii) induction of pro-inflammatory cytokines, TNF-α and IL-6; and (iii) upregulation of RANKL expression with downregulation of osteoprotegerin expression in osteoblasts. Taken together, these results suggest that lipoprotein might be an important bacterial component responsible for bone destruction during bacterial infections through augmentation of osteoclast differentiation and activation. © 2013 American Society for Bone and Mineral Research.
The Cloning and Expression Analysis of Lhx9 During Gonadal Sex Differentiation in the Red‐Eared Slider Turtle, Trachemys scripta, a Species With Temperature‐Dependent Sex Determination
Authors: BIESER KAYLA L. , WIBBELS THANE , MOURAD GEORGE , PALADINO FRANK
Published: April 2013

Many reptiles, including the red‐eared slider turtle (Trachemys scripta), possess a temperature‐dependent sex determination (TSD) mechanism where the temperature at which the developing embryos are incubated dictates the gonadal sex of the animal. A number of mammalian gene orthologues have been identified in the sex determination/differentiation cascade of reptiles with TSD although the exact trigger(s) is not well understood. A potential early regulator of gonadal differentiation, Lhx9, controls the proliferation of gonadal cells in mice and its absence prevents gonadal development and drastically reduces the expression of Sf‐1, a gene that regulates the expression of steroidogenic enzymes in the bipotential gonad. In the current study, we cloned Lhx9 from T. scripta and analyzed its expression throughout the thermosensitive period of gonad development using quantitative PCR. We examined the expression profiles of Lhx9 in embryos incubated under control conditions at male‐ and female‐producing temperatures and with the application of exogenous 17β‐estradiol or an aromatase inhibitor, Letrozole, to induce sex reversal. The T. scripta Lhx9 cDNA and predicted amino acid sequence showed high homology to those of chicken, anole, and mouse. Lhx9 was expressed at both male‐ and female‐producing temperatures with expression levels increasing throughout the thermosensitive period. Letrozole induced sex‐reversal did not alter Lhx9 expression levels. 17β‐estradiol treatments appeared to inhibit or delay gonadal differentiation and resulted in lower Lhx9 expression from the presumptive gonadal ridge region. The structural homology and temporal expression pattern of Lhx9 suggests that this represents a conserved element in the gonadal differentiation cascade of T. scripta. J. Exp. Zool. (Mol. Dev. Evol.) 320B:238–246, 2013. © 2013 Wiley Periodicals, Inc.
Wolbachia in the Malpighian Tubules: Evolutionary Dead‐End or Adaptation?
Authors: FARIA VÍTOR G. , SUCENA ÉLIO
Published: April 2013

Facultative endosymbionts, such as Wolbachia, perpetuate by vertical transmission mostly through colonization of the germline during embryogenesis. The remaining Wolbachia inside the embryo are internalized in progenitor cells of the somatic tissue. This perpetuation strategy triggers a cyclic bacterial bottleneck across host generations. However, throughout the host's life history (Drosophila, for example), some somatic tissues such as the Malpighian tubules (MTs) show large numbers of Wolbachia. It is assumed that Wolbachia present in the progenitor cells of the MTs are confined to this somatic tissue, implicitly considering MTs as an evolutionary dead‐end for these bacteria. Nevertheless, the fact that bacteria can survive and proliferate inside MTs suggests a different fate as they may access the host's reproductive system and persist in the host population through vertical transmission. Indeed, based on the particular physiological and developmental characteristics of MT, as well as of Wolbachia, we argue the bacteria present in the MTs may constitute a secondary pool of vertically transmitted bacteria. Moreover, somatic pools of Wolbachia capable of reaching the gonads and insure vertical transmission may also provide an interesting element to the elucidation of horizontal transmission mechanisms. Finally, we also speculate that somatic pools of Wolbachia may play an important role in host fitness, namely during viral infections. In brief, we argue that the somatic pools of Wolbachia, with special emphasis on the MT subset, deserve experimental attention as putative players in the physiology and evolution of both bacteria and hosts. J. Exp. Zool. (Mol. Dev. Evol.) 320B:195–199, 2013. © 2013 Wiley Periodicals, Inc.
Seafloor structure near the epicenter of the great 25 March 1998 Antarctic Plate earthquake
Authors: Nogi Yoshifumi
Published: April 2013

