bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation and characterization of polyvinyl alcohol‐grafted Fe3O4 magnetic nanoparticles through glutaraldehyde
Authors: Kim Su Yeon , Ramaraj B. , Yoon K. R.
Published: March 2012

Magnetic nanoparticles (MNPs) are of great interest owing to their numerous existing and potential biomedical applications. To further explore the potential of MNPs in biomedical and other fields, we have designed and synthesized polyvinyl alcohol (PVA) polymer grafted Fe3O4 MNPs through glutaraldehyde (GLA) link. The success of this process has been ascertained using Fourier transform infrared (FT‐IR) analysis, thermogravimetric analysis (TGA), X‐ray diffraction (XRD) analysis and scanning electron microscopy (SEM) analysis. The FT‐IR analysis of resultant MNPs show infrared peak characteristics of PVA. TGA analysis clearly shows two major stages of thermal degradation, one corresponding to organic phase of PVA and GLA and another corresponding to Fe3O4 nanoparticles. XRD results and SEM images further support the FT‐IR and TGA results and confirm the presence of PVA layer surrounding Fe3O4 MNP surface. Under SEM examination, the magnetic cores exhibit somewhat irregular shapes varying from spherical, to oval to cubic. Copyright © 2012 John Wiley & Sons, Ltd.
The HLD‐NAC Model for Extended Surfactant Microemulsions
Authors: Acosta Edgar J. , Kiran Sumit K. , Hammond Charles E.
Published: March 2012

It has been confirmed that the structure of the alkyl group of an extended surfactant plays an important role in defining its interfacial properties. Alkyl groups containing a higher degree of β‐branching (C2‐branching) produce microemulsions with a larger characteristic length (ξ, the extent of solubilization in middle phases). This effect is explained on the basis that β‐branching increases the hydrophobicity of the surfactant and decreases the optimal salinity of the microemulsion. Higher salinities produce a dehydration of the surfactant groups that lead to shorter extent of the interactions with the oil and the water. Larger characteristic lengths are desirable if the objective of the formulation is obtaining greater solubilization of oil and water, and lower interfacial tensions. Large characteristic lengths are, in most cases, associated with high interfacial rigidities, which are undesirable if rapid coalescence is required. However, mixtures of branched and linear extended surfactants produce large characteristic lengths and lower interfacial rigidities. The HLD‐NAC model is able to reflect the experimental trends in solubilization of oil and water. The differences between the predictions of the model for the solubilization of oil and water in Type I and II formulations, respectively, highlight the complexities in the conformation of extended surfactants, particularly their PO groups, at oil–water interfaces and the need for advanced scattering techniques to evaluate these conformations.
Inflammation, organomegaly, and muscle wasting despite hyperphagia in a mouse model of burn cachexia
Authors: Pedroso Felipe E. , Spalding Paul B. , Cheung Michael C. , Yang Relin , Gutierrez Juan C. , Bonetto Andrea , Zhan Rui , Chan Ho Lam , Namias Nicholas , Koniaris Leonidas G. , Zimmers Teresa A.
Published: March 2012

Background

Burn injury results in a chronic inflammatory, hypermetabolic, and hypercatabolic state persisting long after initial injury and wound healing. Burn survivors experience a profound and prolonged loss of lean body mass, fat mass, and bone mineral density, associated with significant morbidity and reduced quality of life. Understanding the mechanisms responsible is essential for developing therapies. A complete characterization of the pathophysiology of burn cachexia in a reproducible mouse model was lacking.

Methods

Young adult (12–16 weeks of age) male C57BL/6J mice were given full thickness burns using heated brass plates or sham injury. Food and water intake, organ and muscle weights, and muscle fiber diameters were measured. Body composition was determined by Piximus. Plasma analyte levels were determined by bead array assay.

Results

Survival and weight loss were dependent upon burn size. The body weight nadir in burned mice was 14 days, at which time we observed reductions in total body mass, lean carcass mass, individual muscle weights, and muscle fiber cross‐sectional area. Muscle loss was associated with increased expression of the muscle ubiquitin ligase, MuRF1. Burned mice also exhibited reduced fat mass and bone mineral density, concomitant with increased liver, spleen, and heart mass. Recovery of initial body weight occurred at 35 days; however, burned mice exhibited hyperphagia and polydipsia out to 80 days. Burned mice had significant increases in serum cytokine, chemokine, and acute phase proteins, consistent with findings in human burn subjects.

Conclusions

This study describes a mouse model that largely mimics human pathophysiology following severe burn injury. These baseline data provide a framework for mouse‐based pharmacological and genetic investigation of burn‐injury‐associated cachexia.
Crystal structure of periplasmic catecholate‐siderophore binding protein VctP from Vibrio cholerae at 1.7 Å resolution
Authors: Liu Xiuhua , Du Qian , Wang Zhi , Liu Shiheng , Li Ning , Chen Ying , Zhu Chunyuan , Zhu Deyu , Wei Tiandi , Huang Yan , Xu Sujuan , Gu Lichuan
Published: March 2012

