bluuebunny/crossref_metadata_2025 huggingface dataset:
A Transcultural Strengths Assessment Interview Guide for Parent Caregivers
Authors: Haley Janice M.
Published: August 2008

The Haley Transcultural Strengths Assessment interview guide for parent caregivers is an instrument for nurses and related health care providers to identify, better understand, and promote the development of strengths of parents for children with ongoing, complex health needs. Assisting these caregivers to build on their strengths, as identified through their own cultural perspective, is crucial not only to promote their health and well-being, but also to the quality of care they deliver to their child. The development of the instrument is discussed. The interview guide and description of how to use it are presented. This is a versatile instrument that may be used across cultures in the home or clinical setting, or in research. It frames the strengths of the parent caregiver, so these strengths can be encouraged and woven into the parent's life, promoting a positive sense of energy, empowerment, and harmony.
Effect of bath temperature on nanocrystalline Ni-polytetrafluoroethylene composite coatings prepared by brush electroplating
Authors: Li W. H. , Zhou X. Y. , Xu Z. , Yan M. J.
Published: August 2008

Brush electroplated Ni-polytetrafluoroethylene (PTFE) composite coatings with uniform distribution of PTFE particles in the nanocrystalline Ni matrix were prepared by changing the bath temperature. The effects of the bath temperature on the deposition, microstructure and tribological properties of the composite coatings were investigated. Experimental results show that the PTFE content in coatings, deposition rate and the tribological properties trend to increase with increasing bath temperature, and the composite coating prepared at the bath temperature of 40°C reaches a maximum in surface morphology. However, it is difficult to successfully prepare the composite coatings when the bath temperature is above 40°C owing to their poor adhesion to the substrate. Therefore, some measures should be taken when the composite coatings are prepared at the bath temperatures above 40°C.
IRF-4 functions as a tumor suppressor in early B-cell development
Authors: Acquaviva Jaime , Chen Xiaoren , Ren Ruibao
Published: August 2008

Interferon regulatory factor-4 (IRF-4) is a hematopoietic cell–restricted transcription factor important for hematopoietic development and immune response regulation. It was also originally identified as the product of a proto-oncogene involved in chromosomal translocations in multiple myeloma. In contrast to its oncogenic function in late stages of B lymphopoiesis, expression of IRF-4 is down-regulated in certain myeloid and early B-lymphoid malignancies. In this study, we found that the IRF-4 protein levels are increased in lymphoblastic cells transformed by the BCR/ABL oncogene in response to BCR/ABL tyrosine kinase inhibitor imatinib. We further found that IRF-4 deficiency enhances BCR/ABL transformation of B-lymphoid progenitors in vitro and accelerates disease progression of BCR/ABL-induced acute B-lymphoblastic leukemia (B-ALL) in mice, whereas forced expression of IRF-4 potently suppresses BCR/ABL transformation of B-lymphoid progenitors in vitro and BCR/ABL-induced B-ALL in vivo. Further analysis showed that IRF-4 inhibits growth of BCR/ABL+ B lymphoblasts primarily through negative regulation of cell-cycle progression. These results demonstrate that IRF-4 functions as tumor suppressor in early B-cell development and may allow elucidation of new molecular pathways significant to the lymphoid leukemogenesis by BCR/ABL. The context dependent roles of IRF-4 in oncogenesis should be an important consideration in developing cancer therapies targeting IRF-4.
European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor
Authors: Marin David , Milojkovic Dragana , Olavarria Eduardo , Khorashad Jamshid S. , de Lavallade Hugues , Reid Alistair G. , Foroni Letizia , Rezvani Katayoun , Bua Marco , Dazzi Francesco , Pavlu Jiri , Klammer Matthias , Kaeda Jaspal S. , Goldman John M. , Apperley Jane F.
Published: August 2008

The majority of patients with chronic myeloid leukemia in chronic phase gain substantial benefit from imatinib but some fail to respond or lose their initial response. In 2006, the European LeukemiaNet published recommendations designed to help identify patients responding poorly to imatinib. Patients were evaluated at 3, 6, 12, and 18 months and some were classified as “failure” or “suboptimal responders.” We analyzed outcomes for 224 patients with chronic myeloid leukemia in chronic phase treated in a single institution to validate these recommendations. Patients were followed for a median of 46.1 months. At each time point, patients classified as “failure” showed significantly worse survival, progression-free survival, and cytogenetic response than other patients; for example, based on the assessment at 12 months, the 5-year survival was 87.1% versus 95.1% (P = .02), progression-free survival 76.% versus 90% (P = .002), and complete cytogenetic response rate 26.7% versus 94.1% (P < .001). Similarly, the criteria for “suboptimal response” at 6 and 12 months identified patients destined to fare badly, although criteria at 18 months were less useful. The predictive value of some other individual criteria varied. In general, the LeukemiaNet criteria have useful predictive value, but a case could now be made for combining the categories “failure” and “suboptimal response.”
Identification of low penetrance alleles for lung cancer: The GEnetic Lung CAncer Predisposition Study (GELCAPS)
Authors: Eisen Tim , Matakidou Athena , Houlston Richard ,   the GELCAPS Consortium
Published: August 2008

Background

Part of the inherited risk to lung cancer is likely to include common, low risk alleles. The identification of this class of susceptibility is contingent on association-based analyses. We established GEnetic Lung CAncer Predisposition Study (GELCAPS) to collect DNA and clinico-pathological data from a large series of cases and a series of spouse/partner controls, thereby generating a key resource for the identification of low risk alleles.