The great Antarctic Plate earthquake (M 8.1) that took place on 25 March 1998 was one of the largest oceanic intraplate strike‐slip events ever recorded, but the cause of the earthquake is still unclear. Detailed marine geophysical surveys were conducted near the epicenter of the earthquake, and the results of swath bathymetry and the magnetic and gravity anomalies are presented. The data revealed the detailed structure of a seamount just south of the epicenter of the main shock. Two possible structures, which may represent the faults of the Antarctic Plate earthquake during the first subevent, were inferred from the geophysical data collected during the cruise by taking the uncertainties in the location of the epicenter and the distribution of the aftershocks into account, and the foot of the north‐side escarpment of the seamount may indicate the main fault of the first strike‐slip subevent of the Antarctic Plate earthquake. The north‐side escarpment of the seamount was most likely formed before the Antarctic Plate earthquake, indicating that the earthquake occurred along preexisting structures. The magnetic anomaly and structural trends near the seamount are different from those in adjacent areas, and the area near the seamount is likely a block that was captured during ridge reorganization. Moreover, the area near the seamount may be a crustal fragment that was formed during initial rifting between Antarctica and Australia.
A temporal change of shear wave anisotropy within the marine sedimentary layer associated with the 2011 Tohoku‐Oki earthquake
Authors: Tonegawa Takashi , Fukao Yoshio , Nishida Kiwamu , Sugioka Hiroko , Ito Aki
Published: April 2013

We found persistent reflections of S waves from the bottom of a ∼350 m thick marine sedimentary layer on the outer rise of the Japan Trench, just to the east of the source area of the 2011 great Tohoku‐Oki earthquake (Mw9.0), by auto‐correlating ambient seismic noise recorded on 1 year continuous records of broadband ocean bottom seismometers. The two‐way travel times of reflected S waves, which vary as a function of the polarization direction, indicate a velocity anisotropy of ~1.7% in the sedimentary layer. The fast direction is estimated to be trench parallel, possibly due to cracks or normal faults formed by bending of the plate in the outer rise. The travel time also shows a coseismic velocity reduction of ~2%, with slightly reduced anisotropy, within the layer. The change gradually recovered to pre‐earthquake conditions through 4 months after the earthquake, although recovery was not complete during the period of the observation. We also detected a similar anisotropic structure and magnitude of coseismic velocity reduction in this layer based on S coda of earthquakes with magnitudes greater than 5.0. Such coseismic changes can be explained either by increases of crack density and crack sphericity within the suddenly stressed sedimentary layer or by channeling and networking of water flow in the strongly shaken sedimentary layer.
Three‐dimensional dynamic models of subducting plate‐overriding plate‐upper mantle interaction
Authors: Meyer C. , Schellart W. P.
Published: April 2013

We present fully dynamic generic three‐dimensional laboratory models of progressive subduction with an overriding plate and a weak subduction zone interface. Overriding plate thickness (TOP) is varied systematically (in the range 0–2.5 cm scaling to 0–125 km) to investigate its effect on subduction kinematics and overriding plate deformation. The general pattern of subduction is the same for all models with slab draping on the 670 km discontinuity, comparable slab dip angles, trench retreat, trenchward subducting plate motion, and a concave trench curvature. The narrow slab models only show overriding plate extension. Subduction partitioning (vSP⊥ / (vSP⊥ + vT⊥)) increases with increasing TOP, where trenchward subducting plate motion (vSP⊥) increases at the expense of trench retreat (vT⊥). This results from an increase in trench suction force with increasing TOP, which retards trench retreat. An increase in TOP also corresponds to a decrease in overriding plate extension and curvature because a thicker overriding plate provides more resistance to deform. Overriding plate extension is maximum at a scaled distance of ~200–400 km from the trench, not at the trench, suggesting that basal shear tractions resulting from mantle flow below the overriding plate primarily drive extension rather than deviatoric tensional normal stresses at the subduction zone interface. The force that drives overriding plate extension is 5%–11% of the slab negative buoyancy force. The models show a positive correlation between vT⊥ and overriding plate extension rate, in agreement with observations. The results suggest that slab rollback and associated toroidal mantle flow drive overriding plate extension and backarc basin formation.
Temporal changes in attenuation associated with the 2004 M6.0 Parkfield earthquake
Authors: Kelly C. M. , Rietbrock A. , Faulkner D. R. , Nadeau R. M.
Published: April 2013

Elevated seismic attenuation is often observed in fault zones due to the high degree of fracturing and fluid content. However, temporal changes in attenuation at the time of an earthquake are poorly constrained but can give indications of fracture damage and healing. In this study, spectral ratios between earthquakes within repeating clusters are calculated in an attempt to resolve temporal variations in attenuation at the time of the 2004 M6.0 Parkfield earthquake. A sharp increase in attenuation is observed immediately after the earthquake, which then decays over the next 2 years. Influences of intercluster magnitude variations, time window length and previously reported postseismic velocity changes are investigated. The postseismic decay is fit by a logarithmic function. The timescale of the decay is found to be similar to that in GPS data and ambient seismic noise velocities following the 2004 M6.0 Parkfield earthquake. The amplitude of the attenuation change corresponds to a decrease of approximately 10% in Qp at the time of the earthquake. The greatest changes are recorded on the northeast of the fault trace, consistent with preferential damage in the extensional quadrant behind a north‐westerly propagating rupture tip. Our analysis suggests that significant changes in seismic attenuation and hence fracture dilatancy during coseismic rupture are limited to depths of less than about 5 km.
Modeling swash‐zone hydrodynamics and shear stresses on planar slopes using Reynolds‐Averaged Navier–Stokes equations
Authors: Torres‐Freyermuth Alec , Puleo Jack A. , Pokrajac Dubravka
Published: April 2013

