bluuebunny/crossref_metadata_2025 huggingface dataset:
Extraction of semantic biomedical relations from text using conditional random fields
Authors: Bundschus Markus , Dejori Mathaeus , Stetter Martin , Tresp Volker , Kriegel Hans-Peter
Published: April 2008

Background

The increasing amount of published literature in biomedicine represents an immense source of knowledge, which can only efficiently be accessed by a new generation of automated information extraction tools. Named entity recognition of well-defined objects, such as genes or proteins, has achieved a sufficient level of maturity such that it can form the basis for the next step: the extraction of relations that exist between the recognized entities. Whereas most early work focused on the mere detection of relations, the classification of the type of relation is also of great importance and this is the focus of this work. In this paper we describe an approach that extracts both the existence of a relation and its type. Our work is based on Conditional Random Fields, which have been applied with much success to the task of named entity recognition.

Results

We benchmark our approach on two different tasks. The first task is the identification of semantic relations between diseases and treatments. The available data set consists of manually annotated PubMed abstracts. The second task is the identification of relations between genes and diseases from a set of concise phrases, so-called GeneRIF (Gene Reference Into Function) phrases. In our experimental setting, we do not assume that the entities are given, as is often the case in previous relation extraction work. Rather the extraction of the entities is solved as a subproblem. Compared with other state-of-the-art approaches, we achieve very competitive results on both data sets. To demonstrate the scalability of our solution, we apply our approach to the complete human GeneRIF database. The resulting gene-disease network contains 34758 semantic associations between 4939 genes and 1745 diseases. The gene-disease network is publicly available as a machine-readable RDF graph.

Conclusion

We extend the framework of Conditional Random Fields towards the annotation of semantic relations from text and apply it to the biomedical domain. Our approach is based on a rich set of textual features and achieves a performance that is competitive to leading approaches. The model is quite general and can be extended to handle arbitrary biological entities and relation types. The resulting gene-disease network shows that the GeneRIF database provides a rich knowledge source for text mining. Current work is focused on improving the accuracy of detection of entities as well as entity boundaries, which will also greatly improve the relation extraction performance.
Conserved co-expression for candidate disease gene prioritization
Authors: Oti Martin , van Reeuwijk Jeroen , Huynen Martijn A , Brunner Han G
Published: April 2008

Background

Genes that are co-expressed tend to be involved in the same biological process. However, co-expression is not a very reliable predictor of functional links between genes. The evolutionary conservation of co-expression between species can be used to predict protein function more reliably than co-expression in a single species. Here we examine whether co-expression across multiple species is also a better prioritizer of disease genes than is co-expression between human genes alone.

Results

We use co-expression data from yeast (S. cerevisiae), nematode worm (C. elegans), fruit fly (D. melanogaster), mouse and human and find that the use of evolutionary conservation can indeed improve the predictive value of co-expression. The effect that genes causing the same disease have higher co-expression than do other genes from their associated disease loci, is significantly enhanced when co-expression data are combined across evolutionarily distant species. We also find that performance can vary significantly depending on the co-expression datasets used, and just using more data does not necessarily lead to better prioritization. Instead, we find that dataset quality is more important than quantity, and using a consistent microarray platform per species leads to better performance than using more inclusive datasets pooled from various platforms.

Conclusion

We find that evolutionarily conserved gene co-expression prioritizes disease candidate genes better than human gene co-expression alone, and provide the integrated data as a new resource for disease gene prioritization tools.
A novel function for the presenilin family member spe-4: inhibition of spermatid activation in Caenorhabditis elegans.
Authors: Gosney Ryoko , Liau Wei-Siang , LaMunyon Craig W
Published: April 2008

Background

Sperm cells must regulate the timing and location of activation to maximize the likelihood of fertilization. Sperm from most species, including the nematode Caenorhabditis elegans, activate upon encountering an external signal. Activation for C. elegans sperm occurs as spermatids undergo spermiogenesis, a profound cellular reorganization that produces a pseudopod. Spermiogenesis is initiated by an activation signal that is transduced through a series of gene products. It is now clear that an inhibitory pathway also operates in spermatids, preventing their premature progression to spermatozoa and resulting in fine-scale control over the timing of activation. Here, we describe the involvement of a newly assigned member of the inhibitory pathway: spe-4, a homolog of the human presenilin gene PS1. The spe-4(hc196) allele investigated here was isolated as a suppressor of sterility of mutations in the spermiogenesis signal transduction gene spe-27.