Methods

GELCAPS was one of the first genetic epidemiological trials in the UK to be adopted by the National Cancer Research Network (NCRN) onto its portfolio with the participation of over 100 oncology departments specialising in the management of lung cancer.

Results

Samples from over 5,000 independent lung cancer cases and 2,000 controls have so far been assembled through GELCAPS.

Conclusion

GELCAPS represents one of the largest datasets of its type in the world capable of informing on the contribution of low penetrance alleles to the development of lung cancer and the influence of genetic variation on outcome. In addition our experience in developing the GELCAPS serves to illustrate how large DNA biobanks for genetic analyses can be rapidly generated within the UK using the NCRN.
The Netrin-related domain of Sfrp1 interacts with Wnt ligands and antagonizes their activity in the anterior neural plate
Authors: Lopez-Rios Javier , Esteve Pilar , Ruiz Jose Maria , Bovolenta Paola
Published: August 2008

Background

Secreted frizzled related proteins (SFRPs) are multifunctional modulators of Wnt and BMP (Bone Morphogenetic Protein) signalling necessary for the development of most organs and the homeostasis of different adult tissues. SFRPs fold in two independent domains: the cysteine rich domain (SfrpCRD) related to the extracellular portion of Frizzled (Fz, Wnt receptors) and the Netrin module (SfrpNTR) defined by homologies with molecules such as Netrin-1, inhibitors of metalloproteinases and complement proteins. Due to its structural relationship with Fz, it is believed that SfrpCRD interferes with Wnt signalling by binding and sequestering the ligand. In contrast, the functional relevance of the SfrpNTR has been barely addressed.

Results

Here, we combine biochemical studies, mutational analysis and functional assays in cell culture and medaka-fish embryos to show that the Sfrp1NTR mimics the function of the entire molecule, binds to Wnt8 and antagonizes Wnt canonical signalling. This activity requires intact tertiary structure and is shared by the distantly related Netrin-1NTR. In contrast, the Sfrp1CRD cannot mirror the function of the entire molecule in vivo but interacts with Fz receptors and antagonizes Wnt8-mediated β-catenin transcriptional activity.

Conclusion

On the basis of these results, we propose that SFRP modulation of Wnt signalling may involve multiple and differential interactions among Wnt, Fz and SFRPs.
Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury
Authors: Holt Michael P , Cheng LinLing , Ju Cynthia
Published: August 2008

The role of macrophages in the pathogenesis of acetaminophen (APAP)-induced liver injury remains controversial, as it has been demonstrated that these cells display pro-toxicant and hepato-protective functions. This controversy may stem from the heterogeneity and/or plasticity of macrophages and the difficulty in distinguishing and differentially studying subpopulations of macrophages in the liver. In the present study, using flow cytometric analysis and fluorescence-labeled antibodies against specific cell surface macrophage markers, we were able to, for the first time, identify an APAP-induced macrophage (IM) population distinct from resident Kupffer cells. The data demonstrated that the IMs were derived from circulating monocytes that infiltrated the liver following APAP-induced liver injury. The IMs exhibited a phenotype consistent with that of alternatively activated macrophages and demonstrated the ability to phagocytize apoptotic cells and induce apoptosis of neutrophils. Furthermore, in the absence of the IMs, the resolution of hepatic damage following APAP-induced hepatotoxicity was delayed in CCR2−/− mice compared with wild-type mice. These findings likely contribute to the role of the IMs in the processes of tissue repair, including counteracting inflammation and promoting angiogenesis. The present study also demonstrated the ability of separating populations of macrophages and delineating distinct functions of each group in future studies of inflammatory disease in the liver and other tissues.
Effects of Weight Loss after Bariatric Surgery for Morbid Obesity on Vascular Endothelial Growth Factor-A, Adipocytokines, and Insulin
Authors: García de la Torre Nuria , Rubio Miguel A. , Bordiú Elena , Cabrerizo Lucio , Aparicio Eugenio , Hernández Carmen , Sánchez-Pernaute Andrés , Díez-Valladares Luis , Torres Antonio J. , Puente Montserrat , Charro Aniceto L.
Published: August 2008

Background: Adipocytes regulate blood vessel formation, and in turn endothelial cells promote preadipocyte differentiation through the expression of proangiogenic factors, such as vascular endothelial growth factor (VEGF)-A. Some adipocytokines and hormones also have an effect on vascular development.

Objectives: Our objectives were to analyze the relationship between weight and circulating VEGF-A in morbidly obese subjects before and after bariatric surgery, and investigate the relationship between circulating VEGF-A and certain adipocytokines and hormones regulating adipocytes.

Methods: A total of 45 morbidly obese women and nine lean females were included in the study. Patients underwent bariatric surgery: vertical banded gastroplasty (n = 17), gastric bypass (n = 17), and biliopancreatic diversion (n = 11). Serum samples for VEGF-A, adiponectin, leptin, ghrelin, and insulin were obtained preoperatively and 9–12 months after surgery.