A numerical model solving the Reynolds‐Averaged Navier–Stokes equations, with a volume of fluid‐tracking scheme and turbulence closure, is employed for estimating hydrodynamics in the swash zone. Model results for run‐up distance, water depth, and near‐bed velocity are highly correlated (r2 > 0.97) with ensemble‐averaged dam‐break‐driven swash data. Moreover, modeled bed shear stresses are within 20% of estimates derived from measured velocity profiles. Dam‐break‐driven swash simulations are conducted to determine the effect of foreshore characteristics (bed roughness and foreshore slope) on bore‐induced swash‐zone hydrodynamics and bed shear stresses. Numerical results revealed that the boundary layer vanishes during flow reversal, grows during the backwash, and becomes depth limited at the end of the swash cycle. In general, the uprush experiences larger shear stresses but for a shorter duration than the backwash. Some variability in this pattern is observed depending on the bed roughness, foreshore slope, and cross‐slope location in the swash zone, implying that large spatial gradients in shear stresses can occur on the foreshore. The mean tangential force per unit area supplied to the bed is offshore directed for the simulated cases, with the exception of the mild‐slope (1:25) cases, owing to the skewed nature of swash flows. The temporal evolution of the momentum balance inside the swash zone shows an important contribution to the total force from turbulence and advection at the early/final stage of the swash cycle, whereas the local acceleration does not appear to be a significant contribution.
Clay mineralogy of surface sediments as a tool for deciphering river contributions to the Cariaco Basin (Venezuela)
Authors: Bout‐Roumazeilles V. , Riboulleau A. , du Châtelet E. Armynot , Lorenzoni L. , Tribovillard N. , Murray R. W. , Müller‐Karger F. , Astor Y. M.
Published: April 2013

The mineralogical composition of 95 surface sediment samples from the Cariaco Basin continental shelf and Orinoco delta was investigated in order to constrain the clay‐mineral main provenance and distribution within the Cariaco Basin. The spatial variability of the data set was studied using a geo‐statistical approach that allows drawing representative clay‐mineral distribution maps. These maps are used to identify present‐day dominant sources for each clay‐mineral species in agreement with the geological characteristics of the main river watersheds emptying into the basin. This approach allows (1) identifying the most distinctive clay‐mineral species/ratios that determine particle provenance, (2) evaluating the respective contribution of local rivers, and (3) confirming the minimal present‐day influence of the Orinoco plume on the Cariaco Basin sedimentation. The Tuy, Unare, and Neveri Rivers are the main sources of clay particles to the Cariaco Basin sedimentation. At present, the Tuy River is the main contributor of illite to the western part of the southern Cariaco Basin continental shelf. The Unare River plume, carrying smectite and kaolinite, has a wide westward propagation, whereas the Neveri River contribution is less extended, providing kaolinite and illite toward the eastern Cariaco Basin. The Manzanares, Araya, Tortuga, and Margarita areas are secondary sources of local influence. These insights shed light on the origin of present‐day terrigenous sediments of the Cariaco Basin and help to propose alternative explanations for the temporal variability of clay mineralogy observed in previously published studies.
High‐frequency internal waves near the Luzon Strait observed by underwater gliders
Authors: Rudnick Daniel L. , Johnston T. M. Shaun , Sherman Jeffrey T.
Published: April 2013

Tidal flow through the Luzon Strait produces large internal waves that propagate westward into the South China Sea and eastward into the Pacific. Underwater gliders gathered sustained observations of internal waves during seven overlapping missions from April 2007 through July 2008. A particular focus is the high‐frequency internal waves, where the operational definition of high involves periods shorter than a glider profile taking 3–6 h. Internal wave vertical velocity is estimated from measurements of pressure and glider orientation through two methods: (1) use of a model of glider flight balancing buoyancy and drag along the glider path and (2) high‐pass filtering of the observed glider vertical velocity. By combining high‐frequency vertical velocities from glider flight with low‐frequency estimates from isopycnal depth variations between dives, a spectrum covering five decades of frequency is constructed. A map of the standard deviation of vertical velocity over the survey area shows a decay from the Luzon Strait into the Pacific. The growth of high‐frequency vertical velocity with propagation into the South China Sea is observed through two 2‐week time series stations. The largest observed vertical velocities are greater than 0.2 m s−1 and are associated with displacements approaching 200 m. The high‐frequency waves are observed at regular intervals of 1 day as they ride on diurnal tidal internal waves generated in the Strait.
The similarity between optimal precursor and optimally growing initial error in prediction of Kuroshio large meander and its application to targeted observation
Authors: Wang Qiang , Mu Mu , Dijkstra Henk A.
Published: April 2013

