bluuebunny/crossref_metadata_2025 huggingface dataset:
Is ultrasound alone enough for prenatal screening of trisomy 18? A single centre experience in 69 cases over 10 years
Authors: Lai S. , Lau W. L. , Leung W. C. , Lai F. K. , Chin R.
Published: October 2010

Objectives

To evaluate ultrasound scan and other prenatal screening tests for trisomy 18 in a regional obstetric unit and to review the management approach for women with positive trisomy 18 screening results.

Methods

Prenatal diagnosis databases were accessed to identify fetuses that had confirmed trisomy 18 karyotypes or were at high risk for trisomy 18 on second‐trimester biochemical screening or first‐trimester combined screening tests over a period of 10 years from 1 September 1997 to 30 September 2007.

Results

Sixty‐nine women were confirmed to have trisomy 18 fetuses by karyotyping either prenatally (n = 61) or postnatally/post‐miscarriage (n = 8) during the study period. The detection rate of ultrasound scan ≤14 weeks and 18 to 21 weeks to detect trisomy 18 was 92.7 and 100%, respectively. A total of 80 and 87% of fetuses had two or more ultrasound abnormalities detected in the ≤14 weeks and 18 to 21 weeks anomaly scans, respectively. Forty‐eight women screened positive for trisomy 18 by second‐trimester biochemical screening with human chorionic gonadotrophin (hCG) and alpha fetoprotein (AFP). Only one was true positive (positive predictive value = 1/48 or 2%). Eleven women screened positive for trisomy 18 by first‐trimester combined screening with nuchal translucency scan and maternal serum for pregnancy‐associated plasma protein A (PAPP‐A) and hCG between 11 and 13 + 6 weeks. Three were true positive (positive predictive value = 3/11 or 27%). All four cases with positive screening had ultrasound abnormalities.

Conclusions

Ultrasound scan for fetal anomalies is the most effective screening test for trisomy 18. A policy of conservative management for women with positive second‐trimester biochemical screening or first‐trimester combined screening for trisomy 18 is reasonable in the absence of ultrasound fetal abnormalities. Unnecessary invasive tests can be avoided. Copyright © 2010 John Wiley & Sons, Ltd.
Design of new amphiphilic triblock copoly(2‐oxazoline)s containing a fluorinated segment
Authors: Kempe Kristian , Baumgaertel Anja , Hoogenboom Richard , Schubert Ulrich S.
Published: October 2010

New amphiphilic triblock copoly(2‐oxazoline)s, containing hydrophobic domains with fluorine‐containing blocks, were synthesized. Using microwave radiation as heating source, triblock copolymers with narrow molar mass distributions were obtained by the sequential addition of 2‐ethyl‐2‐oxazoline, 2‐(1‐ethylheptyl)‐2‐oxazoline, and 2‐(2,6‐difluorophenyl)‐2‐oxazoline. The polymers obtained were characterized by size exclusion chromatography, 1H NMR spectroscopy and matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS). To investigate the incorporation of all three monomers into the triblock copolymers, a model polymer was prepared with shorter blocks exhibiting a suitable length to be measured in the reflector mode of a MALDI‐TOF MS. In addition, kinetic investigations on the homopolymerizations of all monomers were performed in nitromethane at 140 °C, yielding the polymerization rates under these conditions. DSC measurements of poly(2‐(1‐ethylheptyl)‐2‐oxazoline) and poly(2‐(2,6‐difluorophenyl)‐2‐oxazoline)) revealing glass transitions at about 33 and 120 °C, respectively. The thermal analysis of a blend of the two polymers showed two glass transitions revealing demixing, which could be an indicating for the immiscibility of the two components in the block copolymers. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
Carbazole‐based conjugated polymers incorporating push/pull organic dyes: Synthesis, characterization, and photovoltaic applications
Authors: Hsu So‐Lin , Chen Chia‐Min , Wei Kung‐Hwa
Published: October 2010

We have synthesized and characterized two new carbazole‐based conjugated polymers, PCDCN and PCDTA, incorporating two strong light‐absorbing organic dyes. These polymers exhibit relatively low band gaps (∼1.5 eV) and broad absorption ranges (from 300 to 700 nm). We fabricated polymer solar cells incorporating these polymers as donors and [6,6]‐phenyl‐C71‐butyric acid methyl ester (PC71BM) as the acceptor. At a blending ratio of 1:4, we obtained power conversion efficiencies, under simulated AM 1.5 (100 mW/cm2) conditions, of 2.31% and 2.47% for the PCDCN‐ and PCDTA‐based devices, respectively. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
Aqueous MADIX/RAFT polymerization of diallyldimethylammonium chloride: Extension to the synthesis of poly(DADMAC)‐based double hydrophilic block copolymers
Authors: Destarac Mathias , Guinaudeau Aymeric , Geagea Roland , Mazieres Stephane , Van Gramberen Eric , Boutin Cecile , Chadel Samy , Wilson James
Published: October 2010

