bluuebunny/crossref_metadata_2025 huggingface dataset:
Polydopamine‐assisted immobilization of trypsin onto monolithic structures for protein digestion
Authors: Rivera José G. , Messersmith Phillip B.
Published: June 2012

Inspired by the catechol‐rich adhesive proteins of the mussel foot, we report a simple and versatile aqueous approach for the immobilization of trypsin onto silica and titania monolithic supports. The method involves in‐situ coating of the monolithic substrates with a catechol‐containing biomimetic polymer (polydopamine) derived from the polymerization of dopamine under alkaline pH, followed by conjugation of trypsin to the polydopamine polymer coating. The trypsin immobilization efficiency onto the monolithic materials was investigated as a function of different preparation parameters such as dopamine concentration and coating time. The enzymatic activity of the immobilized trypsin reactors was evaluated, and mass spectrometry based proteomic analysis was demonstrated by digestion of a model protein. The method presented in this manuscript has broad potential for immobilization of trypsin and other enzymes onto a wide variety of monolithic supports, due to the ability of polydopamine to act as a primer for covalent immobilization of proteins.
Optimization of QuEChERS method for the analysis of organochlorine pesticides in soils with diverse organic matter
Authors: Correia‐Sá Luísa , Fernandes Virgínia C. , Carvalho Manuela , Calhau Conceição , Domingues Valentina F. , Delerue‐Matos Cristina
Published: June 2012

A QuEChERS method has been developed for the determination of 14 organochlorine pesticides in 14 soils from different Portuguese regions with wide range composition. The extracts were analysed by GC‐ECD (where GC‐ECD is gas chromatography‐electron‐capture detector) and confirmed by GC‐MS/MS (where MS/MS is tandem mass spectrometry). The organic matter content is a key factor in the process efficiency. An optimization was carried out according to soils organic carbon level, divided in two groups: HS (organic carbon >2.3%) and LS (organic carbon <2.3%). The method was validated through linearity, recovery, precision and accuracy studies. The quantification was carried out using a matrix‐matched calibration to minimize the existence of the matrix effect. Acceptable recoveries were obtained (70–120%) with a relative standard deviation of ≤16% for the three levels of contamination. The ranges of the limits of detection and of the limits of quantification in soils HS were from 3.42 to 23.77 μg kg−1 and from 11.41 to 79.23 μg kg−1, respectively. For LS soils, the limits of detection ranged from 6.11 to 14.78 μg kg−1 and the limits of quantification from 20.37 to 49.27 μg kg−1. In the 14 collected soil samples only one showed a residue of dieldrin (45.36 μg kg−1) above the limit of quantification. This methodology combines the advantages of QuEChERS, GC‐ECD detection and GC‐MS/MS confirmation producing a very rapid, sensitive and reliable procedure which can be applied in routine analytical laboratories.
Rational development of a selection model for solvent gradients in single‐step separation of ginsenosides from Panax ginseng using high‐speed counter‐current chromatography
Authors: Shehzad Omer , Khan Salman , Ha In Jin , Park Youmie , Kim Yeong Shik
Published: June 2012

A new model of solvent gradients selection was rationally developed for the preparative separation of target compounds. The solvent gradients were selected based on a three‐stage screening process where stationary phase retention was ensured by introducing a new parameter termed as the phase ratio. The phase ratio was calculated after mixing the upper phase of a solvent system with the lower phase of a different solvent system (1:1, v/v). The developed model was applied to the one‐step separation of eight ginsenosides from Panax ginseng. Three gradients were selected on the basis of new model and eight ginsenosides, Rb1, Rb2, Rc, Rd, Re, Rg1, Rf, and Rh1, were efficiently separated by high‐speed counter‐current chromatography coupled with evaporative light scattering detector. The structures of all compounds were characterized by electrospray‐ionization mass spectrometry and nuclear magnetic resonance spectroscopy.
Photonic crystal devices: some basics and selected topics
Authors: De La Rue R.M. , Seassal C.
Published: June 2012

This review article is concerned with basic aspects and some selected topics in photonic crystal (PhC) devices. It starts with a significantly historical aspect of basic principles for photonic crystals that it is hoped will help the reader to develop a critical appreciation of the research literature. It continues by describing topics such as PhC beamsplitters, slow‐light structures, micro‐/nanoresonators, coupled resonator optical waveguides (CROWs) and PhC‐based semiconductor lasers. Emphasis is placed on both the conceptual and the practical matters that need to be addressed in order to fulfill the tasks of designing and realizing devices that exploit photonic crystal principles. The review also addresses some of the problems encountered in the fabrication of photonic crystal devices using the planar technologies of integrated photonics, which are those that are most likely to be used in future commercial production.
A partitioning approach for H∞ control of singular time‐delay systems
Authors: Kchaou Mourad , Tadeo Fernando , Chaabane Mohamed
Published: June 2012

