bluuebunny/crossref_metadata_2025 huggingface dataset:
High‐resolution matrix‐assisted laser desorption/ionization imaging of tryptic peptides from tissue
Authors: Schober Yvonne , Guenther Sabine , Spengler Bernhard , Römpp Andreas
Published: March 2012

RATIONALE

The analysis of proteins by mass spectrometry imaging is an important biomedical application as spatial distributions can be used to identify markers for pathological processes. The direct detection and identification of proteins on tissue can be hindered by a number of factors including limited mass range and fragmentation efficiency as well as incompatibility with formalin‐fixed samples.

METHODS

To overcome some of these limitations, on‐tissue digestion of proteins was followed by detection of the resulting peptides. Trypsin was applied by a spraying device. Matrix‐assisted laser desorption/ionization (MALDI) imaging experiments were performed with a home‐built atmospheric‐pressure imaging source attached to a LTQ Orbitrap mass spectrometer. The mass accuracy under imaging conditions was better than 3 ppm RMS. This allowed for confident identification of tryptic peptides by comparison with liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI‐MS/MS) measurements of an adjacent mouse brain section.

RESULTS

A spatial resolution of 50 µm was obtained for tryptic peptides on tissue. Several tryptic peptides of myelin showed matching spatial distributions, and numerous tryptic peptides of other proteins were identified. MS images were generated with a bin size (mass range used for image generation) of Δm/z = 0.01 u. Examples demonstrate that MS images with lower selectivity can result in misleading information about the spatial distribution of tryptic peptides.

CONCLUSIONS

The presented method combines a significantly improved spatial resolution for tryptic peptides with low‐ppm mass accuracy in a single experiment and thus provides highly reliable and specific information. Copyright © 2012 John Wiley & Sons, Ltd.
Spectral accuracy of a new hybrid quadrupole time‐of‐flight mass spectrometer: application to ranking small molecule elemental compositions
Authors: Jiang Wei , Erve John C. L.
Published: March 2012

RATIONALE

Determining the elemental compositions of unknown molecules is an important goal of analytical chemistry. The isotope pattern revealed by a mass spectrometer provides valuable information regarding the elemental composition of a molecule. In order to employ spectral accuracy considerations for elemental composition determination, it is important to know how faithfully a mass spectrometer can record the isotope pattern and to understand the magnitude of the errors of the relative isotopic abundances.

METHODS

Twenty‐four small molecule drugs and two natural products representing a diverse range of elemental compositions and ranging in molecular weight from 236 to 1663 Da were measured on a new hybrid orthogonal acceleration quadrupole time‐of‐flight (Q‐TOF) mass spectrometer by flow infusion analysis. The similarity between the observed profile isotope pattern and the theoretical isotope pattern, denoted spectral accuracy, was calculated using a computational algorithm in the program MassWorks.

RESULTS

The spectral accuracy for all compounds averaged better than 98%. When using spectral accuracy to rank elemental compositions with the elemental constraints (C1–100H0–200N0–50O0–50F0–5S0–5Cl0–5Br0–5) further restricted by empirical rules and a mass tolerance ≤5 parts‐per‐million, the correct formula was ranked first over 80% of the time. In contrast, when using mass accuracy for ranking, only two compounds (8%) were ranked first. For quinidine and troglitazone, the initial spectral accuracy measurements were lower than expected and further analysis indicated that minor, structurally related components were present.

CONCLUSIONS

Our work has determined the magnitude of spectral accuracy that can be expected on a new Q‐TOF mass spectrometer. In addition, we demonstrate the utility of spectral accuracy measurements both for ranking elemental compositions and also for obtaining insight into the chemical nature of the analyte that might otherwise be overlooked. Copyright © 2012 John Wiley & Sons, Ltd.
A liquid chromatography/tandem mass spectrometry method for measuring the in vivo incorporation of plasma free fatty acids into intramyocellular ceramides in humans
Authors: Blachnio‐Zabielska Agnieszka U. , Persson Xuan‐Mai T. , Koutsari Christina , Zabielski Piotr , Jensen Michael D.
Published: March 2012

RATIONALE

Sphingolipids are important components of cell membranes that serve as cell signaling molecules; ceramide plays a central role in sphingolipid metabolism. De novo ceramide biosynthesis depends on fatty acid availability, but whether muscle uses circulating free fatty acids or pre‐existing intracellular stores is unknown. Our goal was to develop a method to detect the incorporation of intravenously infused [U‐13C]palmitate into intramyocellular ceramides.

METHODS

We used liquid chromatography/tandem mass spectrometry (LC/MS/MS) to measure the concentrations of different sphingolipid species and 13C‐isotopic enrichment of 16:0‐ceramide. Chromatographic separation was performed using ultra‐performance liquid chromatography. The analysis was performed on a triple quadrupole mass spectrometer using a positive ion electrospray ionization source with selected reaction monitoring (SRM).

RESULTS

The sphingolipids ions, except enriched ceramide, were monitored as [M+2+H]+. The [13C16]16:0‐ceramide was monitored as [M+16+H]+. By monitoring two different transitions of the [13C16]16:0‐ceramide (554/536 and 554/264) we could indirectly measure enrichment of the palmitate that is not a part of the sphingoid base. Concentration and enrichment could be measured using 20 mg of muscle obtained from volunteers receiving a low dose [U‐13C]palmitate infusion.