The links between optimal precursor (OPR) and optimally growing initial error (OGIE) in the predictability studies of Kuroshio large meander (LM) are investigated using the Conditional Nonlinear Optimal Perturbation approach within a 1.5‐layer shallow‐water model. The OPR is a kind of initial anomaly that is the easiest to cause the occurrence of Kuroshio LM path. The OGIE refers to another kind of initial perturbation that has the largest effects on the prediction of the LM path. Numerical results show that the spatial structures of OPR and OGIEs are similar and their dominant amplitudes are localized upstream of the occurrence region of Kuroshio LM, i.e., southeast of Kyushu. Their spatial patterns are closely related to the potential vorticity distribution of the reference states. The main features of the nonlinear evolutions of both OPR and OGIEs are also similar, which implies that they have a similar development mechanism. The similarities between OPR and OGIEs indicate that targeted observations may be implemented to improve the prediction of the Kuroshio LM path. We define sensitive areas using the spatial patterns of OGIEs and investigate their usefulness. The results show that the initial errors in sensitive areas have greater impacts on the prediction of the Kuroshio LM path than those in other randomly selected areas. In addition, the prediction is more significantly improved when eliminating the part of initial error in the sensitive area than in other areas.
Estimation of relative phycoerythrin concentrations from hyperspectral underwater radiance measurements––A statistical approach
Authors: Taylor Bettina B. , Taylor Marc H. , Dinter Tilman , Bracher Astrid
Published: April 2013

Phycobiliproteins are a family of water‐soluble pigment proteins that play an important role as accessory or antenna pigments and absorb in the green part of the light spectrum poorly used by chlorophyll a. The phycoerythrins (PEs) are one of four types of phycobiliproteins that are generally distinguished based on their absorption properties. As PEs are water soluble, they are generally not captured with conventional pigment analysis. Here we present a statistical model based on in situ measurements of three transatlantic cruises which allows us to derive relative PE concentration from standardized hyperspectral underwater radiance measurements (Lu). The model relies on Empirical Orthogonal Function (EOF) analysis of Lu spectra and, subsequently, a Generalized Linear Model with measured PE concentrations as the response variable and EOF loadings as predictor variables. The method is used to predict relative PE concentrations throughout the water column and to calculate integrated PE estimates based on those profiles.
Impact of current‐wave interaction on storm surge simulation: A case study for Hurricane Bob
Authors: Sun Yunfang , Chen Changsheng , Beardsley Robert C. , Xu Qichun , Qi Jianhua , Lin Huichan
Published: April 2013

Hurricane Bob moved up the U.S. east coast and crossed over southern New England and the Gulf of Maine [with peak marine winds up to 54 m/s (100 mph)] on 19–20 August 1991, causing significant damage along the coast and shelf. A 3‐D fully wave‐current‐coupled finite‐volume community ocean model system was developed and applied to simulate and examine the coastal ocean responses to Hurricane Bob. Results from process study‐oriented experiments showed that the impact of wave‐current interaction on surge elevation varied in space and time, more significant over the shelf than inside the inner bays. While sea level change along the coast was mainly driven by the water flux controlled by barotropic dynamics and the vertically integrated highest water transports were essentially the same for cases with and without water stratification, the hurricane‐induced wave‐current interaction could generate strong vertical current shear in the stratified areas, leading to a strong offshore transport near the bottom and vertical turbulent mixing over the continental shelf. Stratification could also result in a significant difference of water currents around islands where the water is not vertically well mixed.
A numerical investigation of the dynamics and structure of hyperpycnal river plumes on sloping continental shelves
Authors: Chen Shih‐Nan , Geyer W. Rockwell , Hsu Tian‐Jian
Published: April 2013

A 3‐D hydrodynamic model (Regional Ocean Modeling System) is used to investigate the dynamics and structure of hyperpycnal river plumes over sloping continental shelves. The focus is on the plume's response to varying slopes and settling velocities (ws). The idealized model is configured to represent small mountainous river systems during a flood event. A hyperpycnal sediment concentration of 60 g/L is specified at the river mouth such that the sediment–freshwater mixture is denser than the seawater, causing the plumes to traverse the shelves as undercurrents. A realistic range of shelf slope of 0.001–0.03 is chosen. The settling velocity is varied based on river's carrying capacity. The model‐derived velocity profiles and the entrainment rate compare favorably against prior laboratory experiments. Both cross‐shore and alongshore momentum balances are primarily between gravitational forcing and bottom friction. But, the Coriolis deflection is significant at the plume core in the alongshore momentum budget (i.e., Ekman balance). As the slope increases and settling velocity decreases, hyperpycnal plumes transition from depositional to autosuspending regime. An estimate of critical slope governed by a dimensionless parameter
(qb is buoyancy input) reasonably captures the regime transition. In the depositional regime, the plume's runout (cross‐shore penetration) scales with advective distance: increasing slopes and discharge enhance the gravitational forcing and plume velocity, leading to an increase in runout. In contrast, increasing settling velocity shortens the vertical settling time, thereby reducing the plume's horizontal footprint. For the range of parameters considered, the runout of depositional plumes is confined within 15 km from the mouth, whereas the penetration of autosuspending plumes is essentially unlimited.
Particle filter‐based data assimilation for a three‐dimensional biological ocean model and satellite observations
Authors: Mattern Jann Paul , Dowd Michael , Fennel Katja
Published: April 2013