Macromolecular design by interchange of xanthates/reversible addition fragmentation chain transfer polymerization (MADIX/RAFT) of diallyldimethylammonium chloride (DADMAC) using the hydrophobic O‐ethyl‐S‐(1‐methoxycarbonyl) ethyl dithiocarbonate MADIX/RAFT mediating agent, Rhodixan A1, was investigated. Attempts to obtain an efficient control of DADMAC polymerization in a water/ethanol mixture failed because of significant chain transfer to ethanol. The use of a water‐soluble Rhodixan A1‐terminated acrylamide oligomer as the MADIX/RAFT agent enabled the controlled polymerization of DADMAC in water at 50 °C using the cationic azo initiator V‐50. An excellent agreement was found between experimental and theoretical Mn values throughout polymerization and over a broad range of initial concentration of xanthate. Polydispersity indexes (PDIs) at the end of the polymerization were abnormally high for a process showing a linear increase of Mn with monomer conversion (1.8 < PDI < 2.0). This feature was explained by the measurement of a high transfer constant to xanthate (Cx = 18.8 ± 1.6) but a low interchange transfer constant (Cex = 1.5). Nevertheless, poly(acrylamide)–poly(DADMAC) double hydrophilic block copolymers (DHBCs) of controlled Mn and composition could be successfully synthesized for the first time. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
Highly near‐infrared photoluminescence from aza‐borondipyrromethene‐based conjugated polymers
Authors: Yoshii Ryousuke , Nagai Atsushi , Chujo Yoshiki
Published: October 2010

Near‐infrared (NIR) emissive conjugated polymers were prepared by palladium‐catalyzed Sonogashira polymerization of diiodobenzene‐functionalized aza‐borondipyrromethene (Aza‐BODIPY) monomers, which were substituted at 3 and 5 or 1 and 7 positions on the Aza‐BODIPY core, with 1,4‐diethynyl‐2,5‐dihexadecyloxybenzene or 3,3′‐didodecyl‐2,2′‐diethynyl‐5,5′‐bithiophene. The structures of the polymers were confirmed by 1H NMR, 13C NMR, 11B NMR, Fourier transform infrared (FT‐IR) spectroscopies, and size exclusion chromatography (SEC). The optical properties were then characterized by UV–vis absorption and photoluminescence (PL) spectroscopies, and theoretical calculation using density‐functional theory (DFT) method. The polymers were fusible and soluble in common organic solvents including tetrahydrofuran (THF), o‐xylene, toluene, CHCl3, and CH2Cl2, etc. The UV–vis absorption and PL spectra of the polymers shifted to long wavelength region in comparison with simple Aza‐BODIPY as the counterpart because of extended π‐conjugation of the polymers. The polymers efficiently emitted NIR light with narrow emission bands at 713∼777 nm on excitation at each absorption maximum. Especially, the polymer attached 1,4‐diethynyl‐2,5‐dihexadecyloxybenzene to 3,5‐position on the core revealed intense quantum yields (ϕF = 24%) in this NIR region (753 nm). © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
Lectin‐affinity chromatography brain glycoproteomics and Alzheimer disease: Insights into protein alterations consistent with the pathology and progression of this dementing disorder
Authors: Butterfield D. Allan , Owen Joshua B.
Published: October 2010

Alzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the accumulation of senile plaques and neurofibrillary tangles, and both these pathological hallmarks of AD are extensively modified by glycosylation. Mounting evidence shows that alterations in glycosylation patterns influence the pathogenesis and progression of AD, but the vast number of glycan motifs and potential glycosylation sites of glycoproteins has made the field of glycobiology difficult. However, the advent of glycoproteomics has produced major strides in glycoprotein identification and glycosylation site mapping. The use of lectins, proteins that have strong affinity for specific carbohydrate epitopes, to enrich glycoprotein fractions coupled with modern MS, have yielded techniques to elucidate the glycoproteome in AD. Proteomic studies have identified brain proteins in AD and arguably the earliest form of AD, mild cognitive impairment, with altered affinity for Concanavalin‐A and wheat germ agglutinin lectins that are consistent with the pathology and progression of this disorder. This is a relatively nascent field of proteomics research in brain, so future studies of lectin‐based brain protein separations may lead to additional insights into AD pathogenesis and progression.
Taking a new biomarker into routine use – A perspective from the routine clinical biochemistry laboratory
Authors: Sturgeon Catharine , Hill Robert , Hortin Glen L. , Thompson Douglas
Published: October 2010

There is increasing pressure to provide cost‐effective healthcare based on “best practice.” Consequently, new biomarkers are only likely to be introduced into routine clinical biochemistry departments if they are supported by a strong evidence base and if the results will improve patient management and outcome. This requires convincing evidence of the benefits of introducing the new test, ideally reflected in fewer hospital admissions, fewer additional investigations and/or fewer clinic visits. Carefully designed audit and cost‐benefit studies in relevant patient groups must demonstrate that introducing the biomarker delivers an improved and more effective clinical pathway. From the laboratory perspective, pre‐analytical requirements must be thoroughly investigated at an early stage. Good stability of the biomarker in relevant physiological matrices is essential to avoid the need for special processing. Absence of specific timing requirements for sampling and knowledge of the effect of medications that might be used to treat the patients in whom the biomarker will be measured is also highly desirable. Analytically, automation is essential in modern high‐throughput clinical laboratories. Assays must therefore be robust, fulfilling standard requirements for linearity on dilution, precision and reproducibility, both within‐ and between‐run. Provision of measurements by a limited number of specialized reference laboratories may be most appropriate, especially when a new biomarker is first introduced into routine practice.
Capsaicin induces apoptosis in SCC‐4 human tongue cancer cells through mitochondria‐dependent and ‐independent pathways
Authors: Ip Siu‐Wan , Lan Sheng‐Hui , Huang An‐Cheng , Yang Jai‐Sing , Chen Ya‐Yin , Huang Hui‐Ying , Lin Zen‐Pin , Hsu Yuan‐Man , Yang Mei‐Due , Chiu Chang‐Fang , Chung Jing‐Gung
Published: October 2010