CONCLUSIONS

LC/MS/MS can be used to detect the incorporation of plasma palmitate into muscle ceramides in humans, in vivo. Copyright © 2012 John Wiley & Sons, Ltd.
Practical usefulness of SEM–EDX spectrum subtraction for material identification of individual submicrometer‐sized particles on glass substrate
Authors: Tomita Masato , Isobe Sumiko , Yamamoto Hideki
Published: March 2012

This paper describes the practical usefulness of scanning electron microscope–energy dispersive X‐ray spectroscopy spectrum subtraction for material identification of individual submicrometer‐sized particles on glass substrate. Common peaks of glass elements in the spectra from the substrate only, and those from an individual particle on the substrate are used for the normalization of the spectra for subtraction. After demonstrating an experimental example of common dust particles (metals and oxides) on a glass substrate, Monte Carlo simulation was applied to investigate the details of electron scattering and X‐ray generation behaviors in individual particles on the substrate. Although limitations on usage and geometrical effect are inevitable, the spectrum subtraction described herein is useful for quick identification of small particles on a glass substrate by reducing pronounced peaks and background from the substrate. Copyright © 2012 John Wiley & Sons, Ltd.
Supersymmetric solutions in six dimensions: a linear structure
Authors: Bena Iosif , Giusto Stefano , Shigemori Masaki , Warner Nicholas P.
Published: March 2012

Abstract

The equations underlying all supersymmetric solutions of six-dimensional minimal ungauged supergravity coupled to an anti-self-dual tensor multiplet have been known for quite a while, and their complicated non-linear form has hindered all attempts to systematically understand and construct supersymmetric solutions. In this paper we show that, by suitably re-parameterizing these equations, one can find a structure that allows one to construct supersymmetric solutions by solving a sequence of linear equations. We then illustrate this method by constructing a new class of geometries describing several parallel spirals carrying D1, D5 and P charge and parameterized by four arbitrary functions of one variable. A similar linear structure is known to exist in five dimensions, where it underlies the black hole, black ring and corresponding microstate geometries. The unexpected generalization of this to six dimensions will have important applications to the construction of new, more general such geometries.
Elements of a theory for multiparton interactions in QCD
Authors: Diehl Markus , Ostermeier Daniel , Schäfer Andreas
Published: March 2012

Abstract

We perform a detailed investigation of multiple hard interactions in hadron-hadron collisions. We discuss the space-time, spin and color structure of multiple interactions, classify different contributions according to their power behavior and provide several elements required for establishing all-order factorization. This also allows us to analyze the structure of Sudakov logarithms in double hard scattering. We show how multiparton distributions can be constrained by connecting them with generalized parton distributions and by calculating their behavior at large transverse parton momenta.
Resource productivity and availability impacts for food‐chain length
Authors: Doi Hideyuki
Published: March 2012

Ecologists have focused on food‐chain length (FCL) for the past eight decades as an index of food‐web structure. Here, I review the hypotheses determining FCL with a focus on resource productivity and availability effects on FCL. First, I introduce the mainstream hypotheses to explain FCL variations: productivity, ecosystem size, and disturbance. For the existing productivity and productive space hypotheses, I stress the importance of using resource availability to estimate the productivity effect on FCL. Using a FCL dataset from 15 ponds, I tested the resource stoichiometry effect on FCL for ponds with between carbon:nitrogen ratio of primary producers and FCL. Moreover, I provide a perspective for studying resource availability and stoichiometry effects on FCL and of the alternative hypotheses of productive‐space and ecosystem size. Finally, I suggest the future directions of the FCL study: a resource subsidy and climate change effects on FCL and food‐web structure.
Patient-Reported Outcomes after Acute Carpal Tunnel Release in Patients with Distal Radius Open Reduction Internal Fixation
Authors: Chauhan Aakash , Bowlin Timothy C. , Mih Alexander D. , Merrell Gregory A.
Published: March 2012

Background

Acute carpal tunnel syndrome (CTS) is a complication that can develop after distal radius fractures. Our hypothesis tested whether patient-reported outcomes after acute carpal tunnel release (CTR) performed in combination with distal radius fracture open reduction internal fixation (ORIF) are worse than patient-reported outcomes with only elective CTR as measured by the symptom severity and functional status scales of the Boston carpal tunnel questionnaire (BCTQ).

Methods

A retrospective assessment identified 26 patients treated with acute CTR at the same time as distal radius ORIF, no history of pre-existing CTS or CTR, no other injuries, and >12 months follow-up. Sixteen of these patients (Group A) could be contacted and answered the BCTQ. Group A was age- and sex-matched to control patients (Group B) treated with only elective CTR. A case–control study was performed comparing outcomes of both groups.

Results

The average age of patients was 51±15 years, with an average follow-up of Group A at 49±21 months versus Group B at 55±20 months. The mean symptom severity scale score for Group A was 1.4±0.4 and for Group B was 1.4±0.4. The mean functional status scale score for Group A was 1.4±0.5 and for Group B was 1.3±0.4. The mean total BCTQ score for Group Awas 26.5±7.5 and for Group B was 24.9±7.5. There were no statistical or clinically significant differences between Group A and Group B for symptom severity, functional status, and total BCTQ scores.

