bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of space charge wave on quasilinear theory of the free-electron laser saturation
Authors: Chakhmachi A. , Maraghechi B.
Published: July 2009

A quasilinear theory is presented that describes the self-consistent evolution of the electron beam distribution function and fields in a free-electron laser when the space charge wave is present. In the Raman regime, a high-density electron beam has an appreciable space charge potential. A broad spectrum of waves is assumed in order to have a relatively wide range of resonant particles. A one-dimensional helical magnetic field is considered and the analysis is based on the Vlasov–Maxwell equations. Two coupled differential equations are derived, which, in conjunction with conservation laws, describe the quasilinear development by the diffusion of electrons in the momentum space. This leads to the saturation of the free-electron laser instability by the plateau formation. Analytical expressions for the growth rate and for the diffusion coefficient are derived, which reduced to those in the Compton regime under appropriate conditions. By use of the linear growth rate and diffusion coefficient, an analytical expression for efficiency in Raman regime was derived. A numerical analysis is conducted to study the effects of the spectral width of radiation and the thermal spread of the electron beam on the efficiency.
The human Dcn1-like protein DCNL3 promotes Cul3 neddylation at membranes
Authors: Meyer-Schaller Nathalie , Chou Yang-Chieh , Sumara Izabela , Martin Dale D. O. , Kurz Thimo , Katheder Nadja , Hofmann Kay , Berthiaume Luc G. , Sicheri Frank , Peter Matthias
Published: July 2009

Cullin (Cul)-based E3 ubiquitin ligases are activated through the attachment of Nedd8 to the Cul protein. In yeast, Dcn1 (defective in Cul neddylation 1 protein) functions as a scaffold-like Nedd8 E3-ligase by interacting with its Cul substrates and the Nedd8 E2 Ubc12. Human cells express 5 Dcn1-like (DCNL) proteins each containing a C-terminal potentiating neddylation domain but distinct amino-terminal extensions. Although the UBA-containing DCNL1 and DCNL2 are likely functional homologues of yeast Dcn1, DCNL3 also interacts with human Culs and is able to complement the neddylation defect of yeast
dcn1
Δ cells. DCNL3 down-regulation by RNAi decreases Cul neddylation, and overexpression of a Cul3 mutant deficient in DCNL3 binding interferes with Cul3 function in vivo. Interestingly, DCNL3 accumulates at the plasma membrane through a conserved, lipid-modified motif at the N terminus. Membrane-bound DCNL3 is able to recruit Cul3 to membranes and is functionally important for Cul3 neddylation in vivo. We conclude that DCNL proteins function as nonredundant Cul Nedd8-E3 ligases. Moreover, the diversification of the N termini in mammalian Dcn1 homologues may contribute to substrate specificity by regulating their subcellular localization.
Extinction risks of Amazonian plant species
Authors: Feeley Kenneth J. , Silman Miles R.
Published: July 2009

Estimates of the number, and preferably the identity, of species that will be threatened by land-use change and habitat loss are an invaluable tool for setting conservation priorities. Here, we use collections data and ecoregion maps to generate spatially explicit distributions for more than 40,000 vascular plant species from the Amazon basin (representing more than 80% of the estimated Amazonian plant diversity). Using the distribution maps, we then estimate the rates of habitat loss and associated extinction probabilities due to land-use changes as modeled under 2 disturbance scenarios. We predict that by 2050, human land-use practices will have reduced the habitat available to Amazonian plant species by ≈12–24%, resulting in 5–9% of species becoming “committed to extinction,” significantly fewer than other recent estimates. Contrary to previous studies, we find that the primary determinant of habitat loss and extinction risk is not the size of a species' range, but rather its location. The resulting extinction risk estimates are a valuable conservation tool because they indicate not only the total percentage of Amazonian plant species threatened with extinction but also the degree to which individual species and habitats will be affected by current and future land-use changes.
Scaling laws of human interaction activity
Authors: Rybski Diego , Buldyrev Sergey V. , Havlin Shlomo , Liljeros Fredrik , Makse Hernán A.
Published: July 2009

Even though people in our contemporary technological society are depending on communication, our understanding of the underlying laws of human communicational behavior continues to be poorly understood. Here we investigate the communication patterns in 2 social Internet communities in search of statistical laws in human interaction activity. This research reveals that human communication networks dynamically follow scaling laws that may also explain the observed trends in economic growth. Specifically, we identify a generalized version of Gibrat's law of social activity expressed as a scaling law between the fluctuations in the number of messages sent by members and their level of activity. Gibrat's law has been essential in understanding economic growth patterns, yet without an underlying general principle for its origin. We attribute this scaling law to long-term correlation patterns in human activity, which surprisingly span from days to the entire period of the available data of more than 1 year. Further, we provide a mathematical framework that relates the generalized version of Gibrat's law to the long-term correlated dynamics, which suggests that the same underlying mechanism could be the source of Gibrat's law in economics, ranging from large firms, research and development expenditures, gross domestic product of countries, to city population growth. These findings are also of importance for designing communication networks and for the understanding of the dynamics of social systems in which communication plays a role, such as economic markets and political systems.
Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling
Authors: Miller Gregory E. , Chen Edith , Fok Alexandra K. , Walker Hope , Lim Alvin , Nicholls Erin F. , Cole Steve , Kobor Michael S.
Published: July 2009

