bluuebunny/crossref_metadata_2025 huggingface dataset:
PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice
Authors: Iida Kaori , Li Yulin , McGrath Barbara C , Frank Ami , Cavener Douglas R
Published: August 2007

Background

Deficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was specifically ablated in acinar cells of the exocrine pancreas in mice.

Results

We show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERK's downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4's transcriptional target CHOP have a normal exocrine pancreas.

Conclusion

We conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells.
Expression patterns of semaphorin7A and plexinC1during rat neural development suggest roles in axon guidance and neuronal migration
Authors: Pasterkamp R Jeroen , Kolk Sharon M , Hellemons Anita JCGM , Kolodkin Alex L
Published: August 2007

Background

Although originally identified as embryonic axon guidance cues, semaphorins are now known to regulate multiple, distinct, processes crucial for neuronal network formation including axon growth and branching, dendritic morphology, and neuronal migration. Semaphorin7A (Sema7A), the only glycosylphosphatidylinositol-anchored semaphorin, promotes axon growth in vitro and is required for the proper growth of the mouse lateral olfactory tract in vivo. Sema7A has been postulated to signal through two unrelated receptors, an RGD-dependent α1β1-integrin and a member of the plexin family, plexinC1. β1-integrins underlie Sema7A-mediated axon growth and Sema7A function in the immune system. Sema7A-plexinC1 interactions have also been implicated in immune system function, but the neuronal role of this ligand-receptor pair remains to be explored. To gain further insight into the function(s) of Sema7A and plexinC1 during neural development, we present here a detailed analysis of Sema7A and plexinC1 expression in the developing rat nervous system.

Results

In situ hybridization revealed select expression of Sema7A and plexinC1 in multiple neuronal systems including: the olfactory system, the hypothalamo-hypophysial system, the hippocampus, the meso-diencephalic dopamine system, and the spinal cord. Within these systems, Sema7A and plexinC1 are often expressed in specific neuronal subsets. In general, Sema7A transcript levels increase significantly towards adulthood, whereas plexinC1 expression decreases as development proceeds.

PlexinC1, but not Sema7A, is strongly expressed by distinct populations of migrating neurons. In addition to neuronal expression, Sema7A and plexinC1 transcripts were detected in oligodendrocytes and ependymal cells, respectively.

Conclusion

Sema7A and plexinC1 expression patterns are consistent with these proteins serving both cooperative and separate functions during neural development. The prominent expression of plexinC1 in several distinct populations of migrating neurons suggests a novel role for this plexin family member in neuronal migration.
Thyroid hormone receptor orthologues from invertebrate species with emphasis on Schistosoma mansoni
Authors: Wu Wenjie , Niles Edward G , LoVerde Philip T
Published: August 2007

Background:

Thyroid hormone receptors (TRs) function as molecular switches in response to thyroid hormone to regulate gene transcription. TRs were previously believed to be present only in chordates.

Results:

We isolated two TR genes from the Schistosoma mansoni and identified TR orthologues from other invertebrates: the platyhelminths, S. japonium and Schmidtea mediterranea, the mollusc, Lottia gigantean and the arthropod Daphnia pulex. Phylogenetic analysis of the DNA binding domain and/or ligand binding domain shows that invertebrate and vertebrate TRs cluster together, TRs from the vertebrates and from the jawless vertebrate (lamprey) clustered within separate subgroups, Platyhelminth TRs cluster outside of the vertebrate TR subgroups and that the schistosome TRs and S. mediterranea TRs clustered within separate subgroups.

Alignment of the C-terminus of the A/B domain revealed a conserved TR-specific motif, termed TR 'N-terminus signature sequence', with a consensus sequence of (G/P)YIPSY(M/L)XXXGPE(D/E)X.

Heterodimer formation between S. mansoni TRs and SmRXR1 suggests that the invertebrate TR protein gained the ability to form a heterodimer with RXR. ESMA analysis showed that SmTRα could bind to a conserved DNA core motif as a monomer or homodimer.

Conclusion:

Vertebrate TR genes originated from a common ancestor of the Bilateria. TR genes underwent duplication independently in the Protostomia and Deuterostomia. The duplication of TRs in deuterostomes occurred after the split of jawless and jawed vertebrates. In protostomes, TR genes underwent duplication in Platyhelminths, occurring independently in trematode and turbellarian lineages. Using S. mansoni TRs as an example, invertebrate TRs exhibited the ability to form a dimer with RXR prior to the emergence of the vertebrate TRs and were able to bind to vertebrate TR core DNA elements as a monomer or homodimer.
Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients
Authors: Petitjean Gaël , Al Tabaa Yassine , Tuaillon Edouard , Mettling Clement , Baillat Vincent , Reynes Jacques , Segondy Michel , Vendrell Jean Pierre
Published: August 2007

Background

The presence of HIV-1 preintegration reservoir was assessed in an in vitro experimental model of latent HIV-1 infection, and in patients treated or not with highly active antiretroviral therapy (HAART).