We assimilate satellite observations of surface chlorophyll into a three‐dimensional biological ocean model in order to improve its state estimates using a particle filter referred to as sequential importance resampling (SIR). Particle Filters represent an alternative to other, more commonly used ensemble‐based state estimation techniques like the ensemble Kalman filter (EnKF). Unlike the EnKF, Particle Filters do not require normality assumptions about the model error structure and are thus suitable for highly nonlinear applications. However, their application in oceanographic contexts is typically hampered by the high dimensionality of the model's state space. We apply SIR to a high‐dimensional model with a small ensemble size (20) and modify the standard SIR procedure to avoid complications posed by the high dimensionality of the model state. Two extensions to the SIR include a simple smoother to deal with outliers in the observations, and state‐augmentation which provides the SIR with parameter memory. Our goal is to test the feasibility of biological state estimation with SIR for realistic models. For this purpose we compare the SIR results to a model simulation with optimal parameters with respect to the same set of observations. By running replicates of our main experiments, we assess the robustness of our SIR implementation. We show that SIR is suitable for satellite data assimilation into biological models and that both extensions, the smoother and state‐augmentation, are required for robust results and improved fit to the observations.
Bulk mineralogy of lunar crater central peaks via thermal infrared spectra from the Diviner Lunar Radiometer: A study of the Moon's crustal composition at depth
Authors: Song Eugenie , Bandfield Joshua L. , Lucey Paul G. , Greenhagen Benjamin T. , Paige David A.
Published: April 2013

The central peaks of lunar impact craters are thought to be composed of uplifted material originating from varying depths of the crustal column. The interpreted crystallization sequence of the early lunar magma ocean resulted in an anorthositic upper crust that may become progressively more mafic as it approaches the olivine‐rich mantle. Emissivity spectra from the Lunar Reconnaissance Orbiter (LRO) Diviner Radiometer are used to derive the wavelength location of the Christiansen Feature (CF), which is sensitive to bulk silicate mineralogy. Here a survey of CF values has been performed for the central peaks of 135 complex craters, providing global and regional observations of the heterogeneity of crustal compositions. Crustal thickness models give context to the preimpact depth of the central peak material and its proximity to the crust‐mantle boundary. This study has identified six craters with potentially ultramafic compositions within their central peaks. More common occurrences of mafic material, found in a wide variety of crater central peaks, show a silicate composition roughly similar to mare basalt or an olivine‐bearing gabbro. The range of central peak CF values is similar to that of the rest of the lunar surface. Bulk mineralogy of the central peak material does not appear to be correlated with its crustal depth of origin, suggesting both lateral and vertical heterogeneity in crustal composition rather than a gradual transition from felsic to mafic composition. It is likely that the Moon's extensive cratering history has continually overturned the original crust, erasing any original systematic dependence of composition on depth or proximity to the mantle.
Hydrology of early Mars: Valley network incision
Authors: Matsubara Yo , Howard Alan D. , Gochenour J. Parker
Published: April 2013

Widespread occurrences of valley networks on Mars provide geomorphic evidence for an active hydrologic cycle. To constrain the climatic conditions capable of forming the valley networks, a hydrological model was used to analyze the valley incision depth and volume of eroded valleys. Because the absolute magnitudes of precipitation, runoff, and evaporation are uncertain, we have used the ratio of these quantities (the X‐ratio) to express climatic conditions. The spatial distribution and strength of the correlations between (1) the estimated depth and volume of eroded material and (2) estimated flood magnitude and valley gradients were investigated as a function of the assumed X‐ratio. We also conducted an analysis of conditions required to have appreciable discharge in selected valley networks, which provided the most definitive constraint on Martian paleoclimate. The other methods show a relatively weak dependency of incision depths and volumes upon the assumed X‐ratio. The multiple regression analyses indicate that incision depth is strongly influenced by gradient and weakly related to modeled flood discharge. The factors determining relative depth of incision depend partly on the type of channel bed. However, postflow modification of the valley networks by mass wasting, cratering, aeolian infilling, and ice‐related processes precludes direct determination of bed morphology. Our hydrological analyses suggest that climatic conditions on early Mars were at least as moist as those that occurred in the Great Basin region of the U.S. when large lakes were present during the Pleistocene in terms of the balance of runoff and lake evaporation.
Identification tree based on fragmentation rules for structure elucidation of organophosphorus esters by electrospray mass spectrometry
Authors: Schwarzenberg Adrián , Ichou Farid , Cole Richard B. , Machuron‐Mandard Xavier , Junot Christophe , Lesage Denis , Tabet Jean‐Claude
Published: April 2013