Conclusions

Patients with acute CTR performed at the same time with distal radius ORIF do as well in the long-term as those patients with only elective CTR as measured by the BCTQ. Patients should expect similar recovery of subjective nerve function from acute median nerve dysfunction when CTR is performed with distal radius ORIF as patients with only elective CTR.
Properties of Sodium Methyl Ester Alpha‐Sulfo Alkylate/Trimethylammonium Bromide Mixtures
Authors: Wong Siew Pui , Lim Wen Huei , Cheng Sit‐Foon , Chuah Cheng Hock
Published: March 2012

The surface properties of binary mixtures of anionic sodium methyl ester α‐sulfo alkylate (CmMES) and cationic alkyl trimethylammonium bromide (CnTAB) of different carbon chain length have been studied in the present work. The critical micelle concentration (CMC) that was obtained from the plots of surface tension (γ) versus concentration showed that mixed surfactants have CMC values that were about 10 times lower than their single components. The large negative values for both interaction parameters suggest the existence of strong synergism between the oppositely charged surfactant molecules. The effect of hydrocarbon chain length of either surfactant was also compared and results showed that the effect of cationic surfactant chain length dominated that of the anionic surfactants. It was also discovered that certain mixed surfactant combinations behave differently from the expected trend.
Open reduction of proximal humerus fractures in the adolescent population
Authors: Pandya Nirav K. , Behrends Dominque , Hosalkar Harish S.
Published: March 2012

Purpose

Proximal humerus fractures in the pediatric population are a relatively uncommon injury, with the majority of injuries treated in a closed fashion due to the tremendous remodeling potential of the proximal humerus in the skeletally immature. Yet, in adolescent patients, open treatment is, at times, necessary due to unsatisfactory alignment following a closed reduction, loss of previously achieved closed reduction, and limited remodeling when close to skeletal maturity. The purpose of our study was to examine the open reduction of adolescent proximal humerus fractures.

Methods

A retrospective review of the outcomes of proximal humerus fractures in the adolescent population which were consecutively treated at our institution with open reduction was performed.

Results

Ten children met the inclusion criteria, with a mean age of 14.3 years (±1.3) and a mean weight of 60.7 kg (±14.9) at the time of injury. There were seven Salter-Harris 2 fractures and three Salter-Harris 1 fractures. The largest mean angulation was 55.0° (±33.9) and the largest mean displacement was 87.0 % (±22.8). Intra-operatively, impediments to closed reduction within the fracture site which were found included: periosteum (90.0 %), biceps tendon (90.0 %), deltoid muscle (70.0 %), and comminuted bone (10.0 %). K-wire fixation was most commonly used (70.0 %), followed by flexible nails (20.0 %) and cannulated screws (10.0 %) for fixation. All patients achieved radiographic union at a mean of 4.0 weeks (±0.7), had non-painful full shoulder range of motion and rotator cuff strength at final follow-up (mean 7.7 ± 4.6 months), and returned to pre-injury sporting activities.

Conclusions

The operative treatment of proximal humerus fracture, particularly in adolescents with severe displacement/angulation having failed closed methods of treatment, is increasingly considered to be an acceptable modality of treatment. In addition to the long head of the biceps, periosteum, deltoid muscle, and bone fragments in combination can prevent fracture reduction. Surgeon preference and skill should dictate implant choice, and the risk of physeal damage utilizing these implants in this age group is low.
The relation between bullying, victimization, and adolescents' level of hopelessness
Authors: Siyahhan Sinem , Aricak O. Tolga , Cayirdag‐Acar Nur
Published: March 2012

In this study, 419 Turkish middle school students (203 girls, 216 boys) were surveyed on their exposure to and engagement in bullying, and their level of hopelessness. Our findings suggest that girls were victims of indirect (e.g. gossiping) bullying more than boys. Boys reported being victims of physical (e.g. damaging property) and verbal (e.g. teasing) bullying more than girls. While the level of hopelessness among victims of physical and verbal bullying was higher than non‐victims, no difference was found between the victims of indirect bullying and non‐victims. Students who never talked to their teachers and parents about bullying reported higher levels of hopelessness than others. The implications of the study for intervention and prevention programs are discussed.
Implementing AORN Recommended Practices for Hand Hygiene
Authors: Patrick Marcia , Van Wicklin Sharon A.
Published: March 2012

This article focuses on implementing the revised AORN “Recommended practices for hand hygiene in the perioperative setting.” The content of the document has been expanded and reorganized from the previous iteration and now includes specific activity statements about water temperature, water and soap dispensing controls, the type of dispensers to use, paper towel dispenser requirements, placement of soap and rub dispensers, and regulatory requirements for products and recommendations for hand hygiene practices. A successful hand hygiene program allows end users to have input into the selection and evaluation of products and should include educating personnel about proper hand hygiene, product composition and safety, and how and when to use specific products. Measures for competency evaluation and compliance monitoring include observations, quizzes, skills labs, electronic monitoring systems, handheld device applications, and data collection forms.
FDI determinants in an idiosyncratic country. A reappraisal over the Russian regions during transition years
Authors: Castiglione Concetta , Gorbunova Yulia , Infante Davide , Smirnova Janna
Published: March 2012

We investigate the factors attracting FDI into highly diversified Russian regions during the phase of transition, and verify the impact of transition experience on the current FDI inflow. Using cross-sectional and panel data, we demonstrate that the highly inhomogeneous investment pattern is explained, in addition to classical demand factors, by specific economic and socio-institutional regional characteristics. Russia appears as an idiosyncratic country where foreign investors seek a stable social and institutional context. Using recent FDI data we show that transition experiences influence current FDI inflow, particularly when the strength of the institutional environment and availability of infrastructures are taken into account.
High-protein–low-carbohydrate diet during pregnancy alters maternal plasma amino acid concentration and placental amino acid extraction but not fetal plasma amino acids in pigs
Authors: Metzler-Zebeli Barbara U. , Lang Iris S. , Görs Solvig , Brüssow Klaus-Peter , Hennig Ulf , Nürnberg Gerd , Rehfeldt Charlotte , Otten Winfried , Metges Cornelia C.
Published: March 2012