Children reared in unfavorable socioeconomic circumstances show increased susceptibility to the chronic diseases of aging when they reach the fifth and sixth decades of life. One mechanistic hypothesis for this phenomenon suggests that social adversity in early life programs biological systems in a manner that persists across decades and thereby accentuates vulnerability to disease. Here we examine the basic tenets of this hypothesis by performing genome-wide transcriptional profiling in healthy adults who were either low or high in socioeconomic status (SES) in early life. Among subjects with low early-life SES, there was significant up-regulation of genes bearing response elements for the CREB/ATF family of transcription factors that conveys adrenergic signals to leukocytes, and significant down-regulation of genes with response elements for the glucocorticoid receptor, which regulates the secretion of cortisol and transduces its antiinflammatory actions in the immune system. Subjects from low-SES backgrounds also showed increased output of cortisol in daily life, heightened expression of transcripts bearing response elements for NF-κB, and greater stimulated production of the proinflammatory cytokine interleukin 6. These disparities were independent of subjects' current SES, lifestyle practices, and perceived stress. Collectively, these data suggest that low early-life SES programs a defensive phenotype characterized by resistance to glucocorticoid signaling, which in turn facilitates exaggerated adrenocortical and inflammatory responses. Although these response patterns could serve adaptive functions during acute threats to well-being, over the long term they might exact an allostatic toll on the body that ultimately contributes to the chronic diseases of aging.
Intergenerational resource transfers with random offspring numbers
Authors: Arrow Kenneth J. , Levin Simon A.
Published: July 2009

A problem common to biology and economics is the transfer of resources from parents to children. We consider the issue under the assumption that the number of offspring is unknown and can be represented as a random variable. There are 3 basic assumptions. The first assumption is that a given body of resources can be divided into consumption (yielding satisfaction) and transfer to children. The second assumption is that the parents' welfare includes a concern for the welfare of their children; this is recursive in the sense that the children's welfares include concern for their children and so forth. However, the welfare of a child from a given consumption is counted somewhat differently (generally less) than that of the parent (the welfare of a child is “discounted”). The third assumption is that resources transferred may grow (or decline). In economic language, investment, including that in education or nutrition, is productive. Under suitable restrictions, precise formulas for the resulting allocation of resources are found, demonstrating that, depending on the shape of the utility curve, uncertainty regarding the number of offspring may or may not favor increased consumption. The results imply that wealth (stock of resources) will ultimately have a log-normal distribution.
The Ponzano–Regge model
Authors: Barrett John W , Naish-Guzman Ileana
Published: July 2009

The definition of the Ponzano–Regge state-sum model of three-dimensional quantum gravity with a class of local observables is developed. The main definition of the Ponzano–Regge model in this paper is determined by its reformulation in terms of group variables. The regularization is defined and a proof is given that the partition function is well defined only when a certain cohomological criterion is satisfied. In that case, the partition function may be expressed in terms of a topological invariant, the Reidemeister torsion. This proves the independence of the definition on the triangulation of the 3-manifold and on those arbitrary choices made in the regularization. A further corollary is that when the observable is a knot, the partition function (when it exists) can be written in terms of the Alexander polynomial of the knot. Various examples of observables in S
3 are computed explicitly. Alternative regularizations of the Ponzano–Regge model by the simple cut-off procedure and by the limit of the Turaev–Viro model are discussed, giving successes and limitations of these approaches.
Identification of a Distal GLUT4 Trafficking Event Controlled by Actin Polymerization
Authors: Lopez Jamie A. , Burchfield James G. , Blair Duncan H. , Mele Katarina , Ng Yvonne , Vallotton Pascal , James David E. , Hughes William E.
Published: July 2009

The insulin-stimulated trafficking of GLUT4 to the plasma membrane in muscle and fat tissue constitutes a central process in blood glucose homeostasis. The tethering, docking, and fusion of GLUT4 vesicles with the plasma membrane (PM) represent the most distal steps in this pathway and have been recently shown to be key targets of insulin action. However, it remains unclear how insulin influences these processes to promote the insertion of the glucose transporter into the PM. In this study we have identified a previously uncharacterized role for cortical actin in the distal trafficking of GLUT4. Using high-frequency total internal reflection fluorescence microscopy (TIRFM) imaging, we show that insulin increases actin polymerization near the PM and that disruption of this process inhibited GLUT4 exocytosis. Using TIRFM in combination with probes that could distinguish between vesicle transport and fusion, we found that defective actin remodeling was accompanied by normal insulin-regulated accumulation of GLUT4 vesicles close to the PM, but the final exocytotic fusion step was impaired. These data clearly resolve multiple steps of the final stages of GLUT4 trafficking, demonstrating a crucial role for actin in the final stage of this process.
ADAN: a database for prediction of protein–protein interaction of modular domains mediated by linear motifs
Authors: Encinar J. A. , Fernandez-Ballester G. , Sánchez I. E. , Hurtado-Gomez E. , Stricher F. , Beltrao P. , Serrano L.
Published: July 2009

Motivation: Most of the structures and functions of proteome globular domains are yet unknown. We can use high-resolution structures from different modular domains in combination with automatic protein design algorithms to predict genome-wide potential interactions of a protein. ADAN database and related web tools are online resources for the predictive analysis of ligand–domain complexes. ADAN database is a collection of different modular protein domains (SH2, SH3, PDZ, WW, etc.). It contains 3505 entries with extensive structural and functional information available, manually integrated, curated and annotated with cross-references to other databases, biochemical and thermodynamical data, simplified coordinate files, sequence files and alignments. Prediadan, a subset of ADAN database, offers position-specific scoring matrices for protein–protein interactions, calculated by FoldX, and predictions of optimum ligands and putative binding partners. Users can also scan a query sequence against selected matrices, or improve a ligand–domain interaction.