Results

In resting CD4+ T lymphocytes latently infected in vitro with HIV-1, we demonstrated that the polyclonal activation induced a HIV-1 replication, which could be prevented by the use of an HIV-1 integrase inhibitor. We also showed that this reservoir was labile since the rescuable HIV-1-antigens production from unintegrated HIV-1 genomes declined over time. These data confirm that our experimental approach allows the characterization of a functional unintegrated HIV-1 reservoir. We then explored the preintegration reservoir in HIV-1-infected patients. This reservoir was detected in 11 of 12 untreated patients, in 4 of 10 sustained responders to HAART, and in one incomplete responder. This reservoir was also inducible, labile, and anti-HIV-1 integrase drug inhibited its induction. Finally, this reservoir was associated with the presence of spontaneous HIV-1 antigens producing CD4+ T cells in blood from 3 of 3 untreated patients and 2 of 2 sustained responders to HAART harboring a preintegration reservoir.

Conclusion

This preintegration phase of HIV-1 latency could be a consequence of the ongoing viral replication in untreated patients and of a residual viral replication in treated patients.
Blood genomic profiles of exposures to Venezuelan equine encephalitis in Cynomolgus macaques (Macaca fascicularis)
Authors: Hammamieh Rasha , Barmada Mohsen , Ludwig George , Peel Sheila , Koterski Nick , Jett Marti
Published: August 2007

Background

Lymphocytes provide invaluable whistle blowers of changes due to infections. We use the information registered by these cells using their mRNAs as they encounter the pathogen to develop patterns of expression that correspond to that specific pathogen.

Venezuelan equine encephalitis (VEE) is a mosquito-borne viral disease characterized by fever and one or more of the following: severe headache, back pain, myalgias, prostration, chills, nausea, vomiting, weakness and other flu-like symptoms.

Screening for host mRNA obtained from blood samples after exposure to VEEV may provide the means for early detection of surrogate markers of the impending illness and provide appropriate strategies for treatment.

Results

We have been carrying out gene expression analysis of PBMC exposed to VEEV to extract signatures and diagnostic markers of early exposure to be used in non invasive blood analysis methods.

In this study, we used high throughput gene expression analysis to identify markers of early and late exposures to VEEV in vivo in Cynomolgus macaques (Macaca fascicularis). We carried out cDNA microarrays and real time PCR on blood samples obtained from the NHP model resulting in a panel of host genes that are altered in response to VEEV.

Conclusion

Screening for host mRNA obtained from blood samples after exposure to VEEV may provide the means for early detection of surrogate markers of the impending illness and provide appropriate strategies for treatment.
Mitotic regulation by NIMA-related kinases
Authors: O'Regan Laura , Blot Joelle , Fry Andrew M
Published: August 2007

The NIMA-related kinases represent a family of serine/threonine kinases implicated in cell cycle control. The founding member of this family, the NIMA kinase of Aspergillus nidulans, as well as the fission yeast homologue Fin1, contribute to multiple aspects of mitotic progression including the timing of mitotic entry, chromatin condensation, spindle organization and cytokinesis. Mammals contain a large family of eleven NIMA-related kinases, named Nek1 to Nek11. Of these, there is now substantial evidence that Nek2, Nek6, Nek7 and Nek9 also regulate mitotic events. At least three of these kinases, as well as NIMA and Fin1, have been localized to the microtubule organizing centre of their respective species, namely the centrosome or spindle pole body. Here, they have important functions in microtubule organization and mitotic spindle assembly. Other Nek kinases have been proposed to play microtubule-dependent roles in non-dividing cells, most notably in regulating the axonemal microtubules of cilia and flagella. In this review, we discuss the evidence that NIMA-related kinases make a significant contribution to the orchestration of mitotic progression and thereby protect cells from chromosome instability. Furthermore, we highlight their potential as novel chemotherapeutic targets.
Distribution patterns of small-molecule ligands in the protein universe and implications for origin of life and drug discovery
Authors: Ji Hong-Fang , Kong De-Xin , Shen Liang , Chen Ling-Ling , Ma Bin-Guang , Zhang Hong-Yu
Published: August 2007

Background

Extant life depends greatly on the binding of small molecules (such as ligands) with macromolecules (such as proteins), and one ligand can bind multiple proteins. However, little is known about the global patterns of ligand-protein mapping.

Results

By examining 2,186 well-defined small-molecule ligands and thousands of protein domains derived from a database of druggable binding sites, we show that a few ligands bind tens of protein domains or folds, whereas most ligands bind only one, which indicates that ligand-protein mapping follows a power law. Through assigning the protein-binding orders (early or late) for bio-ligands, we demonstrate that the preferential attachment principle still holds for the power-law relation between ligands and proteins. We also found that polar molecular surface area, H-bond acceptor counts, H-bond donor counts and partition coefficient are potential factors to discriminate ligands from ordinary molecules and to differentiate super ligands (shared by three or more folds) from others.