A high protein–low-carbohydrate diet during pregnancy can cause intra-uterine growth restriction. However, its impact during pregnancy on maternal, umbilical and fetal plasma amino acid (AA) profiles is unknown. A maternal high-protein (30 %)–low-carbohydrate (HP-LC) diet was compared with isoenergetic standard (12·1 % crude protein; ST) and low-protein (6·5 %)–high-carbohydrate (LP-HC) diets fed to nulliparous pregnant sows to examine changes in AA concentrations in maternal, venous and arterial umbilical and fetal plasma in mid and late pregnancy. At 64 and 94 days of pregnancy (dp), sows underwent Caesarean section, and maternal, umbilical and fetal plasma samples were collected. The HP-LC diet mainly affected maternal plasma AA concentrations. Plasma concentrations of Ile and Val were increased and those of Ala, Glu and Gly were decreased (P ≤ 0·05) in HP-LC compared with ST sows at 64 and 94 dp. The LP-HC diet decreased fetal plasma Glu concentration compared with the ST diet at 94 dp. Substantial AA catabolism was reflected by increased (P ≤ 0·05) maternal and fetal plasma urea concentrations with the HP-LC compared with the ST and LP-HC diets at 94 dp. Fractional placental extraction of Val was higher whereas those of Ala, Gln and Glu were lower in the HP-LC compared with the ST sows at 64 and 94 dp (P ≤ 0·05). Reduced fetal mass at 94 dp was accompanied by reduced fetal extraction of Lys and Pro in the HP-LC group (P ≤ 0·05). In conclusion, a maternal HP-LC diet during pregnancy altered maternal plasma composition of many AA and modified placental AA extraction to compensate for imbalanced maternal nutrient intake.
Algorithms for autonomous exploration and estimation in compliant environments
Authors: Goldman R. E. , Bajo A. , Simaan N.
Published: March 2012

This paper investigates algorithms for enabling surgical slave robots to autonomously explore shape and stiffness of surgical fields. The paper addresses methods for estimating shape and impedance parameters of tissue and methods for autonomously exploring perceived impedance during tool interaction inside a tissue cleft. A hybrid force-motion controller and a cycloidal motion path are proposed to address shape exploration. An adaptive exploration algorithm for segmentation of surface features and a predictor-corrector algorithm for exploration of deep features are introduced based on discrete impedance estimates. These estimates are derived from localized excitation of tissue coupled with simultaneous force measurements. Shape estimation is validated inex-vivobovine tissue and attains surface estimation errors of less than 2.5 mm with force sensing resolutions achievable with current technologies in minimally invasive surgical robots. The effect of scan patterns on the accuracy of the shape estimate is demonstrated by comparing the shape estimate of a Cartesian raster scan with overlapping cycloid scan pattern. It is shown that the latter pattern filters the shape estimation bias due to frictional drag forces. Surface impedance exploration is validated to successfully segment compliant environments on flexible inorganic models. Simulations and experiments show that the adaptive search algorithm reduces overall time requirements relative to the complexity of the underlying structures. Finally, autonomous exploration of deep features is demonstrated in an inorganic model andex-vivobovine tissue. It is shown that estimates of least constraint based on singular value decomposition of locally estimated tissue stiffness can generate motion to accurately follow a tissue cleft with a predictor-corrector algorithm employing alternating steps of position and admittance control. We believe that these results demonstrate the potential of these algorithms for enabling “smart” surgical devices capable of autonomous execution of intraoperative surgical plans.
Persistent electrocution mortality of Egyptian Vultures Neophron percnopterus over 28 years in East Africa
Authors: ANGELOV IVAYLO , HASHIM IBRAHIM , OPPEL STEFFEN
Published: March 2012

Electrocution on poorly designed power poles is increasingly shown to pose a threat for the populations of many large raptors. Here we document that a power line in Sudan continues to cause mortality of Egyptian Vultures Neophron percnopterus, a problem that was first identified in 1984. We suggest that this power line may have caused the death of sufficient Egyptian Vultures to partially explain population declines in the Middle East, from where the electrocuted birds may originate. This report highlights the urgent need to plan and retro-fit power lines in Africa with non-lethal support structures.
A FULL NT-STEP INFEASIBLE INTERIOR-POINT ALGORITHM FOR SEMIDEFINITE OPTIMIZATION BASED ON A SELF-REGULAR PROXIMITY
Authors: KHEIRFAM B.
Published: March 2012

We introduce a full NT-step infeasible interior-point algorithm for semidefinite optimization based on a self-regular function to provide the feasibility step and to measure proximity to the central path. The result of polynomial complexity coincides with the best known iteration bound for infeasible interior-point methods.
Wie werden Verbesserungen nach Typ-II-Traumata infolge unterschiedlicher traumabearbeitender Interventionen eingeschätzt?
Authors: Kliem* Sören , Kröger* Christoph , Sarmadi Nico Bayat , Kosfelder Joachim
Published: March 2012