This paper presents a new approach for delay‐dependent H∞ stability analysis and control synthesis for singular systems with delay. By constructing an augmented Lyapunov–Krasovskii functional with a triple‐integral term, and using the partitioning technique, a bounded real lemma is presented to ensure the singular state‐delay system to be regular, impulse free and stable with γ‐disturbance rejection. The proposed result leads to significant performance improvement in system analysis and synthesis. Based on the criterion obtained, a homotopy‐based iterative LMI algorithm is developed to design a static output feedback controller. The feasibility and the effectiveness of theoretical developments are illustrated through numerical examples.Copyright © 2012 John Wiley & Sons, Ltd.
TRANSLATING DEVELOPMENT AID INTO CITY MANAGEMENT: THE BARRIO ACAHUALINCA INTEGRATED DEVELOPMENT PROGRAMME IN MANAGUA, NICARAGUA
Authors: Zapata Campos María José , Zapata Patrik
Published: June 2012

This article seeks to understand how development aid is translated into city management practice in the global South and the implications of this for the power dynamics between municipal governments and international aid agencies. The study examines La Chureca, the rubbish dump and slum of Managua, Nicaragua, and its regeneration programme, the Barrio Acahualinca Integrated Development Programme. In the article, we explore the formulation and initial implementation of the Programme in terms of the construction of an action net in which, by a chain of translations, the Programme was transformed from an aid programme managed by international aid organisations into the management practice of the city of Managua. Despite the silent infiltration of important issues brought to the municipal political agenda by the development aid programme, small acts of defiance and resistance were also enacted by local actors who twisted the Programme to fit local needs. Copyright © 2012 John Wiley & Sons, Ltd.
Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: A Pediatric Oncology Group study: A Report from the Children's Oncology Group
Authors: Granger Meaghan , Grupp Stephan A. , Kletzel Morris , Kretschmar Cynthia , Naranjo Arlene , London Wendy B. , Diller Lisa
Published: June 2012

Background

The Pediatric Oncology Group performed a pilot study to assess the feasibility of tandem high dose chemotherapy (HDC) with stem cell rescue (HDC/SCR). We report here the results of this single arm trial of induction chemotherapy, local control measures (surgery and local radiation), and tandem HDC/SCR.

Procedure

Patients with high risk neuroblastoma (NBL) underwent five cycles of induction chemotherapy and resection of primary tumors. Peripheral blood stem cells (PBSC) were collected after Course 3 without exvivo manipulation. Myeloablative chemotherapy was performed in rapid sequence after induction chemotherapy and surgery. The ability of patients to complete both cycles of HDC/SCR was a primary endpoint. Transplant‐related toxicity, progression‐free survival (PFS) and overall survival (OS) were recorded.

Results

A total of 33 patients were enrolled. Twenty‐two patients completed at least one HDC/SCR procedure and 17 patients completed both. Only one patient had insufficient stem cells collected for both transplants. There was one transplant‐related death; engraftment was rapid and toxicity was as expected. The PFS of the 33 patients treated on this study is 24.2% ± 7.5% and OS is 36.4% ± 8.4% at 5 years. For patients who received at least one transplant PFS is 36.4% ± 11.0% and OS is 45.5% ± 11.2% at 5 years.

Conclusions

The treatment of high risk NBL with tandem HDC/SCR is feasible in terms of transplant‐related mortality and the ability to collect adequate PBSC for two transplants. The outcomes from this intensified treatment have been used to design a Children's Oncology Group Phase III study testing the efficacy of tandem HDC/SCR. Pediatr Blood Cancer 2012; 59: 902–907. © 2012 Wiley Periodicals, Inc.
The use of high‐frequency audiometry increases the diagnosis of asymptomatic hearing loss in pediatric patients treated with cisplatin‐based chemotherapy
Authors: Abujamra Ana Lucia , Escosteguy Juliana Ribas , Dall'Igna Celso , Manica Denise , Cigana Luciana Facchini , Coradini Patrícia , Brunetto André , Gregianin Lauro José
Published: June 2012

Background

Cisplatin may cause permanent cochlear damage by changing cochlear frequency selectivity and can lead to irreversible sensorineural hearing loss. High‐frequency audiometry (HFA) is able to assess hearing frequencies above 8,000 Hz; hence, it has been considered a high‐quality method to monitor and diagnose early and asymptomatic signs of ototoxicity in patients receiving cisplatin.

Procedure

Forty‐two pediatric patients were evaluated for hearing loss induced by cisplatin utilizing HFA, and its diagnostic efficacy was compared to that of standard pure‐tone audiometry and distortion‐product otoacoustic emissions (DPOAEs). The patient population consisted of those who signed an informed consent form and had received cisplatin chemotherapy between 1991 and 2008 at the Hospital de Clínicas de Porto Alegre Pediatric Unit, Brazil.

Results

Forty‐two patients were evaluated. The median age at study assessment was 14.5 years (range 4–37 years). Hearing loss was detected in 24 patients (57%) at conventional frequencies. Alterations of DPOAEs were found in 64% of evaluated patients and hearing loss was observed in 36 patients (86%) when high‐frequency test was added. The mean cisplatin dose was significantly higher (P = 0.046) for patients with hearing impairment at conventional frequencies.