Conclusion

These findings have significant implications for evolution and drug discovery. First, the chronology of ligand-protein binding can be inferred by the power-law feature of ligand-protein mapping. Some nucleotide-containing ligands, such as ATP, ADP, GDP, NAD, FAD, dihydro-nicotinamide-adenine-dinucleotide phosphate (NDP), nicotinamide-adenine-dinucleotide phosphate (NAP), flavin mononucleotide (FMN) and AMP, are found to be the earliest cofactors bound to proteins, agreeing with the current understanding of evolutionary history. Second, the finding that about 30% of ligands are shared by two or more domains will help with drug discovery, such as in finding new functions from old drugs, developing promiscuous drugs and depending more on natural products.
Interactions of TANGO and leukocyte integrin CD11c/CD18 regulate the migration of human monocytes
Authors: Arndt Stephanie , Melle Christian , Mondal Krishna , Klein Gerd , Von Eggeling Ferdinand , Bosserhoff Anja-Katrin
Published: August 2007

The TANGO gene was originally identified as a new member of the MIA gene family. It codes for a protein of yet unknown function. TANGO revealed a very broad expression pattern in contrast to the highly restricted expression pattern determined for the other family members. The only cells lacking TANGO expression are cells of the hematopoietic system. One of the major differences between mature hematopoietic cells and other tissue cells is the lack of adhesion until these cells leave the bloodstream. In this study, we observed that TANGO expression was induced after adhesion of human monocytic cells to substrate. To understand the mechanism of TANGO function during monocyte adhesion we isolated interacting proteins and found an interaction between TANGO and the leukocyte-specific integrin CD11c. In functional assays, we observed reduced attachment of human monocytic cells to fibrinogen, ICAM-1 and to human microvascular endothelial cells (HMECs) after stimulation with recombinant TANGO protein. Additionally, the migrating capacity of premonocytic cells through fibrinogen or HMECs was increased after stimulation of these cells with recombinant TANGO. Therefore, we suggest that TANGO reduced the attachment to fibrinogen or other cell adhesion molecules. As TANGO does not compete for CD11c ligand binding directly, we hypothesize TANGO function by modulation of integrin activity. Taken together, the results from this study present TANGO as a novel ligand for CD11c, regulating migratory processes of hematopoietic cells.
A SELDI-TOF MS study of the genetic and post-translational molecular heterogeneity of eosinophil cationic protein
Authors: Eriksson Jenny , Woschnagg Charlotte , Fernvik Eva , Venge Per
Published: August 2007

Eosinophil cationic protein (ECP), a secretory protein of the eosinophil granulocyte, is a basic and highly heterogeneous protein. This heterogeneity is dependent on polymorphisms in the ECP gene and post-translational modifications, and it affects the functional properties of the protein in terms of cytotoxicity. The aim of this study was to further investigate the molecular heterogeneity, hence, an affinity capture assay based on an antigen-antibody interaction with the surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) technique was developed. Of three monoclonal antibodies tested, that is, EG2, 614, and 652, the 614 mab was chosen for the experiments. ECP heterogeneity of single individuals was studied in extracts of purified blood eosinophils, and the presence of ∼5 major molecular species was demonstrated in each subject. ECP from subjects with different ECP 434(G>C) genotypes (arg97thr) showed mass differences corresponding to the amino acid shift from arginine to threonine. ECP purified from pooled leukocytes of large numbers of healthy blood donors demonstrated an extensive mass heterogeneity with ∼10 major molecular species. By the use of a variety of glucosidases it was shown that this heterogeneity was mainly due to N-linked oligosaccharides on which sialic acid, galactose, and acetylglucosamine was positioned. We conclude that the SELDI-TOF MS technique using specific monoclonal antibodies is a convenient and versatile tool; by means of this technique, we could detect both genetic and post-translational causes of the molecular heterogeneity of the eosinophil cationic protein.
Insulin Resistance Is Unrelated to Circulating Retinol Binding Protein and Protein C Inhibitor
Authors: Promintzer Miriam , Krebs Michael , Todoric Jelena , Luger Anton , Bischof Martin Georg , Nowotny Peter , Wagner Oswald , Esterbauer Harald , Anderwald Christian
Published: August 2007

Context: Recent data suggest that circulating retinol-binding protein (RBP) might be involved in the pathogenesis of insulin resistance. Moreover, protein C inhibitor (PCI), which specifically binds retinoic acid, was found to be increased in myocardial infarction survivors who are also insulin resistant.

Objective: The objective of this study was to investigate the association of insulin resistance with RBP factors and PCI active antigen.

Design and Setting: This was a clinical study.

Patients: Nondiabetic humans with high (IS; n = 20, 14 females, six males, aged 47.2 ± 1.9 yr, body mass index 26 ± 1 kg/m2) and low (IR; n = 20, 14 females, six males, aged 45.5 ± 1.7 yr, body mass index 28 ± 1 kg/m2) insulin-stimulated glucose-disposal (M) participated in this study.

Main Outcome Measures: M was measured by 2-h hyperinsulinemic (40 mU·min−1·m−2)-isoglycemic clamp tests. Measurements of RBP were performed using a nephelometric method and validated using quantitative Western blotting.

Results: M (80–120 min) was higher in IS (10.9 ± 0.6 mg·min−1·kg−1) than IR (4.0 ± 0.2; P < 10−12). Fasting plasma RBP concentrations were comparable between IS and IR measured by both nephelometry (IS: 4.4 ± 0.3; IR: 4.6 ± 0.3 mg/dl, P = 0.6) and quantitative Western blot (IS 7.9 ± 0.5, IR 8.3 ± 0.6 mg/dl; P = 0.6). Fasting plasma PCI active antigen was similar in both groups. Plasma RBP and PCI were not significantly related to M. RBP was positively correlated with uric acid (r = 0.488, P = 0.003), triglycerides (r = 0.592, P < 0.001), prealbumin (r = 0.63, P < 0.0001), and vitamin A (r = 0.75, P < 10−6).