Zusammenfassung. Theoretischer Hintergrund: Bei der Behandlung der posttraumatischen Belastungsstörung (PTBS) nach einem Typ-II-Trauma werden im klinischen Alltag gegenwärtig unterschiedliche traumabearbeitende Interventionen eingesetzt. Fragestellung: Wie werden die Verbesserungen in verschiedenen Symptombereichen (plötzliches Wiedererleben, Vermeidung, Übererregung, Dissoziation und zusätzliche Symptomatik) in Abhängigkeit von dem Einsatz unterschiedlicher traumabearbeitender Interventionen von den Behandlern retrospektiv eingeschätzt? Methode: Aus einer Umfrage unter Psychologischen Psychotherapeuten (N = 272) wurden die Fälle ausgewählt, bei denen die Therapeuten (1) ein Ereignis nannten, das einem Typ-II-Trauma zugeordnet werden konnte, und (2) angaben, traumabearbeitende Interventionen gemäß der traumafokussierenden, kognitiven Verhaltenstherapie (TF-KVT), der Methode des Eye Movement Desensitization and Reprocessing (EMDR-Methode) oder der Psychodynamisch-imaginativen Traumatherapie (PITT) durchgeführt zu haben (n = 37). Außerdem beurteilten die Therapeuten retrospektiv die Verbesserungen in den Symptombereichen zu Therapieende. Ergebnisse: Über 40% der Therapeuten gaben an, die Vorstellungsübungen bzw. Bearbeitung des Täter Introjekts gemäß der PITT eingesetzt zu haben, gefolgt von den traumabearbeitenden Interventionen der TF KVT (35.1%) und der EMDR Methode (21.6%). Die Therapeuten, die Interventionen eines der beiden zuletzt genannten Verfahren einsetzten, schätzten die Verbesserungen in den verschiedenen Symptombereichen höher ein als diejenigen, die angaben, eine Intervention gemäß der PITT durchgeführt zu haben. Schlussfolgerungen: Die retrospektiven Einschätzungen der Verbesserungen durch die Therapeuten stehen im Einklang mit den Empfehlungen der Behandlungsleitlinien zur PTBS.
Dynamics of wind‐driven circulation in a shallow lagoon with strong horizontal density gradient
Authors: Jia Peng , Li Ming
Published: March 2012

Albemarle‐Pamlico Sound (APS) is a shallow lagoonal estuary with weak stratification but strong horizontal density gradient. Idealized and realistic model simulations are conducted to examine the dynamics of wind‐driven circulation in APS. Two dimensionless parameters, the Ekman (Ek) and Wedderburn (W) numbers, are found to be two key parameters in controlling the flow pattern and dynamics. Circulation in Albemarle Sound and northern Pamlico Sound is primarily driven by wind‐forcing, and shows laterally sheared flows withEk approaching 1 and Wexceeding 1. Analysis of the along‐channel momentum equation shows a balance among the wind stress, barotropic pressure gradient due to sea level setup, and bottom friction, while the vertical vorticity is primarily determined by the balance between the wind stress curl and bottom stress curl. In contrast, circulation in southern Pamlico Sound is driven by both wind and gravitational forces, and shows vertically sheared two‐layer flows with lowEk and Waround 1. Both baroclinic and barotropic pressure gradients act against the wind stress to drive the two‐layer flows. A regime diagram in the parameter space ofEk and W is used to summarize variability of circulation pattern on the seasonal time scale. Northern Pamlico Sound is characterized by high Ek and high W values and laterally sheared currents. Southern Pamlico Sound is usually characterized by low Ek and low W values and vertically sheared flows but featuring laterally sheared flows during the fall when Ek averages to over 0.5.
Uncertainties in relative atmospheric angular momentum computed from zonal winds in reanalysis data
Authors: Lehmann Elfrun , Névir Peter
Published: March 2012

Numerous fields of computational Earth system research require a precise account of variations in the relative atmospheric angular momentum (AAM). Since zonal winds from reanalysis data sets of ERA‐40 (ECMWF) and NCEP1 (NCEP/NCAR) are frequently used to compute relative AAM estimates it is critically important to understand uncertainties in these data products. Here, we discuss the varying degree of structural and internal uncertainties associated with ERA‐40 and NCEP1 zonal wind data in the tropical Pacific troposphere and lower stratosphere. We assess these uncertainties by quantifying differences in relative AAM computed from reanalyses wind data (1958–2000), that are subsequently compared to a 10‐year record of radiosonde observations carried out in the tropical Pacific where reanalyses data differ most. While our analysis suggests that in general differences between reanalysis data and observed tropical winds in the Pacific are not significantly different from each other, we found varying degrees of discrepancies at each radiosonde site. Zonal winds in NCEP1 data (RMS = 1.84 ms−1) reproduce less bias in tropospheric easterly winds than ERA‐40 (RMS = 3 ms−1), while for the lower stratosphere ERA‐40 data fit better westerly winds (RMS = 3.95 ms−1) than NCEP1 (RMS = 5.03 ms−1). Anomalies in zonal tropical wind fields can be induced by large mountain and friction torques that efficiently affect Earth's rotation rate. Hence, a precise account of the wind term in reanalysis data directly determines the accuracy of computed estimates of relative AAM.
Numerical investigation of deformation mechanics in fold‐and‐thrust belts: Influence of rheology of single and multiple décollements
Authors: Ruh Jonas B. , Kaus Boris J. P. , Burg Jean‐Pierre
Published: March 2012