Although there have been advances in the fields of surgery, radiotherapy, and chemotherapy of tongue cancer, the cure rates are still not substantially satisfactory. Capsaicin (trans‐8‐methyl‐N‐vanillyl‐6‐nonenamide) is the major pungent ingredient of hot chili pepper and has been reported to have an antitumor effect on many human cancer cell types. The molecular mechanisms of the antitumor effect of capsaicin are not yet completely understood. Herein, we investigated whether capsaicin induces apoptosis in human tongue cancer cells. Capsaicin decreased the percentage of viable cells in a dose‐dependent manner in human tongue cancer SCC‐4 cells. In addition, capsaicin produced DNA fragmentation, decreased the DNA contents (sub‐G1 phase), and induced G0/G1 phase arrest in SCC‐4 cells. We demonstrated that capsaicin‐induced apoptosis is associated with an increase in reactive oxygen species and Ca2+ generations and a disruption of the mitochondrial transmenbrane potential (ΔΨm). Treatment with capsaicin induced a dramatic increase in caspase‐3 and ‐9 activities, as assessed by flow cytometric methods. A possible mechanism of capsaicin‐induced apoptosis is involved in the activation of caspase‐3 (one of the apoptosis‐executing enzyme). Confocal laser microscope examination also showed that capsaicin induced the releases of AIF, ATF‐4, and GADD153 from mitochondria of SCC‐4 cells. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.
Antioxidant and metabolic impairment result in DNA damage in arsenic‐exposed individuals with severe dermatological manifestations in Eastern India
Authors: Maiti Smarajit , Chattopadhyay Sandip , Deb Bimal , Samanta Tanmoy , Maji Gurupada , Pan Bappaditya , Ghosh Amar , Ghosh Debidas
Published: October 2010

Arsenic is an environmental toxicant, free‐radical generator, carcinogenic agent, and aging promoter. Recently, blood samples were analyzed from individuals (control‐ male 12, female 13; arsenic‐exposed‐ male 16, female 14; and exposed to ≥100 μg/L As, ≥10 y) with dermatological symptoms in few affected villages in Eastern India to unravel their hematopoietic, metabolic, and antioxidant profiles. White blood cells recovered from buffy coat were used for DNA fragmentation test. Present observation suggests that significant number of individuals developed pigmentation and palmoplantar hyperkeratosis with black‐brownish patch on their body and many of those developed carcinomas. Hematopoietic data show a significant increase in eosinophil and decrease in monocyte count in either sex. Though insignificant, an increase in neutrophil in female and lymphocyte count in male arsenic‐exposed individuals are supported by the earlier report on sex dimorphic immune sensitization. Significant increase in serum alanine transaminase in both sexes and bilirubin only in male suggests the eventuality of hepatic disintegration. Arsenic exposure significantly decreased serum amylase in female. A significant decrease in antioxidant components like catalase, soluble thiol, and recently recognized uric acid worsened the situation by generating free radicals as observed in significant rise in malondialdehyde level, which finally increased DNA fragmentation and arsenic‐associated mutagenesis and carcinogenesis. This could attribute to lowering in immune competence and related necrotic and/or apoptotic manifestations. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.
Short Chain Saturated Fatty Acids Decrease Circulating Cholesterol and Increase Tissue PUFA Content in the Rat
Authors: Legrand Philippe , Beauchamp Erwan , Catheline Daniel , Pédrono Frédérique , Rioux Vincent
Published: October 2010

This study investigates the effect of various dietary saturated fatty acid (SFA) profiles on plasma lipid parameters and tissue fatty acid composition in rats. The experiment was designed to monitor polyunsaturated fatty acids (PUFA) levels, while examining different amounts and types of SFA. Four isocaloric diets were prepared, containing 10–11 mol% of fatty acids (FA) as linoleic acid (LNA) and 2.5 mol% as α‐linolenic acid (ALA), leading to an identical and well‐balanced LNA/ALA ratio. The initial rapeseed oil/corn oil mixture providing ALA and LNA was enriched with olive oil to prepare the olive oil diet. The butterfat diet was supplemented with butterfat, containing short‐chain SFA (C4:0–C10:0, 17 mol% of FA), lauric acid (C12:0, 3.2 mol%), myristic acid (C14:0, 10.5 mol%) and palmitic acid (C16:0, 14.5 mol%). The saturates diet was supplemented with trilaurin, trimyristin and tripalmitin to obtain the same level of lauric, myristic and palmitic acids as the butterfat diet, without the short‐chain SFA. The trimyristin diet was enriched with trimyristin only. The results showed that the butterfat diet contributed to specific effects, compared to the olive oil diet and the saturates and trimyristin diets: a decrease in plasma total, LDL‐ and HDL‐cholesterol, higher tissue storage of ALA and LNA, and a higher level of (n‐3) highly unsaturated fatty acids in some tissues. This study supports the hypothesis that in diets with identical well‐balanced LNA/ALA ratios, short chain SFA may decrease circulating cholesterol and increase tissue polyunsaturated fatty acid content in the rat.
Genetic base and relatedness of Indian early maturing potato (Solanum tuberosum) selections
Authors: KUMAR R. , KANG G. S. , PANDEY S. K. , GOPAL J.
Published: October 2010