VctP, one of the two essential siderophore‐binding PBPs from the pathogen Vibrio cholerae, plays an important role in the transport of enterobactin and vibriobactin, which have quite different configurations of iron coordination, from the periplasm to the inner membrane. The current study reports the crystal structure of VctP from V. cholerae N16961 at 1.7 Å resolution. A structural comparison of VctP with its homologues and the results of molecular docking indicate that enterobactin and vibriobactin share the same binding pocket. Significantly, a basic triad consisting of Arg137, Arg226 and Arg270 is used to balance the three negative charges of ferric‐enterobactin, while a basic dyad consisting of Arg137 and Arg270 is used to balance the two negative charges of ferric‐vibriobactin.
Stability of peptide–HLA‐I complexes and tapasin folding facilitation – tools to define immunogenic peptides
Authors: Geironson Linda , Røder Gustav , Paulsson Kajsa
Published: March 2012

Only a small fraction of the peptides generated inside the cell end up being presented by HLA‐I on the cell surface. High stability of peptide–HLA‐I complexes and a low HLA‐I tapasin‐facilitation have been proposed to predict immunogenicity. We here set out to investigate if these parameters correlated and defined immunogenic peptides. Both peptide–HLA–B∗08:01 and peptide–HLA–A∗02:01 complexes showed small differences in tapasin‐facilitation and larger differences in stability. This suggests that the stability of immunogenic peptide–HLA‐I complexes vary above an HLA‐I allomorph dependent lower limit (e.g. >2 h for HLA–A∗02:01), immunogenicity predicted by tapasin‐facilitation may be defined by an equally allomorph unique upper value (e.g. tapasin‐facilitation <1.5 for HLA–A∗02:01), and variation above the stability‐threshold does not directly reflect a variation in tapasin‐facilitation.
ALDH+ tumor‐initiating cells exhibiting gain in NOTCH1 gene copy number have enhanced regrowth sensitivity to a γ‐secretase inhibitor and irinotecan in colorectal cancer
Authors: Arcaroli John J. , Powell Rebecca W. , Varella-Garcia Marileila , McManus Martine , Tan Aik Choon , Quackenbush Kevin S. , Pitts Todd M. , Gao Dexiang , Spreafico Anna , Dasari Arvind , Touban Basel M. , Messersmith Wells A.
Published: March 2012

The Notch signaling pathway has been shown to be upregulated in colorectal cancer (CRC) and important for the self‐renewal of cancer stem cells. In this study, we evaluated the efficacy of PF‐03084014, a γ‐secretase inhibitor, in combination with irinotecan to identify the effects of treatment on tumor recurrence and the tumor‐initiating population in our CRC preclinical explant model. The combination of PF‐03084014 and irinotecan had the greatest effect at reducing tumor growth on four CRC tumors when compared with treatment with PF‐03084014 or irinotecan alone. The combination significantly reduced tumor recurrence in two CRC explants (CRC001 and CRC036) after treatment was discontinued. Both of these tumors exhibited elevated baseline levels of Notch pathway activation as well as an increase in NOTCH1 gene copy number when compared with the two CRC explants (CRC026 and CRC027) where tumors reappeared quickly after termination of treatment. Isolation and injection of aldehyde dehydrogenase (ALDH+ and ALDH−) cells in an in vivo explant model demonstrated that the ALDH+ cell population were tumorigenic. Evaluation of the ALDH+ cells after 28 days of treatment showed that the combination reduced the ALDH+ population in the tumors that did not regrow. Furthermore, ALDH+ cells from CRC001 and CRC027 were injected in vivo and treated immediately for 28 days. Two months after treatment, tumors were evident in the combination treatment group for CRC027 but not for CRC036. These results indicate the combination of PF‐03084014 and irinotecan may be effective in reducing tumor recurrence in CRC patients whose tumors exhibit elevated levels of the Notch pathway.
Inverted ductal papilloma arising from the buccal minor salivary gland: A case report and immunohistochemical study
Authors: Kato Hisashi , Ota Yoshihide , Sasaki Masashi , Kaneko Akihiro , Sekido Yasutomo , Tsukinoki Keiichi
Published: March 2012

Oral inverted ductal papilloma is a rare, benign epithelial tumor that exhibits an endophytic growth pattern and is found almost exclusively in the minor salivary glands. We report on a case of inverted ductal papilloma in the buccal mucosa. We also performed an immunohistochemical study. The tumor cells were positive for cytokeratin and epithelial membrane antigen, while negative for calponin, S‐100 protein, α‐SMA, vimentin, and desmin. This result indicated that the lesion arises from the excretory duct near the oral mucosal surface but not the myoepithelial cells. In addition, Ki‐67 labeling index of 3.96% indicated the low level of proliferation.
U–Pb geochronology of zircons from fossiliferous sediments of the Hajnáčka I maar (Slovakia) – type locality of the MN 16a biostratigraphic subzone
Authors: HURAI VRATISLAV , PAQUETTE JEAN-LOUIS , HURAIOVÁ MONIKA , SABOL MARTIN
Published: March 2012

Lacustrine sediments of the Hajnáčka I maar of southern Slovakia contain teeth and skeletal remains of a mammal fauna, including index Early Villanyian arvicoline rodents. U–Pb dating of magmatic zircons extracted from the redeposited fossiliferous maar sediments revealed a total of six volcanic events. The oldest age of 3.43 Ma was interpreted as that corresponding to the initial phreato-magmatic eruption that created the maar. Most zircons grouped around 3.06 ± 0.03 Ma, the age attributed to the catastrophic eruption that killed the mammal assemblage thriving within and around the maar studied. This age coincides with the 3.1 Ma boundary between the MN 16a and 16b subzones of the European Mammal Neogene chronostratigraphic scale estimated from the succession of Early Villanyian palaeontological localities according to the hypsometry of rodent teeth. Younger zircon ages overlapped those of the neighbouring basaltic lava flows, necks and dykes, thus recording superimposed effusions. The youngest 1.58 Ma old zircon defines the age limit for the final redeposition of the fossiliferous sediments in the maar drainage lake regime.
Helminth parasite proteomics: from experimental models to human infections
Authors: MUTAPI FRANCISCA
Published: March 2012