Thin‐skinned fold‐and‐thrust belts related to convergence tectonics develop by scraping off a rock sequence along a weaker basal décollement often formed by water‐saturated shale layers or low‐viscosity salt horizons. A two‐dimensional finite element model with a viscoelastoplastic rheology is used to investigate the structural evolution of fold‐and‐thrust belts overlying different types of décollements. In addition, the influence of multiple weak layers in the stratigraphic column is studied. Model shale décollements are frictional, with lower friction angles as the cover sequence. Model salt layers behave linear viscous, due to a lower viscosity as the cover sequence, or with a power law rheology. Single viscous décollement simulations have been compared to an analytical solution concerning faulting versus folding. Results show that fold‐and‐thrust belts with a single frictional basal décollement generate thrust systems ramping from the décollement to the surface. Spacing between thrust ramps depends on the thickness of the cover sequence. The structural evolution of simulations with an additional low‐frictional layer depends on the strength relationship between the basal and the intersequential décollement. Tectonic underplating and antiformal stacking occur if the within‐sequence décollement is weaker. In the frontal part of models, deformation is restricted to the upper part and imbrication occurs with a wavelength depending on the depth of the intermediate weak layer. “Salt” décollement with a viscosity of 1018 Pa⋅s leads to isolated box folds (detachment folds). Multiple salt layers (1018 Pa⋅s) result in long‐wavelength folding. Our results for both frictional and viscous décollements are in bulk agreement with the Mohr‐Coulomb type, critical wedge theory.
Imaging Cerebral 2-Ketoisocaproate Metabolism with Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging
Authors: Butt Sadia A , Søgaard Lise V , Magnusson Peter O , Lauritzen Mette H , Laustsen Christoffer , Åkeson Per , Ardenkjær-Larsen Jan H
Published: March 2012

The branched chain amino acid transaminase (BCAT) has an important role in nitrogen shuttling and glutamate metabolism in the brain. The purpose of this study was to describe the cerebral distribution and metabolism of hyperpolarized 2-keto[1-13C]isocaproate (KIC) in the normal rat using magnetic resonance modalities. Hyperpolarized KIC is metabolized to [1-13C]leucine (leucine) by BCAT. The results show that KIC and its metabolic product, leucine, are present at imageable quantities 20 seconds after end of KIC administration throughout the brain. Further, significantly higher metabolism was observed in hippocampal regions compared with the muscle tissue. In conclusion, the cerebral metabolism of hyperpolarized KIC is imaged and hyperpolarized KIC may be a promising substrate for evaluation of cerebral BCAT activity in conjunction with neurodegenerative disease.
Chemoinformatic Approaches to Target Identification
Authors: Gregori-Puigjané Elisabet , Keiser Michael J.
Published: March 2012

Many on-market drugs bind to multiple protein targets at therapeutic concentrations. Such ‘off-target’ binding contributes to drug efficacy and also to adverse drug effects. In some cases, newly identified off-targets may represent drug repositioning opportunities. This chapter presents chemoinformatic methods used to predict drug off-target binding on a broad scale, in the context of their application to target identification and target-specific toxicity.
In Silico Lead Generation Approaches in Multi-Target Drug Discovery
Authors: Ma Xiaohou , Chen Yuzong
Published: March 2012

Increasingly sophisticated in silico screening methods are being applied to facilitate MTDD at the hit generation and optimization stages. Structure-based and ligand-based methods have been used individually and in combination to identify novel compounds. These will be described in this chapter and a number of examples will be provided.
The Challenges of Multi-Target Lead Optimization
Authors: Richard Morphy J.
Published: March 2012

During multi-target lead optimization, medicinal chemists must address three principal challenges. First, the various desired activities must be adequately balanced and the activity profile of any active metabolites must also be considered. Second, undesired activities associated with side effects need to be removed. Third, a pharmacokinetic profile appropriate for the desired route of administration, usually oral, must be obtained. Given the extent of these challenges, the need for a high quality lead compound is paramount.
Combination Agents Versus Multi-Targeted Agents – Pros and Cons
Authors: Monzon Jose G. , Dancey Janet
Published: March 2012

Cancer, in all its various forms, is perhaps the archetypical multi-factorial disease and it is therefore not surprising that single-target drugs are rarely useful as anti-cancer agents when used on their own. Traditional cancer therapy has relied on effective drug combinations and the more recent emergence of compounds that simultaneously modulate multiple targets has added to the oncology armoury and raised the question as to which approach, drug combinations or single compound multi-targeted drug, is to be preferred. This chapter reviews the basis for combining existing drugs and how these combinations are selected, and compares these with multi-targeted drugs (MTDs) such as sunitinib, a broad-spectrum kinase inhibitor that inhibits a range of growth factors. Whether using physical combinations or MTDs, or indeed combinations of MTDs, the choice of which targets and which pathways to attack is crucial and the rationale for selecting these is discussed in detail. The NCI Cancer Therapy Evaluation Program, designed to facilitate trials of novel combinations, will aid in the rational selection of targets and pathways to combine in future MTDs. The pros and cons of combinations and MTDs in terms of the relative challenges in clinical development are examined, and the systematic use of biomarkers, better approaches to patient selection, and improved design of trials to take account of the heightened potential for acute and delayed on- and off-target toxicities are highlighted.
Designing Drugs with Dual Activity: Novel Dual Angiotensin II and Endothelin Receptor Antagonists
Authors: Murugesan Natesan
Published: March 2012