Pedigree analysis was used to study the genetic background of 66 Indian early maturing potato selections, the pedigree of which was traced back to 35 ancestors. Six of the 35 contributed 0·42 of the genetic base, which shows the narrow genetic base of Indian early maturing genotypes. Genotypes 2814 (a)1 (f=0·145) and 3069 (d)4 (f=0·145) were the ancestors which appeared most frequently. Based on the coefficient of relationship, the 66 selections were grouped into seven groups with one common ancestor in almost all the selections within a group. The genotypes Kufri Ashoka, Kufri Pukhraj, AGB-69-1, Kufri Jyoti, Kufri Alankar, Kufri Lauvkar and Kufri Kuber were identified as very important parents/ancestors, carrying specific gene complexes valuable in new selections. Crosses between selections from different diversity groups can result in the selection of useful clones while increasing or maintaining genetic diversity, which is desirable to ensure sustainable breeding progress in the future.
Health service resource needs for pandemic influenza in developing countries: a linked transmission dynamics, interventions and resource demand model
Authors: KRUMKAMP R. , KRETZSCHMAR M. , RUDGE J. W. , AHMAD A. , HANVORAVONGCHAI P. , WESTENHOEFER J. , STEIN M. , PUTTHASRI W. , COKER R.
Published: October 2010

We used a mathematical model to describe a regional outbreak and extrapolate the underlying health-service resource needs. This model was designed to (i) estimate resource gaps and quantities of resources needed, (ii) show the effect of resource gaps, and (iii) highlight which particular resources should be improved. We ran the model, parameterized with data from the 2009 H1N1v pandemic, for two provinces in Thailand. The predicted number of preventable deaths due to resource shortcomings and the actual resource needs are presented for two provinces and for Thailand as a whole. The model highlights the potentially huge impact of health-system resource availability and of resource gaps on health outcomes during a pandemic and provides a means to indicate where efforts should be concentrated to effectively improve pandemic response programmes.
Diameters in Supercritical Random Graphs Via First Passage Percolation
Authors: DING JIAN , KIM JEONG HAN , LUBETZKY EYAL , PERES YUVAL
Published: October 2010

We study the diameter of1, the largest component of the Erdős–Rényi random graph(n,p) in the emerging supercritical phase,i.e., forp=$\frac{1+\epsilon}n$where ε3n→ ∞ and ε =o(1). This parameter was extensively studied for fixed ε > 0, yet results for ε =o(1) outside the critical window were only obtained very recently. Prior to this work, Riordan and Wormald gave precise estimates on the diameter; however, these did not cover the entire supercritical regime (namely, when ε3n→ ∞ arbitrarily slowly). Łuczak and Seierstad estimated its order throughout this regime, yet their upper and lower bounds differed by a factor of$\frac{1000}7$.

We show that throughout the emerging supercritical phase,i.e., for any ε =o(1) with ε3n→ ∞, the diameter of1is with high probability asymptotic toD(ε,n) = (3/ε)log(ε3n). This constitutes the first proof of the asymptotics of the diameter valid throughout this phase. The proof relies on a recent structure result for the supercritical giant component, which reduces the problem of estimating distances between its vertices to the study of passage times in first-passage percolation. The main advantage of our method is its flexibility. It also implies that in the emerging supercritical phase the diameter of the 2-core of1is w.h.p. asymptotic to$\frac23 D(\epsilon,n)$, and the maximal distance in1between any pair of kernel vertices is w.h.p. asymptotic to$\frac{5}9D(\epsilon,n)$.
The Diameter of Sparse Random Graphs
Authors: RIORDAN OLIVER , WORMALD NICHOLAS
Published: October 2010

In this paper we study the diameter of the random graph G(n, p), i.e., the largest finite distance between two vertices, for a wide range of functions p = p(n). For p = λ/n with λ > 1 constant we give a simple proof of an essentially best possible result, with an Op(1) additive correction term. Using similar techniques, we establish two-point concentration in the case that np → ∞. For p =(1 + ε)/n with ε → 0, we obtain a corresponding result that applies all the way down to the scaling window of the phase transition, with an Op(1/ε) additive correction term whose (appropriately scaled) limiting distribution we describe. Combined with earlier results, our new results complete the determination of the diameter of the random graph G(n, p) to an accuracy of the order of its standard deviation (or better), for all functions p = p(n). Throughout we use branching process methods, rather than the more common approach of separate analysis of the 2-core and the trees attached to it.
Developments for vegetation fluorescence retrieval from spaceborne high‐resolution spectrometry in the O2‐A and O2‐B absorption bands
Authors: Guanter L. , Alonso L. , Gómez‐Chova L. , Meroni M. , Preusker R. , Fischer J. , Moreno J.
Published: October 2010