Results

Through mapping, complementation tests, DNA sequencing, and transformation rescue, we determined that allele hc196 is a mutation in the spe-4 gene. Our data show that spe-4(hc196) is a bypass suppressor that eliminates the need for the spermiogenesis signal transduction. On its own, spe-4(hc196) has a recessive, temperature sensitive spermatogenesis-defective phenotype, with mutants exhibiting (i) defective spermatocytes, (ii) defective spermatids, (iii) premature spermatid activation, and (iv) spermatozoa defective in fertilization, in addition to a small number of functional sperm which appear normal microscopically.

Conclusion

A fraction of the sperm from spe-4(hc196) mutant males progress directly to functional spermatozoa without the need for an activation signal, suggesting that spe-4 plays a role in preventing spermatid activation. Another fraction of spermatozoa from spe-4(hc196) mutants are defective in fertilization. Therefore, prematurely activated spermatozoa may have several defects: we show that they may be defective in fertilization, and earlier work showed that they obstruct sperm transfer from males at mating. hc196 is a hypomorphic allele of spe-4, and its newly-discovered role inhibiting spermiogenesis may involve known proteolytic and/or calcium regulatory aspects of presenilin function, or it may involve yet-to-be discovered functions.
Evidence of a chimeric genome in the cyanobacterial ancestor of plastids
Authors: Gross Jeferson , Meurer Jörg , Bhattacharya Debashish
Published: April 2008

Background

Horizontal gene transfer (HGT) is a vexing fact of life for microbial phylogeneticists. Given the substantial rates of HGT observed in modern-day bacterial chromosomes, it is envisaged that ancient prokaryotic genomes must have been similarly chimeric. But where can one find an ancient prokaryotic genome that has maintained its ancestral condition to address this issue? An excellent candidate is the cyanobacterial endosymbiont that was harnessed over a billion years ago by a heterotrophic protist, giving rise to the plastid. Genetic remnants of the endosymbiont are still preserved in plastids as a highly reduced chromosome encoding 54 – 264 genes. These data provide an ideal target to assess genome chimericism in an ancient cyanobacterial lineage.

Results

Here we demonstrate that the origin of the plastid-encoded gene cluster for menaquinone/phylloquinone biosynthesis in the extremophilic red algae Cyanidiales contradicts a cyanobacterial genealogy. These genes are relics of an ancestral cluster related to homologs in Chlorobi/Gammaproteobacteria that we hypothesize was established by HGT in the progenitor of plastids, thus providing a 'footprint' of genome chimericism in ancient cyanobacteria. In addition to menB, four components of the original gene cluster (menF, menD, menC, and menH) are now encoded in the nuclear genome of the majority of non-Cyanidiales algae and plants as the unique tetra-gene fusion named PHYLLO. These genes are monophyletic in Plantae and chromalveolates, indicating that loci introduced by HGT into the ancestral cyanobacterium were moved over time into the host nucleus.

Conclusion

Our study provides unambiguous evidence for the existence of genome chimericism in ancient cyanobacteria. In addition we show genes that originated via HGT in the cyanobacterial ancestor of the plastid made their way to the host nucleus via endosymbiotic gene transfer (EGT).
MDM2 gene SNP309 T/G and p53gene SNP72 G/C do not influence diffuse large B-cell non-Hodgkin lymphoma onset or survival in central European Caucasians
Authors: Bittenbring Joerg , Parisot Frédérique , Wabo Alain , Mueller Monika , Kerschenmeyer Lynn , Kreuz Markus , Truemper Lorenz , Landt Olfert , Menzel Alain , Pfreundschuh Michael , Roemer Klaus
Published: April 2008

Background

SNP309 T/G (rs2279744) causes higher levels of MDM2, the most important negative regulator of the p53 tumor suppressor. SNP72 G/C (rs1042522) gives rise to a p53 protein with a greatly reduced capacity to induce apoptosis. Both polymorphisms have been implicated in cancer. The SNP309 G-allele has recently been reported to accelerate diffuse large B-cell lymphoma (DLBCL) formation in pre-menopausal women and suggested to constitute a genetic basis for estrogen affecting human tumorigenesis. Here we asked whether SNP309 and SNP72 are associated with DLBCL in women and are correlated with age of onset, diagnosis, or patient's survival.

