bluuebunny/crossref_metadata_2025 huggingface dataset:
Three dimensional optical modeling of amorphous silicon thin film solar cells using the finite-difference time-domain method including real randomly surface topographies
Authors: Lacombe Jürgen , Sergeev Oleg , Chakanga Kambulakwao , von Maydell Karsten , Agert Carsten
Published: July 2011

In this paper, modeling of light propagation in silicon thin film solar cells without using any fitting parameter is presented. The aim is to create a realistic view of the light trapping effects and of the resulting optical generation rate in the absorbing semiconductor layers. The focus is on real three dimensional systems. Our software Sentaurus tcad, developed by Synopsys, has the ability to import real topography measurements and to model the light propagation using the finite-difference time-domain method. To verify the simulation, we compared the measured and simulated angular distribution functions of a glass/SnO2:F transparent conducting oxide system for different wavelengths. The optical generation rate of charge carriers in amorphous silicon thin film solar cells including rough interfaces is calculated. The distribution of the optical generation rate is correlated with the shape of the interface, and the external quantum efficiencies are calculated and compared to experimental data.
High performance small molecule photodetector with broad spectral response range from 200 to 900 nm
Authors: Wu Shuang-hong , Li Wen-lian , Chu Bei , Su Zi-sheng , Zhang Feng , Lee C. S.
Published: July 2011

We demonstrate a photodetector (PD) with broad spectral response by taking the advantages of more flexible device design in using small molecule materials. The optimized device shows an external quantum efficiency of over 20% from 200 to 900 nm. The high performance is achieved by jointing two donor (D)/acceptor (A) hetero-junctions [m-MTDATA(D)/TiOPc(A) and TiOPc(D)/F16CuPc: PTCDI-C8(A)] such that photoresponses over the deep-ultraviolet (UV) and visible-near infrared regions can be independently optimized. By choosing D- and A-materials with matched energy level alignment, high carrier mobility, and balanced carrier transporting properties, the present PD shows a fast response of 56 ns. The high speed and deep-UV sensitivity might lead to potential military applications such as missile tracking in addition to optical communications, chemical/biological sensing etc.
Trap density of GeNx/Ge interface fabricated by electron-cyclotron-resonance plasma nitridation
Authors: Fukuda Yukio , Otani Yohei , Toyota Hiroshi , Ono Toshiro
Published: July 2011

We have investigated GeNx/Ge interface properties using Si3N4(7 nm)/GeNx(2 nm)/Ge metal-insulator-semiconductor structures fabricated by the plasma nitridation of Ge substrates using an electron-cyclotron-resonance-generated nitrogen plasma. The interface trap density (Dit) measured by the conductance method is found to be distributed symmetrically in the Ge band gap with a minimum Dit value lower than 3 × 1011 cm−2eV−1 near the midgap. This result may lead to the development of processes for the fabrication of p- and n-Ge Schottky-barrier (SB) source/drain metal-insulator-semiconductor field-effect transistors using chemically and thermally robust GeNx dielectrics as interlayers for SB source/drain contacts and high-κ gate dielectrics.
Boosting jet power in black hole spacetimes
Authors: Neilsen David , Lehner Luis , Palenzuela Carlos , Hirschmann Eric W. , Liebling Steven L. , Motl Patrick M. , Garrett Travis
Published: July 2011

The extraction of rotational energy from a spinning black hole via the Blandford–Znajek mechanism has long been understood as an important component in models to explain energetic jets from compact astrophysical sources. Here we show more generally that the kinetic energy of the black hole, both rotational and translational, can be tapped, thereby producing even more luminous jets powered by the interaction of the black hole with its surrounding plasma. We study the resulting Poynting jet that arises from single boosted black holes and binary black hole systems. In the latter case, we find that increasing the orbital angular momenta of the system and/or the spins of the individual black holes results in an enhanced Poynting flux.
Structural characterization of filaments formed by human Xrcc4–Cernunnos/XLF complex involved in nonhomologous DNA end-joining
Authors: Ropars Virginie , Drevet Pascal , Legrand Pierre , Baconnais Sonia , Amram Jeremy , Faure Guilhem , Márquez José A. , Piétrement Olivier , Guerois Raphaël , Callebaut Isabelle , Le Cam Eric , Revy Patrick , de Villartay Jean-Pierre , Charbonnier Jean-Baptiste
Published: July 2011

Cernunnos/XLF is a core protein of the nonhomologous DNA end-joining (NHEJ) pathway that processes the majority of DNA double-strand breaks in mammals. Cernunnos stimulates the final ligation step catalyzed by the complex between DNA ligase IV and Xrcc4 (X4). Here we present the crystal structure of the
X
4
1–157
-Cernunnos
1–224
complex at 5.5-Å resolution and identify the relative positions of the two factors and their binding sites. The X-ray structure reveals a filament arrangement for
X
4
1–157
and Cernunnos
1–224
homodimers mediated by repeated interactions through their N-terminal head domains. A filament arrangement of the X4–Cernunnos complex was confirmed by transmission electron microscopy analyses both with truncated and full-length proteins. We further modeled the interface and used structure-based site-directed mutagenesis and calorimetry to characterize the roles of various residues at the X4–Cernunnos interface. We identified four X4 residues (Glu
55
, Asp
58
, Met
61
, and Phe
106
) essential for the interaction with Cernunnos. These findings provide new insights into the molecular bases for stimulatory and bridging roles of Cernunnos in the final DNA ligation step.
Sensitization of BCL-2–expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737
Authors: Oakes Samantha R. , Vaillant François , Lim Elgene , Lee Lily , Breslin Kelsey , Feleppa Frank , Deb Siddhartha , Ritchie Matthew E. , Takano Elena , Ward Teresa , Fox Stephen B. , Generali Daniele , Smyth Gordon K. , Strasser Andreas , Huang David C. S. , Visvader Jane E. , Lindeman Geoffrey J.
Published: July 2011