Organophosphorus compounds have played important roles as pesticides, chemical warfare agents and extractors of radioactive material. Structural elucidation of phosphonates poses a particular challenge because their initial forms can be hydrolyzed, thus, degradation products may predominate in samples acquired in the field. The analysis of non‐volatile organophosphorus compounds and their degradation products is possible using electrospray tandem mass spectrometry ESI‐MS/MS. Here, we present a generic strategy that allows the unambiguous identification of substituents for two families of organophosphorus compounds: the phosphonates and phosphates. General fragmentation rules were deduced based on the study of decomposition pathways of 55 organophosphorus esters, including examples found in the literature. Multistage MS (MSn) experiments at high resolution in a hybrid mass spectrometer provide accurate mass measurements, whereas collision‐induced dissociation experiments in a triple quadrupole give access to small fragment ions. The creation of a specific nomenclature for each possible structure of organophosphorus compound, depending on the alkyl side chain linked to the oxygen, was achieved by applying these fragmentation rules. This led to the creation of an ‘identification tree’ based upon the unique consecutive decomposition pathways uncovered for each individual compound. Hence, seven structural motifs were created that orient an unequivocal identification using the ‘identification tree’. Despite the similar structures of the ensemble of phosphate and phosphonate esters, distinct identifications based upon characteristic neutral losses and diagnostic fragment ions were possible in all cases. Copyright © 2013 John Wiley & Sons, Ltd.
Estrogen receptor‐β ligand treatment after disease onset is neuroprotective in the multiple sclerosis model
Authors: Wisdom Amy J. , Cao Yuan , Itoh Noriko , Spence Rory D. , Voskuhl Rhonda R.
Published: April 2013

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and neurodegeneration. Current MS treatments were designed to reduce inflammation in MS rather than directly to prevent neurodegeneration. Estrogen has well‐documented neuroprotective effects in a variety of disorders of the CNS, including experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of MS. Treatment with an estrogen receptor‐β (ERβ) ligand is known to ameliorate clinical disease effectively and provide neuroprotection in EAE. However, the protective effects of this ERβ ligand have been demonstrated only when administered prior to disease (prophylactically). Here we tested whether ERβ ligand treatment could provide clinical protection when treatment was initiated after onset of disease (therapeutically). We found that therapeutic treatment effectively ameliorated clinical disease in EAE. Specifically, ERβ ligand‐treated animals exhibited preserved axons and myelin compared with vehicle‐treated animals. We observed no difference in the number of T lymphocytes, macrophages, or microglia in the CNS of vehicle‐ vs. ERβ ligand‐treated animals. Our findings show that therapeutically administered ERβ ligand successfully treats clinical EAE, bearing translational relevance to MS as a candidate neuroprotective agent. © 2013 Wiley Periodicals, Inc.
Analysing conjoint data with OLS and PLS regression: a case study with wine
Authors: Jaeger Sara R , Mielby Line H , Heymann Hildegarde , Jia Yilin , Frøst Michael B
Published: April 2013

BACKGROUND

This paper presents a case study with wine where two statistical methods for the analysis of rating‐based conjoint analysis data were applied. Traditionally, ordinary least squares (OLS) regression is used to estimate the relative importance of the experimental factors and the part‐worth utilities of factor levels. Partial least squares (PLS) regression, which is a popular tool in sensory and consumer science, can also be used for the analysis of interval‐level conjoint data.

RESULTS

Using conjoint analysis, purchase intentions for Californian red and white wine were obtained from a convenience sample of young US adults (n ≈ 250). OLS and PLS regression uncovered the same systematic patterns in the data: negative utility associated with more expensive wine, and positive utility associated with famous wine regions. While OLS regression provided more accessible top‐line results, an advantage of PLS regression was the graphical format of results. This provided easy insight to individual differences in the importance attached to the factors driving purchase intention.

CONCLUSION

OLS and PLS regression can complement each other in the analysis of interval‐level conjoint data. Dual analysis can help to ensure that the right insights are drawn from the study and communicated to internal/external clients. It may also facilitate communication within project teams. © 2013 Society of Chemical Industry
Low‐temperature conditioning induces chilling tolerance in ‘Hayward’ kiwifruit by enhancing antioxidant enzyme activity and regulating en‐dogenous hormones levels
Authors: Yang Qingzhen , Zhang Zhengke , Rao Jingping , Wang Yuping , Sun Zhenying , Ma Qiushi , Dong Xiaoqing
Published: April 2013

BACKGROUND

To understand the mechanisms leading to the enhanced chilling tolerance of kiwifruit by low‐temperature conditioning (LTC, 12 °C for 3 days), this study investigated the effect of LTC on chilling tolerance and changes in antioxidant enzyme activities and endogenous hormones.

RESULTS

LTC significantly alleviated chilling injury in kiwifruit. Fruits treated with LTC maintained lower respiration and ethylene production and higher firmness. Furthermore, this treatment inhibited the accumulation of malondialdehyde, superoxide radicals and hydrogen peroxide and the increase in membrane permeability and increased the activities of superoxide dismutase, catalase, ascorbate peroxidase and peroxidase under chilling stress. The treatment also maintained higher levels of endogenous abscisic acid (ABA), indole‐3‐acetic acid (IAA) and zeatin riboside (ZR), lower gibberellic acid (GA3) levels and higher ABA/GA3 and ABA/IAA ratios.