Conclusion

The results suggest that HFA is more effective than pure‐tone audiometry and DPOAEs in detecting hearing loss, particularly at higher frequencies. It may be a useful tool for testing new otoprotective agents, beside serving as an early diagnostic method for detecting hearing impairment. Pediatr Blood Cancer 2013; 60: 474–478. © 2012 Wiley Periodicals, Inc.
Peripheral neuroblastic tumors with genotype–phenotype discordance: A report from the Children's Oncology Group and the International Neuroblastoma Pathology Committee
Authors: Suganuma Rie , Wang Larry L. , Sano Hideki , Naranjo Arlene , London Wendy B. , Seeger Robert C. , Hogarty Michael D. , Gastier‐Foster Julie M. , Look A. Thomas , Park Julie R. , Maris John M. , Cohn Susan L. , Amann Gabriele , Beiske Klaus , Cullinane Catherine J. , d'Amore Emanuele S.G. , Gambini Claudio , Jarzembowski Jason A. , Joshi Vijay V. , Navarro Samuel , Peuchmaur Michel , Shimada Hiroyuki
Published: June 2012

Background

Of 4,706 peripheral neuroblastic tumors (pNTs) registered on the Children's Cancer Group and Children's Oncology Group Neuroblastoma Study between 1989 and 2010, 51 cases (1.1%) had genotype–phenotype discordance characterized by MYCN amplification (indicating poor prognosis) and Favorable Histology (indicating better prognosis).

Procedure

To distinguish prognostic subgroups in the genotype–phenotype discordant pNTs, two subgroups, “conventional” and “bull's eye,” were identified based on the nuclear morphology. The “conventional” tumors (35 cases) included: Neuroblastoma, poorly differentiated subtype (NB‐PD, 26 cases) with “salt‐and‐pepper” nuclei; neuroblastoma, differentiating subtype (4 cases); ganglioneuroblastoma, intermixed (3 cases); and ganglioneuroma, maturing subtype (2 cases). The “bull's eye” tumors included NB‐PD with prominent nucleoli (16 cases). Clinicopathologic characteristics of these two subgroups were analyzed. N‐myc protein expression was tested immunohistochemically on available tumors.

Results

No significant difference was found between these two subgroups in the distribution of prognostic factors such as age at diagnosis, clinical stage, histopathology category/subtype, mitosis‐karyorrhexis index, ploidy, 1p LOH, and unbalanced 11q LOH. However, prognosis of the patients with “conventional” tumors (5‐year EFS 85.7 ± 12.2%; OS 89.3 ± 10.3%) was significantly better than those with “bull's eye” tumors (EFS 31.3 ± 13.0%; OS 42.9 ± 16.2%; P = 0.0010 and 0.0008, respectively). Immunohistochemically all (11/11) tested “conventional” tumors were negative, and 10/11 tested “bull's eye” tumors were positive for N‐myc protein expression.

Conclusions

Based on the presence or absence of prominent nucleoli (the putative site of RNA synthesis/accumulation leading to N‐myc protein expression), two prognostic subgroups, “conventional” with a better prognosis and “bull's eye” with a poor prognosis, were distinguished among the genotype–phenotype discordant pNTs. Pediatr Blood Cancer 2013; 60: 363–370. © 2012 Wiley Periodicals, Inc.
Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: A Children's Oncology Group study
Authors: Warwick Anne B. , Malempati Suman , Krailo Mark , Melemed Allen , Gorlick Richard , Ames Matthew M. , Safgren Stephanie L. , Adamson Peter C. , Blaney Susan M.
Published: June 2012

Background

Pemetrexed is a multi‐targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile.

Procedure

Pemetrexed, at a dose of 1910 mg/m2, was administered as a 10‐minute intravenous infusion every 21 days. Patients also received vitamin B12, daily multivitamin supplementation, and dexamethasone. A two‐stage design (10 + 10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non‐brainstem high‐grade glioma.

Results

Seventy‐two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3–23). Sixty‐eight were evaluable for response. The median number of cycles administered was 2 (range 1–13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4–13) cycles, was observed in five patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n = 1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%).

Conclusions

Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti‐tumor activity in the childhood tumors studied. Pediatr Blood Cancer 2013;60:237–241. © 2012 Wiley Periodicals, Inc.
Metronomic therapy for malignant peripheral nerve sheath tumor in neurofibromatosis type 1
Authors: Chaudhary Narendra , Borker Anupama
Published: June 2012

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive tumor especially in the patients with neurofibromatosis type 1 (NF1). Without a complete surgical excision, prognosis is guarded. We describe a 10‐year‐old male with NF1 with MPNST, who had a local relapse within 5 weeks of surgical excision. Chemoradiotherapy did not result in tumor regression. Initiation of palliative oral metronomic therapy resulted in complete remission after six cycles. The patient continues to be in remission, 20 months after completion of nine cycles of metronomic therapy. Metronomic therapy may be effective in MPNST where conventional chemotherapy and radiotherapy fails. Pediatr Blood Cancer 2012; 59: 1317–1319. © 2012 Wiley Periodicals, Inc.
Proteome analysis of spinal cord during the clinical course of monophasic experimental autoimmune encephalomyelitis
Authors: Farias Alessandro S. , Martins‐de‐Souza Daniel , Guimarães Leandro , Pradella Fernando , Moraes Adriel S. , Facchini Gustavo , Novello José Camillo , Santos Leonilda M. B.
Published: June 2012