Results: Obese patients showed significantly higher VEGF-A levels than controls (306.3 ± 170.3 vs. 187.6 ± 91.9 pg/ml; P = 0.04), decreasing to 246.1 ± 160.4 after surgery (P < 0.001), with no differences among surgical procedures. In controls there was an inverse correlation between VEGF-A and ghrelin (r = −0.85; P <.01), but not in obese patients. Leptin and insulin concentrations were increased in obese patients, with a significant decrease shown after weight loss with surgery. Conversely, adiponectin concentrations were lower in obese patients, with a significant increase shown after weight loss with surgery. Ghrelin was higher in controls than obese patients, decreasing after gastric bypass and biliopancreatic diversion, but not after vertical banded gastroplasty.

Conclusion: Serum VEGF-A levels are significantly higher in obese patients than in lean controls, decreasing after weight loss with bariatric surgery, behaving similarly to other hormones related to adipose mass like leptin and insulin.
Development of an Adrenocorticotropin-Responsive Human Adrenocortical Carcinoma Cell Line
Authors: Parmar Jeniel , Key Rebecca E. , Rainey William E.
Published: August 2008

Context: The molecular mechanisms regulating adrenal steroidogenesis continue to be defined. The only current human adrenocortical cell line is the NCI-H295 and its substrains. One of the strains, H295R, has retained the ability to respond to angiotensin II (Ang II); however, it lacks ACTH responsiveness. An ACTH-responsive human adrenocortical model would add significantly to studies directed at defining the molecular control of corticosteroid biosynthesis.

Objective: The objective of the study was to develop a human adrenal cell line that retained both Ang II- and ACTH-regulated corticosteroid production.

Design: Human adrenocortical carcinoma (HAC) cells were isolated from an adrenal tumor removed from a girl presenting with virilization and hypertension. Clonal populations of cells were established and characterized. HAC cells were treated with ACTH, Ang II, and forskolin, followed by examination of steroidogenic enzyme mRNA expression using quantitative real-time PCR and steroid production.

Results: HAC clone 15 (HAC15) cells responded to treatment with ACTH, Ang II, and forskolin, with increased cortisol and aldosterone production. ACTH, Ang II, and forskolin also increased expression of mRNA, encoding all enzymes needed for cortisol and aldosterone biosynthesis, namely steroidogenic acute regulatory protein, cholesterol side-chain cleavage, cytochrome P450 17α-hydroxylase-17, 20-lyase, 3β-hydroxysteroid dehydrogenase type II, 21-hydroxylase, 11β-hydroxylase, and 11β-aldosterone synthase. In addition, the cells expressed mRNA for ACTH receptor (MC2R) and Ang II receptor. MC2R protein was also expressed in HAC15 cells.

Conclusion: The current study describes the development and characterization of an ACTH- and Ang II-responsive human adrenal cell line. The HAC15 cell line should provide an important model system for defining the molecular mechanisms regulating aldosterone and cortisol production.
Making bigger brains–the evolution of neural-progenitor-cell division
Authors: Fish Jennifer L. , Dehay Colette , Kennedy Henry , Huttner Wieland B.
Published: August 2008

Relative brain size differs markedly between species. This variation might ultimately result from differences in the cell biology of neural progenitors, which might underlie their different proliferative potential. On the basis of the cell-biological properties of neural progenitors of animals of varying brain size and complexity (namely, Drosophila melanogaster, rodents and primates), we hypothesize that the evolution of four related cell-biological features has contributed to increases in neuron number. Three of these features–the pseudostratification of the progenitor layer, the loss of (Inscuteable-mediated) mitotic-spindle rotation and the evolution of proteins (such as Aspm) that maintain the precision of symmetric progenitor division–affect the mode of cell division in the apically dividing progenitors of the ventricular zone. The fourth feature, however, concerns the evolution of the basally dividing progenitors of the subventricular zone. In rodents, these basal (or intermediate) progenitors lack cell polarity, whereas in primates a subpopulation of radial, presumably polarized, progenitors has evolved (outer-subventricular-zone progenitors). These cells undergo basal mitoses and are thought to retain epithelial characteristics. We propose the epithelial-progenitor hypothesis, which argues that evolutionary changes that promote the maintenance of epithelial features in neural progenitors, including outer-subventricular-zone progenitors, have been instrumental in the expansion of the cerebral cortex in primates.
FFAT rescues VAPA-mediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation
Authors: Prosser Derek C. , Tran Duvinh , Gougeon Pierre-Yves , Verly Carine , Ngsee Johnny K.
Published: August 2008

The VAMP-associated proteins termed VAP are a small gene family of proteins characterised by the presence of an N-terminal major sperm protein (MSP) domain. The P56S mutation of the B isoform (VAPB) has been linked to late-onset amyotrophic lateral sclerosis (ALS8) and its expression causes formation of large ER aggregates. Overexpression of the wild-type A isoform (VAPA) but not the B isoform (VAPB), inhibited ER-to-Golgi transport of membrane proteins. This transport block by VAPA was primarily due to decreased segregation of membrane cargo into ER vesicles. We also found that VAPA inhibited lateral diffusion of membrane proteins, most likely through its stable association with microtubules. The MSP domain of VAP is known to interact with the FFAT motif (two phenylalanines in an acidic tract) of proteins involved in sterol regulation. Overexpression of FFAT restored ER-to-Golgi transport and lateral diffusion of membrane proteins, and resolved the large ER aggregates in VAPB-P56S. Application of a FFAT peptide restored in vitro ER vesicle budding and disrupted VAP-microtubule association. Thus, overexpression of the two VAP isoforms causes retention of ER membrane proteins by impeding lateral diffusion and their incorporation into transport vesicles. This inhibitory effect can be relieved by expression of the FFAT motif.
Cytosolic PLA2α activation in Purkinje neurons and its role in AMPA-receptor trafficking
Authors: Mashimo Masato , Hirabayashi Tetsuya , Murayama Toshihiko , Shimizu Takao
Published: August 2008