Overexpression of the prosurvival protein BCL-2 is common in breast cancer. Here we have explored its role as a potential therapeutic target in this disease. BCL-2, its anti-apoptotic relatives MCL-1 and BCL-XL, and the proapoptotic BH3-only ligand BIM were found to be coexpressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers. To determine whether the BH3 mimetic ABT-737 that neutralizes BCL-2, BCL-XL, and BCL-W had potential efficacy in targeting BCL-2–expressing basal-like triple-negative tumors, we generated a panel of primary breast tumor xenografts in immunocompromised mice and treated recipients with either ABT-737, docetaxel, or a combination. Tumor response and overall survival were significantly improved by combination therapy, but only for tumor xenografts that expressed elevated levels of BCL-2. Treatment with ABT-737 alone was ineffective, suggesting that ABT-737 sensitizes the tumor cells to docetaxel. Combination therapy was accompanied by a marked increase in apoptosis and dissociation of BIM from BCL-2. Notably, BH3 mimetics also appeared effective in BCL-2–expressing xenograft lines that harbored p53 mutations. Our findings provide in vivo evidence that BH3 mimetics can be used to sensitize primary breast tumors to chemotherapy and further suggest that elevated BCL-2 expression constitutes a predictive response marker in breast cancer.
Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1
Authors: Croker Ben A. , O'Donnell Joanne A. , Nowell Cameron J. , Metcalf Donald , Dewson Grant , Campbell Kirsteen J. , Rogers Kelly L. , Hu Yifang , Smyth Gordon K. , Zhang Jian-Guo , White Michael , Lackovic Kurt , Cengia Louise H. , O'Reilly Lorraine A. , Bouillet Philippe , Cory Suzanne , Strasser Andreas , Roberts Andrew W.
Published: July 2011

During immune responses, neutrophils must integrate survival and death signals from multiple sources to regulate their lifespan. Signals that activate either the Bcl-2- or death receptor-regulated apoptosis pathways can provide powerful stimuli for neutrophils to undergo cell death, but whether they act cooperatively in parallel or directly cross-talk in neutrophils is not known. Previous studies suggested that Bcl-2 family proteins are not required for Fas-induced cell death in neutrophils, but did not examine whether they could modulate its rapid onset. By monitoring the rate of change in neutrophil viability associated with activation of the Fas-triggered death receptor pathway using real-time cell imaging, we show that the Bcl-2-related proteins Bid, Bax, and Bak accelerate neutrophil apoptosis but are not essential for cell death. Increased Bcl-2 or Mcl-1 expression prevents efficient induction of apoptosis by Fas stimulation indicating that the Bcl-2-regulated apoptosis pathway can directly interfere with Fas-triggered apoptosis. Fas has been shown to initiate NFκB activation and gene transcription in cell lines, however gene transcription is not altered in Fas-activatedBid−/−neutrophils, indicating that apoptosis occurs independently of gene transcription in neutrophils. The specification of kinetics of neutrophil apoptosis by Bid impacts on the magnitude of neutrophil IL-1β production, implicating a functional role for the Bcl-2-regulated pathway in controlling neutrophil responses to FasL. These data demonstrate that the intrinsic apoptosis pathway directly controls the kinetics of Fas-triggered apoptosis in neutrophils.
Gender, achievement and the ‘Gold Standard’: differential performance in the GCE A level examination
Authors: Elwood Jannette
Published: July 2011

While interest in gender‐related differences in performance in examinations and assessment in the UK has been considerable, it has tended to focus on the compul‐ sory phase of schooling, particularly at age 16. This lack of attention to gender‐related differences in examinations at 18+ is somewhat surprising since outcomes at this stage of education are critical in terms of life chances and entry into higher and further edu‐ cation. This article discusses the picture of gendered achievement in the GCE A level examination. Trends in differential performance over time are examined and expla‐ nations put forward as to why these differences in performance occur. Explanations proposed cover links between gendered styles of learning and the style of examining; the statistical and educational impact of self‐selecting populations on performance patterns; and the contribution of different assessment techniques to differences in male and female examination performance. Finally, suggestions of where action might be taken to rectify the differences observed are given. The discussion in the article is supported by data from two research projects that have studied in detail the inter‐ action of examination systems and gender.
Matching teaching to learning
Authors: Beresford John
Published: July 2011