Methods

SNP309 and SNP72 were PCR-genotyped in a case-control study that included 512 controls and 311 patients diagnosed with aggressive NHL. Of these, 205 were diagnosed with DLBCL.

Results

The age of onset was similar in men and women. The control and patients group showed similar SNP309 and SNP72 genotype frequencies. Importantly and in contrast to the previous findings, similar genotype frequencies were observed in female patients diagnosed by 51 years of age and those diagnosed later. Specifically, 3/20 female DLBCL patients diagnosed by 51 years of age were homozygous for SNP309 G and 2/20 DLBCL females in that age group were homozygous for SNP72 C. Neither SNP309 nor SNP72 had a significant influence on event-free and overall survival in multivariate analyses.

Conclusion

In contrast to the previous study on Ashkenazi Jewish Caucasians, DLBCL in pre-menopausal women of central European Caucasian ethnicity was not associated with SNP309 G. Neither SNP309 nor SNP72 seem to be correlated with age of onset, diagnosis, or survival of patients.
Extensor-tendons reconstruction using autogenous palmaris longus tendon grafting for rheumatoid arthritis patients
Authors: Chu Po-Jung , Lee Hung-Maan , Hou Yao-Tung , Hung Sheng-Tsai , Chen Jung-Kuei , Shih Jui-Tien
Published: April 2008

Background

The purpose of the study is to retrospectively review the clinical outcome of our study population of middle-aged RA patients who had suffered extensor-tendon rupture. We reported the outcome of autogenous palmaris tendon grafting of multiple extensor tendons at wrist level in 14 middle-aged rheumatoid patients.

Methods

Between Feb. 2000 to Feb. 2004, thirty-six ruptured wrist level extensor tendons were reconstructed in fourteen rheumatoid patients (11 women and three men) using autogenous palmaris longus tendon as a free interposition graft. In each case, the evaluation was based on both subjective and objective criteria, including the range of MCP joint flexion after surgery, the extension lag at the metacarpophalangeal joint before and after surgery, and the ability of the patient to work.

Results and Discussion

The average of follow-up was 54.1 months (range, 40 to 72 months). The average range of MCP joint flexion after reconstruction was 66°. The extension lag at the metacarpophalangeal joint significantly improved from a preoperative mean of 38° (range, 25°–60°) to a postoperative mean of 16° (range, 0°–30°). Subjectively all patients were satisfied with the clinical results, and achieved a return to their level of ability before tendon rupture. We found good functional results in our series of interposition grafting using palmaris longus to reconstruct extensor tendon defects in the rheumatoid patients.

Conclusion

Reconstruction for multiple tendon ruptures is a salvage procedure that is often associated with extensor lag and impairment of overall function. Early aggressive treatment of extensor tendon reconstruction using autogenous palmaris longus tendon as a free interposition graft in the rheumatoid wrist is another viable option to achieve good clinical functional result.
Does preservation of the sub-valvular apparatus during mitral valve replacement affect long-term survival and quality of life? A Microsimulation Study
Authors: Rao Christopher , Hart Jonathan , Chow Andre , Siannis Fotios , Tsalafouta Polyxeni , Murtuza Bari , Darzi Ara , Wells Frank C , Athanasiou Thanos
Published: April 2008

Background

Techniques to preserve the sub-valvular apparatus in order to reduce morbidity and mortality following mitral valve replacement have been frequently reported. However, it is uncertain what impact sub-valvular apparatus preservation techniques have on long-term outcomes following mitral valve replacement. This study investigated the effect of sub-valvular apparatus preservation on long-term survival and quality of life following mitral valve replacement.

Methods

A microsimulation model was used to compare long-term survival and quality-adjusted life years following mitral valve replacement after conventional valve replacement and sub-valvular apparatus preservation. Probabilistic sensitivity analysis and alternative analysis were performed to investigate uncertainty associated with the results.