Cytosolic phospholipase A2α (cPLA2α) selectively releases arachidonic acid from membrane phospholipids and has been proposed to be involved in the induction of long-term depression (LTD), a form of synaptic plasticity in the cerebellum. This enzyme requires two events for its full activation: Ca2+-dependent translocation from the cytosol to organelle membranes in order to access phospholipids as substrates, and phosphorylation by several kinases. However, the subcellular distribution and activation of cPLA2α in Purkinje cells and the role of arachidonic acid in cerebellar LTD have not been fully elucidated. In cultured Purkinje cells, stimulation of AMPA receptors, but not metabotropic glutamate receptors, triggered translocation of cPLA2α to the somatic and dendritic Golgi compartments. This translocation required Ca2+ influx through P-type Ca2+ channels. AMPA plus PMA, a chemical method for inducing LTD, released arachidonic acid via phosphorylation of cPLA2α. AMPA plus PMA induced a decrease in surface GluR2 for more than 2 hours. Interestingly, this reduction was occluded by a cPLA2α-specific inhibitor. Furthermore, PMA plus arachidonic acid caused the prolonged internalization of GluR2 without activating AMPA receptors. These results suggest that cPLA2α regulates the persistent decrease in the expression of AMPA receptors, underscoring the role of cPLA2α in cerebellar LTD.
Analysing the applicability of eddy current non-destructive technique for testing the wear of ‘steel—steel’ and ‘cast iron—cast iron’ tribological situations
Authors: Gorkunov E S , Kharlamov V V , Kogan L Kh , Zadvorkin S M
Published: August 2008

The results of surface wear investigation of ‘steel—steel’ and ‘cast iron—cast iron’ friction pairs by the eddy current and X-ray diffraction techniques are reported. Information on the behaviour of the properties of the surface layer as it wears can be determined using an eddy current transducer, and this is verified by the X-ray diffraction analysis of the same layer. It has been found that at the stages of steady-state and heavy wear, there is a correlation between the readings of the eddy current instrument and the extent of the linear wear of the tribological contact surface.
High-stress three-body abrasive wear of treated and untreated oil palm fibre-reinforced polyester composites
Authors: Yousif B F , El-Tayeb N S M
Published: August 2008

The aim of this study is to investigate the effect of treated and untreated oil palm fibres on high-stress three-body abrasive wear characteristics of polyester composites. Experimental tests were conducted at different applied loads (5–20 N) and two different rotational speeds (50 and 100 r/min) for 0.18 km sliding distance using a dry sand/steel wheel apparatus. The flow of the sand particles (560–900 μm) was 4.5 g/s. Morphologies of the worn surface of the composites were studied using a scanning electron microscope (SEM). Pull-out test was carried out to evaluate the interfacial adhesion characteristics of treated and untreated fibres. The results revealed that composites based on treated oil palm fibres exhibited better wear performance compared with untreated ones, i.e. the interfacial adhesion of treated fibres to the polyester was better than untreated fibres. Moreover, treated oil palm fibres were found to reduce the porosity of the composite, which in turn stabilized the surface tribo-characteristics. Based on the SEM analysis, the wear mechanisms were predominated by pitting, grooving, microcracking, microcutting, and fracture in the polyester region.
Diverse approaches to the controlled generation of nanotextured surfaces
Authors: Ramsden Jeremy J.
Published: August 2008

Smooth, chemically uniform surfaces are seldom found in nature. Mimicry of natural variegation is a powerful approach for controlling chemical affinity at the nanoscale. Molecular recognition is one of the fundamental concepts underlying the functioning of living cells, and it depends on a particular relationship between the nanoscale, i.e., molecular, variegations of two potentially interacting molecular partners. The primary subject matter of this paper is how to articially generate appropriate nanoscale texture at the surfaces of materials. Excluding "pick and place" chemistry, in which essentially a Maxwellian demon intervenes to place objects with atomic precision, and nowadays achievable through an adaptation of atomic force microscopy, on the grounds that it is too slow to be practicable for fabricating useful quantities of material, three approaches are explored in some detail: (i) "powder", i.e., mixing at least two individually monofunctional (with respect to the ultimate molecular recognition task) precursor components (possibly with secondary functionality enabling them to appropriately self-assemble on a substratum); (ii) mixing polymers with the possibility of phase separation and frustrated phase separation with block copolymers; and (iii) felting. The emphasis is on processes that create more or less irregular structures, rather than regular arrays. The final section deals with the metrology of nanotexture.
Retrometabolic drug design: Principles and recent developments
Authors: Bodor Nicholas , Buchwald Peter
Published: August 2008

Retrometabolic drug design incorporates two major systematic approaches: the design of soft drugs (SDs) and of chemical delivery systems (CDSs). Both aim to design new, safe drugs with an improved therapeutic index by integrating structure-activity and -metabolism relationships; however, they achieve it by different means: whereas SDs are new, active therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their desired therapeutic effect, CDSs are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. General principles and recent developments are briefly reviewed with various illustrative examples from different therapeutic areas with special focus on soft corticosteroids and on brain targeting.
New catalytic transformations of carboxylic acids
Authors: Gooßen Lukas J. , Gooßen Käthe , Rodríguez Nuria , Blanchot Mathieu , Linder Christophe , Zimmermann Bettina
Published: August 2008