The induction of autoimmune encephalomyelitis (EAE) in Lewis rats results in a period of exacerbation followed by complete recovery. Therefore, this model is widely used for studying the evolution of multiple sclerosis. In the present investigation, differentially expressed proteins in the spinal cord of Lewis rats during the evolution of EAE were assessed using the combination of 2DE and MALDI‐TOF MS. The majority of the differentially expressed proteins were identified during the acute phase of EAE, in relation to naïve control animals. On the other hand, recovered rats presented a similar protein expression pattern in comparison with the naïve ones. This observation can be explained, at least in part, by the intense catabolism existent in acute phase due to nervous tissue damage. In recovered rats, we have described the upregulation of proteins that are apparently involved in the recovery of damaged tissue, such as light and medium neurofilaments, glial fibrillary acidic protein, tubulins subunits, and quaking protein. These proteins are involved mainly in cell growth, myelination, and remyelination as well as in astrocyte and oligodendrocyte maturation. The present study has demonstrated that the inflammatory response, characterized by an increase of the proliferative response and infiltration of autoreactive T lymphocytes in the central nervous system, occurs simultaneously with neurodegeneration.
RAFT polymerization of vinyl methacrylate and subsequent conjugation via enzymatic thiol‐ene chemistry
Authors: Yhaya Firdaus , Sutinah Arlingga , Gregory Andrew M. , Liang Mingtao , Stenzel Martina H.
Published: June 2012

The polymerization of vinyl methacrylate (VMA) allows the synthesis of polymers with pendant double bonds. When this polymerization was undertaken in the presence of 2‐cyanopropyl dithiobenzoate as reversible addition–fragmentation chain transfer agent, it led almost exclusively to vinylester functional sidegroups, which were available for further reactions. The vinylester functionality could not be functionalized using common thiol‐ene catalysts, but could be activated using Candida antarctica lipase B (CAL‐B) (Novozyme 435). The reaction between PVMA and various thiols in N, N‐dimethyl formamide in the presence of CAL‐B led exclusively to the formation of the anti‐Markovnikov product. The rate of reaction between PVMA and 1‐butanethiol was monitored using 1H NMR. The reaction was complete within 72 h. Similar results were obtained with other small‐sized thiols such as 2‐mercaptoethanol, 3‐mercaptopropionic acid, and 2‐(trimethylsilyl)ethanethiol, while more bulky thiols, such as secondary thiols, thiols with long alkyl chains, and sterically demanding thiols, such as mono(6‐deoxy‐6‐mercapto)‐β‐cyclodextrin, only led to lower conversions. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012
Producing bimodal molecular weight distribution polymers through facile one‐pot/one‐step RAFT polymerization
Authors: Jiang Hongjuan , Zhang Lifen , Qin Jian , Zhang Wei , Cheng Zhenping , Zhu Xiulin
Published: June 2012

Well‐defined bimodal molecular weight distribution (MWD) polystyrene and polystyrene‐b‐poly(acrylonitrile) were successfully synthesized using a pair of mono/difunctional trithiocarbonate RAFT agents 1 and 2 via one‐pot RAFT polymerization. The kinetics of RAFT polymerization for styrene in bulk with a molar ratio of [St]0:[AIBN]0:[1]0:[2]0 = 1200:1:2.5:2.5 was studied at 75°C. The results indicated that the system showed excellent controllability and “living” characteristics to both higher and lower molecular weight fractions, providing an efficient and facile way to producing bimodal MWD (co)polymers with both controlled molecular weight (MW) and MWD in molecular level, and the plausible mechanism was discussed in this work. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012
Longitudinal analysis of the relations between opportunities to learn about science and the development of interests related to science
Authors: Alexander Joyce M. , Johnson Kathy E. , Kelley Ken
Published: June 2012

Relations between parental reports of children's interests related to science and opportunities for science learning were examined longitudinally in 192 children between ages 4 and 7 years. Science interests were tracked during 1‐year periods (ages 4–5, 5–6, and 6–7) and were more prevalent among boys, particularly prior to age 6 years. Gender differences did emerge in terms of frequencies of opportunities for science learning during all 3 years. Longitudinal path analyses tested relations between children's science interests and their opportunities for science learning. Our data suggest that early science interests were strong predictors of later opportunities to engage in informal science learning, whereas the opposite pattern (early opportunities predicting later science interests) was not found. Young girls' expressed science interests led parents to subsequently increase opportunities for science learning during the following year. Although boys followed this pattern early in the study, over time boys received similar levels of science opportunities regardless of their interest. Bases for gender differences in early science interests and implications for later science learning in school are considered. © 2012 Wiley Periodicals, Inc. Sci Ed 96:763–786, 2012
Probabilistic verification of Herman’s self-stabilisation algorithm
Authors: Kwiatkowska Marta , Norman Gethin , Parker David
Published: June 2012

Herman’s self-stabilisation algorithm provides a simple randomised solution to the problem of recovering from faults in an
N
-process token ring. However, a precise analysis of the algorithm’s maximum execution time proves to be surprisingly difficult. McIver and Morgan have conjectured that the worst-case behaviour results from a ring configuration of three evenly spaced tokens, giving an expected time of approximately 0.15
N
2
. However, the tightest upper bound proved to date is 0.64
N
2
. We apply probabilistic verification techniques, using the probabilistic model checker PRISM, to analyse the conjecture, showing it to be correct for all sizes of the ring that can be exhaustively analysed. We furthermore demonstrate that the worst-case execution time of the algorithm can be reduced by using a biased coin.
On termination and invariance for faulty channel machines
Authors: Bouyer Patricia , Markey Nicolas , Ouaknine Joël , Schnoebelen Philippe , Worrell James
Published: June 2012