Availability: ADAN is accessible at http://adan-embl.ibmc.umh.es/ or http://adan.crg.es/.

Contact:  gregorio@umh.es
Normalization of peak intensities in bottom-up MS-based proteomics using singular value decomposition
Authors: Karpievitch Yuliya V. , Taverner Thomas , Adkins Joshua N. , Callister Stephen J. , Anderson Gordon A. , Smith Richard D. , Dabney Alan R.
Published: July 2009

Motivation: LC-MS allows for the identification and quantification of proteins from biological samples. As with any high-throughput technology, systematic biases are often observed in LC-MS data, making normalization an important preprocessing step. Normalization models need to be flexible enough to capture biases of arbitrary complexity, while avoiding overfitting that would invalidate downstream statistical inference. Careful normalization of MS peak intensities would enable greater accuracy and precision in quantitative comparisons of protein abundance levels.

Results: We propose an algorithm, called EigenMS, that uses singular value decomposition to capture and remove biases from LC-MS peak intensity measurements. EigenMS is an adaptation of the surrogate variable analysis (SVA) algorithm of Leek and Storey, with the adaptations including (i) the handling of the widespread missing measurements that are typical in LC-MS, and (ii) a novel approach to preventing overfitting that facilitates the incorporation of EigenMS into an existing proteomics analysis pipeline. EigenMS is demonstrated using both large-scale calibration measurements and simulations to perform well relative to existing alternatives.

Availability: The software has been made available in the open source proteomics platform DAnTE (Polpitiya et al., 2008)) (http://omics.pnl.gov/software/), as well as in standalone software available at SourceForge (http://sourceforge.net).

Contact:  yuliya@stat.tamu.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
A multi-dimensional evidence-based candidate gene prioritization approach for complex diseases–schizophrenia as a case
Authors: Sun Jingchun , Jia Peilin , Fanous Ayman H. , Webb Bradley T. , van den Oord Edwin J.C.G. , Chen Xiangning , Bukszar Jozsef , Kendler Kenneth S. , Zhao Zhongming
Published: July 2009

Motivation: During the past decade, we have seen an exponential growth of vast amounts of genetic data generated for complex disease studies. Currently, across a variety of complex biological problems, there is a strong trend towards the integration of data from multiple sources. So far, candidate gene prioritization approaches have been designed for specific purposes, by utilizing only some of the available sources of genetic studies, or by using a simple weight scheme. Specifically to psychiatric disorders, there has been no prioritization approach that fully utilizes all major sources of experimental data.

Results: Here we present a multi-dimensional evidence-based candidate gene prioritization approach for complex diseases and demonstrate it in schizophrenia. In this approach, we first collect and curate genetic studies for schizophrenia from four major categories: association studies, linkage analyses, gene expression and literature search. Genes in these data sets are initially scored by category-specific scoring methods. Then, an optimal weight matrix is searched by a two-step procedure (core genes and unbiased P-values in independent genome-wide association studies). Finally, genes are prioritized by their combined scores using the optimal weight matrix. Our evaluation suggests this approach generates prioritized candidate genes that are promising for further analysis or replication. The approach can be applied to other complex diseases.

Availability: The collected data, prioritized candidate genes, and gene prioritization tools are freely available at http://bioinfo.mc.vanderbilt.edu/SZGR/.

Contact:  zhongming.zhao@vanderbilt.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A
Authors: Yashiro-Ohtani Yumi , He Yiping , Ohtani Takuya , Jones Mary E. , Shestova Olga , Xu Lanwei , Fang Terry C. , Chiang Mark Y. , Intlekofer Andrew M. , Blacklow Stephen C. , Zhuang Yuan , Pear Warren S.
Published: July 2009

Precise control of the timing and magnitude of Notch signaling is essential for the normal development of many tissues, but the feedback loops that regulate Notch are poorly understood. Developing T cells provide an excellent context to address this issue. Notch1 signals initiate T-cell development and increase in intensity during maturation of early T-cell progenitors (ETP) to the DN3 stage. As DN3 cells undergo β-selection, during which cells expressing functionally rearranged TCRβ proliferate and differentiate into CD4+CD8+progeny, Notch1 signaling is abruptly down-regulated. In this report, we investigate the mechanisms that control Notch1 expression during thymopoiesis. We show that Notch1 and E2A directly regulateNotch1transcription in pre-β-selected thymocytes. Following successful β-selection, pre-TCR signaling rapidly inhibitsNotch1transcription via signals that up-regulate Id3, an E2A inhibitor. Consistent with a regulatory role for Id3 inNotch1down-regulation, post-β-selected Id3-deficient thymocytes maintainNotch1transcription, whereas enforced Id3 expression decreasesNotch1expression and abrogates Notch1-dependent T-cell survival. These data provide new insights intoNotch1regulation in T-cell progenitors and reveal a direct link between pre-TCR signaling andNotch1expression during thymocyte development. Our findings also suggest new strategies for inhibiting Notch1 signaling in pathologic conditions.
Regulation of transgenes in three-dimensional cultures of primary mouse mammary cells demonstrates oncogene dependence and identifies cells that survive deinduction
Authors: Jechlinger Martin , Podsypanina Katrina , Varmus Harold
Published: July 2009