A series of metal-catalyzed processes are presented, in which carboxylic acids act as sources of either carbon nucleophiles or electrophiles, depending on the catalyst employed, the mode of activation, and the reaction conditions. A first reaction mode is the addition of carboxylic acids or amides over C-C multiple bonds, giving rise to enol esters or enamides, respectively. The challenge here is to control both the regio- and stereoselectivity of these reactions by the choice of the catalyst system. Alternatively, carboxylic acids can efficiently be decarboxylated using new Cu catalysts to give aryl-metal intermediates. Under protic conditions, these carbon nucleophiles give the corresponding arenes. If carboxylate salts are employed instead of the free acids, the aryl-metal species resulting from the catalytic decarboxylation can be utilized for the synthesis of biaryls in a novel cross-coupling reaction with aryl halides, thus replacing stoichiometric organometallic reagents. An activation with coupling reagents or simple conversion to esters allows the oxidative addition of carboxylic acids to transition-metal catalysts under formation of acyl-metal species, which can either be reduced to aldehydes, or coupled with nucleophiles. At elevated temperatures, such acyl-metal species decarbonylate, so that carboxylic acids become synthetic equivalents for aryl or alkyl halides, e.g., in Heck reactions.
High-temperature gradient HPLC and LC-NMR for the analysis of complex polyolefins
Authors: Pasch Harald , Heinz Lars-Christian , Macko Tibor , Hiller Wolf
Published: August 2008

The synthesis and characterization of polyolefins continues to be one of the most important areas for academic and industrial polymer research. One consequence of the development of new "tailor-made" polyolefins is the need for new and improved analytical techniques for the analysis of polyolefins with respect to molar mass and chemical composition distribution. The present article briefly reviews different new and relevant techniques for polyolefin analysis. Crystallization analysis fractionation is a powerful new technique for the analysis of short-chain branching in linear low-density polyethylene (LLDPE) and the analysis of polyolefin blends and copolymers regarding chemical composition. For the fast analysis of the chemical composition distribution, a new high-temperature gradient high-performance liquid chromatography (HPLC) system has been developed. The efficiency of this system for the separation of various olefin copolymers is demonstrated. The correlation between molar mass and chemical composition can be accessed by on-line coupling of high-temperature size exclusion chromatography (HT-SEC) and 1H NMR spectroscopy. It is shown that the on-line NMR analysis of chromatographic fractions yields information on microstructure and tacticity in addition to molar mass and copolymer composition.
The duality of chemistry: Chemistry for peaceful purposes versus chemical weapons
Authors: Trapp Ralf
Published: August 2008

In April 1997, the Chemical Weapons Convention (CWC) entered into force, banning chemical weapons (CW) worldwide and requiring their destruction under international verification by 2007, a date that has since been extended to 2012. At the same time, the CWC aims to prevent the recurrence of CW, including their possible use by non-State actors such as terrorists. The CWC is an agreement between governments, but it also sets norms that apply, through national laws and ethical principles, to the individual scientist and engineer. Many chemists, however, have had little or no exposure during their training and professional life to the ethical norms and regulatory requirements of the CWC. At the same time, advances in the life sciences are creating enormous opportunities - with the potential of being quite beneficial to humankind but also prone to abuse. Education and awareness-raising about the norms and principles enshrined in the CWC are therefore becoming increasingly important. Through its activities in the field of chemistry education as well as its links to the chemical industry, IUPAC has responsibility, as well as capacity, to promote professional conduct that is in full compliance with the norms of the CWC.
Oxygenases for oxygen sensing
Authors: Loenarz Christoph , Chowdhury Rasheduzzaman , Schofield Christopher J. , Flashman Emily
Published: August 2008

In animals, cellular and physiological responses to oxygen level variations are regulated via the post-translational modification of the heterodimeric hypoxia-inducible transcription factor (HIF). Hydroxylation of the HIF-α subunit at either of two conserved prolyl residues enables binding to the von Hippel-Lindau protein (pVHL) elongin C/B complex (VCB) which targets HIF-α for degradation via the ubiquitin proteasome pathway. Hydroxylation of an asparaginyl residue in the C-terminal transcriptional activation domain of HIF-α reduces its interaction with the transcriptional coactivator p300. Thus, post-translational hydroxylation is used both to "make" (HIF-VCB) and "break" (HIF-p300) protein-protein interactions in the hypoxic response. The requirement for oxygen of the HIF prolyl and asparaginyl hydroxylases in catalysis links changes in oxygen concentration and transcription of the gene array that enables cells to adapt to hypoxia. All four identified human HIF hydroxylases are members of the Fe(II) and 2-oxoglutarate (2OG)-dependent family of oxygenases. Inhibition of HIF hydroxylases mimics the hypoxic response resulting in the upregulation of erythropoietin (EPO), vascular endothelial growth factor (VEGF), and other proteins of biomedicinal importance. We briefly review biochemical analyses on the HIF hydroxylases and discuss how their structural and mechanistic characteristics may make them suited to their oxygen-sensing role.
Mechanical Stimulation of Mesenchymal Stem Cell Proliferation and Differentiation Promotes Osteogenesis While Preventing Dietary-Induced Obesity
Authors: Luu Yen Kim , Capilla Encarnacion , Rosen Clifford J , Gilsanz Vicente , Pessin Jeffrey E , Judex Stefan , Rubin Clinton T
Published: August 2008