Schistosomiasis is a major human helminth infection endemic in developing countries. Urogenital schistosomiasis, caused byS. haematobium, is the most prevalent human schistosome disease in sub-Saharan Africa. Currently control of schistosome infection is by treatment of infected people with the anthelmintic drug praziquantel, but there are calls for continued efforts to develop a vaccine against the parasites. In order for successful vaccine development, it is necessary to understand the biology and molecular characteristics of the parasite. Ultimately, there is need to understand the nature and dynamics of the relationship between the parasite and the natural host. Thus, my studies have focused on molecular characterization of different parasite stages and integrating this information with quantitative approaches to investigate the nature and development of protective immunity against schistosomes in humans. Proteomics has proved a powerful tool in these studies allowing the proteins expressed by the parasite to be characterized at a molecular and immunological level. In this review, the application of proteomic approaches to understanding the human-schistosome relationship as well as testing specific hypotheses on the nature and development of schistosome-specific immune responses is discussed. The contribution of these approaches to informing schistosome vaccine development is highlighted.
Staying in school for lunch instead of eating in fast-food restaurants: results of a quasi-experimental study among high-school students
Authors: Beaulieu Dominique , Godin Gaston
Published: March 2012

Objective

Following the adoption of food policies replacing unhealthy products by healthy foods in school, the present study tested the effectiveness of an intervention aimed at encouraging high-school students to stay in school for lunch instead of eating in fast-food restaurants.

Design

A 12-week multi-strategy intervention targeting specific determinants of behaviour was evaluated via a quasi-experimental pre- and post-intervention design. A self-administered questionnaire was employed based on the theory of planned behaviour.

Setting

An experimental (n 129) and a control school (n 112) in central Canada.

Subjects

High-school students aged 12 to 17 years.

Results

Compared with control school students, those in the experimental school significantly increased the mean number of days that they stayed in school for lunch (relative risk = 1·55; 95 % CI 1·06, 2·27; P = 0·024), as well as the proportion who remained in school for lunch every day (relative risk = 1·21; 95 % CI 1·04, 1·40; P = 0·014). Among the psychosocial variables targeted, only self-efficacy appeared to be influenced by the intervention, mainly because of a decline in control group values. Mediation analysis indicated a significant mediating effect of self-efficacy on the mean number of days that students stayed in school for lunch (bias-corrected and accelerated point estimate = 0·079; 95 % CI 0·0059, 0·1958).

Conclusions

These results suggest that interventions aimed at enhancing self-efficacy can successfully contribute to students staying in school during lunch time. Such interventions should be considered in obesity prevention programmes adapted to high-school students.
Achtsamkeit, Selbstwert und Selbstwertstabilität
Authors: Burg Jan M. , Michalak Johannes
Published: March 2012

Zusammenfassung. Hintergrund: Es gibt theoretische Gründe anzunehmen, dass Achtsamkeit ein stabiles, also sicheres, Gefühl von Selbstwert begünstigen sollte. Fragestellung: Gibt es einen Zusammenhang zwischen Achtsamkeit und Höhe und Stabilität des Selbstwerts? Methode: Eine Stichprobe von N = 42 Psychologiestudenten bearbeitete zur Erfassung von Achtsamkeit einen Fragebogen, sowie eine computergestützte, nonverbale Aufgabe, die auf der Atemmeditation basiert. Zusätzlich zum Selbstwert-Level wurde die Selbstwertstabilität als Indikator eines sicheren Selbstwerts erfasst. Ergebnisse: Es zeigten sich positive Korrelationen zwischen Achtsamkeitsmaßen und Höhe des Selbstwerts sowie zwischen Achtsamkeitsmaßen und Selbstwertstabilität. Schlussfolgerung: Die Befunde unterstützen die Hypothese, dass Achtsamkeit mit hohem und sicherem Selbstwert assoziiert ist, und sprechen somit für die Bedeutsamkeit von Achtsamkeit bezüglich psychologischer Gesundheit und Wohlbefinden.
Entwicklung, Validierung und Normierung des Rasch-basierten Depressionsscreenings
Authors: Forkmann Thomas , Böcker Maren , Wirtz Markus , Norra Christine , Gauggel Siegfried
Published: March 2012