A
channel machine
consists of a finite controller together with several fifo channels; the controller can read messages from the head of a channel and write messages to the tail of a channel. In this paper we focus on channel machines with
insertion errors
, i.e., machines in whose channels messages can spontaneously appear. We consider the
invariance
problem: does a given insertion channel machine have an infinite computation all of whose configurations satisfy a given predicate? We show that this problem is primitive-recursive if the predicate is closed under message losses. We also give a non-elementary lower bound for the invariance problem under this restriction. Finally, using the previous result, we show that the satisfiability problem for the safety fragment of Metric Temporal Logic is non-elementary.
Deterministic concurrent strategies
Authors: Winskel Glynn
Published: June 2012

Nondeterministic concurrent strategies—those strategies compatible with copy-cat behaving as identity w.r.t. composition—have been characterised as certain maps of event structures. This leads to a bicategory of general concurrent games in which the maps are nondeterministic concurrent strategies. This paper explores the important sub-bicategory of
deterministic
concurrent strategies. It is shown that
deterministic
strategies in a game can be identified with certain subgames, with the benefit that the bicategory of deterministic games becomes equivalent to a technically-simpler order-enriched category. Via a characterisation, deterministic strategies are shown to coincide with the
receptive ingenuous strategies
of Melliès and Mimram. Deterministic strategies determine
closure operators
, in accord with an early definition of Abramsky and Melliès. Known subcategories appear as special cases: Berry’s order-enriched category of
dI-domains and stable functions
arises as a full subcategory in which the games comprise solely of Player moves; the
`simple games’
of Hyland et al., a basis for much of game semantics, form a subcategory in which the games permit no concurrency, Player-Opponent moves alternate and Opponent always moves first.
The Safety-Critical Java memory model formalised
Authors: Cavalcanti Ana , Wellings Andy , Woodcock Jim
Published: June 2012

Safety-Critical Java (SCJ) is a version of Java for real-time programming, restricted to facilitate certification of implementations of safety-critical systems. Its development is the result of an international effort involving experts from industry and academia. What we provide here is, as far as we know, the first formalisation of the SCJ model of memory regions. We use Hoare and He’s unifying theories of programming (UTP), enabling the integration of our theory with refinement models for object orientation and concurrency. In developing the SCJ theory, we also make a contribution to UTP by providing a general theory of invariants (an instance of which is used in the SCJ theory). The results presented here are a first essential ingredient to formalise the novel programming paradigm embedded in SCJ, and enable the justification and development of formal reasoning techniques based on refinement.
Reflections on an Intellectual Partner: My Life with Linda Datcher Loury
Authors: Loury Glenn Cartman
Published: June 2012

My intellectual partnership with Linda Datcher Loury began 37 years ago at MIT. It ended with her tragic, premature death last September. As a husband and a father, I will miss my wife tremendously, of course. And, as a scholar, I will see things a little less clearly, express myself a bit less surely, and ponder the often incomprehensible nature of social life with less confidence without my intellectual companion and life partner. The light of my understanding has grown dimmer and the path ahead is unclear.
Conformational dynamics of yeast calmodulin in the Ca2+‐bound state probed using NMR relaxation dispersion
Authors: Ogura Kenji , Okamura Hideyasu , Katahira Masato , Katoh Etsuko , Inagaki Fuyuhiko
Published: June 2012

Most calmodulin (CaM) in apo and Ca2+‐bound states show a dumb‐bell‐like structure, involving the N‐ and C‐terminal domains, connected with a flexible linker. However, Ca2+‐bound yeast calmodulin (yCaM) takes on a unique globular structure; the target‐binding site of this protein is autoinhibited. We applied NMR relaxation dispersion experiments to yCaM in the Ca2+‐bound state. The amide 15N and 1HN relaxation dispersion profiles indicated the presence of conformational dynamics for specific residues at the interface between the N‐ and C‐terminal domains. We conclude that these conformational dynamics were derived from the mobility of the C‐terminal domain.
Safety and biomarker effects of solanezumab in patients with Alzheimer's disease
Authors: Farlow Martin , Arnold Steven E. , van Dyck Christopher H. , Aisen Paul S. , Snider B. Joy , Porsteinsson Anton P. , Friedrich Stuart , Dean Robert A. , Gonzales Celedon , Sethuraman Gopalan , DeMattos Ronald B. , Mohs Richard , Paul Steven M. , Siemers Eric R.
Published: June 2012

Objectives

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti‐β‐amyloid (Aβ) antibody, in patients with mild‐to‐moderate Alzheimer's disease. Cognitive measures were also obtained.

Methods

In this phase 2, randomized, double‐blind, placebo‐controlled clinical trial, 52 patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer's Disease Assessment Scale–cognitive portion was administered.

Results

Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ1–40 and Aβ1–42 in plasma increased in a dose‐dependent manner. Antibody treatment similarly increased total Aβ1–40 and Aβ1–42 in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ1–40 in CSF (P < .01), but increased unbound Aβ1–42 in CSF in a dose‐dependent manner. The Alzheimer's Disease Assessment Scale–cognitive portion was unchanged after the 12‐week antibody administration.