Mesenchymal stem cells (MSCs) are defined by their ability to self-renew and differentiate into the cells that form mesodermal tissues such as bone and fat. Low magnitude mechanical signals (LMMS) have been shown to be anabolic to bone and have been recently reported to suppress the development of fat in normal animals fed a regular diet. Using male C57BL/6J mice, the ability of LMMS (0.2g, 90-Hz signal applied for 15 min/d, 5 d/wk) to simultaneously promote bone formation and prevent diet-induced obesity was correlated to mechanical influences on the molecular environment of the bone marrow, as indicated by the population dynamics and lineage commitment of MSCs. Six weeks of LMMS increased the overall marrow-based stem cell population by 37% and the number of MSCs by 46%. Concomitant with the increase in stem cell number, the differentiation potential of MSCs in the bone marrow was biased toward osteoblastic and against adipogenic differentiation, as reflected by upregulation of the transcription factor Runx2 by 72% and downregulation of PPARγ by 27%. The phenotypic impact of LMMS on MSC lineage determination was evident at 14 wk, where visceral adipose tissue formation was suppressed by 28%, whereas trabecular bone volume fraction in the tibia was increased by 11%. Translating this to the clinic, a 1-yr trial in young women (15–20 yr; n = 48) with osteopenia showed that LMMS increased trabecular bone in the spine and kept visceral fat at baseline levels, whereas control subjects showed no change in BMD, yet an increase in visceral fat. Mechanical modulation of stem cell proliferation and differentiation indicates a unique therapeutic target to aid in tissue regeneration and repair and may represent the basis of a nonpharmacologic strategy to simultaneously prevent obesity and osteoporosis.
Scenes Unseen: The Parahippocampal Cortex Intrinsically Subserves Contextual Associations, Not Scenes or Places Per Se
Authors: Bar Moshe , Aminoff Elissa , Schacter Daniel L.
Published: August 2008

The parahippocampal cortex (PHC) has been implicated in both place/scene processing and episodic memory. We proposed that this region should instead be seen as intrinsically mediating contextual associations and not place/scene processing or episodic memory exclusively. Given that place/scene processing and episodic memory both rely on associations, this modified framework provides a platform for reconciling what seemed like different roles assigned to the same region. Comparing scenes with scenes, we show here that the PHC responds significantly more strongly to scenes with rich contextual associations compared with scenes of equal visual qualities but less associations. This result adds unequivocal support to the view that the PHC mediates contextual associations in general rather than places or scenes proper, and necessitates a revision of the current view that the PHC contains a dedicated place/scenes “module.”
Dynamic Regulation of the Kv2.1 Voltage-Gated Potassium Channel during Brain Ischemia through Neuroglial Interaction
Authors: Misonou Hiroaki , Thompson Scott M. , Cai Xiang
Published: August 2008

The physiological significance of neuroglial interactions in the CNS has been emphasized in neurological conditions such as epilepsy and brain ischemia. The Kv2.1 voltage-gated potassium channel is unique in its ability to form large clusters in the plasma membrane of neuronal cell bodies. We have previously shown that brain ischemia causes rapid dephosphorylation of Kv2.1 subunits and resultant activation of the ion channel function. However, the physiological significance of the channel clustering is unknown. Here we present evidence that clustered Kv2.1 channels in the neuronal plasma membrane are juxtaposed to axosomatic synapses and associated with astrocytic processes expressing high levels of glutamate transporters. In acute cortical slices, ischemic stress rapidly resulted in the dephosphorylation and dispersion of Kv2.1. Selective inhibition of metabolism in astrocytes was sufficient to induce Kv2.1 dephosphorylation in neurons. Interestingly, these effects were blocked by the antagonists of ionotropic glutamate receptors, indicating the involvement of glutamate as the signal mediator between astrocytes and neurons. Furthermore, the pharmacological inhibition of glial glutamate transporter GLT-1 induced the similar Kv2.1 dephosphorylation, whereas exogenous glutamate alone was not efficacious. These results suggest that ischemic stress rapidly causes the dysfunction of glutamate transporters in astrocytes and resultant accumulation of glutamate in the extracellular space. The elevated glutamate may subsequently activate ionotropic glutamate receptors and result in the dephosphorylation of Kv2.1 in neurons. These findings implicate that Kv2.1 clusters are strategically situated at neuroglial junctions to achieve the rapid modulation after ischemic stress via glutamate signaling.
Regulator of G-Protein Signaling 10 Promotes Dopaminergic Neuron Survival via Regulation of the Microglial Inflammatory Response
Authors: Lee Jae-Kyung , McCoy Melissa K. , Harms Ashley S. , Ruhn Kelly A. , Gold Stephen J. , Tansey Malú G.
Published: August 2008