The debate about appropriate teaching strategies for effective learning to take place is by no means a new one. It now has an added poignancy with recent energetic government initiatives to pursue student performance targets. Recent research suggests that extending teachers’ pedagogic repertoires is an important element in maximizing academic outcomes, and that students’ views of their own education provide important insights for improving teaching and learning in schools. This article looks at a technique, derived from the work of Kolb and used in a range of secondary schools, to audit the range of teaching styles used and to compare these with the learning preferences of students. Results suggest that students favour a greater element of ‘social learning’ than they are currently receiving.
Strong resistance of silicene nanoribbons towards oxidation
Authors: De Padova Paola , Quaresima Claudio , Olivieri Bruno , Perfetti Paolo , Le Lay Guy
Published: July 2011

Silicene, the new allotropic form of silicon, represents an interesting promise for future new nanostructured materials. Here, we investigate the room temperature oxidation of a one-dimensional grating of silicene nanoribbons grown on a Ag(1 1 0) surface by high-resolution Si 2p core level photoemission spectroscopy and low-energy electron diffraction observations. The oxidation process starts at very high oxygen exposures, about 104 times higher than on the clean Si(1 1 1)7 × 7 surface, which demonstrates the low reactivity of silicene to molecular oxygen. Ar+sputtering produces defects, which enhance the oxidation uptake.
Carrier density-dependent transport in poly(3-methylthiophene): from injection-limited to space-charge-limited current
Authors: Anjaneyulu P , Suchand Sangeeth C S , Menon Reghu
Published: July 2011

Current–voltage (I–V) and impedance measurements were carried out in doped poly(3-methylthiophene) devices by varying the carrier density. As the carrier concentration reduces the I–V characteristics indicate that the conduction mechanism is limited by metal–polymer interface, as also observed in impedance data. The temperature dependence of I–V in moderately doped samples shows a trap-controlled space-charge-limited conduction (SCLC); whereas in lightly doped devices injection-limited conduction is observed at lower bias and SCLC at higher voltages. The carrier density-dependent quasi-Fermi level adjustment and trap-limited transport could explain this variation in conduction mechanism. Capacitance measurements at lower frequencies and higher bias voltages show a sign change in values due to the significant variations in the relaxation behaviour for lightly and moderately doped samples. The electrical hysteresis increases as carrier density is reduced due to the time scales involved in the de-trapping of carriers.
Drift velocity and longitudinal diffusion coefficient of electrons in pure ethene
Authors: Takatou Junpei , Sato Hiroshi , Nakamura Yoshiharu
Published: July 2011

Drift velocity and longitudinal diffusion coefficient of electrons in pure ethene were measured over a wide E/N range from 0.03 to 1000 Td (1 Td = 10−17 V cm2) with a newly constructed electron drift apparatus. The accuracy of the present drift velocity and longitudinal diffusion coefficient was estimated to be ±0.5% and ±3%, respectively. The present results were compared with other two-carbon-atom hydrocarbon molecules with different C–C bonds, ethane and acetylene.
Investigation of the effect of dielectric barrier discharge plasma actuators on the radar cross section of an object
Authors: Wolf S , Arjomandi M
Published: July 2011

The application of dielectric barrier discharge (DBD) plasma as an electromagnetic absorber was investigated by determining the radar cross section (RCS) of a rectangular, flat plate with a DBD plasma actuator array installed on one of its sides. In order to justify the experimental results, the expected effect of plasma actuation on RCS was analysed by determining the attenuation effect of the plasma with the Lorentz model. Due to the very limited life time of the free electrons and the small extent of the plasma sheath, the attenuation was found to be only minimal.

The theoretical results have been verified by comparing the measured RCS values of a plate with and without plasma actuation applied on it in a high-frequency anechoic lab. As expected, no significant influence of DBD plasma on RCS was detected. In addition, it was found that the high voltage power supply used as a part of DBD circuitry produced a high level of disturbance even in the microwave range.
Analytical study of thermal annealing behaviour of erbium emission in Er2O3-sol–gel silica films
Authors: Abedrabbo S , Lahlouh B , Fiory A T
Published: July 2011

Room-temperature 1535 nm band photoluminescence in ∼126 nm silica films (6 at% doping), produced by spin coating an Er2O3 and tetraethylorthosilicate sol–gel formulation on silicon substrates, was studied as a function of vacuum furnace annealing (500–1050 °C). Emission is strongly enhanced for annealing near 850 °C, which is shown by modelling the temperature dependence as arising from thermally activated removal of hydroxyl ions. Suitability of such a process for silicon-based applications is discussed.
Inward pinch of high-Z impurity in a rotating tokamak plasma: effects of atomic processes, radial electric field and Coulomb collisions
Authors: Hoshino K. , Toma M. , Shimizu K. , Nakano T. , Hatayama A. , Takizuka T.
Published: July 2011

The transport of high-Z impurity in a toroidally rotating tokamak plasma is investigated analytically and numerically. It is shown that the inward pinch is driven by the atomic processes of ionization/recombination along the particle orbit both in co- and ctr-rotating plasmas. This inward pinch is enhanced by the radial electric field. It is derived that the negative and positive radial electric fields cause the inward pinch and the outward movement (unpinch) of the high-Z impurity, respectively, under the influence of Coulomb collisions with the rotating background plasma. In the ctr-rotation case, the inward pinch becomes significant with increasing toroidal rotation velocity, because the directions of both pinches are inwards. On the other hand, in the co-rotation case, these pinches have opposite directions. Therefore, the unpinch due to the positive radial electric field is decreased by the inward pinch due to the atomic processes. These tendencies are consistent with the tungsten accumulation observed in the JT-60U rotation scan experiment.
MARCH ubiquitin ligases alter the itinerary of clathrin-independent cargo from recycling to degradation
Authors: Eyster Craig A. , Cole Nelson B. , Petersen Shariska , Viswanathan Kasinath , Früh Klaus , Donaldson Julie G.
Published: July 2011