Conclusions: Our data demonstrate that healthy, insulin-resistant humans do not show altered plasma retinol binding factors, such as RBP and PCI. Both do not significantly correlate with insulin sensitivity. Thus, our findings do not support the hypothesis of insulin sensitivity modulation by proteins involved in retinol transport.
Relationships of Urinary Adrenal Steroids at Age 8 Years with Birth Weight, Postnatal Growth, Blood Pressure, and Glucose Metabolism
Authors: Honour John W. , Jones Richard , Leary Sam , Golding Jean , Ong Ken K. , Dunger David B.
Published: August 2007

Introduction: Overactivity of the hypothalamic-pituitary-adrenal axis through a program set by early growth patterns is hypothesized to lead to central obesity, insulin resistance, and hypertension. We therefore examined links between adrenal steroid production and birth weight, rapid early growth, and body mass index (BMI), blood pressure, waist circumference, and resistance to insulin in early childhood through the action of adrenal steroids.

Methods: Timed overnight urine samples were collected in 461 children from a large representative birth cohort. In total 244 boys and 188 girls aged 8.2–8.4 yr completed the protocol. The excretion rates of individual steroids were measured to determine total androgen and cortisol metabolites. Indices of activity of 5α-androgen reduction of androgens and cortisol metabolites and 11β-hydroxy steroid dehydrogenase activity were calculated.

Results: In both boys and girls, total urinary androgen and cortisol metabolites were positively related to current height, weight, BMI, and waist circumference. Girls had higher urine androgen metabolite levels and 5α-androgen indexes than boys, and in girls higher androgen metabolite excretion was associated with lower birth weight and faster postnatal weight gain. After adjustment for current BMI, total cortisol metabolites and 11β-hydroxy steroid dehydrogenase index were not related to birth weight or postnatal weight gain in either sex.

Conclusions: These data confirm early growth associations in this cohort seen with plasma levels of adrenal androgens at age 8 yr, at least in girls. Larger studies and follow-up during puberty are needed to exclude the possibility of programming of cortisol metabolism by early growth.
Exon Splice Enhancer Mutation (GH-E32A) Causes Autosomal Dominant Growth Hormone Deficiency
Authors: Petkovic Vibor , Lochmatter Didier , Turton James , Clayton Peter E. , Trainer Peter J. , Dattani Mehul T. , Eblé Andrée , Robinson Iain C. , Flück Christa E. , Mullis Primus E.
Published: August 2007

Context and Objective: Alteration of exon splice enhancers (ESE) may cause autosomal dominant GH deficiency (IGHD II). Disruption analysis of a (GAA) (n) ESE motif within exon 3 by introducing single-base mutations has shown that single nucleotide mutations within ESE1 affect pre-mRNA splicing.

Design, Setting, and Patients: Confirming the laboratory-derived data, a heterozygous splice enhancer mutation in exon 3 (exon 3 + 2 A→C) coding for GH-E32A mutation of the GH-1 gene was found in two independent pedigrees, causing familial IGHD II. Because different ESE mutations have a variable impact on splicing of exon 3 of GH and therefore on the expression of the 17.5-kDa GH mutant form, the GH-E32A was studied at the cellular level.

Interventions and Results: The splicing of GH-E32A, assessed at the protein level, produced significantly increased amounts of 17.5-kDa GH isoform (55% of total GH protein) when compared with the wt-GH. AtT-20 cells coexpressing both wt-GH and GH-E32A presented a significant reduction in cell proliferation as well as GH production after forskolin stimulation when compared with the cells expressing wt-GH. These results were complemented with confocal microscopy analysis, which revealed a significant reduction of the GH-E32A-derived isoform colocalized with secretory granules, compared with wt-GH.

Conclusion: GH-E32A mutation found within ESE1 weakens recognition of exon 3 directly, and therefore, an increased production of the exon 3-skipped 17.5-kDa GH isoform in relation to the 22-kDa, wt-GH isoform was found. The GH-E32A mutant altered stimulated GH production as well as cell proliferation, causing IGHD II.
Transcriptional Inhibition of Oxytocin Receptor Expression in Human Myometrial Cells by Melatonin Involves Protein Kinase C Signaling
Authors: Sharkey James , Olcese James
Published: August 2007

Context: Our laboratory recently characterized the expression of the melatonin receptors in the human myometrium and showed that the expression of these receptors is suppressed during late pregnancy.

Objective: In an effort to understand better the significance of melatonin in the human myometrium, we explored the mechanisms through which this hormone influences the expression of the oxytocin receptor in vitro.

Design: The stable melatonin analog iodomelatonin was presented to cultured telomerase-immortalized myometrial cells of the human telomerase reverse transcriptase line under physiological doses and durations. Pharmacological inhibitors of melatonin binding, gene transcription, phospholipase C, and protein kinase C signaling were used to define the mechanism of melatonin action.