Conclusions

Antibody administration was well tolerated with doses up to 400 mg weekly. The dose‐dependent increase in unbound CSF Aβ1–42 suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ1–42 from amyloid plaques.
Inclusion of radiobiological factors in prostate brachytherapy treatment planning
Authors: Knaup Courtney , Mavroidis Panayiotis , Swanson Gregory , Stathakis Sotirios , Baltas Dimos , Papanikolaou Niko
Published: June 2012

Purpose: Comparison of prostate seed implant treatment plans is currently based on evaluation of dose-volume histograms and doses to the tumour and normal structures. However, these do not account for effects of varying dose-rate, tumour repopulation and other biological effects. In this work, incorporation of the radiobiological response is used to obtain a more inclusive and clinically relevant treatment plan evaluation tool.

Materials and Methods: Ten patients were evaluated. For each patient, six different treatment plans were created on the Prowess system. Plans with iodine-125 used a prescription dose of 145 Gy while plans with palladium-103 used 115 Gy. The biologically effective dose was used together with the tumour control probability and the normal tissue complication probabilities of urethra, bladder, rectum and surrounding tissue to evaluate the effectiveness of each treatment plan. Results from the radiobiological evaluation were compared to standard dose quantifiers.

Results: The use of response probabilities is seen to provide a simpler means of treatment evaluation compared to standard dose quantifiers. This allows for different treatment plans to be quickly compared. Additionally, the use of radiobiologically-based plan evaluation allows for optimisation of seed type and initial seed strengths to find the ideal balance of TCP and NTCP.

Conclusion: The goal of this work was to incorporate the biological response to obtain a more complete and clinically relevant treatment plan evaluation tool. This resulted in a simpler means of plan evaluation that may be used to compare and optimise prostate seed implant treatment plans.
Kinematics of the Chugach metamorphic complex, southern Alaska: Plate geometry in the north Pacific margin during the Late Cretaceous to Eocene
Authors: Scharman Mitchell R. , Pavlis Terry L.
Published: June 2012

The Paleogene plate geometry of the north Pacific margin is poorly constrained because all of the plates involved, except the trailing Pacific plate, have been subducted. However, the kinematic history of the Chugach metamorphic complex in southern Alaska constrains plate configurations because of its link to ridge‐subduction. We synthesize recent regional mapping of the complex, finite strain data, and geochronology to show that progressive deformation records the Paleogene triple junction interaction occurred over a period of less than 2 m.y. across ∼350 km of the margin. We document that 140–190 km of distributed dextral shear occurred across the complex during the latest phase of deformation in the complex. This analysis suggests dextral motion of at least 70–95 mm/yr which can account for most, or all, of the margin parallel plate motion during a brief period of the Eocene. We use these results to compare and evaluate possible plate configurations based on older and newer plate motion models. Using modern plate motion models it is difficult to reconcile a Kula‐Farallon ridge‐subduction model with the available data, but our preferred plate geometry model involving a Kula‐Resurrection ridge provides a reasonable explanation for our observations.
Properties of the magnetospheric backward wave oscillator inferred from CLUSTER measurements of VLF chorus elements
Authors: Titova E. , Demekhov A. , Kozelov B. , Santolík O. , Macúšová E. , Rauch J.‐L. , Trotignon J.‐G. , Gurnett D. , Pickett J.
Published: June 2012

According to the backward wave oscillator (BWO) model, a sharp gradient (or step‐like deformation) on the electron distribution function is the most important factor in chorus generation, but such a feature is very difficult to observe directly. The properties of the step in the BWO model determine the dimensionless parameterqquantifying the excess of the energetic electron flux above the absolute‐instability threshold. This parameter, in turn, is related to the frequency sweep rate of chorus elements, which we obtained by using data from the WBD instrument onboard the CLUSTER satellites in the equatorial region for more than 7000 chorus elements. Then, using the CLUSTER data for the plasma density and magnetic field, we calculatedq assuming the validity of the BWO theory and found that the q values depend only weakly on the density; the average values of q ≈ 7 for the lower band chorus (f/fce < 0.5) and q ≈ 13 for the upper band (f/fce > 0.5). These q values constitute a large excess over the generation threshold (q > 3) resulting from numerical simulation of discrete elements with rising frequency and are thus consistent with the simulations. Another important feature of the q parameter is the significant scatter of its values during each Cluster passage of the generation region. Using the obtained q values we estimate the relative height of the step in the electron distribution function to lie in the range from 0.01 to 0.3.
Ionospheric and thermospheric variations associated with prompt penetration electric fields
Authors: Lu G. , Goncharenko L. , Nicolls M. J. , Maute A. , Coster A. , Paxton L. J.
Published: June 2012