Following endocytosis, internalized plasma membrane proteins can be recycled back to the cell surface or trafficked to late endosomes/lysosomes for degradation. Here we report on the trafficking of multiple proteins that enter cells by clathrin-independent endocytosis (CIE) and determine that a set of proteins (CD44, CD98, and CD147) found primarily in recycling tubules largely failed to reach late endosomes in HeLa cells, whereas other CIE cargo proteins, including major histocompatibility complex class I protein (MHCI), trafficked to both early endosome antigen 1 (EEA1) and late endosomal compartments in addition to recycling tubules. Expression of the membrane-associated RING-CH 8 (MARCH8) E3 ubiquitin ligase completely shifted the trafficking of CD44 and CD98 proteins away from recycling tubules to EEA1 compartments and late endosomes, resulting in reduced surface levels. Cargo affected by MARCH expression, including CD44, CD98, and MHCI, still entered cells by CIE, suggesting that the routing of ubiquitinated cargo occurs after endocytosis. MARCH8 expression led to direct ubiquitination of CD98 and routing of CD98 to late endosomes/lysosomes.
RhoGDIα-dependent balance between RhoA and RhoC is a key regulator of cancer cell tumorigenesis
Authors: Giang Ho T. T. , Stultiens Audrey , Dubail Johanne , Lapière Charles M. , Nusgens Betty V. , Colige Alain C. , Deroanne Christophe F.
Published: July 2011

RhoGTPases are key signaling molecules regulating main cellular functions such as migration, proliferation, survival, and gene expression through interactions with various effectors. Within the RhoA-related subclass, RhoA and RhoC contribute to several steps of tumor growth, and the regulation of their expression affects cancer progression. Our aim is to investigate their respective contributions to the acquisition of an invasive phenotype by using models of reduced or forced expression. The silencing of RhoC, but not of RhoA, increased the expression of genes encoding tumor suppressors, such as nonsteroidal anti-inflammatory drug–activated gene 1 (NAG-1), and decreased migration and the anchorage-independent growth in vitro. In vivo, RhoC small interfering RNA (siRhoC) impaired tumor growth. Of interest, the simultaneous knockdown of RhoC and NAG-1 repressed most of the siRhoC-related effects, demonstrating the central role of NAG-1. In addition of being induced by RhoC silencing, NAG-1 was also largely up-regulated in cells overexpressing RhoA. The silencing of RhoGDP dissociation inhibitor α (RhoGDIα) and the overexpression of a RhoA mutant unable to bind RhoGDIα suggested that the effect of RhoC silencing is indirect and results from the up-regulation of the RhoA level through competition for RhoGDIα. This study demonstrates the dynamic balance inside the RhoGTPase network and illustrates its biological relevance in cancer progression.
Phosphorylation of Serine 114 on Atg32 mediates mitophagy
Authors: Aoki Yoshimasa , Kanki Tomotake , Hirota Yuko , Kurihara Yusuke , Saigusa Tetsu , Uchiumi Takeshi , Kang Dongchon
Published: July 2011

Mitophagy, which selectively degrades mitochondria via autophagy, has a significant role in mitochondrial quality control. When mitophagy is induced in yeast, mitochondrial residential protein Atg32 binds Atg11, an adaptor protein for selective types of autophagy, and it is recruited into the vacuole along with mitochondria. The Atg11–Atg32 interaction is believed to be the initial molecular step in which the autophagic machinery recognizes mitochondria as a cargo, although how this interaction is mediated is poorly understood. Therefore, we studied the Atg11–Atg32 interaction in detail. We found that the C-terminus region of Atg11, which included the fourth coiled-coil domain, interacted with the N-terminus region of Atg32 (residues 100–120). When mitophagy was induced, Ser-114 and Ser-119 on Atg32 were phosphorylated, and then the phosphorylation of Atg32, especially phosphorylation of Ser-114 on Atg32, mediated the Atg11–Atg32 interaction and mitophagy. These findings suggest that cells can regulate the amount of mitochondria, or select specific mitochondria (damaged or aged) that are degraded by mitophagy, by controlling the activity and/or localization of the kinase that phosphorylates Atg32. We also found that Hog1 and Pbs2, which are involved in the osmoregulatory signal transduction cascade, are related to Atg32 phosphorylation and mitophagy.
Cla4 kinase triggers destruction of the Rac1-GEF Cdc24 during polarized growth inUstilago maydis
Authors: Frieser Sonja Helene , Hlubek Andrea , Sandrock Björn , Bölker Michael
Published: July 2011