The endogenous peptides angiotensin II (Ang II) and endothelin-1 (ET-1) are powerful vasoconstrictors and mitogens and both peptides have been implicated in the pathogenesis of hypertension and other related disorders. Studies in animal models have demonstrated that simultaneous blockade of angiotensin type 1 (AT1) and endothelin type A (ETA) receptors produced greater therapeutic benefits than antagonizing either AT1 or ETA receptors alone. Merging together, by rational design, the structural features of the AT1 receptor antagonist irbesartan with key structural elements in a biphenylsulfonamide ETA receptor antagonist (BMS-193884) followed by additional optimization provided compound 8 (BMS-346567) as a dual action receptor antagonist (DARA), which potently blocked both AT1 and ETA receptors. In rats, DARA 8 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than either AT1 or ETA receptor antagonists alone. DARA 8 clearly demonstrated superiority over irbesartan (an AT1 receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT1 and ETA receptor blockade in a single molecule. In phase I and phase II clinical trials, DARA 8 was found to be safe and well tolerated and demonstrated statistically significant greater reductions in blood pressure than placebo in hypertensive patients. Overall, these preclinical and clinical data demonstrate that the DARA mechanism has the potential to be a significant new addition to the armamentarium of anti-hypertensive drugs.
Ethyl Urea Inhibitors of the Bacterial Type II Topoisomerases DNA Gyrase (GyrB) and Topoisomerase IV (ParE)
Authors: East Stephen P. , Czaplewski Lloyd G. , Haydon David J.
Published: March 2012

The discovery of new antibacterials to combat the emergence of resistant organisms is of global importance. One strategy to reduce the development of resistance in new drugs is to identify a single pharmacophore that has the ability to target more than one essential bacterial enzyme. This opportunity has already been realised with certain drugs from the quinolone/fluoroquinolone class of antibiotics, and these drugs act via the GyrA and ParC subunits on the bacterial type II topoisomerases DNA gyrase and topoisomerase IV. This class of enzymes also presents a second opportunity for single pharmacophore multi-target inhibitors as they contain similarly conserved binding sites on the GyrB and ParE subunits which are responsible for the hydrolysis of ATP, a critical step in these enzymes’ function. Competitive inhibitors of ATP have been shown to inhibit both GyrB and ParE and to reduce spontaneous resistance in vitro which is indicative of dual-target action. This chapter will focus on one chemical class of dual-targeting DNA gyrase and topoisomerase IV inhibitors, the ethyl ureas, and will present some of the preclinical data supporting their mechanism of action as a novel series of antibacterials.
Tamoxifen Loaded Auto-Assembled Nanoparticles for Oral Delivery: Cytotoxicity and Permeability Studies
Authors: Barbieri S. , Sonvico F. , Bouchemal K. , Ponchel G. , Colombo P.
Published: March 2012

The purpose of this study was to characterise and study on cell cultures chitosan/lecithin nanoparticles loaded with tamoxifen (TAM-NCL). The mucoadhesion and the permeation through excised rat intestinal mucosa of the nanoparticles was also investigated.

TAM-NCL were prepared by injection of methanol solution of lecithin and TAM in a chitosan solution. Cytotoxicity was investigated by MTT test using CaCo-2 and MCF-7 cells at different times and using different concentrations of TAM-NCL. The permeation studies through rat intestinal mucosa were performed in ex-vivo experiments using the Ussing chambers.

The TAM-NCL cytotoxicity experiments towards MCF-7 cells showed that only after 24 or 48 h cells viability was reduced. This is in accordance with previous drug release data in which the release of TAM from nanoparticles occurred only when enzymes degraded nanoparticle components.

Concerning the permeation trough the intestinal wall, nanoparticles slightly increased tamoxifen permeation compared to a control suspension of tamoxifen. However using enzymes able to degrade specifically the components of the nanoparticles (i.e. lipase contained in pancreatin) the tamoxifen flux trough the intestinal mucosa increased significantly. This increase was negated if a dialysis membrane is interposed as a barrier separating the nanoparticles from the mucosal surface. The permeation experiments on rat intestinal tissue showed then that mucoadhesion and enzymatic degradation of nanocarriers are required to increase the drug flux through the rat intestinal mucosa when chitosan/lecithin nanoparticles are employed as drug delivery system.
Influence of the Structural Characteristics of Silver and Gold Nanoparticles on the Surface-Enhancement Factors of the Raman Signals from Aromatic Amines
Authors: Smith Katrina A. , Sing Chong Ngee , Donthula Kiran , Guat Ooi Beng
Published: March 2012

Gold colloids were found to be more effective than silver colloids for surface-enhanced Raman scattering (SERS) using a laser excitation wavelength of 785 nm. The SERS signals are highly dependent on the morphology and size distribution of the nanoparticles or nanostructures. The aggregation characteristics of nanoparticles directly correlated with the presence of SERS “hot spots” for signal generation. Both nanostar and Klarite™ are capable of yielding enhancement factors up to the order of 106. The filling of pyramidal holes in the Klarite™ substrate with nanostar was found to be synergistic in improving the enhancement factors of the 4-aminobiphenyl from 1.4 x 106 for Klarite™ alone to 3.3 x 106 when combined with nanostar. The use of gold colloid, nanostar, and Klarite™ substrate allows the detection limits of o-toluidine, 4-aminobiphenyl, and 2-naphthylamine to be achieved at the levels of 0.1-1 mg/L, which is applicable for most instances of environmental monitoring with or without analyte pre-concentration.
Formulation and Evaluation of Solid Lipid Nanoparticulate Gel for Antiacne Therapy
Authors: Kumar Ajay , Gulati Neha , Gupta Randhir , MK Koshy , Saraf Shubhini A.
Published: March 2012