Results: Our results reveal that melatonin significantly inhibits oxytocin receptor mRNA expression primarily via the melatonin 2 receptor. The melatonin-dependent decrease in oxytocin receptor transcripts involves suppression of gene transcription rather than enhanced rates of transcript degradation. Melatonin effects were abolished by pretreating the cells with the phospholipase C inhibitor U73122 or the protein kinase C inhibitor C1.

Conclusions: Melatonin, like oxytocin, can negatively regulate oxytocin receptor transcription in human myometrial cells via modulation of protein kinase C signaling. This is consistent with the hypothesis that the reduced melatonin receptor expression during late pregnancy, which occurs at a time when oxytocin receptors are up-regulated, may be physiologically important for the subsequent timing of labor.
Estradiol Fatty Acid Esters in Adipose Tissue and Serum of Pregnant and Pre- and Postmenopausal Women
Authors: Badeau Maija , Vihma Veera , Mikkola Tomi S. , Tiitinen Aila , Tikkanen Matti J.
Published: August 2007

Context: The 17β-estradiol fatty acid esters are hormone derivatives with long-lasting estrogenic effect. They are transported in serum lipoproteins and thought to be sequestered in adipose tissue.

Objective: Our objective was to determine the 17β-estradiol fatty acid ester concentrations in serum and adipose tissue in women of various hormonal states.

Design: After several chromatographic steps separating esterified from free estradiol, time-resolved fluoroimmunoassay was used as a quantifying tool.

Participants: Samples were obtained from pregnant women undergoing cesarean section (n = 13), or premenopausal (n = 8) and postmenopausal women (n = 6) during gynecological surgery.

Main Outcome Measures: 17β-Estradiol and 17β-estradiol fatty acid ester concentrations in serum, and visceral and sc adipose tissue were examined.

Results: The ratio of esterified to free estradiol in plasma increased with decreasing estradiol level from 0.5% in pregnant, to 15% in premenopausal and 110% in postmenopausal women. Estradiol esters constituted about 10% of the free estradiol present in adipose tissue in pregnancy. In nonpregnant women, most of the adipose tissue estradiol was in esterified form, the median ester to free ratio being elevated to 150–490%. After menopause, the overwhelming majority of estradiol in both free and esterified form was present in adipose tissue.

Conclusions: The overall higher ester to free estradiol ratio in adipose tissue than in serum indicates active esterification capacity in adipose tissue. The predominance of esterified and free estradiol in postmenopausal adipose tissue compared with serum suggests in situ production and storage. Whether the estradiol esters have an independent physiological role in adipose tissue remains to be clarified.
Nato's Transformation and New Partnerships: The Mediterranean
Authors: Minuto-Rizzo Alessandro
Published: August 2007

Alessandro Minuto-Rizzo is deputy secretary-general of the North Atlantic Treaty Organization and an architect of its transformation and expansion.
The International Court of Justice and Border-Conflict Resolution in Africa: The Bakassi Peninsula Conflict
Authors: Anyu J. Ndumbe
Published: August 2007

J. Ndumbe Anyu is associate professor of public administration and public policy at the University of the District of Columbia.
Montenegro and the Politics of Postcommunist Transition: 1990 to 2006
Authors: Kovacevic Filip
Published: August 2007

Filip Kovacevic is a professor at the University of Montenegro.
Islam and Minorities: Need for a Liberal Framework
Authors: Kumaraswamy P. R.
Published: August 2007

P. R. Kumaraswamy is associate professor at the school of International Studies, Jawarlal Nehru University, New Delhi.
Phosphorylation of synapsin domain A is required for post-tetanic potentiation
Authors: Fiumara Ferdinando , Milanese Chiara , Corradi Anna , Giovedì Silvia , Leitinger Gerd , Menegon Andrea , Montarolo Pier Giorgio , Benfenati Fabio , Ghirardi Mirella
Published: August 2007

Post-tetanic potentiation (PTP) is a form of homosynaptic plasticity important for information processing and short-term memory in the nervous system. The synapsins, a family of synaptic vesicle (SV)-associated phosphoproteins, have been implicated in PTP. Although several synapsin functions are known to be regulated by phosphorylation by multiple protein kinases, the role of individual phosphorylation sites in synaptic plasticity is poorly understood. All the synapsins share a phosphorylation site in the N-terminal domain A (site 1) that regulates neurite elongation and SV mobilization. Here, we have examined the role of phosphorylation of synapsin domain A in PTP and other forms of short-term synaptic enhancement (STE) at synapses between cultured Helix pomatia neurons. To this aim, we cloned H. pomatia synapsin (helSyn) and overexpressed GFP-tagged wild-type helSyn or site-1-mutant helSyn mutated in the presynaptic compartment of C1-B2 synapses. We found that PTP at these synapses depends both on Ca2+/calmodulin-dependent and cAMP-dependent protein kinases, and that overexpression of the non-phosphorylatable helSyn mutant, but not wild-type helSyn, specifically impairs PTP, while not altering facilitation and augmentation. Our findings show that phosphorylation of site 1 has a prominent role in the expression of PTP, thus defining a novel role for phosphorylation of synapsin domain A in short-term homosynaptic plasticity.
P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFNγ
Authors: Christova Rossitza , Jones Tania , Wu Pei-Jun , Bolzer Andreas , Costa-Pereira Ana P. , Watling Diane , Kerr Ian M. , Sheer Denise
Published: August 2007