The advent of targeted therapies for cancer has provoked interest in experimental models for the systematic study of oncogene dependence. To that end, we developed a three-dimensional (3D) culture system to analyze the responses of primary mouse mammary epithelial cells to the induction and deinduction of oncogenes. Mammary cells derived from normal virgin mice, or from tritransgenic mice (TetO-MYC;TetO-KrasG12D;MMTV-rtTA) in which MYC and mutant Kras can be regulated by doxycycline, develop from single cells into polarized acini. Lumen formation occurs without apparent apoptosis, and the hollow spheres of cells enlarge by division, with metaphase plates oriented perpendicularly to the apical surface. When MYC and KrasG12D are induced, the acini enlarge and form solid, depolarized spheres. Upon deinduction of MYC and KrasG12D the solid structures regress, leaving a repolarized monolayer of viable cells. These cells display a phenotype consistent with progenitors of mammary epithelium: They exclude Hoechst dye 33342, and reform acini in 3D cultures and repopulate mammary fat pads more efficiently than cells harvested from uninduced acini. Moreover, cells in the surviving spheres retain the ability to respond to reinduction and thus may represent the type of cells that give rise to recurrent tumors.
The protein phosphatase 2A functions in the spindle position checkpoint by regulating the checkpoint kinase Kin4
Authors: Chan Leon Y. , Amon Angelika
Published: July 2009

In budding yeast, a surveillance mechanism known as the spindle position checkpoint (SPOC) ensures accurate genome partitioning. In the event of spindle misposition, the checkpoint delays exit from mitosis by restraining the activity of the mitotic exit network (MEN). To date, the only component of the checkpoint to be identified is the protein kinase Kin4. Furthermore, how the kinase is regulated by spindle position is not known. Here, we identify the protein phosphatase 2A (PP2A) in complex with the regulatory subunit Rts1 as a component of the SPOC. Loss of PP2A-Rts1 function abrogates the SPOC but not other mitotic checkpoints. We further show that the protein phosphatase functions upstream of Kin4, regulating the kinase's phosphorylation and localization during an unperturbed cell cycle and during SPOC activation, thus defining the phosphatase as a key regulator of SPOC function.
Paracrine signaling in a bacterium
Authors: López Daniel , Vlamakis Hera , Losick Richard , Kolter Roberto
Published: July 2009

Cellular differentiation is triggered by extracellular signals that cause target cells to adopt a particular fate. Differentiation in bacteria typically involves autocrine signaling in which all cells in the population produce and respond to the same signal. Here we present evidence for paracrine signaling in bacterial populations—some cells produce a signal to which only certain target cells respond. Biofilm formation in Bacillus involves two centrally important signaling molecules, ComX and surfactin. ComX triggers the production of surfactin. In turn, surfactin causes a subpopulation of cells to produce an extracellular matrix. Cells that produced surfactin were themselves unable to respond to it. Likewise, once surfactin-responsive cells commenced matrix production, they no longer responded to ComX and could not become surfactin producers. Insensitivity to ComX was the consequence of the extracellular matrix as mutant cells unable to make matrix responded to both ComX and surfactin. Our results demonstrate that extracellular signaling was unidirectional, with one subpopulation producing a signal and a different subpopulation responding to it. Paracrine signaling in a bacterial population ensures the maintenance, over generations, of particular cell types even in the presence of molecules that would otherwise cause those cells to differentiate into other cell types.
Interpreting spatial information and regulating mitosis in response to spindle orientation: Figure 1.
Authors: Burke Daniel J.
Published: July 2009

The spindle position checkpoint (SPOC) is a regulatory mechanism that ensures accurate segregation of chromosomes in polarized cells during mitosis. In this issue of Genes & Development, Chan and Amon (pp. 1639–1649) identify a phosphoprotein phosphatase (Rts1-PP2A) as a new member of the checkpoint in budding yeast and define its role in interpreting spatial information during mitosis.
Identification of deleterious mutations within three human genomes
Authors: Chun Sung , Fay Justin C.
Published: July 2009

Each human carries a large number of deleterious mutations. Together, these mutations make a significant contribution to human disease. Identification of deleterious mutations within individual genome sequences could substantially impact an individual's health through personalized prevention and treatment of disease. Yet, distinguishing deleterious mutations from the massive number of nonfunctional variants that occur within a single genome is a considerable challenge. Using a comparative genomics data set of 32 vertebrate species we show that a likelihood ratio test (LRT) can accurately identify a subset of deleterious mutations that disrupt highly conserved amino acids within protein-coding sequences, which are likely to be unconditionally deleterious. The LRT is also able to identify known human disease alleles and performs as well as two commonly used heuristic methods, SIFT and PolyPhen. Application of the LRT to three human genomes reveals 796–837 deleterious mutations per individual, ∼40% of which are estimated to be at <5% allele frequency. However, the overlap between predictions made by the LRT, SIFT, and PolyPhen, is low; 76% of predictions are unique to one of the three methods, and only 5% of predictions are shared across all three methods. Our results indicate that only a small subset of deleterious mutations can be reliably identified, but that this subset provides the raw material for personalized medicine.
Sieve Element Ca2+ Channels as Relay Stations between Remote Stimuli and Sieve Tube Occlusion inVicia faba
Authors: Furch Alexandra C.U. , van Bel Aart J.E. , Fricker Mark D. , Felle Hubert H. , Fuchs Maike , Hafke Jens B.
Published: July 2009