Dimorphic switching from budding to filamentous growth is a characteristic feature of many pathogenic fungi. In the fungal model organism Ustilago maydis polarized growth is induced by the multiallelic b mating type locus and requires the Rho family GTPase Rac1. Here we show that mating type–induced polarized growth involves negative feedback regulation of the Rac1-specific guanine nucleotide exchange factor (GEF) Cdc24. Although Cdc24 is essential for polarized growth, its concentration is drastically diminished during filament formation. Cdc24 is part of a protein complex that also contains the scaffold protein Bem1 and the PAK kinase Cla4. Activation of Rac1 results in Cla4-dependent degradation of the Rac1-GEF Cdc24, thus creating a regulatory negative feedback loop. We generated mutants of Cdc24 that are resistant to Cla4-dependent destruction. Expression of stable Cdc24 variants interfered with filament formation, indicating that negative feedback regulation of Cdc24 is critical for the establishment of polarized growth.
Functional ESCRT machinery is required for constitutive recycling of claudin-1 and maintenance of polarity in vertebrate epithelial cells
Authors: Dukes Joseph D. , Fish Laura , Richardson Judith D. , Blaikley Elizabeth , Burns Samir , Caunt Christopher J. , Chalmers Andrew D. , Whitley Paul
Published: July 2011

Genetic screens in Drosophila have identified regulators of endocytic trafficking as neoplastic tumor suppressor genes. For example, Drosophila endosomal sorting complex required for transport (ESCRT) mutants lose epithelial polarity and show increased cell proliferation, suggesting that ESCRT proteins could function as tumor suppressors. In this study, we show for the for the first time to our knowledge that ESCRT proteins are required to maintain polarity in mammalian epithelial cells. Inhibition of ESCRT function caused the tight junction protein claudin-1 to accumulate in intracellular vesicles. In contrast E-cadherin and occludin localization was unaffected. We investigated the cause of this accumulation and show that claudin-1 is constitutively recycled in kidney, colon, and lung epithelial cells, identifying claudin-1 recycling as a newly described feature of diverse epithelial cell types. This recycling requires ESCRT function, explaining the accumulation of intracellular claudin-1 when ESCRT function is inhibited. We further demonstrate that small interfering RNA knockdown of the ESCRT protein Tsg101 causes epithelial monolayers to lose their polarized organization and interferes with the establishment of a normal epithelial permeability barrier. ESCRT knockdown also reduces the formation of correctly polarized three-dimensional cysts. Thus, in mammalian epithelial cells, ESCRT function is required for claudin-1 trafficking and for epithelial cell polarity, supporting the hypothesis that ESCRT proteins function as tumor suppressors.
Impact of Counter‐Urbanization on Size, Population Mix, and Welfare of an Agricultural Region
Authors: Feinerman Eli , Finkelshtain Israel , Tchetchik Anat , Delgo Mordehai
Published: July 2011

The article explains the phenomenon of counter‐urbanization, which has become prominent in most developed countries. We develop a model that provides an economic rationalization for the observed willingness of incumbent farmers of a rural region to absorb nonfarmer urban migrants. The analytical findings show that counter‐urbanization increases the region's welfare‐maximizing population, decreases the optimal number of incumbent farmers, and increases the per capita welfare. The empirical results, which are based on data from rural Israel, demonstrate that while the optimal population of farmers decreases slightly, the total optimal population of the region more than triples and farmers' per capita welfare almost doubles.
Spatial Price Discrimination in Agricultural Product Procurement Markets: A Computational Economics Approach
Authors: Graubner Marten , Balmann Alfons , Sexton Richard J.
Published: July 2011

Significant transport costs and spatially distributed supply and processing create oligopsony power in agricultural markets. Price discrimination expressed in the form of partial or complete absorption of freight charges by processors is often observed in these environments, but we understand little about how these pricing decisions are made. Analytical approaches are often intractable. As an alternative, we propose a computational economics approach to analyze a general spatial competition model and study firms' choices of spatial pricing policy. Instead of the commonly presumed free‐on‐board pricing, we find that buyers choose price discrimination, either through uniform delivered pricing or through partial freight absorption.
Inferring statin-induced gene regulatory relationships in primary human hepatocytes
Authors: Schröder Adrian , Wollnik Johannes , Wrzodek Clemens , Dräger Andreas , Bonin Michael , Burk Oliver , Thomas Maria , Thasler Wolfgang E. , Zanger Ulrich M. , Zell Andreas
Published: July 2011

Motivation: Statins are the most widely used cholesterol-lowering drugs. The primary target of statins is HMG-CoA reductase, a key enzyme in cholesterol synthesis. However, statins elicit pleitropic responses including beneficial as well as adverse effects in the liver or other organs. Today, the regulatory mechanisms that cause these pleiotropic effects are not sufficiently understood.

Results: In this work, genome-wide RNA expression changes in primary human hepatocytes of six individuals were measured at up to six time points upon atorvastatin treatment. A computational analysis workflow was applied to reconstruct regulatory mechanisms based on these drug–response data and available knowledge about transcription factor (TF) binding specificities and protein–drug interactions. Several previously unknown TFs were predicted to be involved in atorvastatin-responsive gene expression. The novel relationships of nuclear receptors NR2C2 and PPARA on CYP3A4 were successfully validated in wet-lab experiments.

Availability: Microarray data are available at the Gene Expression Omnibus (GEO) database at www.ncbi.nlm.nih.gov/geo/, under accession number GSE29868.