Epidemiological studies suggest that chronic use of nonsteroidal anti-inflammatory drugs lowers the incidence of Parkinson's disease (PD) in humans and implicate neuroinflammatory processes in the death of dopamine (DA) neurons. Here, we demonstrate that regulator of G-protein signaling 10 (RGS10), a microglia-enriched GAP (GTPase accelerating protein) for Gα subunits, is an important regulator of microglia activation. Flow-cytometric and immunohistochemical analyses indicated that RGS10-deficient mice displayed increased microglial burden in the CNS, and exposure to chronic systemic inflammation induced nigral DA neuron loss measured by unbiased stereology. Primary microglia isolated from brains of RGS10-deficient mice displayed dysregulated inflammation-related gene expression profiles under basal and stimulated conditionsin vitrocompared with that of primary microglia isolated from wild-type littermates. Similarly, knockdown of RGS10 in the BV2 microglia cell line resulted in dysregulated inflammation-related gene expression, overproduction of tumor necrosis factor (TNF), and enhanced neurotoxic effects of BV2 microglia on the MN9D dopaminergic cell line that could be blocked by addition of the TNF decoy receptor etanercept. Importantly, ablation of RGS10 in MN9D dopaminergic cells further enhanced their vulnerability to microglial-derived death-inducing inflammatory mediators, suggesting a role for RGS10 in modulating the sensitivity of dopaminergic neurons against inflammation-mediated cell death. Together, our findings indicate that RGS10 limits microglial-derived TNF secretion and regulates the functional outcome of inflammatory stimuli in the ventral midbrain. RGS10 emerges as a novel drug target for prevention of nigrostriatal pathway degeneration, the neuropathological hallmark of PD.
Endogenous Homer Proteins Regulate Metabotropic Glutamate Receptor Signaling in Neurons
Authors: Kammermeier Paul J.
Published: August 2008

Group I metabotropic glutamate receptors (mGluR1 and mGluR5) are important neuronal mediators of postsynaptic signaling that influence synaptic strength, plasticity, and other factors. Regulation of group I mGluR localization and function by Homer proteins appears to be a viable means for neurons to fine-tune these processes. The presence of different Homer isoforms can act as a switch to reprioritize mGluR1 and mGluR5 signaling at the point of IP3receptor activation by promoting or reducing activation of specific downstream effectors. Furthermore, these Homer-dependent effects on mGluR signaling may mechanistically underlie many of the long-term changes in neuronal function associated with changes in Homer protein expression described in the recent literature. However, most studies focusing on mGluR regulation by Homer proteins used relatively long-term overexpression. Thus, a definitive demonstration of mGluR1/5 signal regulation by natively expressed Homer proteins has been elusive. I examined the ability of endogenous Homer 1a to alter mGluR signaling in rat sympathetic neurons and hippocampal autapses using pituitary adenylate cyclase activating peptide (PACAP) to induce native Homer 1a expression. In sympathetic neurons, both Homer 1a overexpression and PACAP treatment reversed the decrease in mGluR1-mediated calcium current modulation associated with Homer 2b expression. In hippocampal autapses, PACAP treatment uncoupled postsynaptic mGluR5 from EPSC inhibition, similar to the effect of Homer 1a overexpression. In both cases, RNA silencing of Homer 1a but not control RNA interference treatment prevented the PACAP effect, suggesting that it resulted specifically from native Homer 1a expression.
Wnt Regulates Axon Behavior through Changes in Microtubule Growth Directionality: A New Role for Adenomatous Polyposis Coli
Authors: Purro Silvia A. , Ciani Lorenza , Hoyos-Flight Monica , Stamatakou Eleanna , Siomou Eliza , Salinas Patricia C.
Published: August 2008

Axon guidance and target-derived signals control axonal behavior by regulating the cytoskeleton through poorly defined mechanisms. In particular, how these signaling molecules regulate the growth and directionality of microtubules is not well understood. Here we examine the effect of Wnts on growth cone remodeling, a process that precedes synapse formation. Time-lapse recordings reveal that Wnt3a rapidly inhibits growth cone translocation while inducing growth cone enlargement. These changes in axonal behavior are associated with changes in the organization of microtubules. Time-lapse imaging of EB3-GFP (green fluorescent protein)-labeled microtubule plus-ends demonstrates that Wnt3a regulates microtubule directionality, resulting in microtubule looping, growth cone pausing, and remodeling. Analyses of Dishevelled-1 (Dvl1) mutant neurons demonstrate that Dvl1 is required for Wnt-mediated microtubule reorganization and axon remodeling. Wnt signaling directly affects the microtubule cytoskeleton by unexpectedly inducing adenomatous polyposis coli (APC) loss from microtubule plus-ends. Consistently, short hairpin RNA knockdown of APC mimics Wnt3a function. Together, our findings define APC as a key Wnt signaling target in the regulation of microtubule growth direction.
Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats
Authors: Latrémolière Alban , Mauborgne Annie , Masson Justine , Bourgoin Sylvie , Kayser Valérie , Hamon Michel , Pohl Michel
Published: August 2008