Results

Our Analysis suggests that patients survive longer if the sub-valvular apparatus are preserved (65.7% SD 1.5%, compared with 58.1% SD 1.6% at 10 years). The quality adjusted life years gained over a 10 year period where also greater after sub-valvular apparatus preservation. (6.54 QALY SD 0.07 QALY, compared with 5.61 QALY, SD 0.07 QALY). The superiority of preservation techniques was insensitive to patient age, parameter or model uncertainty.

Conclusion

This study suggests that long-term outcomes may be improved when the sub-valvular apparatus are preserved. Given the lack of empirical data further research is needed to investigate health-related quality of life after mitral valve replacement, and to establish whether outcomes differ between preservation techniques.
Left atrial giant thrombus infected by Escherichia Coli. Case report
Authors: Dedeilias Panagiotis , Roussakis Antonios , Koletsis Efstratios N , Zervakis Dimitrios , Hountis Panagiotis , Prokakis Christos , Balaka Christina , Bolos Konstantinos
Published: April 2008

Background

Left atrial thrombi are mostly related to mitral valve disease. The differential diagnosis of clots and myxomas in the left atrium is mostly based on echocardiography. Infection of intracardiac thrombi is extremely rare and mostly reported in ventricular clots or aneurysms following myocardial infarction.

Case presentation

We present the case of a 65 year old female with a history of mitral valve disease and chronic atrial fibrillation who suffered repeated embolic strokes and a giant infected clot in the left atrium. Although the patient underwent prompt surgery with removal of the clot and valve replacement the complication of septic emboli to the CNS led her to death. To the best of our knowledge this is the second report of an infected left atrial thrombus.

Conclusion

The case is a representative example of a neglected and undertreated patient with catastrophic consequences. Anticoagulant therapy in patients with mitral valve disease and atrial fibrillation should be applied according the currently available guidelines and standards in order to avoid analogous paradigms in the future. Mitral valve substitution should be considered in patients with mitral valve disease presenting thromboembolic complications. Surgery should be considered as the treatment of choice in cases of organized left atrial thrombus and suspected tumor or infected mass.
A logic-based diagram of signalling pathways central to macrophage activation
Authors: Raza Sobia , Robertson Kevin A , Lacaze Paul A , Page David , Enright Anton J , Ghazal Peter , Freeman Tom C
Published: April 2008

Background

The complex yet flexible cellular response to pathogens is orchestrated by the interaction of multiple signalling and metabolic pathways. The molecular regulation of this response has been studied in great detail but comprehensive and unambiguous diagrams describing these events are generally unavailable. Four key signalling cascades triggered early-on in the innate immune response are the toll-like receptor, interferon, NF-κB and apoptotic pathways, which co-operate to defend cells against a given pathogen. However, these pathways are commonly viewed as separate entities rather than an integrated network of molecular interactions.

Results

Here we describe the construction of a logically represented pathway diagram which attempts to integrate these four pathways central to innate immunity using a modified version of the Edinburgh Pathway Notation. The pathway map is available in a number of electronic formats and editing is supported by yEd graph editor software.

Conclusion

The map presents a powerful visual aid for interpreting the available pathway interaction knowledge and underscores the valuable contribution well constructed pathway diagrams make to communicating large amounts of molecular interaction data. Furthermore, we discuss issues with the limitations and scalability of pathways presented in this fashion, explore options for automated layout of large pathway networks and demonstrate how such maps can aid the interpretation of functional studies.
Eosinopenia is a reliable marker of sepsis on admission to medical intensive care units
Authors: Abidi Khalid , Khoudri Ibtissam , Belayachi Jihane , Madani Naoufel , Zekraoui Aicha , Zeggwagh Amine Ali , Abouqal Redouane
Published: April 2008

Introduction

Eosinopenia is a cheap and forgotten marker of acute infection that has not been evaluated previously in intensive care units (ICUs). The aim of the present study was to test the value of eosinopenia in the diagnosis of sepsis in patients admitted to ICUs.

Methods

A prospective study of consecutive adult patients admitted to a 12-bed medical ICU was performed. Eosinophils were measured at ICU admission. Two intensivists blinded to the eosinophils classified patients as negative or with systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, or septic shock.