Zusammenfassung. Theoretischer Hintergrund: Vor dem Hintergrund hoher Prävalenzraten für depressive Störungen bei somatisch Erkrankten sowie artifizieller Effekte bei wiederholten Messungen wurde das Rasch-basierte Depressionsscreening (DESC) entwickelt. Fragestellung: Der Entwicklungs-, Validierungs- und Normierungsprozess des Verfahrens wird zusammengefasst und die Nützlichkeit für die klinische Praxis diskutiert. Methoden: Ausgehend von der Aachener Depressionsitembank ( Forkmann et al., 2009 ) wurde das DESC anhand von N = 333 psychisch/somatisch erkrankten Patienten (Alter M = 43,6 Jahre; 46,2% Frauen) mittels Strukturmodellierung und Rasch-Analyse entwickelt, an verschiedenen klinischen Stichproben überprüft und bevölkerungsrepräsentativ normiert (N = 2 .509). Ergebnisse: Eindimensionalität und Rasch-Modellkonformität der Parallelformen wurden bestätigt und Cut-Off-Werte mit guter Sensitivität und Spezifität bestimmt. Die Paralleltestreliabilität war in allen Stichproben >0.9. Schlussfolgerungen: Mit dem DESC steht ein neues Verfahren mit guten psychometrischen Eigenschaften zur Verfügung, das das Instrumentarium zur Depressionsdiagnostik sinnvoll ergänzt.
Die Ruminationsfacetten Brooding und Reflection
Authors: Huffziger Silke , Kühner Christine
Published: March 2012

Zusammenfassung. Theoretischer Hintergrund: Brooding und Reflection gelten als unterschiedlich adaptive Ruminationsfacetten, die mit einer international häufig verwendeten 10-Item-Version des Response Styles Questionnaire (RSQ) erfasst werden. Fragestellung: Ziel war die psychometrische Evaluation der deutschsprachigen Version dieses Kurzfragebogens (RSQ-10D). Methode: Anhand zweier Stichproben junger Erwachsener (n1 = 166, n2 = 172) wurden konfirmatorische Faktorenanalysen durchgeführt. Weitere Analysen erfolgten zusätzlich bei akut Depressiven (n = 53). Ergebnisse: Das Brooding-Reflection-Modell erreichte nach Modellierung zweier Paare kovariierender Fehlerterme einen akzeptablen Modellfit. Beide Skalen zeigten akzeptable interne Konsistenzen und Retestreliabilitäten. Korrelationen mit konstruktnahen Skalen waren plausibel und legen eine geringere Dysfunktionalität von Reflection nahe. Schlussfolgerungen: Trotz überwiegend akzeptabler Gütekriterien erachten wir eine weitere Validierung der Brooding-Reflection Differenzierung für wünschenswert.
Effective shear stress of graded sediments
Authors: Buscombe D. , Conley D. C.
Published: March 2012

A meta‐analysis of fractional mobilization data from 14 sets of experiments, totaling 103 different mixed sand and gravel beds and flow conditions, has been carried out in order to identify an expression for effective shear stress, here defined as the component of bed shear stress that is directly involved in transporting each grain size fraction in graded sediment. In doing so we test the assumption that excess stress should be defined solely in terms of a critical stress rather than effective stress, which exhibits sensitivity to the flow stage. In contrast to the approach which evaluates the size‐distribution effects on motion threshold by comparing inferred transport rates, an alternative approach is utilized which is based on the skill of reproducing the measured, mobilized particle size distribution. A simple equation is developed for mobilization of sediment mixtures, based on a well‐established transport law, and employing a classical “hiding function” approach to the problem of mitigating the bias toward mobilizing fine material in the mixture. We use inverse methods to find the optimal form of the hiding function which provides the best fit with the data. We find that the hiding function is indeed sensitive to the flow and bed composition. On this basis, a simple deterministic equation is proposed for fraction‐specific effective stress, which outperforms the next best existing formula based on critical stress by 34% on aggregate.
Data‐based estimates of suboxia, denitrification, and N2O production in the ocean and their sensitivities to dissolved O2
Authors: Bianchi Daniele , Dunne John P. , Sarmiento Jorge L. , Galbraith Eric D.
Published: March 2012

Oxygen minimum zones (OMZs) are major sites of fixed nitrogen removal from the open ocean. However, commonly used gridded data sets such as the World Ocean Atlas (WOA) tend to overestimate the concentration of O2 compared to measurements in grids where O2 falls in the suboxic range (O2 < 2–10 mmol m−3), thereby underestimating the extent of O2 depletion in OMZs. We evaluate the distribution of the OMZs by (1) mapping high‐quality oxygen measurements from the WOCE program, and (2) by applying an empirical correction to the gridded WOA based on in situ observations. The resulting suboxic volumes are a factor 3 larger than in the uncorrected gridded WOA. We combine the new oxygen data sets with estimates of global export and simple models of remineralization to estimate global denitrification and N2O production. We obtain a removal of fixed nitrogen of 70 ± 50 Tg year−1 in the open ocean and 198 ± 64 Tg year−1 in the sediments, and a global N2O production of 6.2 ± 3.2 Tg year−1. Our results (1) reconcile water column denitrification rates based on global oxygen distributions with previous estimates based on nitrogen isotopes, (2) revise existing estimates of sediment denitrification down by 1/3d through the use of spatially explicit fluxes, and (3) provide independent evidence supporting the idea of a historically balanced oceanic nitrogen cycle. These estimates are most sensitive to uncertainties in the global export production, the oxygen threshold for suboxic processes, and the efficiency of particle respiration under suboxic conditions. Ocean deoxygenation, an expected response to anthropogenic climate change, could increase denitrification by 14 Tg year−1 of nitrogen per 1 mmol m−3 of oxygen reduction if uniformly distributed, while leaving N2O production relatively unchanged.
Thermomechanical model reconciles contradictory geophysical observations at the Dead Sea Basin
Authors: Petrunin Alexey G. , Meneses Rioseco Ernesto , Sobolev Stephan V. , Weber Michael
Published: March 2012