This paper presents a comprehensive modeling investigation of ionospheric and thermospheric variations during a prompt penetration electric field (PPEF) event that took place on 9 November 2004, using the Thermosphere‐Ionosphere‐Mesosphere Electrodynamic General Circulation Model (TIMEGCM). The simulation results reveal complex latitudinal and longitudinal/local‐time variations in vertical ion drift in the middle‐ and low‐latitude regions owing to the competing influences of electric fields and neutral winds. It is found that electric fields are the dominant driver of vertical ion drift at the magnetic equator; at midlatitudes, however, vertical ion drift driven by disturbance meridional winds exceeds that driven by electric fields. The temporal evolution of the UT‐latitude electron density profile from the simulation depicts clearly a super‐fountain effect caused by the PPEF, including the initial slow‐rise of the equatorial F‐layer peak height, the split of the F‐layer peak density, and the subsequent downward diffusion of the density peaks along magnetic field lines. Correspondingly, low‐latitude total electron content (TEC) becomes bifurcated around the magnetic equator. The O/N2column density ratio, on the other hand, shows very little variations during this PPEF event, excluding composition change as a potential mechanism for the TEC variations. By using realistic, time‐dependent, high‐latitude electric potential and auroral precipitation patterns to drive the TIMEGCM, the model is able to successfully reproduce the large vertical ion drift of ∼120 m/s over the Jicamarca incoherent radar (IS) in Peru, which is the largest daytime ion drift ever recorded by the radar. The simulation results are validated with several key observations from IS radars, ground GPS‐TEC network, and the TIMED‐GUVI O/N2column density ratio. The model‐data intercomparison also reveals some deficiencies in the TIMEGCM, particularly the limitations imposed by its upper boundary height as well as the prescribed O+ flux.
Particle fluxes and condensational uptake over sea ice during COBRA
Authors: Whitehead J. D. , Dorsey J. R. , Gallagher M. W. , Flynn M. J. , McFiggans G. , Carpenter L. J.
Published: June 2012

Particle fluxes were measured over sea ice at Hudson Bay, Canada, during the COBRA experiment in February and March, 2008. Eddy covariance particle fluxes were measured using a condensation particle counter and an ultrasonic anemometer on a 2.5 m mast on the sea ice. After applying appropriate corrections and filtering, the mean net deposition velocity was 0.12 ± 0.11 mm s−1 for particles measured with a CPC 3776 (lower size threshold, Dp50 = 2.5 nm) and was at the detection limit of the measurement system. No evidence of nucleation events was seen. Two optical particle counters (at heights 0.2 and 1.35 m on the mast) allowed size segregated fluxes of particles in the accumulation and coarse mode diameter range 0.3–20 μm to be derived using the aerodynamic flux gradient method. Strong net emission fluxes were observed around midday, 3rd March, when winds increased to around 10 m s−1, suggesting ice particle resuspension. The fluxes during this period had a significant influence on the derived condensational loss rate to the available particle surfaces, kt. Number fluxes were greatest in the smallest size channels, while the largest sizes dominated the mass flux. Number fluxes also increased with wind speed, and this relationship was strongest for the smaller sizes. Particle mass size distributions showed an enhanced mode around 400 nm (dry size). Values of kt were well approximated by the molecular regime and were found to be much smaller and less variable than values derived for marine air.
Metabolic stratification driven by surface and subsurface interactions in a terrestrial mud volcano
Authors: Cheng Ting-Wen , Chang Yung-Hsin , Tang Sen-Lin , Tseng Ching-Hung , Chiang Pei-Wen , Chang Kai-Ti , Sun Chih-Hsien , Chen Yue-Gau , Kuo Hung-Chi , Wang Chun-Ho , Chu Pao-Hsuan , Song Sheng-Rong , Wang Pei-Ling , Lin Li-Hung
Published: June 2012

Terrestrial mud volcanism represents the prominent surface geological feature, where fluids and hydrocarbons are discharged along deeply rooted structures in tectonically active regimes. Terrestrial mud volcanoes (MVs) directly emit the major gas phase, methane, into the atmosphere, making them important sources of greenhouse gases over geological time. Quantification of methane emission would require detailed insights into the capacity and efficiency of microbial metabolisms either consuming or producing methane in the subsurface, and establishment of the linkage between these methane-related metabolisms and other microbial or abiotic processes. Here we conducted geochemical, microbiological and genetic analyses of sediments, gases, and pore and surface fluids to characterize fluid processes, community assemblages, functions and activities in a methane-emitting MV of southwestern Taiwan. Multiple lines of evidence suggest that aerobic/anaerobic methane oxidation, sulfate reduction and methanogenesis are active and compartmentalized into discrete, stratified niches, resembling those in marine settings. Surface evaporation and oxidation of sulfide minerals are required to account for the enhanced levels of sulfate that fuels subsurface sulfate reduction and anaerobic methanotrophy. Methane flux generated by in situ methanogenesis appears to alter the isotopic compositions and abundances of thermogenic methane migrating from deep sources, and to exceed the capacity of microbial consumption. This metabolic stratification is sustained by chemical disequilibria induced by the mixing between upward, anoxic, methane-rich fluids and downward, oxic, sulfate-rich fluids.
Microsomal Prostaglandin E2 Synthase-1
Authors: KOEBERLE ANDREAS , WERZ OLIVER
Published: June 2012