Damage induces remote occlusion of sieve tubes in Vicia faba by forisome dispersion, triggered during the passage of an electropotential wave (EPW). This study addresses the role of Ca2+ channels and cytosolic Ca2+ elevation as a link between EPWs and forisome dispersion. Ca2+ channel antagonists affect the initial phase of the EPW as well as the prolonged plateau phase. Resting levels of sieve tube Ca2+ of ∼50 nM were independently estimated using Ca2+-selective electrodes and a Ca2+-sensitive dye. Transient changes in cytosolic Ca2+ were observed in phloem tissue in response to remote stimuli and showed profiles similar to those of EPWs. The measured elevation of Ca2+ in sieve tubes was below the threshold necessary for forisome dispersion. Therefore, forisomes need to be associated with Ca2+ release sites. We found an association between forisomes and endoplasmic reticulum (ER) at sieve plates and pore-plasmodesma units where high-affinity binding of a fluorescent Ca2+ channel blocker mapped an increased density of Ca2+ channels. In conclusion, propagation of EPWs in response to remote stimuli is linked to forisome dispersion through transiently high levels of parietal Ca2+, release of which depends on both plasma membrane and ER Ca2+ channels.
Arabidopsis tRNA Adenosine Deaminase Arginine Edits the Wobble Nucleotide of Chloroplast tRNAArg(ACG) and Is Essential for Efficient Chloroplast Translation
Authors: Delannoy Etienne , Le Ret Monique , Faivre-Nitschke Emmanuelle , Estavillo Gonzalo M. , Bergdoll Marc , Taylor Nicolas L. , Pogson Barry J. , Small Ian , Imbault Patrice , Gualberto José M.
Published: July 2009

RNA editing changes the coding/decoding information relayed by transcripts via nucleotide insertion, deletion, or conversion. Editing of tRNA anticodons by deamination of adenine to inosine is used both by eukaryotes and prokaryotes to expand the decoding capacity of individual tRNAs. This limits the number of tRNA species required for codon-anticodon recognition. We have identified the Arabidopsis thaliana gene that codes for tRNA adenosine deaminase arginine (TADA), a chloroplast tRNA editing protein specifically required for deamination of chloroplast (cp)-tRNAArg(ACG) to cp-tRNAArg(ICG). Land plant TADAs have a C-terminal domain similar in sequence and predicted structure to prokaryotic tRNA deaminases and also have very long N-terminal extensions of unknown origin and function. Biochemical and mutant complementation studies showed that the C-terminal domain is sufficient for cognate tRNA deamination both in vitro and in planta. Disruption of TADA has profound effects on chloroplast translation efficiency, leading to reduced yields of chloroplast-encoded proteins and impaired photosynthetic function. By contrast, chloroplast transcripts accumulate to levels significantly above those of wild-type plants. Nevertheless, absence of cp-tRNAArg(ICG) is compatible with plant survival, implying that two out of three CGN codon recognition occurs in chloroplasts, though this mechanism is less efficient than wobble pairing.
Atomic pair distribution function analysis from the ARCS chopper spectrometer at the Spallation Neutron Source
Authors: Božin E. S. , Juhás P. , Zhou W. , Stone M. B. , Abernathy D. L. , Huq A. , Billinge S. J. L.
Published: July 2009

Neutron powder-diffraction-based atomic pair distribution functions (PDFs) are reported from the new wide-angular-range chopper spectrometer ARCS at the Spallation Neutron Source at Oak Ridge National Laboratory. The spectrometer was run in white-beam mode with no Fermi chopper. The PDF patterns of Ni and Al2O3were refined using the PDFfit method and the results compared with data collected at the NPDF diffractometer at Los Alamos National Laboratory. The resulting fits are of high quality, demonstrating that quantitatively reliable powder diffraction data can be obtained from ARCS when operated in this configuration.
Mycobacterial antigen-induced T helper type 1 (Th1) and Th2 reactivity of peripheral blood mononuclear cells from diabetic and non-diabetic tuberculosis patients andMycobacterium bovisbacilli Calmette–Guérin (BCG)-vaccinated healthy subjects
Authors: Al-Attiyah R J , Mustafa A S
Published: July 2009