The Dead Sea Transform (DST) comprises a boundary between the African and Arabian plates. During the last 15–20 m.y. more than 100 km of left lateral transform displacement has been accumulated on the DST and about 10 km thick Dead Sea Basin (DSB) was formed in the central part of the DST. Widespread igneous activity since some 20 Ma ago and especially in the last 5 m.y., thin (60–80 km) lithosphere constrained by seismic data and absence of seismicity below the Moho, seem to be quite natural for this tectonically active plate boundary. However, surface heat flow values of less than 50–60 mW/m2 and deep seismicity in the lower crust (deeper than 20 km) reported for this region are apparently inconsistent with the tectonic settings specific for an active continental plate boundary and with the crustal structure of the DSB. To address these inconsistencies which comprise what we call the “DST heat‐flow paradox,” we have developed a numerical model that assumes an erosion of initially thick and cold lithosphere just before or during the active faulting at the DST. The optimal initial conditions for the model are defined using transient thermal analysis. From the results of our numerical experiments we conclude that the entire set of observations for the DSB can be explained within the classical pull‐apart model assuming that the lithosphere has been thermally eroded at about 20 Ma and the uppermost mantle in the region have relatively weak rheology consistent with experimental data for wet olivine or pyroxenite.
Cenozoic tectono‐thermal history of the Tordrillo Mountains, Alaska: Paleocene‐Eocene ridge subduction, decreasing relief, and late Neogene faulting
Authors: Benowitz Jeff A. , Haeussler Peter J. , Layer Paul W. , O'Sullivan Paul B. , Wallace Wes K. , Gillis Robert J.
Published: March 2012

Topographic development inboard of the continental margin is a predicted response to ridge subduction. New thermochronology results from the western Alaska Range document ridge subduction related orogenesis. K‐feldspar thermochronology (KFAT) of bedrock samples from the Tordrillo Mountains in the western Alaska Range complement existing U‐Pb,40Ar/39Ar and AFT (apatite fission track) data to provide constraints on Paleocene pluton emplacement, and cooling as well as Late Eocene to Miocene vertical movements and exhumation along fault‐bounded blocks. Based on the KFAT analysis we infer rapid exhumation‐related cooling during the Eocene in the Tordrillo Mountains. Our KFAT cooling ages are coeval with deposition of clastic sediments in the Cook Inlet, Matanuska Valley and Tanana basins, which reflect high‐energy depositional environments. The Tordrillo Mountains KFAT cooling ages are also the same as cooling ages in the Iliamna Lake region, the Kichatna Mountains of the western Alaska Range, and Mt. Logan in the Wrangell‐St. Elias Mountains, thus rapid cooling at this time encompasses a broad region inboard of, and parallel to, the continental margin extending for several hundred kilometers. We infer these cooling events and deposition of clastic rocks are related to thermal effects that track the eastward passage of a slab window in Paleocene‐Eocene time related to the subduction of the proposed Resurrection‐Kula spreading ridge. In addition, we conclude that the reconstructed KFATmaxnegative age‐elevation relationship is likely related to a long period of decreasing relief in the Tordrillo Mountains.
Neutral thermospheric dynamics observed with two scanning Doppler imagers: 3. Horizontal wind gradients
Authors: Anderson C. , Conde M. , McHarg M. G.
Published: March 2012

This is the third and final article in a series of papers reporting on observations of the 630.0 nm thermospheric airglow emission by two spatially separated scanning Doppler imagers (SDI's) in Alaska. In this article, bistatic winds derived from the combined measurements of both instruments in a region of field‐of‐view overlap were used to derive local‐scale maps of horizontal neutral wind gradients. Averaged over the bistatic ‘field‐of‐view’, these gradient estimates were compared with the monostatic gradient estimates routinely produced by the two SDI's. The key findings to emerge from this study include: 1) the bistatic gradient estimate agreed very well with monostatic estimates for the majority of the time which, given the very different methods involved in each technique, gives us great confidence in our ability to measure F‐region neutral wind gradients; 2) the strongest gradient was that which describes the magnetic meridional shear of the zonal wind, which is driven by momentum deposition from convecting ions; 3) vortical flow was more often observed than divergent flow, and both types of flow showed systematic variations with magnetic local time; 4) viscous heating due to non‐negligible gradients was on the order of 10−11 Wm−3 which, while small compared to typical F‐region Joule heating rates, may be comparable to particle heating, and in a time‐integrated sense may be an appreciable source of heating.
Mesoanalysis of the interactions of precipitating convection and the boundary layer
Authors: Sun Ruiyu , Krueger Steven K.
Published: March 2012

The Oklahoma Mesonet surface wind data and the Arkansas Basin River Forecast Center (ABRFC) gridded hourly precipitation data from May to August, 1997, were used to demonstrate and evaluate a new method for the area‐averaged near‐cloud‐base updraft and downdraft mass fluxes from statistics of the surface divergence field. When precipitation is used as a proxy for near‐cloud‐base mass fluxes, the preliminary results indicate that surface divergence is fairly well correlated with the precipitation and that the surface divergence lags the precipitation. These results suggest that it is possible to use the proposed method to infer the near‐cloud‐base mass fluxes. Two CRM simulations of convective systems were also used to evaluate the method. The results show there is a good correlation between the inferred and true near‐cloud‐base mass fluxes except for some differences in timing and at peak values. An alternative to the original near‐cloud‐base mass flux method using the surface divergence statistics is to use the surface precipitation.
Inversion of backscatter ionograms and TEC data for over‐the‐horizon radar
Authors: Fridman Sergey V. , Nickisch L. J. , Hausman Mark
Published: March 2012