The prostanoids and leukotrienes (LTs) formed from arachidonic acid (AA) via the cyclooxygenase (COX)-1/2 and 5-lipoxygenase (5-LO) pathway, respectively, mediate inflammatory responses, chronic tissue remodelling, cancer, asthma and autoimmune disorders, but also possess homeostatic functions in the gastrointestinal tract, uterus, brain, kidney, vasculature and host defence. Based on the manifold functions of these eicosanoids, the clinical use of non-steroidal anti-inflammatory drugs (NSAIDs), a class of drugs that block formation of all prostanoids, is hampered by severe side-effects including gastrointestinal injury, renal irritations and cardiovascular risks. Therefore, anti-inflammatory agents interfering with eicosanoid biosynthesis require a well-balanced pharmacological profile to minimize these on-target side-effects. Current anti-inflammatory research aims at identifying compounds that can suppress the massive formation of pro-inflammatory prostaglandin (PG)E2 without affecting homeostatic PGE2 and PGI2 synthesis. The inducible microsomal prostaglandin E2 synthase-1 (mPGES-1) is one promising target enzyme. We will give an overview about the structure, regulation and function of mPGES-1 and then present novel inhibitors of mPGES-1 that may possess a promising pharmacological profile.
Inhibitors of Cytosolic Phospholipase A2α as Anti-inflammatory Drugs
Authors: LEHR MATTHIAS
Published: June 2012

Arachidonic acid derivatives, like prostaglandins and leukotrienes, as well as the alkyl-ether phospholipid platelet-activating factor (PAF) are highly active substances with diverse biological actions. Elevated levels of these lipid mediators in response to a variety of stimuli have been implicated in the pathology of many inflammatory diseases. The rate-limiting step in the generation of prostaglandins, leukotrienes and PAF, respectively, is the cleavage of the sn-2-ester of membrane phospholipids by a phospholipase A2 (PLA2). Among the superfamily of PLA2 enzymes, cytosolic PLA2α (cPLA2α, also referred to as group IVA PLA2) is thought to play the primary role in this biochemical reaction. Therefore, inhibition of cPLA2α activity is an attractive approach to the control of inflammatory disorders.

In this chapter the main groups of cPLA2α inhibitors are described and the problems associated with the development of clinical active drug candidates are discussed. Furthermore, in-vivo data obtained with such compounds in pre-clinical animal models of inflammation will be presented.
Janus Kinases – Just Another Kinase or a Paradigm Shift for the Treatment of Autoimmune Disease?
Authors: SKYNNER MICHAEL , JEFFREY PHIL , BINKS MICHAEL , WOODROW MICHAEL
Published: June 2012

Janus Kinase (JAK) is a discrete set of four tyrosine kinases that are emerging as key targets for drug discovery. These, it is anticipated, will deliver a second generation of selective and safe kinase drugs. JAK inhibitors are breaking new ground, not only in their high level of target selectivity, but also in delivering efficacy in new indications outside oncology. Here we review the clinical opportunity for targeting these kinases, the underpinning biology and chemistry and key compounds at the spearhead of these efforts, tofacitinib (CP-690,550) and INCB28050.
S1P Receptor Agonists
Authors: MILLER CRAIG A.
Published: June 2012

The Sphingosine-1-Phosphate (S1P) family of G-protein coupled receptors (S1P1-5) plays diverse roles under physiological and pathological conditions. Down-regulation of the S1P1 receptor on immune cells causes lymphopenia via sequestration of certain lymphocytes in the secondary lymphoid organs. In the CNS, the S1P1,3,5 receptors promote cell survival and extension. As such, small-molecule intervention along the S1P axis represents a powerful manifold for treatment of immunological diseases such as multiple sclerosis. In 2010 the US FDA approved Finglimod (FTY720/Gilenya®, Novartis) as the first orally bioavailable, disease-modifying agent for the treatment of relapsing-remitting multiple sclerosis. Fingolimod undergoes bioactivation in vivo through invasion of the S1P biosynthetic pathway to a phosphate metabolite, which is an active agonist against four of the five known S1P receptors, thereby eliciting the immunomodulary and CNS protective effects in man.

The considerable success of Fingolimod has generated intense interest in the pharmaceutical industry to develop second-generation S1P receptor agonists with improved safety, efficacy or convenience. This effort has been challenged by deriving various constellations of selectivities, solubility, pharmacokinetic half-lives and in some cases blood-brain barrier penetrability for a phospholipid receptor target that is opposed to compounds with drug-like properties. The various approaches to overcome these challenges as well as the current understanding of S1P receptor biology will be discussed in this chapter.
Stability of gyrotron operation in very high-order modes
Authors: Sinitsyn O. V. , Nusinovich G. S. , Antonsen T. M.
Published: June 2012

This study was motivated by the desire to increase the power, which can be delivered by gyrotrons in long pulse and continuous regimes. Since the admissible power level is determined by the density of ohmic losses in resonator walls, to increase the radiated power a gyrotron should operate in higher order modes. Using an existing gyrotron developed for plasma experiments in the International Thermonuclear Experimental Reactor as a base model, the stability of operation of such a gyrotron in modes with larger number of radial variations was studied. It is shown that the power level achievable in such gyrotrons in stable single mode regimes is close to 1.5 MW. The power level 1.7–1.8 MW can be realized in regimes where the oscillations of the desired mode are accompanied by excitation of distant sidebands whose power is about 1% level of the power of the operating mode. Finally, in the case of operation at the 2-MW level, either the desired mode loses its stability and is replaced by less efficient oscillations of a mode with a smaller azimuthal index or oscillations of the operating mode are accompanied by excitation of sidebands with equally spaced frequencies.