CONCLUSION

The results suggested that LTC alleviated chilling injury in kiwifruit by improving antioxidant enzyme activities and maintaining higher levels of endogenous ABA, IAA and ZR, lower GA3 levels and higher ABA/GA3 and ABA/IAA ratios. © 2013 Society of Chemical Industry
Renewable Aromatic–Aliphatic Copolyesters Derived from Rapeseed
Authors: Kreye Oliver , Oelmann Stefan , Meier Michael A. R.
Published: April 2013

Novel (co)polyesters are synthesized from rapeseed‐derived renewable starting materials. Aliphatic monomers are obtained from oleic and erucic acid via thiol‐ene addition, whereas ferulic acid is used for the synthesis of aromatic monomers. Copolyesters with different ratios of these monomers are prepared via base‐catalyzed transesterification reactions under neat conditions. Both monomer and polymer synthesis are optimized to achieve a high yield using environmentally benign synthetic procedures. A focus is put on applying less‐toxic reagents (i.e., avoiding halogenated compounds) and on minimizing the produced waste, in order to meet the requirements of green chemistry. The resulting thioether‐bearing (co)polyester series is analyzed, and finally oxidized to sulfone analogues. The thermal properties before and after oxidation are then compared.

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Dimer radical cation of 4‐thiouracil: a pulse radiolysis and theoretical study
Authors: Prasanthkumar K. P. , Suresh Cherumuttathu H. , Aravindakumar C. T.
Published: April 2013

Pulse radiolysis with optical absorption detection has been used to study the reactions of hydroxyl radical (OH•) with 4‐thiouracil (4TU) in aqueous medium. The transient absorption spectrum for the reaction of OH• with 4TU is characterized by λmax 460 nm at pH 7. A second‐order rate constant k(4TU+OH) of 1.7 × 1010 M−1 s−1 is determined via competition kinetics method. The transient is envisaged as a dimer radical cation [4TU]2•+, formed via the reaction of an initially formed radical cation [4TU]•+ with another 4TU. The formation constant of [4TU]2•+ is 1.8 × 104 M−1. The reactions of dibromine radical ion (Br2•−) at pH 7, dichlorine radical ion (Cl2•−) at pH 1, and azide radical (N3•) at pH 7 with 4TU have also produced transient with λmax 460 nm. Density functional theory (DFT) studies at BHandHLYP/6–311 + G(d,p) level in aqueous phase showed that [4TU]2•+ is characterized by a two‐centerthree electron (2c‐3e) [−S∴S−] bond. The interaction energy of [−S∴S−] bond in [4TU]2•+ is −13.01 kcal mol−1. The predicted λmax 457 nm by using the time‐dependent DFT method for [4TU]2•+ is in agreement with experimental λmax. Theoretical calculations also predicted that compared with [4TU]2•+, 4‐thiouridine dimer is more stable, whereas 4‐thiothymine dimer is less stable. Copyright © 2013 John Wiley & Sons, Ltd.
Metabolite identification of a new tyrosine kinase inhibitor, HM781‐36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry
Authors: Kim Eunyoung , Kim Hankyong , Suh Kweehyun , Kwon Sechang , Lee Gwansun , Park Na Hyun , Hong Jongki
Published: April 2013

RATIONALE

HM781‐36B (1‐[4‐[4‐(3,4‐dichloro‐2‐fluorophenylamino)‐7‐methoxyquinazolin‐6‐yloxy]‐piperidin‐1‐yl]prop‐2‐en‐1‐one hydrochloride) is a new anticancer drug to treat advanced solid tumors in clinical trial. In order to understand the behavior of HM781‐36B in vitro and in vivo we validated an analytical method for HM781‐36B and its major metabolites in plasma.

METHODS

In vivo and in vitro metabolism of HM781‐36B was studied in dog plasma, urine and feces as well as using human and dog liver microsomes with extraction by ethyl acetate or methyl tert‐butyl ether, respectively, and successfully separated by high‐performance liquid chromatography diode‐array detection mass spectrometry (HPLC‐DAD/MS). Ten metabolites were identified by LC/ESI‐ion trap mass spectrometry (MS, MS2, MS3 and MRM) and LC/Q‐TOF‐MS/MS for exact mass measurement. For accurate characterization of the major metabolites, authentic standards (M1, M2, M4, and M10) were synthesized.

RESULTS

Ten metabolites of HM781‐36B in an in vitro mixture were separated and identified by LC/ESI‐MSn. The MS/MS spectral patterns of the parent drug and metabolites exhibited two characteristic ions (A‐ and B‐type ions) attributed to the cleavage of the ether bond between the piperidine ring and the quinazoline ring, providing important information on the site of chemical conversion during the metabolism. Six hydroxylated derivatives including dehalogenation and demethylation, two N‐oxide forms, a demethylated form and de‐acryloylpiperideine metabolites were observed.