Solar‐induced chlorophyll fluorescence is a weak electromagnetic signal emitted in the red and far‐red spectral regions by vegetation chlorophyll under excitation by solar radiation. Chlorophyll fluorescence has been demonstrated to be a close proxy to vegetation physiological functioning. The basis for fluorescence retrieval from passive space measurements is the exploitation of the O2‐A and O2‐B atmospheric absorption features to isolate the fluorescence signal from the solar radiation reflected by the surface and the atmosphere. High spectral resolution measurements and a precise modeling of the atmospheric radiative transfer in the visible and near‐infrared regions are mandatory. Recent developments for fluorescence retrieval from passive high spectral resolution spaceborne measurements are presented in this work, which has been performed in preparation of the FLuorescence EXplorer (FLEX) mission, which is currently under development by the European Space Agency. A large data set of FLEX‐like measurements has been simulated for the purpose of methodology development and testing. Issues related to vegetation chlorophyll fluorescence retrieval from space, a description of the proposed methodology, initial results from simulated test cases, and general guidelines for the specification of fluorescence retrieval instruments are presented and discussed in this work.
Sustainable urban water supply in south India: Desalination, efficiency improvement, or rainwater harvesting?
Authors: Srinivasan Veena , Gorelick Steven M. , Goulder Lawrence
Published: October 2010

Indian megacities face severe water supply problems owing to factors ranging from growing population to high municipal pipe leakage rates; no Indian city provides 24/7 water supply. Current approaches to addressing the problem have been “utility centric,” overlooking the significance of decentralized activities by consumers, groundwater extraction via private wells, and aquifer recharge by rainwater harvesting. We propose a framework that makes it possible to evaluate a wider range of centralized and decentralized policies than previously considered. The framework was used to simulate water supply and demand in a simulation model of Chennai, India. Three very different policies, supply augmentation, efficiency improvement, and rainwater harvesting, were evaluated using the model. The model results showed that none of the three policies perfectly satisfied our criteria of efficiency, reliability, equity, financial viability, and revenue generation. Instead, a combination of rainwater harvesting and efficiency improvement best meets these criteria.
Location and mechanism of very long period tremor during the 2008 eruption of Okmok Volcano from interstation arrival times
Authors: Haney M. M.
Published: October 2010

We describe continuous, very long period (VLP) tremor that occurred during the 2008 eruption of Okmok Volcano, Alaska. Due to its low frequency content in band from the 0.2–0.4 Hz, the wave field of the VLP tremor is relatively free of path effects. From continuous recordings of the VLP tremor on 2 three‐component broadband and 3 single‐component short‐period instruments, we devise a method to locate the epicenter of the tremor based on interstation arrival times computed with cross correlation. We find the epicenter since the vertical and radial components of the VLP tremor wave field are dominated by Rayleigh waves and the time shifts are related to lateral propagation. Over the 4 h period studied, this procedure yields a location NNW of Cone D, close to the new cone built over the course of the eruption. Similar analysis using the transverse horizontal components from the 2 three‐component broadband instruments yields strong constraints on the source mechanism of the VLP tremor. We observe an anomalous interstation arrival time due to the existence of a nodal plane in the Love wave radiation pattern. The orientation of a compensated linear vector dipole (CLVD) source estimated from the transverse components closely aligns with the regional maximum horizontal stress direction. The depth of the CLVD source is constrained by matching the vertical components to the Rayleigh wave radiation pattern at all five stations. We find the VLP tremor source depth to be 2 km BSL, positioned between the magma chamber at Okmok (>3 km BSL) and the surface.
Dynamic interaction networks in a hierarchically organized tissue
Authors: Kirouac Daniel C , Ito Caryn , Csaszar Elizabeth , Roch Aline , Yu Mei , Sykes Edward A , Bader Gary D , Zandstra Peter W
Published: October 2010

Intercellular (between cell) communication networks maintain homeostasis and coordinate regenerative and developmental cues in multicellular organisms. Despite the importance of intercellular networks in stem cell biology, their rules, structure and molecular components are poorly understood. Herein, we describe the structure and dynamics of intercellular and intracellular networks in a stem cell derived, hierarchically organized tissue using experimental and theoretical analyses of cultured human umbilical cord blood progenitors. By integrating high‐throughput molecular profiling, database and literature mining, mechanistic modeling, and cell culture experiments, we show that secreted factor‐mediated intercellular communication networks regulate blood stem cell fate decisions. In particular, self‐renewal is modulated by a coupled positive–negative intercellular feedback circuit composed of megakaryocyte‐derived stimulatory growth factors (VEGF, PDGF, EGF, and serotonin) versus monocyte‐derived inhibitory factors (CCL3, CCL4, CXCL10, TGFB2, and TNFSF9). We reconstruct a stem cell intracellular network, and identify PI3K, Raf, Akt, and PLC as functionally distinct signal integration nodes, linking extracellular, and intracellular signaling. This represents the first systematic characterization of how stem cell fate decisions are regulated non‐autonomously through lineage‐specific interactions with differentiated progeny.
The Discovery of OSI-906, a Small-molecule Inhibitor of the Insulin-like Growth Factor-1 and Insulin Receptors
Authors: Mulvihill Mark J. , Buck Elizabeth
Published: October 2010