Responses resulting from injury to the trigeminal nerve exhibit differences compared with those caused by lesion of other peripheral nerves. With the aim of elucidating the physiopathological mechanisms underlying cephalic versus extracephalic neuropathic pain, we determined the time course expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1β, neuronal injury (ATF3), macrophage/microglial (OX-42), and satellite cells/astrocyte (GFAP) markers in central and ganglion tissues in rats that underwent unilateral chronic constriction injury (CCI) to either infraorbital nerve (IoN) (cephalic area) or sciatic nerve (SN) (extracephalic area). Whereas CCI induced microglial activation in both models, we observed a concomitant upregulation of IL-6 and ATF3 in the ipsilateral dorsal horn of the lumbar cord in SN-CCI rats but not in the ipsilateral spinal nucleus of the trigeminal nerve (Sp5c) in IoN-CCI rats. Preemptive treatment with minocycline (daily administration of 20 mg/kg, i.p., for 2 weeks) partially prevented pain behavior and microglial activation in SN-CCI rats but was ineffective in IoN-CCI rats. We show that IL-6 can upregulate OX-42 and ATF3 expression in cultured microglia and neurons from spinal cord, respectively, as well as in the dorsal horn after acute intrathecal administration of the cytokine. We propose that IL-6 could be one of the promoters of the signaling cascade leading to abnormal pain behavior in SN-CCI but not IoN-CCI rats. Our data further support the idea that different pathophysiological mechanisms contribute to the development of cephalic versus extracephalic neuropathic pain.
Dynamic Premotor-to-Parietal Interactions during Spatial Imagery
Authors: Sack Alexander T. , Jacobs Christianne , De Martino Federico , Staeren Noel , Goebel Rainer , Formisano Elia
Published: August 2008

The neurobiological processes underlying mental imagery are a matter of debate and controversy among neuroscientists, cognitive psychologists, philosophers, and biologists. Recent neuroimaging studies demonstrated that the execution of mental imagery activates large frontoparietal and occipitotemporal networks in the human brain. These previous imaging studies, however, neglected the crucial interplay within and across the widely distributed cortical networks of activated brain regions. Here, we combined time-resolved event-related functional magnetic resonance imaging with analyses of interactions between brain regions (functional and effective brain connectivity) to unravel the premotor–parietal dynamics underlying spatial imagery. Participants had to sequentially construct and spatially transform a mental visual object based on either verbal or visual instructions. By concurrently accounting for the full spatiotemporal pattern of brain activity and network connectivity, we functionally segregated an early from a late premotor–parietal imagery network. Moreover, we revealed that the modality-specific information upcoming from sensory brain regions is first sent to the premotor cortex and then to the medial-dorsal parietal cortex, i.e., top-down from the motor to the perceptual pole during spatial imagery. Importantly, we demonstrate that the premotor cortex serves as the central relay station, projecting to parietal cortex at two functionally distinct stages during spatial imagery. Our approach enabled us to disentangle the multicomponential cognitive construct of mental imagery into its different cognitive subelements. We discuss and explicitly assign these mental subprocesses to each of the revealed effective brain connectivity networks and present an integrative neurobiological model of spatial imagery.
Beobachtbarkeitsanalyse von verteilt-parametrischen Systemen – Ein differentialgeometrischer Ansatz (Observability Analysis of Distributed Parameter Systems – A Differential Geometrical Approach)
Authors: Rieger Karl , Schlacher Kurt
Published: August 2008

Zur Untersuchung der Systemeigenschaft Beobachtbarkeit von verteilt-parametrischen Systemen wird zunächst eine geeignete Beschreibung für diese Klasse von Systemen im Rahmen der Differentialgeometrie eingeführt. Weiters wird dann insbesondere die Beobachtbarkeit von dynamischen Systemen entlang einer Trajektorie diskutiert, eine geometrische Veranschaulichung für diese Systemeigenschaft gegeben und eine systemtheoretische Analyse basierend auf Transformationsgruppen vorgestellt. Mit Hilfe eines infinitesimalen Invarianzkriteriums können (lokale) Bedingungen für die (Nicht-)Beobachtbarkeit gewonnen werden. Die Anwendung der vorgeschlagenen Methoden auf die Klasse der konzentriert-parametrischen Systeme zeigt, dass diese Kriterien in die bekannten übergehen. Die allgemeine Theorie wird durch ein Beispiel illustriert.
Al/Si and Ca/Eu short range order in Ca/Eu-bicchulite, studied by FTIR spectroscopy
Authors: Rahmoun Nouri-Said , Peters Lars , Knorr Karsten , Depmeier Wulf
Published: August 2008

Powder FTIR spectra of the solid solution series |(Ca2 – xEux)4(OH)8|[(Al2 + xSi1 – x)4O24]-SOD, 0 ≤ x ≤ 1, were taken at room temperature. All members, including the mineral bicchulite, |Ca8(OH)8|[Al8Si4O24]-SOD, have a sodalite-type structure. Spectra taken in the hydroxyl region (4000 − 3000 cm−1) yield information related to the local structural states of the pseudo-cubane-like (Ca2 + x
Eu2 – x
)(OH)4-clusters, 0 ≤ x ≤ 2. Three different patterns of short range order could be identified. Depending on x, different concentrations of Ca4(OH)4, EuCa3(OH)4, and Eu2Ca2(OH)4 clusters are found, whereas Eu3Ca(OH)4 or Eu4(OH)4 clusters are not observed. Hence, short range order is maintained such that each SOD cage of an all-alumina framework contains two Ca and two Eu per cluster. The positions of the framework stretching and bending modes shift linearly towards lower wavenumbers with increasing Al content. The shifts are correlated with changes of the framework geometry. Furthermore, Alrich samples show splitting of the stretching and bending modes. This is interpreted as the change of the local environment of Al due to the substitution of Eu3+ for Ca2+. With the use of deuteration experiments a more detailed assignment could be achieved, especially for the M—OH absorption bands. Finally, changes in the line shape, resulting from cation ordering, are studied by autocorrelation analysis. In particular, samples of intermediate composition show large broadening parameters, Δ
corr
, suggesting high degrees of local structural heterogeneity.