Transcriptional activation of the major histocompatibility complex (MHC) by IFNγ is a key step in cell-mediated immunity. At an early stage of IFNγ induction, chromatin carrying the entire MHC locus loops out from the chromosome 6 territory. We show here that JAK/STAT signalling triggers this higher-order chromatin remodelling and the entire MHC locus becomes decondensed prior to transcriptional activation of the classical HLA class II genes. A single point mutation of STAT1 that prevents phosphorylation is sufficient to abolish chromatin remodelling, thus establishing a direct link between the JAK/STAT signalling pathway and human chromatin architecture. The onset of chromatin remodelling corresponds with the binding of activated STAT1 and the chromatin remodelling enzyme BRG1 at specific sites within the MHC, and is followed by RNA-polymerase recruitment and histone hyperacetylation. We propose that the higher-order chromatin remodelling of the MHC locus is an essential step to generate a transcriptionally permissive chromatin environment for subsequent activation of classical HLA genes.
Development of a virtual machining and inspection system for ultra-precision diamond turning
Authors: Lee W B , Cheung C F , Li J G , To S , Du J J , Yin Z Q
Published: August 2007

The conventional approach to establish optimal processing conditions in ultraprecision diamond turning is empirical in nature. The achievement of a super mirror finish and submicrometre form accuracy in many current industrial applications still depends much on the experience and skills of the machine operators through trial cutting tests when new materials or new machine tools are used. In this paper, a virtual machining and inspection system (VMIS) is presented for ultra-precision diamond turning. The development of the VMIS aims at creating a virtual manufacturing environment for the optimization of process parameters and evaluating the quality of machined surface through various modelbased simulation modules. The VMIS is validated through a series of practical cutting tests conducted on a two-axis computer numerical control ultra-precision turning machine. The experimental results agree well with the simulated data.
Specialist knowledge identification, classification, and usage in company-specific new product development processes
Authors: Cross M S , Sivaloganathan S
Published: August 2007

New product development is a complex process that requires industry-specific knowledge to produce commercially viable solutions, and it is this specialist knowledge that enables organizations to develop competitive advantage in their marketplaces. This research, conducted over 3 years at a UK capital equipment manufacturer, investigated the role of specialist knowledge in the design and development of products. The study concluded that, although different knowledge components are required for different projects, it is possible to adopt a generic approach to specialist knowledge identification, classification, and usage in new product developments. The current paper presents five methods that were used to identify specialist knowledge from engineering projects. The knowledge was then classified into ten categories that describe the specialist knowledge types used during commercial design projects. A model is presented illustrating when each specialist knowledge category is required in a typical development project. Organizations can use this approach to capture and structure the specialist knowledge components for a given product type, thus making available the knowledge to the wider organization and improving the organization's competitive advantage. The study was conducted as part of a project ‘Developing company-specific design models’, described in an earlier work.
Friction stir spot welding of AA6082-T6: Influence of the most relevant process parameters and comparison with classic mechanical fastening techniques
Authors: Fratini L , Barcellona A , Buffa G , Palmeri D
Published: August 2007

The results of an experimental study on friction stir spot welding (FSSW) of AA6082-T6 are reported. In particular, process mechanics is highlighted and joint strength is considered in relation to varying the most relevant process parameters. Furthermore, the results obtained are compared with those derived from the application of traditional mechanical fastening techniques such as clinching and riveting. In this way the effectiveness of FSSW is highlighted.
Design principles for mechatronic systems based on information content
Authors: Xu Yong , Zou Huijun
Published: August 2007

This study classifies design parameters in mechatronic systems as structure parameters and time-domain parameters. Time-domain parameters influence (or decide) working states and performance specifications of a mechatronic system. Based on information content defined for design parameters, the control principle of time-domain parameters, the priority principle of greater information content, and the maximum-control-efficiency principle are presented as guidelines for mechatronic design, together with the definitions of the mechatronic ratio and control efficiency. The example of the solid slicing manufacturing (SSM) system shows that, in addition to applying more controllers to minimize the number of time-domain parameters, mechatronic design also needs to search for an optimal design scheme with maximum control efficiency. Such a scheme may be obtained through reducing the number of uncertainties, limiting the uncertainty information content, and/or integrating the components.
Selection of optimal conditions in the surface grinding process using a differential evolution approach
Authors: Krishna A Gopala
Published: August 2007

The selection of machining parameters in any machining process significantly affects the production rate, quality, and cost of a component. The present work involves the application of a recently developed global optimization technique called differential evolution to optimize the machining parameters of a surface grinding process. The wheel speed, workpiece speed, depth of dressing, lead of dressing, cross-feed rate, wheel diameter, wheel width, grinding ratio, wheel bond percentage, and grain size are considered as the process variables. The production cost, production rate, and surface finish are evaluated for the optimal grinding conditions, subject to the constraints of thermal damage, wheel wear parameter, and machine tool stiffness. An example is taken from the literature to compare the results obtained by the proposed approach with other approaches.
Simulation of distortion induced in assemblies by spot welding
Authors: Fan X , Masters I , Roy R , Williams D
Published: August 2007