Over‐the‐horizon radar (OTHR) uses ionospheric reflection to propagate HF transmissions to long range (∼500–5000 km). The ionosphere acts as a dynamic “mirror” that varies diurnally, seasonally, and with the solar cycle. Geolocation of targets observed by OTHR (Coordinate Registration (CR)) requires accurate real‐time ionospheric modeling and HF propagation calculations to convert radar‐measured target signal delays and beam steers to geographical position. We merged our backscatter ionogram (BI) leading edge inversion algorithm CREDO with our more advanced ionospheric data assimilation capability, GPS Ionospheric Inversion (GPSII). The combined algorithm produces a dynamic model of electron density for a fixed geographical region. The model is consistent with BI leading edge data, vertical sounding data, as well as with absolute and relative total electron content (TEC) data from a number of GPS/LEO receivers. Incorporation of additional ionospheric data beyond conventional OTHR vertical and oblique backscatter soundings is expected to enhance the fidelity of real‐time ionosphere models, resulting in improved OTHR Coordinate Registration metric accuracy. Initial tests of the OTHR CR supported by the new ionospheric inversion algorithm indicate noticeable improvement of CR accuracy in comparison with legacy techniques.
Fine‐scale velocity structure of upper oceanic crust from full waveform inversion of downward continued seismic reflection data at the Lucky Strike Volcano, Mid‐Atlantic Ridge
Authors: Arnulf A. F. , Harding A. J. , Singh S. C. , Kent G. M. , Crawford W.
Published: March 2012

We present a fine‐scale 2D velocity structure beneath the Lucky Strike Volcano on the Mid‐Atlantic Ridge (MAR) using an elastic full waveform inversion (FWI) method. The FWI is a data driven procedure that allows simultaneous exploitation of both reflections and refractions energy in multi‐channel seismic data to create a single self‐consistent, high‐resolution velocity image of the upper crust that can be used for geologic interpretation. The long‐wavelength background P‐wave velocity model required by the local optimization approach was created using a combination of downward continuation and 3D first‐arrival travel‐time tomography. The elastic waveform inversion was applied to carefully windowed downward continued data, where wide‐angle reflections and refractions arrive in front of the water‐wave and are thus isolated from the high‐amplitude seafloor scattering energy that is particularly acute in areas of rough igneous seafloor. Waveform inversion reduces the misfit of the initial model by 76% after 19 iterations and strongly reduced the size of the residuals relative to the signal size. The final model shows fine scale structure beneath the northern part of the Lucky Strike volcano on a resolution of tens of meters. Evidence for successive lava sequences testifies to the constructional origin of the upper section of layer 2A. Normal faults are revealed within the shallow crust and are strongly correlated with seafloor observations.
Top‐down estimate of dust emissions through integration of MODIS and MISR aerosol retrievals with the GEOS‐Chem adjoint model
Authors: Wang Jun , Xu Xiaoguang , Henze Daven K. , Zeng Jing , Ji Qiang , Tsay Si‐Chee , Huang Jianping
Published: March 2012

Predicting the influences of dust on atmospheric composition, climate, and human health requires accurate knowledge of dust emissions, but large uncertainties persist in quantifying mineral sources. This study presents a new method for combined use of satellite‐measured radiances and inverse modeling to spatially constrain the amount and location of dust emissions. The technique is illustrated with a case study in May 2008; the dust emissions in Taklimakan and Gobi deserts are spatially optimized using the GEOS‐Chem chemical transport model and its adjoint constrained by aerosol optical depth (AOD) that are derived over the downwind dark‐surface region in China from MODIS (Moderate Resolution Imaging Spectroradiometer) reflectance with the aerosol single scattering properties consistent with GEOS‐chem. The adjoint inverse modeling yields an overall 51% decrease in prior dust emissions estimated by GEOS‐Chem over the Taklimakan‐Gobi area, with more significant reductions south of the Gobi Desert. The model simulation with optimized dust emissions shows much better agreement with independent observations from MISR (Multi‐angle Imaging SpectroRadiometer) AOD and MODIS Deep Blue AOD over the dust source region and surface PM10concentrations. The technique of this study can be applied to global multi‐sensor remote sensing data for constraining dust emissions at various temporal and spatial scales, and hence improving the quantification of dust effects on climate, air quality, and human health.
New evidence of cloud invigoration from TRMM measurements of rain center of gravity
Authors: Heiblum Reuven H. , Koren Ilan , Altaratz Orit
Published: March 2012