Solid lipid nanoparticles (SLN) are colloidal carrier systems providing controlled release profiles for many substances. These are interesting nanoparticulate delivery systems produced from solid lipids. Erythromycin-loaded SLN were prepared using glyceryl behenate as solid lipid by microemulsion technique and evaluated for particle size, zeta potential as well as entrapment efficiency of this lipophilic drug. The formulation was optimized using taguchi design L9 orthogonal array. The formulated SLNs were found to be relatively uniform in size (355.29 nm) with a negative zeta potential (−15.90 mV). The average drug entrapment efficiency and loading were 51.65%. The ultimate objective of the present study was to formulate erythromycin loaded solid lipid nanoparticulate (ESLN) gel and compare it with conventional gel of erythromycin with respect to ex-vivo release and primary skin irritation studies. ESLN gel produced significantly higher deposition of erythromycin in skin than conventional gel. Release mechanism was found to be a coupling of diffusion and erosion. The obtained results for primary skin irritation studies displayed no erythema or edema on intact rat skin. The SLN based gel described in this study elicited prolonged activity of upto 24 h.
Nanoparticles in Organic Solvents with Polymers – Stability and Consequences upon Material Synthesis through Spray Drying and Melt Moulding
Authors: Rudolph M. , Turan C. , Kirchberg S. , Ziegmann G. , Peuker U.A.
Published: March 2012

It is a well accepted fact that nanoparticles and their industrial and commercial use have the potential to improve properties of modern materials substantially. Especially polymeric materials are attractive for incorporating nanoparticles with special properties only apparent in the nanoscale. One main consideration in processing such composite materials is to prevent the nanoparticles from agglomerating or even worse aggregating. In this paper a modular process method is presented based on a mixture of sterically stabilized nanoparticles in an organic solvent with soluble polymers and subsequent spray drying to quickly yet thermally carefully remove the solvent. The method has the potential for large scale production of highly filled nanoparticle-polymer-composites. However the bottleneck of this method is the unknown interaction of polymers and stabilized nanoparticles. We present the impact of depletion flocculation and subsequent phase separation or stabilization by adsorbing polymers on the dispersion of the nanoparticles. It is shown that the processing method is more adequate when compared to traditional melt moulding. The best magnetite nanoparticle stability in dichloromethane is achieved using ricinoleic acid. Besides flocculates we can identify separate primary particles in the composite. The size of the floccules is in the lower micrometer range for nanoparticles 15 nm in size.
Thermal Investigation of Copper-Doped-Zirconia Nanoparticles
Authors: Mikac L. , Ivanda M. , Štefanić G. , Musić S. , Furić K. , Car D.
Published: March 2012

Detailed thermal studies were carried out to determine the nano-structural changes in zirconia (ZrO2) ceramics upon incorporation of different amounts of the Cu2+ cations. In order to calculate the mean particle size and particle size distribution of ZrO2-CuO (ZC) system low frequency Raman spectroscopy (LFRS) was used. The results show that the particle growth is insignificant up to the temperature of 450°C for all the samples due to annealing of inner defects. With further increase of the temperature the nanoparticles grow rapidly with discontinuity at 540°C which is connected with the phase transition from tetragonal to monoclinic phase.
Highly-branched Poly(N-isopropyl Acrylamide)
Authors: Rimmer Stephen
Published: March 2012

Solutions of stimulus responsive polymers are desolvated at a lower critical solution temperature (LCST) from aqueous media. The temperature of this transition is modified by a number of key environmental variables such as ionic strength and pH. Thus, polymer systems that are responsive to temperature, pH and salt concentration are well-known. However, only a few examples of highly branched stimulus responsive polymers are available and until our work highly branched versions of the most studied responsive polymer, poly(N-isopropyl acrylamide, had not been reported. Here we review our work on highly branched (poly(N-isopropyl acrylamide)s (HB-PNIPAM). We describe their synthesis using self-condensing vinyl reversible addition fragmentation chain transfer (RAFT) polymerisations with polymerisable styrene dithionate esters. In some instances the residual end group from the RAFT process is useful but we also show how, following modification of the end groups to carboxylic acids, a wide range of other functionalities with uses in the life sciences can be produced. The LCST of HB-PNIPAM decreases as the degree of branching increases but we observed a strong dependence of the LCST on end group structure. Highly polar end groups, such as the RGD peptide, can reverse this trend so that the LCST increases with degree of branching as the concentration of end groups increases. HB-PNIPAMs with either polar end groups or containing hydrophilic monomer sequences form colloidal sub-micron particles above the LCST, rather than the usual flocs. These particles, with appropriate functionalisation, have been used by us to both purify recombinant proteins and to transfer human cells. An important aspect of the biological function of proteins is the conformational change that accompanies protein-protein binding. This refolding process is driven by binding and we have shown that a similar phase change can be induced in HB-PNIPAM by binding to bacteria. The hyperbranched architecture is a key aspect of the function of these materials because unlike linear architectures with pendant ligands the branched architecture allows the ligands to be available for binding both above and below the LCST.