The insulin-like growth factor-1 and insulin receptors (IGF-1R and IR, respectively) are closely related transmembrane receptor tyrosine kinases. Both receptors have been implicated in the promotion of growth and survival of human tumor cells and therefore have become attractive targets for anti-cancer drug discovery. Herein, we describe the path leading to the discovery and development of OSI-906, a selective, orally bioavailable, low molecular weight dual inhibitor of IGF-1R and IR with demonstrated in vivo efficacy in xenograft models. This discovery was enabled through the use of rational, structure-based drug design to optimize both the binding affinity for IGF-1R/IR and achieve a high degree of selectivity versus other kinases. Emperical medicinal chemistry in combination with high speed analoging synthetic strategies were utilized to expedite the optimization process. Finally, a streamlined testing cascade of in vitro and in vivo IGF-1R and IR models were used to assess for pharmacokinetics, pharmacodynamics, efficacy and safety as well as to enable structure-activity development, compound stratification and optimization. Finally, biomarker and combinatorial drug strategies were applied to facilitate a clinical development plan for this agent.
The Discovery of UK-390957: the Challenge of Targeting a Short Half-life, Rapid Tmax SSRI
Authors: Andrews Mark D. , Middleton Donald S.
Published: October 2010

With the realisation that selective serotonin reuptake inhibitors (SSRIs) are effective in treating premature ejaculation (PE), a project was started to identify a short T1/2, rapid Tmax compound suitable for on-demand dosing. It was anticipated that the key to achieving such a profile was to reduce the volume of distribution (VD) relative to the marketed SSRI antidepressants, which have high VD, late Tmax and long T1/2. Initial work focused on reducing VD in the sertraline template 3. While a moderate reduction in VD was achieved and sulfonamide 14 (UK-373911) was identified as a clinical candidate, this strategy was ultimately unsuccessful as 14 had an extremely long T1/2 in man. The key to finding compounds with the properties we desired was to switch to a diphenyl ether template which had an inherently lower VD. Early analogues had the desired low VD, and resulting short T1/2 and rapid Tmax, but gave circulating active metabolites. Incorporation of a metabolically vulnerable thioether resulted in metabolism to essentially inactive sulfoxide metabolites and led to the identification of the sulfonamide 63 (UK-390957) as a clinical candidate. Profiling in man showed that we had achieved our desired target of a rapid Tmax and short T1/2 and 63 was progressed to Phase II studies for the treatment of PE. That structure can be more important than physicochemical properties in determining volume is supported by the fact that the SSRI dapoxetine, marketed for the treatment of PE, has a low volume, comparable with 63, despite being significantly more lipophilic.
The Discovery of GS-9131, an Amidate Prodrug of a Novel Nucleoside Phosphonate HIV Reverse Transcriptase Inhibitor
Authors: Mackman Richard
Published: October 2010

First line therapy for treatment-naïve HIV patients typically include the combination of two drugs from the nucleoside or nucleotide class (N(t)RTIs), that target the viral reverse transcriptase (RT), along with either a non-nucleoside RT inhibitor (NNRTI) or HIV protease inhibitor. The N(t)RTIs therefore play an important role as the backbone of choice in HIV regimens, prompting the initiation of a research program aimed at discovering a novel, next generation N(t)RTI. The chapter describes the medicinal strategy that was used to develop a novel nucleoside phosphonate, including structure based design rationales to improve potency, resistance and selectivity. The novel NtRTI GS-9148 (22) that was discovered demonstrated a favorable resistance profile toward many clinically relevant N(t)RTI resistant isolates, and encompassed a rationally designed fluorine group to improve selectivity. To effectively deliver 22 and its active phosphorylated metabolite into lymphoid cells harboring replicating HIV, a unique prodrug strategy was employed. Prodrugs were designed as substrates of lysosomal cathepsin A, a peptidase highly expressed in lymphoid cells, to effectively target in vivo delivery of 22 to the lymphatic system. Ethylalaninyl phosphonamidate prodrug GS-9131 (32) successfully targeted 22 to peripheral blood mononuclear cells upon oral dosing in Beagle dogs (3 mg /kg) and resulted in intracellular active metabolite levels exceeding 9.0 μM, a level 5-fold higher than the HIV RT IC50 of 22. The favorable preclinical profile of 32 led to its nomination as a clinical candidate for the treatment of HIV patients harboring N(t)RTI resistant virus.
A Case History on the Challenges of Central Nervous System and Dual Pharmacology Drug Discovery
Authors: Fish Paul V. , Harrison Anthony , Wakenhut Florian , Whitlock Gavin A.
Published: October 2010

This chapter describes the case history of a drug discovery project targeting a centrally penetrant, dual serotonin/noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence, and highlights how key drug-like properties required for the discovery, and progression of a candidate molecule to clinical studies were successfully addressed. In particular, the medicinal chemistry strategies associated with balancing dual pharmacology with the required level of selectivity, BBB penetration, minimal CYP2D6 metabolism and pharmacokinetics are described. The use of a high confidence in vivo model and a bulk-sparing preclinical toxicology package to allow rapid determination of human pharmacokinetics were particularly important in the successful prosecution of this project.
Uncoupling Neuroprotection from Immunosuppression: the Discovery of ILS-920
Authors: Graziani Edmund I.
Published: October 2010

Natural product scaffolds are privileged structures that have withstood the pressures of eons of natural selection and have demonstrated utility in human medicine. They therefore represent a potential bridge to balancing risk and innovation in drug discovery and can complement modern synthetic approaches to medicinal chemistry. Our team explored modulating the activity of a medically useful natural product in order to modulate this activity towards a desired profile, while at the same time learning how structural changes affect mechanism, employing contemporary tools of chemical biology.