Contact:  andreas.zell@uni-tuebingen.de; adrian.schroeder@uni-tuebingen.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Age and growth of striped marlin (Kajikia audax) in the Southwest Pacific Ocean
Authors: Kopf R. Keller , Davie Peter S. , Bromhead Donald , Pepperell Julian G.
Published: July 2011

Kopf, R. K., Davie, P. S., Bromhead, D., and Pepperell, J. G. 2011. Age and growth of striped marlin (Kajikia audax) in the Southwest Pacific Ocean. – ICES Journal of Marine Science, 68: 1884–1895. This study describes the first validated model of age and growth developed for striped marlin (Kajikia audax). Daily periodicity of otolith microincrements was corroborated by back-calculated hatch dates that matched the known spawning season in the Southwest Pacific Ocean (SWPO). Yearly annulus formation in fin-spine sections was corroborated by daily otolith microincrements and by a marginal increment analysis. Ages of females ranged from 140 d to 8.5 years in fish between 990 mm and 2872 mm lower-jaw fork length (LJFL), and ages of males from 130 d to 7.0 years in fish between 1120 mm and 2540 mm LJFL. Sex-specific differences in growth were significant, with females growing to a larger asymptotic size and greater age than males. An instantaneous growth rate of 3.1 mm d–1 at 6 months and an estimated length of 1422–1674 mm LJFL by age 1 year makes this species among the fastest growing bony fish. Implications of these findings are discussed in relation to commercial longline and recreational fisheries management of striped marlin in the SWPO and in relation to the biology of pelagic fish growth.
Growth hormone and ageing
Authors: Gibney James , Ho Ken K. Y.
Published: July 2011

Ageing is characterized by undesirable changes in body composition and a decline in many physiological functions, leading to reduced physical fitness and increased susceptibility to illness. With the projected growth of the elderly population worldwide, the ageing process is likely to give rise to increasing demands on health and welfare service budgets. The WHO projects that between the years 2000 and 2050, the world’s population of persons aged 60 and over will more than triple, from 600 million to 2 billion (1). The proportion of the EU population aged 65 years and over is predicted to rise from 17.1% in 2008 to 30.0% in 2060, and the proportion aged 80 and over to rise from 4.4% to 12.1% over the same period (2).

Ageing is a complex and poorly understood process. In recent years, there has been considerable interest in the role of the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. Prior to 1985, supplies of GH were limited as it was obtainable only from human pituitary tissue, largely restricting its use to the treatment of childhood short stature. The development of recombinant GH has made available theoretically infinite supplies of GH, and allowed exploration of the role of GH in adult pathophysiology.

While GH is best recognized for its stimulation of longitudinal bone growth in childhood, recent evidence has demonstrated that GH continues to play a central role in adulthood in the regulation of fat and protein metabolism, body composition, and many physiological functions. The steady decline in GH secretion through adulthood, termed the ‘somatopause,’ raises the possibility of involvement of the GH/IGF-1 axis in the structural and functional changes that accompany advancing age.

This chapter explores the role of the somatopause and reviews the evidence for GH as a strategy for modifying age-related deterioration.
Endocrinology of the menopause and hormone replacement therapy
Authors: Burger Henry G. , Teede Helena J.
Published: July 2011

A major endocrine function of the human ovary is the production of oestradiol, a hormone essential for the development of the secondary sex characteristics, for normal reproduction, and for the integrity of the cardiovascular, skeletal, and central nervous systems in particular. Oestradiol is a product of the granulosa cells, and hence its secretion is dependent largely on the presence of ovarian follicles. The number of those follicles falls steeply in the last 10 years or so of reproductive life (1), to approach zero at around the time of final menses (Fig. 10.1.2.1). This results in a profound decline in oestradiol production, to levels less than 10% of those observed during reproductive life. The question of whether the consequences of this decline are to be regarded as ‘natural,’ or as giving rise to a pathological state of oestrogen deficiency, is a controversial one. This chapter describes the endocrine changes which take place from the mid-reproductive years through to the postmenopausal years, and addresses the consequences of these changes and their possible prevention.
Male reproductive health and ageing
Authors: Handelsman David J.
Published: July 2011

Since antiquity, the waning of male virility with age and the seemingly inexhaustible repertoire of remedies to stave if off have been intertwined human interests in the vain quest for immortality. Advancing age impacts on all aspects of male reproductive health— sexuality, fertility and androgenization. Increasing longevity throughout society creates a compelling need to promote healthy ageing. The resemblance between some features of ageing and those of younger androgen-deficient men, whose disabilities are readily corrected by testosterone replacement, has long raised interest in whether biochemical androgen deficiency in older men contributes actively to their somatic ageing rather than representing simply a passive barometer of health, or an epiphenomenon of the parallel age-related deterioration of the reproductive with nonreproductive systems. However, if declining androgen secretion with advancing age is clinically significant, or even if it can be overcome pharmacologically, androgen therapy has the potential to improve quality of life for older men. Unlike women where menopause demarcates abruptly the virtually complete cessation of gonadal steroid secretion, male reproductive senescence is a gradual, progressive, but inconsistent and incomplete process varying markedly between individuals in tempo and severity, and accentuated by concomitant ill health. Congruent with wider medical priorities in care of the aged, the goal of management is to coexist with, rather than to eradicate, degenerative diseases. More realistic goals are to improve physical and mental functioning and quality of life so as to prolong enjoyable, independent living, to prevent the preventable, and to delay the inevitable.
Ageing and thyroid disease
Authors: Mariotti Stefano
Published: July 2011