Much of the recent focus regarding aerosol effects on convective clouds and rain patterns has been on the possible invigoration of convective clouds by aerosols. Here we approach the issue using new methods, as rain vertical profiles' center of gravity (RCOG) and spread (RS) from TRMM are combined with aerosol optical depth (AOD) measurements from MODIS to examine this effect in various marine regions worldwide. Careful attention is also given to the meteorological, spatial and temporal variance in each region, as we try to extract and isolate the regional aerosol effect out of the dominant dynamic forcing. We show that for the majority of cases, high AOD values are correlated with higher RCOG and larger RS, indicating significant invigoration of the rain vertical distribution by aerosols.
The importance of plasma β conditions for magnetic reconnection at Saturn's magnetopause
Authors: Masters A. , Eastwood J. P. , Swisdak M. , Thomsen M. F. , Russell C. T. , Sergis N. , Crary F. J. , Dougherty M. K. , Coates A. J. , Krimigis S. M.
Published: March 2012

Magnetic reconnection is an important process that occurs at the magnetopause boundary of Earth's magnetosphere because it leads to transport of solar wind energy into the system, driving magnetospheric dynamics. However, the nature of magnetopause reconnection in the case of Saturn's magnetosphere is unclear. Based on a combination of Cassini spacecraft observations and simulations we propose that plasma βconditions adjacent to Saturn's magnetopause largely restrict reconnection to regions of the boundary where the adjacent magnetic fields are close to anti‐parallel, severely limiting the fraction of the magnetopause surface that can become open. Under relatively low magnetosheathβconditions we suggest that this restriction becomes less severe. Our results imply that the nature of solar wind‐magnetosphere coupling via reconnection can vary between planets, and we should not assume that the nature of this coupling is always Earth‐like. Studies of reconnection signatures at Saturn's magnetopause will test this hypothesis.
Enhanced Neuronal Excitability in Adult Rat Brainstem Causes Widespread Repetitive Brainstem Depolarizations with Cardiovascular Consequences
Authors: Richter Frank , Bauer Reinhard , Ebersberger Andrea , Lehmenkühler Alfred , Schaible Hans-Georg
Published: March 2012

The brainstem of the adult rat is relatively resistant to spreading depolarization (SD) but after enhancement of excitability SD can be evoked by local application of KCl. In the present experiments, we observed that the enhanced excitability even triggers prolonged periods of repetitive depolarizations (RDs), which elicit significant cardiovascular changes. In contrast to KCl-evoked SDs with amplitudes of ∼24 mV and spreading velocity of 4 mm/min, spontaneous RDs had amplitudes of 7 to 12 mV, propagated up to 30 times faster than KCl-evoked SDs, and depolarized larger brainstem areas including the contralateral side. Similarly as SD, RDs depended on glutamatergic neurotransmission and were blocked by MK-801 or by the calcium channel blocker agatoxin. They depended on sodium channels and were blocked by tetrodotoxin. Functionally, the invasion of RDs into the spinal trigeminal and other nuclei evoked bursts of action potentials, indicating that specific neuronal systems are affected. In fact, during episodes of RDs the blood pressure and the local blood flow at the surface of the brainstem and the cortex increased substantially. Brainstem RDs did not propagate into the cerebral cortex. We propose to consider brainstem RPs as a pathophysiological mechanism whose significance for brainstem disease states should be further explored.
Clinical Need and Rationale for Multi-Target Drugs in Psychiatry
Authors: Shahid Mohammed
Published: March 2012

High attrition in attempts to discover new pharmacological agents for the treatment of psychiatric disorders has triggered a decline in R&D investment in important disease categories such as schizophrenia and mood disorders. Poor knowledge about disease molecular pathology and molecular target validation coupled with notable costly failures involving clinical trials with highly novel and selective single target agents (STAs) have contributed to the development of this trend. One positive development arising from the current situation is the renewed interest in investigating approaches involving multi-target agents (MTAs), which have historically shown a strong track record of success and utility in the treatment of psychiatric disorders. However, it is clear that the traditional serendipity-dependent drug discovery approach for multi-target agents is suboptimal and has to evolve towards a new model of rationally designed and tailored MTAs. It is of course highly challenging to optimise compounds across several therapeutic targets whilst minimising potential broad receptor promiscuity as well as other properties to generate high quality drug candidates. Nevertheless, recent developments in medicinal chemistry approaches and pharmacological evaluation suggest that feasibility for tailored MTAs is not unrealistic. Appropriately designed MTAs, such as hybrids of validated and unprecedented novel molecular targets, offer a multi-functional pharmacology with the potential for multi-symptomatic efficacy and multi-indicational use. If successful this will help to address the compelling unmet medical need and the treatment requirements of schizophrenia and mood disorder patients as well as easing the burden of carers and the societal costs arising from these devastating illnesses.
Drug Molecules and Biology: Network and Systems Aspects
Authors: Young Malcolm P. , Zimmer Steven , Whitmore Alan V.
Published: March 2012

Complex biological networks are strikingly robust to deletion or interruption of their components. This robustness may be mediated by network features that we can now target specifically through network analysis. Network components (‘nodes’) differ greatly in importance depending upon the extent to which a node is connected to other nodes (‘degree’), the extent to which a node connects otherwise unconnected clusters (‘betweenness’) and the extent to which there are alternative pathways through a network (‘redundancy’). While networks are highly robust to random deletions of nodes, they are much more susceptible to targeted deletions prioritised by network properties such as degree and betweenness. A small number of combinations of, for example, five proteins can have a very great impact on network integrity in most biological networks. The strategy of network pharmacology-based approaches such as combinatorial network impact analysis is to find these very few high impact protein combinations that should be addressed simultaneously in order to yield high therapeutic efficacy.
Designing Multi-Target Drugs: In Vitro Panel Screening – Biological Fingerprinting
Authors: Mason Jonathan S.
Published: March 2012