Rapamycin is an immunosuppressive natural product inhibitor of mammalian target of rapamycin (mTOR). We tested the hypothesis that modification of rapamycin at the mTOR binding region could provide non-immunosuppressive compounds with potent neuroprotective activity and significant efficacy in an animal model of ischemic stroke. Employing cell-based screening of our existing rapamycin analog (rapalog) collection, we identified Diels-Alder adduct formation at the C19,C22 diene as a potential synthetic strategy. The subsequent preparation of biologically active, non-immunosuppressive rapalogs has yielded a clinical compound, ILS-920. Preliminary investigations of the chemical biology of the compound suggest that the in vivo efficacy of ILS-920 derives from the compound’s dual functions as a potential activator of glucocorticoid and other steroid receptors via dissociation of FK506 binding protein 52 (FKBP52) from the receptor complexes, and as an inhibitor of L-type voltage gated Ca2+ channels via binding to the β1 subunit.
Polymer Nanocomposites by Emulsion and Suspension Polymerization
Authors: Bourgeat-Lami Elodie , Ming W M , Van Herk A M , Essawy H , Sebenik U , Krajnc M , Sahoo P K , Yang J , Lee L J , Choi S H , Xie Xiao-Lin , Mai Y W , Leiza J R , Lin J , Qu B , Charpentier P A , Shailaja D , Lin King-Fu ,   Royal Society of Chemistry
Published: October 2010

Polymer nanocomposites revolutionized research in the composites area by achieving the nanoscale dispersion of the inorganic filler (clay platelets) in the polymer matrices after suitable surface modifications of the filler phase. A large number of polymer matrices were tried and nanocomposites with varying degrees of successes were achieved with these polymer systems. The majority of the synthesis are carried out by melt blending which frequently result in the full exfoliation of the filler. However, advanced techniques provide a number of advantages as compared to the melt blending and lead to more uniform composites with enhanced properties. There are a number of recent advances in these methods such as the use of reactive surfactants, modified initiators, advanced clay surface modifications, use of a variety of fillers, inverse polymerization, and miniemulsion polymerization methods which have further led the generation of advanced exfoliated nanocomposites. Until now, most of the published research has been scattered throughout the literature. This book provides a single comprehensive source of information about one of the most important facets of polymer nanocomposites technology: synthesis in emulsion and suspension. These polymerization methods lead to the generation of the well delaminated polymer nanocomposites with a wide range of polymer matrices. This book serves as both a professional reference for experienced researchers and a valuable text for newcomers to the field. It makes the reader aware of the potential commercial use of these recent developments.
Polymer–Layered Double Hydroxide Nanocomposites by Emulsion and Suspension Polymerization
Authors: Qiu LongZhen , Qu BaoJun
Published: October 2010

LDHs, also known as anionic clays or hydrotalcite (HT)-like materials, are a family of materials consisting of positively charged brucite-like layers with intercalated anion and water molecules. The relatively weak interlayer bonding and excellent expanding properties of LDHs make them suitable for achieving well-dispersed nanocomposites through intercalation process like layered silicates. In the present chapter, we first give a brief review on the synthesis of LDHs, their organic modification, and the conventional strategies for preparing polymer/LDH nanocomposites. Then we summarize and discuss the up-to-date results obtained from the polymer/LDH nanocomposites prepared by emulsion and suspension polymerization in detail, including their synthesis, characterization, and potential applications.

Owing to their heterogeneous reaction systems, emulsion and suspension polymerization provide effective ways to achieve water-insoluble polymer /LDH nanocomposites in aqueous system. These strategies allow combining the nanocomposite synthesis procedure with the synthesis and modification procedure of LDHs in one system, which makes the production more efficient. Otherwise, the emulsion and suspension polymerization show many advantages, such as environment friendly, excellent heat control, low viscosity, and high molecular weight products obtained by fast polymerization rates. The nanocomposites obtained by emulsion and suspension polymerization exhibit enhanced thermal stability, improved flame retardancy, and good optical properties.
Polymer–Magnesium Hydroxide Nanocomposites by Emulsion Polymerization
Authors: Xie Xiao-Lin , Liu Sheng-Peng , Du Fei-Peng , Mai Yiu-Wing
Published: October 2010

With ever increasing awareness of environmental sustainability and tighter legislation, in-situ emulsion polymerization process has been widely adopted to prepare halogen-free flame retardant polymer/MH (magnesium hydroxide) nanocomposites with homogenous dispersion. Such composites possess excellent thermal stability, low flammability, good rheological properties and superb mechanical properties. They can be beneficially used as flame retardant adhesives and coatings, elastomers and plastics.

We believe in-situ emulsion polymerization is an efficient method to modify the surface of nano-MHs. We can adjust the thickness of the polymer shell covered on the nano-MH surface by controlling the ratio of monomer to nano-MHs; we can easily adjust the solubility parameter of polymers or copolymers covered on the nano-MHs, and disperse the modified nano-MHs in any polymer matrix uniformly, and hence enhance the interfacial interaction between nano-MHs and polymer. Hence, we have the tools to fabricate high-performance polymer/MH nanocomposites. Finally, to overcome the formation of homopolymer during in-situ monomer/nano-MH emulsion polymerization or copolymerization, surface-initiated in-situ emulsion polymerization seems to be a promising method not yet explored to-date.
Expository Writing in Children and Adolescents: A Classroom Assessment Tool
Authors: Nippold Marilyn A. , Sun Lei
Published: October 2010