Results

A total of 177 patients were enrolled. In discriminating noninfected (negative + SIRS) and infected (sepsis + severe sepsis + septic shock) groups, the area under the receiver operating characteristic curve was 0.89 (95% confidence interval (CI), 0.83 to 0.94). Eosinophils at <50 cells/mm3 yielded a sensitivity of 80% (95% CI, 71% to 86%), a specificity of 91% (95% CI, 79% to 96%), a positive likelihood ratio of 9.12 (95% CI, 3.9 to 21), and a negative likelihood ratio of 0.21(95% CI, 0.15 to 0.31). In discriminating SIRS and infected groups, the area under the receiver operating characteristic curve was 0.84 (95% CI, 0.74 to 0.94). Eosinophils at <40 cells/mm3 yielded a sensitivity of 80% (95% CI, 71% to 86%), a specificity of 80% (95% CI, 55% to 93%), a positive likelihood ratio of 4 (95% CI, 1.65 to 9.65), and a negative likelihood ratio of 0.25 (95% CI, 0.17 to 0.36).

Conclusion

Eosinopenia is a good diagnostic marker in distinguishing between noninfection and infection, but is a moderate marker in discriminating between SIRS and infection in newly admitted critically ill patients. Eosinopenia may become a helpful clinical tool in ICU practices.
Serum Retinol Binding Protein 4 Is Related to Insulin Resistance and Nonoxidative Glucose Metabolism in Lean and Obese Women with Normal Glucose Tolerance
Authors: Kowalska Irina , Strączkowski Marek , Adamska Agnieszka , Nikolajuk Agnieszka , Karczewska-Kupczewska Monika , Otziomek Elżbieta , Górska Maria
Published: April 2008

Context: Retinol-binding protein (RBP) 4 is secreted by adipose tissue and is postulated to be a determinant of insulin sensitivity. The mechanisms of RBP4 insulin desensitizing action remain unclear.

Objective: The aim of the present study was to estimate the relationships between serum RBP4 concentration with insulin sensitivity and oxidative and nonoxidative glucose metabolism in lean and obese women.

Design and Participants: The study group consisted of 67 women with normal glucose tolerance, 27 lean and 40 overweight or obese. Insulin sensitivity was estimated with the euglycemic hyperinsulinemic clamp. Glucose and lipid oxidation was measured with indirect calorimetry in the basal state and during the last 30 min of the clamp. Nonoxidative glucose metabolism was calculated in insulin-stimulated conditions by subtracting glucose oxidation from total glucose metabolism.

Results: There was no difference in serum RBP4 concentration between lean and obese women. Serum RBP4 was inversely related to insulin sensitivity and nonoxidative glucose metabolism in the entire group (r = −0.36, P =0.003 in both cases) and within the subgroups of lean (r = −0.41, P =0.034 and r = −0.41, P =0.031) and obese women (r = −0.41, P =0.009 and r = −0.40, P =0.01, respectively). These relationships were independent of potential confounding factors. RBP4 levels were not associated with oxidative metabolism of glucose or lipid.

Conclusions: Our data indicate that serum RBP4 is related to decreased insulin sensitivity, mostly through its association with nonoxidative glucose metabolism.
The gradient of Gurken, a long-range morphogen, is directly regulated by Cbl-mediated endocytosis
Authors: Chang Wei-Ling , Liou Willisa , Pen Hsiao-Chung , Chou He-Yen , Chang Yu-Wei , Li Wei-How , Chiang Wei , Pai Li-Mei
Published: April 2008

The asymmetric localization of gurken mRNA and post-translational sorting mechanisms are responsible for the polar distribution of Gurken protein in Drosophila. However, endocytosis of Egfr, the receptor for Gurken in the follicle cells, also plays a role in shaping the extracellular gradient of the Gurken morphogen. Previously, we have found that mutation in the Cbl gene caused elevated Egfr signaling along the dorsoventral axis, and resulted in dorsalization phenotypes in embryos and egg shells. Here, we report that overexpression of the Cbl long isoform significantly changed Gurken distribution. Using an HRP-Gurken fusion protein, we demonstrate that internalization of the Gurken-Egfr complex depends on the activity of Cbl. Increased levels of CblL promote the internalization of this complex, leading to the reduction of free ligands. The Gurken-Egfr complex trafficks through the Rab5/Rab7 associated endocytic pathway to the lysosomal degradation compartment for signaling termination. We observe endocytic Gurken not only in the dorsal but also in the ventral follicle cells, which is, to our knowledge, the first visualization of Gurken on the ventral side of egg chambers. Our results show that Gurken travels towards the lateral/posterior of the egg chamber in the absence of Cbl,suggesting that Cbl actively regulates Gurken distribution through promoting endocytosis and subsequent degradation.
PAP- and GLD-2-type poly(A) polymerases are required sequentially in cytoplasmic polyadenylation and oogenesis inDrosophila
Authors: Benoit Perrine , Papin Catherine , Kwak Jae Eun , Wickens Marvin , Simonelig Martine
Published: April 2008