The relationship between ageing and the thyroid has been the object of intensive investigation (1) for several pathophysiological, epidemiological, and clinical reasons. Symptoms of ageing can easily be confused with hypothyroidism, and decreased thyroid function was once believed to be a hallmark of senescence. Thyroid diseases are common in the elderly, but their clinical manifestations are different from those seen in younger patients, being more vague, subtle, and often hidden by concurrent diseases. The interpretation of thyroid function tests is often difficult in elderly individuals, due to age-associated changes of thyroid physiology, alterations of thyroid function tests secondary to nonthyroidal illness, and/or drug intake. Treatment of thyroid disease deserves special attention in elderly patients due to the increased risk of complications and/or drug interactions. If untreated, thyroid dysfunctions may lead to significant morbidity in elderly people, mostly through an aggravation of coexistent cardiovascular disease. A remarkable exception to this concept is represented by mild hypothyroidism, which in the oldest elderly population appears to be associated with no harm, and possibly increased survival.
Endocrinology in the critically ill
Authors: Vervenne Hilke , Van den Berghe Greet
Published: July 2011

Critical illness is any condition requiring support of failing vital organ systems, without which survival would not be possible. It is characterized by striking alterations in the hypothalamic-anterior-pituitary axes that are known to contribute to the high risk of morbidity and mortality.
Endocrine abnormalities in HIV infection
Authors: Stanley Takara L. , Grinspoon Steven K.
Published: July 2011

Approximately 33 million people worldwide are living with HIV infection, and more than 2 million individuals are newly infected each year (1). Sub-Saharan Africa bears the majority of the disease burden, with 67% of all HIV cases and 75% of all HIV/AIDS related deaths occurring in this region (2). Although access to antiretroviral therapy has improved significantly over the past decade, antiretrovirals are available to only about 30% of those who need them (2). Availability of antiretroviral therapy greatly impacts the endocrine manifestations of HIV infection: individuals treated with antiretrovirals may develop peripheral fat loss, abdominal obesity, insulin resistance, and hyperlipidemia, whereas untreated individuals may develop undernutrition, wasting, and end-organ effects of opportunistic infections such as primary adrenal insufficiency secondary to adrenal destruction (Box 10.2.4.1). In all individuals with HIV infection, regardless of treatment, gonadal function, thyroid function, and bone mineral density may also be decreased, and salt and water balance may be affected (Box 10.2.4.2). The purpose of this chapter is to review the endocrine manifestations of HIV infection, including pathogenesis and treatment.
Immunoendocrinopathy syndromes
Authors: Scherbaum W. A. , Schott M.
Published: July 2011

Autoimmune endocrinopathies arise from immunological abnormalities, which cause endocrine dysfunction by mimicking hormone action, by blocking the binding of hormones to their receptors, or by autoimmune-mediated destruction of endocrine glands. They include autoimmune polyglandular syndromes type I and type II, syndromes with anti-insulin receptor antibodies, POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) and thymic tumours with associated endocrinopathy. Box 10.2.5.1 gives an overview of the autoimmune endocrinopathies discussed in this chapter.
Parathyroid anatomy, hormone synthesis, secretion, action, and receptors
Authors: Hendy Geoffrey N. , Goltzman David
Published: July 2011

Humans have two pairs of parathyroid glands lying in the anterior cervical region. The fetal parathyroid glands begin developing at 5 weeks from the third and fourth pharyngeal pouches. The third pharyngeal pouch, which contains tissue that will become the thymus and parathyroid, migrates downward and gives rise to the two inferior parathyroid glands normally located at the lower poles of the thyroid. The fourth pharyngeal pouch does not migrate and gives rise to the two upper parathyroid glands, which normally are attached to the upper poles of the thyroid (1).
Familial hypocalciuric hypercalcaemia
Authors: Brown Edward M.
Published: July 2011

Familial hypocalciuric hypercalcaemia (FHH) is a generally asymptomatic form of mild to moderate, parathyroid hormone (PTH)-dependent hypercalcaemia, which was initially confused with the more common hypercalcaemic disorder, primary hyperparathyroidism (PHPT) (1–3). Subsequent studies showed that FHH differs from PHPT in several important respects, although distinguishing between these two conditions can still be difficult on a clinical basis alone (4). Urinary calcium excretion is lower in the former than in the latter, and in FHH, unlike PHPT, hypercalcaemia recurs rapidly following surgical treatment with anything less than total parathyroidectomy. Indeed, given FHH’s generally benign natural history, surgery is usually ill advised (3).