This article describes a study that examined the development of expository writing in children and adolescents, using a task that could easily be administered by the speech-language pathologist to students in their classrooms at school. The task is presented and methods for analyzing and interpreting the results using a computer program are described. Excerpts from essays that were written by children and adolescents with typical development are discussed.
Sports activities, body weight and smoking in relation to low‐back pain: a population‐based case‐referent study
Authors: Mortimer M. , Wiktorin C. , Pernold G. , Svensson H. , Vingård E. , Music‐Norrtälje study group
Published: October 2010

The study aims to describe the influence of sports activities, high body weight and smoking on low‐back pain. The results were obtained from a population‐based case‐referent study, the Musculoskeletal Intervention Center (MUSIC)‐Norrtälje study. In all, 342 male and 449 female cases, and 662 male and 948 female referents participated. Neither low‐intensity training many hours/week (>=5 h) nor high‐intensity training few (1–2 h), intermediate (3–4 h) or many hours (>=5 h) per week affected the risk of low‐back pain among men. Few (1–2) hours with high‐intensity training increased the relative risk of low‐back pain among women, RR 1.6 (1.1–2.4). An increased risk of low‐back pain was found for men with high body weight, RR 2.2 (CI 1.2–3.9) but not for women. Smoking did not influence the risk of low‐back pain.
Houston, We've had a Problem… … Offshoring, is Employment and the is Discipline: Perception is not Reality
Authors: Hirschheim Rudy , Newman Mike
Published: October 2010

We believe that the information system (IS) discipline has a major and urgent problem to contend with: the general public appears to believe that there are ‘no jobs in IS’ because of offshoring. They see the offshoring of IS jobs as an inevitable consequence of economic and competitive pressures to drive down labor costs, which leads them to conclude that there is no future in IS. In particular, the discipline is suffering from the erosion of its student base and in this article we explore some of the reasons as to why this is occurring; focussing specifically on the role offshoring may be playing on the perception that there are no jobs in IS. Despite fairly robust figures showing that there are virtually as many IS jobs now as ever before, the public's perception appears to be at odds with this. We thus examine where these beliefs may have come from and in our stakeholder action plan we suggest some radical solutions to align perception with reality.
Interpretation of macropore shape transformation in crystalline silicon upon high temperature processing
Authors: Ghannam Moustafa Y. , Alomar Abdulazeez S. , Poortmans Jef , Mertens Robert P.
Published: October 2010

A physical interpretation is proposed for the sequence of transformations that macropores embedded in crystalline silicon undergo during high temperature treatments. First, cylindrical pores spheroidize by surface diffusion at constant volume. In the presence of stress and due to perturbation in the spherical symmetry stored elastic energy competes with cavity surface energy transforming large cavities by surface diffusion into an oblate shape with a major radius that continuously expands. At a critical condition close to the Griffith fracture criterion, the cavity collapses catastrophically into an ultrathin uniform slit that splits one or more thin crystalline film off the original substrate. On the other hand, if the stress is not high enough or the major radius of the cavity is not large enough the cavity does not collapse and maintains a rounded shape. Annealing in an ambient gas with a high partial pressure enhances the surface reaction which accelerates cavity growth and wall smoothening. The proposed theory agrees well with experimental observations.
The first experimental results from x-ray imaging crystal spectrometer for KSTAR
Authors: Lee S. G. , Bak J. G. , Nam U. W. , Moon M. K. , Shi Y. , Bitter M. , Hill K.
Published: October 2010

The x-ray imaging crystal spectrometer (XICS) for the Korea Superconducting Tokamak Advanced Research has been first applied for the experimental campaign in 2009. The XICS was designed to provide measurements of the profiles of the ion and electron temperatures from the heliumlike argon (Ar XVII) spectra. The basic functions of the XICS are properly working although some satellites lines are not well matched with the expected theoretical values. The initial experimental results from the XICS are briefly described.
Characterization of a linear device developed for research on advanced plasma imaging and dynamics
Authors: Chung J. , Lee K. D. , Seo D. C. , Nam Y. U. , Choi M. C.
Published: October 2010

Within the scope of long term research on imaging diagnostics for steady-state plasmas and understanding of edge plasma physics through diagnostics with conventional spectroscopic methods, we have constructed a linear electron cyclotron resonance (ECR) plasma device named Research on Advanced Plasma Imaging and Dynamics (RAPID). It has a variety of axial magnetic field profiles provided by eight water-cooled magnetic coils and two dc power supplies. The positions of the magnetic coils are freely adjustable along the axial direction and the power supplies can be operated with many combinations of electrical wiring to the coils. Here, a 6 kW 2.45 GHz magnetron is used to produce steady-state hydrogen, helium, and argon plasmas with central magnetic fields of 875 and/or 437.5 G (second harmonic). In order to achieve the highest possible plasma performance within the limited input parameters, wall conditioning experiments were carried out. Chamber bake-out was achieved with heating coils that were wound covering the vessel, and long-pulse electron cyclotron heating discharge cleaning was also followed after 4 days of bake-out. A uniform bake-out temperature (150 °C) was achieved by wrapping the vessel in high temperature thermal insulation textile and by controlling the heating coil current using a digital control system. The partial pressure changes were observed using a residual gas analyzer, and a total system pressure of 5×10−8 Torr was finally reached. Diagnostic systems including a millimeter-wave interferometer, a high resolution survey spectrometer, a Langmuir probe, and an ultrasoft x-ray detector were used to provide the evidence that the plasma performance was improved as we desired. In this work, we present characterization of the RAPID device for various system conditions and configurations.