Patients with diabetes mellitus are more susceptible to tuberculosis (TB), and the clinical conditions of diabetic TB patients deteriorate faster than non-diabetic TB patients, but the immunological basis for this phenomenon is not understood clearly. Given the role of cell-mediated immunity (CMI) in providing protection against TB, we investigated whether CMI responses in diabetic TB patients are compromised. Peripheral blood mononuclear cells (PBMC) obtained from diabetic TB patients, non-diabetic TB patients and Mycobacterium bovis bacilli Calmette–Guérin (BCG)-vaccinated healthy subjects were cultured in the presence of complex mycobacterial antigens and pools of M. tuberculosis regions of difference (RD)1, RD4, RD6 and RD10 peptides. The PBMC were assessed for antigen-induced cell proliferation and secretion of T helper 1 (Th1) [interferon (IFN)-γ, interleukin (IL)-2, tumour necrosis factor (TNF)-β], and Th2 (IL-4, IL-5, IL-10) cytokines as CMI parameters. All the complex mycobacterial antigens and RD1pool stimulated strong proliferation of PBMC of all groups, except moderate responses to RD1pool in healthy subjects. In response to complex mycobacterial antigens, both IFN-γ and TNF-β were secreted by PBMC of all groups whereas diabetic TB patients secreted IL-10 with concentrations higher than the other two groups. Furthermore, in response to RD peptides, IFN-γ and IL-10 were secreted by PBMC of diabetic TB patients only. The analyses of data in relation to relative cytokine concentrations showed that diabetic TB patients had lower Th1 : Th2 cytokines ratios, and a higher Th2 bias. The results demonstrate a shift towards Th2 bias in diabetic TB patients which may explain, at least in part, a faster deterioration in their clinical conditions.
Vitamin D and respiratory health
Authors: Hughes D A , Norton R
Published: July 2009

Vitamin D is now known to be of physiological importance outside of bone health and calcium homeostasis, and there is mounting evidence that it plays a beneficial role in the prevention and/or treatment of a wide range of diseases. In this brief review the known effects of vitamin D on immune function are described in relation to respiratory health. Vitamin D appears capable of inhibiting pulmonary inflammatory responses while enhancing innate defence mechanisms against respiratory pathogens. Population-based studies showing an association between circulating vitamin D levels and lung function provide strong justification for randomized controlled clinical trials of vitamin D supplementation in patients with respiratory diseases to assess both efficacy and optimal dosage.
Neutralization of interleukin‐1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice
Authors: Clausen Fredrik , Hånell Anders , Björk Maria , Hillered Lars , Mir Anis K. , Gram Hermann , Marklund Niklas
Published: July 2009

Interleukin‐1β (IL‐1β) may play a central role in the inflammatory response following traumatic brain injury (TBI). We subjected 91 mice to controlled cortical impact (CCI) brain injury or sham injury. Beginning 5 min post‐injury, the IL‐1β neutralizing antibody IgG2a/k (1.5 μg/mL) or control antibody was infused at a rate of 0.25 μL/h into the contralateral ventricle for up to 14 days using osmotic minipumps. Neutrophil and T‐cell infiltration and microglial activation was evaluated at days 1–7 post‐injury. Cognition was assessed using Morris water maze, and motor function using rotarod and cylinder tests. Lesion volume and hemispheric tissue loss were evaluated at 18 days post‐injury. Using this treatment strategy, cortical and hippocampal tissue levels of IgG2a/k reached 50 ng/mL, sufficient to effectively inhibit IL‐1βin vitro. IL‐1β neutralization attenuated the CCI‐induced cortical and hippocampal microglial activation (P < 0.05 at post‐injury days 3 and 7), and cortical infiltration of neutrophils (P < 0.05 at post‐injury day 7). There was only a minimal cortical infiltration of activated T‐cells, attenuated by IL‐1β neutralization (P < 0.05 at post‐injury day 7). CCI induced a significant deficit in neurological motor and cognitive function, and caused a loss of hemispheric tissue (P < 0.05). In brain‐injured animals, IL‐1β neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits (P < 0.05) without influencing neurological motor function. Our results indicate that IL‐1β is a central component in the post‐injury inflammatory response that, in view of the observed positive neuroprotective and cognitive effects, may be a suitable pharmacological target for the treatment of TBI.
Choice strategies in Drosophila are based on competition between olfactory memories
Authors: Yin Yan , Chen Nannan , Zhang Shixing , Guo Aike
Published: July 2009

The brain mechanisms by which animals deal with multiple experiences to predict outcomes are not yet fully understood. We explored the choice strategies that flies use to assess degrees of disadvantage, as well as how flies weigh past and recent experiences to guide decisions. Drosophila were exposed to two conditioning events in a T‐maze: an odor paired with an electric shock followed by a second odor paired with an electric shock of a different intensity. Subsequently, flies were forced to choose between the two odors. We found that flies chose to avoid the more ‘dangerous’ odor by a linear subtraction mechanism that was based on two coexisting memories. We also found that flies weighed experiences of the same danger level (60 V electric shocks) according to the times when the experiences had occurred. More recent experiences had a greater impact and past experiences gradually became ‘overlooked’ during decisions as the time delay between the two events lengthened. However, the past memory was not so much disrupted as it was overshadowed by recent memories during decisions. Finally, when a past experience was more disadvantageous, wild‐type flies were able to coordinate both the temporal factor and the degree of disadvantage into their decisions. By contrast, amnesiac mutant flies made choices completely according to the temporal factor, ignoring the degree of disadvantage. Taken together, wild‐type flies are able to store multiple olfactory memories and can coherently evaluate learned experiences to guide their decisions according to the degree of disadvantage and/or the temporal factor.
l‐Glutamine‐induced apoptosis in microglia is mediated by mitochondrial dysfunction
Authors: Svoboda Nina , Kerschbaum Hubert H.
Published: July 2009