The phenotype of FHH implicated some abnormality in the sensing and/or handling of calcium by parathyroid and kidney (3, 5). For more than two decades after its initial description, however, the genetic defect in FHH was unknown. In 1992, the major genetic locus for this condition was identified on the long arm of chromosome 3 (6). The following year saw the cloning of a G protein-coupled extracellular calcium (Ca2+
o)-sensing receptor (CaSR) mediating direct regulation of PTH secretion by Ca2+
o (7). The CaSR’s function and its location of its gene on the same region chromosome 3 in humans made it an obvious candidate gene for FHH. Shortly thereafter, heterozygous inactivating mutations in the CaSR were identified in several FHH families (8). Moreover, patients with a related condition, neonatal severe hyperparathyroidism (NSHPT), also turned out to harbour inactivating CaSR mutations in the homozygous, compound heterozygous, and in a milder disorder, neonatal hyperparathyroidism (NHPT), in the heterozygous state (8). This chapter reviews the clinical and biochemical features of FHH, its genetics, pathophysiology, and pathogenesis, and its relationship to NSHPT.
Hypocalcaemic disorders, hypoparathyroidism, and pseudohypoparathyroidism
Authors: Thakker Rajesh V.
Published: July 2011

Extracellular calcium ion concentration is tightly regulated through the actions of parathyroid hormone (PTH) on kidney and bone (Fig. 4.5.1). The intact peptide is secreted by the parathyroid glands at a rate that is appropriate to and dependent upon the prevailing extracellular calcium ion concentration. The causes of hypocalcaemia (Box 4.5.1) can be classified according to whether serum PTH concentrations are low (that is hypoparathyroid disorders) or high (that is disorders associated with secondary hyperparathyroidism) (1–6). The most common causes of hypocalcaemia are hypoparathyroidism, a deficiency or abnormal metabolism of vitamin D, acute or chronic renal failure, and hypomagnesaemia. This chapter will initially review the clinical features and management of hypocalcaemia, and then discuss the specific hypocalcaemic disorders.
Hypercalcaemic and hypocalcaemic syndromes in children
Authors: Ardeshirpour Laleh , Carpenter Thomas O.
Published: July 2011

The calcium-regulating system employs an intricate network of homoeostatic signals and targets in order to meet the body’s mineral demands. Mineral requirements vary considerably throughout progressive stages of development, in large part reflecting the changing mineral demands of skeletal growth, and representing characteristic features of the calcium homoeostatic system during childhood years. As a consequence, this system must be adaptable to the wide-ranging mineral demands occurring throughout the life cycle. Furthermore, the numerous factors involved in calcium homoeostasis allow for compensatory mechanisms to limit the severity of disease when an isolated insult occurs to the system. Indeed, many heritable disorders of mineral homoeostasis become evident in early childhood and are best recognized when viewed in the light of mineral requirements during infancy and childhood. As understanding of the relevant physiology is central to formulating approaches to management of such problems, we review these disorders in the context of physiology specific to childhood to provide the basis for understanding hypocalcaemia and hypercalcaemia in this age group.
Osteoporosis
Authors: Eastell Richard
Published: July 2011

Osteoporosis affects an estimated 75 million people in Europe, the USA, and Japan combined (1). It is a preventable and a treatable condition, yet many patients with fractures remain unrecognized and untreated.
Thyroid disorders and bone disease
Authors: Cheung Moira S. , Gogakos Apostolos I. , Bassett J.H. Duncan , Williams Graham R.
Published: July 2011

Osteoporosis is defined as a bone mineral density (BMD) of 2.5 or more standard deviations below that of a young adult (T score ≤ −2.5). It is characterized by reduced bone mass, low BMD, deterioration of bone microarchitecture, and an increased susceptibility to fragility fracture. The prevalence of postmenopausal osteoporosis increases with age from 6% at 50 years of age to over 50% at age 80 and the lifetime incidence of fracture for a 50 year old in the UK is 40% for women and 13% for men. Osteoporosis is a worldwide public health burden that costs an estimated £1.7 billion in the UK, $15 billion in the USA, and £32 billion in Europe per annum (see Chapter 4.7).
Paget’s disease of bone
Authors: Papapoulos Socrates E.
Published: July 2011

In 1876, Sir James Paget presented to the Royal Medical and Chirurgical Society of London an account of his experience with a previously unrecognized disease of the skeleton, which he termed osteitis deformans and has since born his name. Paget’s disease of bone is a focal skeletal disorder which progresses slowly and leads to changes in the shape and size of affected bones and to skeletal, articular, and vascular complications. In some parts of the world it is the second most common bone disorder after osteoporosis. The disease is easily diagnosed and effectively treated but its pathogenesis is largely unknown (1–3).
Glucocorticoid-induced osteoporosis
Authors: Mazziotti Gherardo , Giustina Andrea , Canalis Ernesto , Bilezikian John P.
Published: July 2011

Synthetic glucocorticoids are used in a wide variety of disorders including autoimmune, pulmonary, and gastrointestinal diseases, as well as in patients following organ transplantation and with malignancies. Although the indications for glucocorticoids in these various conditions are clear, their use is fraught with a host of potential side effects. In particular, glucocorticoids are detrimental to bone and glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis (1). Despite the fact that glucocorticoids can cause bone loss and fractures, many patients receiving or initiating long-term glucocorticoid therapy are not evaluated for their skeletal health. Furthermore, patients often do not receive specific preventive or therapeutic agents when indicated. New knowledge of the pathophysiological mechanisms underlying GIO has been accompanied by the availability of effective strategies to prevent and treat GIO (1).