The design of multi-target drugs requires an understanding of the polypharmacology of compounds, both desired and undesired/unexpected. In vitro panel screening, enabling the use of biological fingerprints, is a key experimental step towards this. Molecules are also usually described by their chemical structure and by fingerprints derived from this. These range from 2D structure based, that only represent the underlying structure that gives rise to the properties recognised by a biological target, to 3D pharmacophores or molecular interaction fields. These latter descriptions much better represent how the protein binding sites would ‘see’ a molecule; however, all of these have many limitations, including the need for conformational approximations for the 3D structure-based approaches. More recently, experimental profiling data has been generated for broad set of drugs and preclinical compounds that enables a molecule to be described by a fingerprint of binding affinity to a diverse set of biological targets (pharmacological and ‘anti-targets’ such as CYP450 metabolic enzymes). These results show that small changes in structure can cause large changes in broad biological profile, and that a structure-based analysis/clustering of compounds, for selecting different hits, leads or clinical candidates, often does not provide a differentiation that is relevant in biological space. The data show that ‘selective’ versus ‘non-selective’ compounds, and the type of off-target effects, are not evident from a ‘chemotype’ approach. In vitro panel screening and the concept of ‘biological fingerprints’ as a better way to describe compounds of biological interest is described in this chapter, focusing on the power of these descriptors versus structure-based descriptors to differentiate compounds and enable the selection of the best lead compounds.
Target/s Identification Approaches – Experimental Biological Approaches
Authors: Superti-Furga Giulio , Huber Kilian , Winter Georg
Published: March 2012

The unravelling of the human genome has not only opened a new avenue for an enhanced understanding of how a given repertoire of genetic information is able to create, maintain and regulate the physiological requirements for a living human organism but it has also defined a set of genes and their products which in case of aberrant activity, thus causing dysregulation and disease, might also be of relevance as potential drug targets. The challenge, of course, is how to pick the right one among some several thousand candidates of which according to predictions probably only a few can be considered ‘druggable’. On the other hand, there are many well-known drugs or natural products, originating from phenotypic screening, which are efficacious in treating human disorders, yet their targets and mode of action have remained elusive. Finally, lack of knowledge of a compound's protein target profile may not only lead to costly failures in drug development programmes but could also cause severe side effects in patients. Therefore, target deconvolution is a critical process for drug discovery from many perspectives. In the following chapter we will discuss various conceptually different approaches which have been developed in order to identify potential drug targets in settings of human disease. To meet the requirement of comprehensiveness and to avoid any systematic bias, the methods presented include both genomic as well as proteomic strategies ranging from yeast haplo-insufficiency profiling (HIP) to chemical proteomics using human tissues.
Targeting Protein–Protein Interactions: Dual Inhibitors of Bcl-2 and Bcl-xL
Authors: Wendt Michael D.
Published: March 2012

The discovery of dual inhibitors of anti-apoptotic proteins Bcl-2 and Bcl-xL is described. Bcl-xL and Bcl-2 act through protein–protein interactions with other members of the Bcl family, creating specific obstacles deriving from the nature of these targets – high protein binding, hydrophobicity, and low oral bioavailability. Access to soluble, stable versions of the target proteins allowed structural biology support that was crucial to this effort. Solving this problem with respect to Bcl-xL, and later Bcl-2, followed by parallel assay development allowed understanding of similarities and differences in the two target proteins. Fragment screening was used to navigate the early stage of the project, while structure-based drug design was employed throughout. Early compounds were somewhat Bcl-xL selective, while later compounds much more potent against both targets, particularly Bcl-2, leading to robust potentiation of standard chemotherapeutics and single agent activity in a variety of hematological cancers. ABT-737, a large, hydrophobic compound, was initially selected as a development candidate. Later, efforts to derive an orally bioavailable compound from the same chemical series culminated in the discovery of ABT-263, a rationally designed Bcl-2/Bcl-xL inhibitor, which is currently in phase II clinical trials for cancer.
The Rational Design of Triple Reuptake Inhibitors for the Treatment of Depression
Authors: Weikert Robert J.
Published: March 2012

Despite advances in treatment, major depression continues to be a disabling condition that exacts an enormous toll on society, both socially and economically. A significant advance in the treatment of depression was associated with the discovery of the selective serotonin reuptake inhibitors (SSRIs), agents that increase brain levels of serotonin, and the serotonin and norepinephrine reuptake inhibitors (SNRIs), which exert their action on both the serotonergic and noradrenergic pathways. Unfortunately, only one-third of patients respond positively to SSRI/SNRI treatment, and they are associated with a considerable delay in the onset of action. In order to improve on both remission rates and time to onset, many psychiatrists add an additional drug to a patient's SSRI or SNRI regimen. A widely used drug for this augmentation strategy is bupropion, a norepinephrine and dopamine reuptake inhibitor (NDRI). This combination results in the increase of synaptic concentrations of serotonin, norepinephrine, and dopamine, effectively creating a triple reuptake inhibitor (TRI). This chapter will focus on our strategies to discover novel triple reuptake inhibitors through scaffold hopping. In addition to potency optimization, strategies utilized to address other inherent issues such as blood–brain barrier penetration, microsomal clearance, hERG interactions, and drug–drug interactions will also be discussed.