Under physiological conditions, astrocytes take up l‐glutamate from the synaptic gap, metabolize it to l‐glutamine and return it to neurons, where l‐glutamine is metabolized to l‐glutamate and stored in neurotransmitter vesicles. However, under pathological conditions, such as hepatic failure, l‐glutamine and ammonium are elevated globally in the brain. The Trojan horse hypothesis of l‐glutamine toxicity assumes that intramitochondrial hydrolysis of l‐glutamine enhances ammonium locally and leads to mitochondrial dysfunction. In the present study, we show that exposure of murine primary microglia as well as of the microglial cell‐line BV‐2 to l‐glutamine promotes chromatin condensation and formation of crescent‐like structures in the nucleus. Furthermore, l‐glutamine induced an increase in annexin‐V labelling, cell shrinkage (apoptotic volume decrease), cell fragmentation and formation of apoptotic bodies. Inhibition of the phosphate‐activated glutaminase with 6‐diazo‐5‐oxo‐l‐norleucine suppressed chromatin condensation and annexin‐V labelling in l‐glutamine‐exposed cells. In addition, inhibition of the glutamine synthetase with l‐methionine sulfoximine suppressed chromatin condensation and annexin‐V labelling in ammonium‐exposed cells. l‐Glutamine and ammonium enhanced production of reactive oxygen species, as detected with CM‐H2DCFDA. Apoptosis, induced by l‐glutamine, was inhibited either by the radical scavenger α‐tocopherol or by the nitric oxide synthase blocker N G‐methyl‐l‐arginine. Cyclosporin A, a ligand of the permeability transition pore complex component cyclophilin D, prevented l‐glutamine‐triggered apoptosis. Furthermore, blockade of caspase‐9 activity with Z‐LEHD‐FMK prevented l‐glutamine‐triggered apoptosis. Taken together, our results indicate that hydrolysis of l‐glutamine and, accordingly, accumulation of ammonium in mitochondria induce the intrinsic pathway of apoptosis, characterized by mitochondrial dysfunction and activation of caspase‐9, which activates caspase‐3.
Overexpression of 5‐HT2C receptors in forebrain leads to elevated anxiety and hypoactivity
Authors: Kimura Atsuko , Stevenson Paula L. , Carter Roderick N. , MacColl Gavin , French Karen L. , Paul Simons J. , Al‐Shawi Raya , Kelly Valerie , Chapman Karen E. , Holmes Megan C.
Published: July 2009

The 5‐HT2C receptor has been implicated in mood and eating disorders. In general, it is accepted that 5‐HT2C receptor agonists increase anxiety behaviours and induce hypophagia. However, pharmacological analysis of the roles of these receptors is hampered by the lack of selective ligands and the complex regulation of receptor isoforms and expression levels. Therefore, the exact role of 5‐HT2C receptors in mood disorders remain controversial, some suggesting agonists and others suggesting antagonists may be efficacious antidepressants, while there is general agreement that antagonists are beneficial anxiolytics. In order to test the hypothesis that increased 5‐HT2C receptor expression, and thus increased 5‐HT2C receptor signalling, is causative in mood disorders, we have undertaken a transgenic approach, directly altering the 5‐HT2C receptor number in the forebrain and evaluating the consequences on behaviour. Transgenic mice overexpressing 5‐HT2C receptors under the control of the CaMKIIα promoter (C2CR mice) have elevated 5‐HT2C receptor mRNA levels in cerebral cortex and limbic areas (including the hippocampus and amygdala), but normal levels in the hypothalamus, resulting in > 100% increase in the number of 5‐HT2C ligand binding sites in the forebrain. The C2CR mice show increased anxiety‐like behaviour in the elevated plus‐maze, decreased wheel‐running behaviour and reduced activity in a novel environment. These behaviours were observed in the C2CR mice without stimulation by exogenous ligands. Our findings support a role for 5‐HT2C receptor signalling in anxiety disorders. The C2CR mouse model offers a novel and effective approach for studying disorders associated with 5‐HT2C receptors.
Bar pressing for food: differential consequences of lesions to the anterior versus posterior pedunculopontine
Authors: Wilson David I. G. , MacLaren Duncan A. A. , Winn Philip
Published: July 2009

The pedunculopontine tegmental nucleus (PPTg) is in a key position to participate in operant reinforcement via its connections with the corticostriatal architecture and the medial reticular formation. Indeed, previous work has demonstrated that rats bearing lesions of the whole PPTg are impaired when learning to make two bar presses for amphetamine reinforcement. Anterior and posterior portions of the PPTg make different anatomical connections, including preferential projections by the anterior PPTg to substantia nigra pars compacta dopamine neurons and by the posterior PPTg to ventral tegmental area dopamine neurons. We wanted to assess the effects of anterior and posterior PPTg ibotenate lesions on rats learning simple and more complex schedules of natural reinforcement. We trained rats with lesions to the anterior PPTg (n = 11) and the posterior PPTg (n = 5) [and appropriate controls (n = 15)] to bar press for food on a variety of fixed‐ratio and variable‐ratio reinforcement schedules and then during extinction. We found that posterior PPTg‐lesioned rats bar pressed at lower rates, were slower to learn to bar press, and often had deficits characteristic of impaired learning and/or motivation. In contrast, anterior PPTg‐lesioned rats learned to bar press for reinforcement at normal rates. However, they made errors of perseveration and anticipation throughout many schedules, and pressed at a higher rate than controls during extinction, deficits best characterized as reflecting disorganized response control. Together, these data suggest that the anterior PPTg and posterior PPTg (and their related circuits) contribute differently to reinforcement learning, incentive motivation, and response control, processes that are considered to malfunction in drug addiction.
Antidepressant treatment facilitates dopamine release and drug seeking behavior in a genetic animal model of depression
Authors: Roth‐Deri Ilana , Friedman Alexander , Abraham Lital , Lax Elad , Flaumenhaft Yakov , Dikshtein Yahav , Yadid Gal
Published: July 2009