Maintaining dimensional tolerances during the manufacture of vehicle bodies is important to the automotive sector. With the industry's drive towards continuous improvement there is increasing focus on the effect of the joining process on the final assembly. A simulation tool that can predict the distortion resulting from assembly offers potential time- and cost-savings throughout design and manufacture. Although individual spot welds have been studied in detail, to-date methods to predict the distortion of a final assembly have concentrated on the variation of the constituent components. In the current paper simulation is used to predict the distortion of an assembly owing to spot welding using a local/global approach where the local distortion occurring around a single spot weld is projected onto a global assembly at each of the weld locations. The comparisons of the simulations of the assemblies with coordinate measuring machine (CMM) data under different clamping conditions suggest sufficient agreement with experimental data to be of value to engineers. A number of possible enhancements are suggested to improve the accuracy of final shape prediction.
Strengths, weaknesses, opportunities, and threats analysis for frameworks of world-class maintenance
Authors: Mishra R Prasad , Anand G , Kodali R
Published: August 2007

The term ‘world-class maintenance (WCMt)’ is being used frequently nowadays and refers to the collection of best practices in maintenance. Different researchers and consultants have proposed several frameworks of WCMt representing these best practices. If an organization or a maintenance manager wants to implement a framework, it may not be easy for him or her to identify a single framework from a variety of frameworks that are reported in the literature. Thus the task of choosing a particular framework has become a major issue for the managers. Hence in this paper, an attempt has been made to perform an analysis for comparing different WCMt frameworks based on their strengths, weaknesses, opportunities, and threats (SWOT). In addition to this, a comparative study of WCMt with other maintenance systems has been carried out to understand the similarities and differences. The SWOT analysis of frameworks revealed a list of best practices in maintenance to be considered by an organization, when it attempts to achieve a world-class status in maintenance apart from the weaknesses and threats associated with each framework. Such an analysis can prove valuable as a decision aid for the operations or maintenance manager while making a decision of choosing a suitable framework of WCMt.
An investigation into deformation mechanisms in the rolling of complex sheets with internal defects
Authors: Chen D-C
Published: August 2007

This study conducts a finite element analysis of the plastic deformation and bonding behaviour of complex aluminium-copper sheets containing internal defective voids in the asymmetrical cold rolling process. The influences of the roll diameter, the thickness ratio of the upper/lower sheet layers, the total sheet thickness at the entrance, and the sheet thickness reduction ratio on the dimensions of the internal void at the exit and the effective stress/strain distributions in the complex sheet are examined. Additionally, the evolution of closing of the correlation between the upper/lower voids under different rolling process parameters is explored. The present numerical results provide a valuable insight into the deformation mechanisms involved in the cold rolling of complex sheets with internal defects.
A method for optimizing process parameters in layer-based rapid prototyping
Authors: Vosniakos G-C , Maroulis T , Pantelis D
Published: August 2007

In layer-based rapid prototyping, a volumetric object is approximated as a pile of slices with vertical walls. Process parameter selection in layer-based prototyping is a multicriteria multiparameter optimization problem. A number of criteria may be used for assessing the prototype's quality. Volumetric accuracy of shape approximation and building time are just two criteria taken in this work as an example. Criteria depend on process parameters, most commonly in a mutually contradictory manner. Model orientation and slice thickness constitute the minimum of process parameters to be considered, but others may also be added. For this reason, a neural network is used, trained by a number of input-output vectors, when analytical formulae representing the dependency of criteria on process parameters are not possible to develop and/or available numerical models take too long to execute. Neural network meta-models are used in the evaluation (cost) function of a genetic algorithm, each representing a particular criterion, and criteria are weighted according to the user's particular view. A case study is presented, referring to a wax model prototyping machine in which a particular tree for investment casting is built. A new criterion for assessing the quality of shape approximation is introduced, namely the local volumetric error per slice.
Turning of hardened AISI 4340 steel using coated carbide inserts
Authors: de Lima J G , de Ávila R F , Abrão A M
Published: August 2007

The machining of hardened steels employing polycrystalline cubic boron nitride and ceramic tooling has been comprehensively investigated over the last 20 years; however, the development of newer cemented carbide grades has extended the use of this group of materials to the machining of steels hardened up to 45 HRC (Rockwell C). The current paper is therefore concerned with continuous turning of AISI 4340 steel hardened from 250 to 525 HV using coated carbide tools in order to investigate whether this cutting tool grade is capable of providing a satisfactory performance when machining a steel with increasing levels of hardness. Machining forces, tool life, and wear mechanisms were assessed and the results indicated that the relationship between the hardness of the work material and the machining force is not straightforward. In general, the machining force components increased with the work material hardness, however, the cutting force decreased slightly as the work hardness increased from 250 to 345 HV. Tool wear was lower when machining the 345 HV workpiece compared with cutting the 250 HV steel. Finally, abrasion was the principal wear mechanism observed and catastrophic failure took place when attempting to machine the 525 HV steel.
A Detection Method for Oscillating Chemical Reactions by Resonance Light Scattering Technique
Authors: Yan Ping , Li Yuan Fang , Huang Cheng Zhi
Published: August 2007