CONCLUSIONS

The LC/ESI‐ion trap MSn technique was effective in obtaining structural information and yielded diagnostic ions for the identification of diverse metabolites. The multiple metabolic pathways of HM781‐36B were suggested in in vitro and in vivo samples and the dihydroxylation (M1) and demethylation (M2) appeared to be the major metabolites. Copyright © 2013 John Wiley & Sons, Ltd.
Escalation with overdose control for phase I drug‐combination trials
Authors: Shi Yun , Yin Guosheng
Published: April 2013

Dose finding for combined drugs has grown rapidly in oncology drug development. The escalation with overdose control (EWOC) method is a popular model‐based dose‐finding approach to single‐agent phase I clinical trials. When two drugs are combined as a treatment, we propose a two‐dimensional EWOC design for dose finding on the basis of a four‐parameter logistic regression model. During trial conduct, we continuously update the posterior distribution of the maximum tolerated dose (MTD) combination to find the most appropriate dose combination for each cohort of patients. The probability that the next assigned dose combination exceeds the MTD combination can be controlled by a feasibility bound, which is based on a prespecified quantile level of the MTD distribution such as to reduce the possibility of overdosing. We determine dose escalation, de‐escalation, or staying at the same doses by searching the MTD combination along the rows and columns in a two‐drug combination matrix, respectively. We conduct simulation studies to examine the performance of the two‐dimensional EWOC design under various practical scenarios, and illustrate it with a trial example. Copyright © 2013 John Wiley & Sons, Ltd.
Fabrication of Highly Stretchable Conductors via Morphological Control of Carbon Nanotube Network
Authors: Lin Lin , Liu Siyao , Fu Sirui , Zhang Shuangmei , Deng Hua , Fu Qiang
Published: April 2013

Stretchable conductors, which can keep their excellent electrical conductivity while highly stretched, have been investigated extensively due to their wide range of applications in flexible and stretchable electronics, wearable displays, etc.; however, their preparation is often complicated and expensive. Herein, an efficient method to prepare high performance stretchable conductors through morphological control of conductive networks formed with carbon nanotubes (CNTs) in an elastomer matrix is reported. It is observed that an interface‐mediated method could be used to align randomly oriented filler during stretching and to induce buckling of CNTs during relaxation. Further morphological studies indicate the possible formation of a wavy CNT structure induced by cyclic pre‐straining. Subsequent thermal annealing is observed to collapse the oriented network and improve the local contacts between conductive networks. Through such a simple procedure, a conductivity of nearly 1000 S m−1 and a stretchability of 200% can be achieved for composites containing 20 wt% CNTs. CNTs are observed to buckle over a large area in polymer bulk, and the combination of pre‐straining and thermal annealing modifies the conductive network in the elastomer matrix. As a general method, this could be used for easy fabrication of high‐performance stretchable conductors for arbitrary‐shaped objects on a large scale.
Cross‐Linked g‐C3N4/rGO Nanocomposites with Tunable Band Structure and Enhanced Visible Light Photocatalytic Activity
Authors: Li Yibing , Zhang Haimin , Liu Porun , Wang Dan , Li Ying , Zhao Huijun
Published: April 2013

Cross‐linked rather than non‐covalently bonded graphitic carbon nitride (g‐C3N4)/reduced graphene oxide (rGO) nanocomposites with tunable band structures have been successfully fabricated by thermal treatment of a mixture of cyanamide and graphene oxide with different weight ratios. The experimental results indicate that compared to pure g‐C3N4, the fabricated CN/rGO nanocomposites show narrowed bandgaps with an increased in the rGO ratio. Furthermore, the band structure of the CN/rGO nanocomposites can be readily tuned by simply controlling the weight ratio of the rGO. It is found that an appropriate rGO ratio in nanocomposite leads to a noticeable positively shifted valence band edge potential, meaning an increased oxidation power. The tunable band structure of the CN/rGO nanocomposites can be ascribed to the formation of C−O−C covalent bonding between the rGO and g‐C3N4 layers, which is experimentally confirmed by Fourier transform infrared (FT‐IR) and X‐ray photoelectron (XPS) data. The resulting nanocomposites are evaluated as photocatalysts by photocatalytic degradation of rhodamine B (RhB) and 4‐nitrophenol under visible light irradiation (λ > 400 nm). The results demonstrate that the photocatalytic activities of the CN/rGO nanocomposites are strongly influenced by rGO ratio. With a rGO ratio of 2.5%, the CN/rGO‐2.5% nanocomposite exhibits the highest photocatalytic efficiency, which is almost 3.0 and 2.7 times that of pure g‐C3N4 toward photocatalytic degradation of RhB and 4‐nitrophenol, respectively. This improved photocatalytic activity could be attributed to the improved visible light utilization, oxidation power, and electron transport property, due to the significantly narrowed bandgap, positively shifted valence band‐edge potential, and enhanced electronic conductivity.