Anhedonia and lack of motivation are core symptoms of depression. In contrast, hyper‐motivation and euphoria characterize intoxicated states. In order to explore the relationship between these two behavioral states we examined cocaine self‐administration tasks in an animal model of depression [Flinders Sensitive Line (FSL) rats]. We found that FSL rats exhibit sub‐sensitivity in their cocaine‐seeking behavior, which was normalized following a chronic treatment with the antidepressant desipramine. However, when the cocaine dosage was increased, FSL rats demonstrated a similar cocaine‐seeking behavior to that of controls. In light of dopamine’s central role in modulating cocaine reinforcement, we examined dopaminergic neurotransmission in the nucleus accumbens, a brain region implicated in the rewarding and hedonic effects of substances of misuse. FSL rats exhibited low but dose‐dependent increases in extracellular levels of dopamine in the nucleus accumbens after acute intravenous cocaine injection. Furthermore, by using the dopamine transporter blocker GBR‐12909 we were able to demonstrate that the low extracellular dopamine levels, observed in FSL rats, were a consequence of low dopamine release in the nucleus accumbens, as opposed to the possibility of increased uptake. Treatment of FSL rats with the antidepressant desipramine raised cocaine‐ and GBR‐12909‐induced dopamine release to the level of controls. This treatment also resulted in increased cocaine‐seeking behavior.
Rescue of abnormal phenotypes in δ2 glutamate receptor‐deficient mice by the extracellular N‐terminal and intracellular C‐terminal domains of the δ2 glutamate receptor
Authors: Torashima Takashi , Iizuka Akira , Horiuchi Hajime , Mitsumura Kazuhiro , Yamasaki Miwako , Koyama Chiho , Takayama Kiyohiko , Iino Masae , Watanabe Masahiko , Hirai Hirozaku
Published: July 2009

The δ2 glutamate receptor (GluRδ2) is expressed predominantly in cerebellar Purkinje cells. GluRδ2 knock‐out mice show impaired synaptogenesis and loss of long‐term depression (LTD) at parallel fiber/Purkinje cell synapses, and persistent multiple climbing fiber (CF) innervation of Purkinje cells, resulting in severe ataxia. To identify domains critical for GluRδ2 function, we produced various GluRδ2 deletion constructs. Using lentiviral vectors, those constructs were expressed in Purkinje cells of GluRδ2‐deficient mice at postnatal day (P) 6 or 7, and rescue of abnormal phenotypes was examined beyond P30. Most constructs failed to rescue the defects of GluRδ2‐deficient mice, mainly because they were not efficiently transferred to the postsynaptic sites. However, a construct carrying only the extracellular N‐terminal domain (NTD) and the intracellular C‐terminal domain (CTD) linked with the fourth transmembrane domain of GluRδ2 (NTD‐TM4‐CTD) caused incomplete, but significant rescue of ataxia, consistent with relatively better transport of the construct to the synapses. Notably, the expression of NTD‐TM4‐CTD in GluRδ2‐deficient Purkinje cells restored abrogated LTD, and aberrant CF territory in the molecular layer. Although the expression of NTD‐TM4‐CTD failed to rescue persistent multiple CF innervation of GluRδ2‐deficient Purkinje cells, a similar construct in which only TM4 was replaced with a transmembrane domain of CD4 successfully rescued the multiple CF innervation, probably due to more efficient transport of the protein to postsynaptic sites. These results suggest that NTD and CTD are critical domains of GluRδ2, which functions substantially without conventional ligand binding and ion channel structures.
Convergent structural responses of tropical forests to diverse disturbance regimes
Authors: Kellner James R. , Asner Gregory P.
Published: July 2009

Size frequency distributions of canopy gaps are a hallmark of forest dynamics. But it remains unknown whether legacies of forest disturbance are influencing vertical size structure of landscapes, or space‐filling in the canopy volume. We used data from LiDAR remote sensing to quantify distributions of canopy height and sizes of 434 501 canopy gaps in five tropical rain forest landscapes in Costa Rica and Hawaii. The sites represented a wide range of variation in structure and natural disturbance history, from canopy gap dynamics in lowland Costa Rica and Hawaii, to stages and types of stand‐level dieback on upland Mauna Kea and Kohala volcanoes. Large differences in vertical canopy structure characterized these five tropical rain forest landscapes, some of which were related to known disturbance events. Although there were quantitative differences in the values of scaling exponents within and among sites, size frequency distributions of canopy gaps followed power laws at all sites and in all canopy height classes. Scaling relationships in gap size at different heights in the canopy were qualitatively similar at all sites, revealing a remarkable similarity despite clearly defined differences in species composition and modes of prevailing disturbance. These findings indicate that power‐law gap‐size frequency distributions are ubiquitous features of these five tropical rain forest landscapes, and suggest that mechanisms of forest disturbance may be secondary to other processes in determining vertical and horizontal size structure in canopies.