In this contribution, a resonance light-scattering (RLS) detection method is proposed for the measurements of oscillating reaction with H2O2–KSCN–CuSO4–NaOH close system as an example. The seasonal change of oscillating chemical reactions concerning the particle size is examined, and the qualitative analytical information could be obtained from this straightforward and expeditious approach.
Efficient Conversion of Carbon Dioxide to Methanol Using Copper Catalyst by a New Low-temperature Hydrogenation Process
Authors: Liu Yong , Zhang Yi , Wang Tiejun , Tsubaki Noritatsu
Published: August 2007

By employing a new low-temperature process for methanol synthesis, high activity of methanol production from CO2 hydrogenation was achieved at 443 K and 5 MPa in a slurry-phase reactor over the copper catalysts prepared by an oxalate-gel coprecipitation (OC) method.
A Review of the Stern Review on the Economics of Climate Change
Authors: Weitzman Martin L
Published: August 2007

The Stern Review calls for immediate decisive action to stabilize greenhouse gases because “the benefits of strong, early action on climate change outweighs the costs.” The economic analysis supporting this conclusion consists mostly of two basic strands. The first strand is a formal aggregative model that relies for its conclusions primarily upon imposing a very low discount rate. Concerning this discount-rate aspect, I am skeptical of the Review's formal analysis, but this essay points out that we are actually a lot less sure about what interest rate should be used for discounting climate change than is commonly acknowledged. The Review's second basic strand is a more intuitive argument that it might be very important to avoid possibly large uncertainties that are difficult to quantify. Concerning this uncertainty aspect, I argue that it might be recast into sound analytical reasoning that might justify some of the Review's conclusions. The basic issue here is that spending money to slow global warming should perhaps not be conceptualized primarily as being about consumption smoothing as much as being about how much insurance to buy to offset the small change of a ruinous catastrophe that is difficult to compensate by ordinary savings.
Association of classical and related inflammatory markers with high-sensitivity C-reactive protein in healthy individuals: results from the Stanislas cohort
Authors: Berrahmoune Hind , Herbeth Bernard , Lamont John V. , Lambert Daniel , Blankenberg Stefan , Tiret Laurence , FitzGerald Peter S. , Siest Gérard , Visvikis-Siest Sophie
Published: August 2007

Clin Chem Lab Med 2007;45:1339–46.
Preservation of RNA for functional analysis of separated alleles in yeast: comparison of snap-frozen and RNALater® solid tissue storage methods
Authors: Dekairelle Anne-France , Van der Vorst Sébastien , Tombal Bertrand , Gala Jean-Luc
Published: August 2007

Clin Chem Lab Med 2007;45:1283–7.
The effect of endurance exercise-induced lactacidosis on biochemical markers of bone turnover
Authors: Herrmann Markus , Müller Miriam , Scharhag Jürgen , Sand-Hill Marga , Kindermann Wilfried , Herrmann Wolfgang
Published: August 2007

Clin Chem Lab Med 2007;45:1381–9.
High plasma levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8) characterize patients prone to ventricular fibrillation complicating myocardial infarction
Authors: Elmas Elif , Lang Siegfried , Erik Dempfle Carl , Kälsch Thorsten , Hannak Dieter , Sueselbeck Tim , Wolpert Christian , Borggrefe Martin , Brueckmann Martina
Published: August 2007

Clin Chem Lab Med 2007;45:1360–5.
Clinical significance of the laboratory determination of low serum copper in adults
Authors: Kumar Neeraj , Butz John A. , Burritt Mary F.
Published: August 2007

Clin Chem Lab Med 2007;45:1402–10.
The Representation of Complex Images in Spatial Frequency Domains of Primary Visual Cortex
Authors: Zhang Jing X. , Rosenberg Ari , Mallik Atul K. , Husson T. Robert , Issa Naoum P.
Published: August 2007

The organization of cat primary visual cortex has been well mapped using simple stimuli such as sinusoidal gratings, revealing superimposed maps of orientation and spatial frequency preferences. However, it is not yet understood how complex images are represented across these maps. In this study, we ask whether a linear filter model can explain how cortical spatial frequency domains are activated by complex images. The model assumes that the response to a stimulus at any point on the cortical surface can be predicted by its individual orientation, spatial frequency, and temporal frequency tuning curves. To test this model, we imaged the pattern of activity within cat area 17 in response to stimuli composed of multiple spatial frequencies. Consistent with the predictions of the model, the stimuli activated low and high spatial frequency domains differently: at low stimulus drift speeds, both domains were strongly activated, but activity fell off in high spatial frequency domains as drift speed increased. To determine whether the filter model quantitatively predicted the activity patterns, we measured the spatiotemporal tuning properties of the functional domainsin vivoand calculated expected response amplitudes from the model. The model accurately predicted cortical response patterns for two types of complex stimuli drifting at a variety of speeds. These results suggest that the distributed activity of primary visual cortex can be predicted from cortical maps like those of orientation and SF preference generated using simple, sinusoidal stimuli, and that dynamic visual acuity is degraded at or before the level of area 17.