Cytoplasmic polyadenylation has an essential role in activating maternal mRNA translation during early development. In vertebrates, the reaction requires CPEB, an RNA-binding protein and the poly(A) polymerase GLD-2. GLD-2-type poly(A) polymerases form a family clearly distinguishable from canonical poly(A) polymerases (PAPs). In Drosophila, canonical PAP is involved in cytoplasmic polyadenylation with Orb, the DrosophilaCPEB, during mid-oogenesis. We show that the female germline GLD-2 is encoded by wispy. Wispy acts as a poly(A) polymerase in a tethering assay and in vivo for cytoplasmic polyadenylation of specific mRNA targets during late oogenesis and early embryogenesis. wispy function is required at the final stage of oogenesis for metaphase of meiosis I arrest and for progression beyond this stage. By contrast, canonical PAP acts with Orb for the earliest steps of oogenesis. Both Wispy and PAP interact with Orb genetically and physically in an ovarian complex. We conclude that two distinct poly(A)polymerases have a role in cytoplasmic polyadenylation in the female germline,each of them being specifically required for different steps of oogenesis.
A single point mutation in the LN domain of LAMA2 causes muscular dystrophy and peripheral amyelination
Authors: Patton Bruce L. , Wang Bing , Tarumi Yukie S. , Seburn Kevin L. , Burgess Robert W.
Published: April 2008

Mutations in the gene encoding the basal lamina (BL) component laminin α2 (LAMA2) cause merosin-deficient congenital muscular dystrophy 1A (MDC1A), a complex disorder that includes hypomyelination and myodegeneration. In dystrophia muscularis (dy) mice bearing Lama2 mutations, myofibers and Schwann cells fail to assemble stable BLs, which are thought to be crucial for myofiber survival and Schwann cell differentiation. Here, we describe defects in a new allele of Lama2 in mice, nmf417, in which a point mutation substitutes Arg for Cys79 at a universally conserved CxxC motif in the laminin N-terminal (LN) domain; this domain mediates laminin-laminin interactions. nmf417 homozygosity caused progressive myodegeneration and severe peripheral amyelination in nerve roots, similar to previous Lama2 mutations, but without the pervasive BL thinning previously associated with the disorder. In direct contrast to the previously characterized dy and dy2J alleles, nmf417 homozygous myofibers frequently had thickened BLs. Severe amyelination in nmf417-mutant nerve roots suggested complete laminin 2 inactivation for Schwann cells, although myelinated fibers had normal BLs. The results reveal crucial roles for the LN domain CxxC motif in both nerve and muscle, but challenge expected relationships between LN-domain function, Ln2 activity and BL stability. The nmf417 mutation provides a defined animal model in which to investigate mechanisms and treatments for moderate forms of MDC1A.
In vivo role of lipid adducts on Wingless
Authors: Franch-Marro Xavier , Wendler Franz , Griffith Janice , Maurice Madelon M. , Vincent Jean-Paul
Published: April 2008

Two lipids (palmitate and palmitoleic acid) are appended onto Wnt proteins. It has been suggested that palmitate is required for signalling, whereas palmitoleic acid is necessary for progression through the secretory pathway. By mutating the relevant amino acids, we have investigated how these adducts contribute to the secretion and signalling activity of Wingless, the main Drosophila member of the Wnt family. Analysis of Wingless with a Cysteine 93 to Alanine mutation ([C93A]Wingless) shows that palmitoylation is essential for signalling activity in vivo (as well as in cultured cells). Moreover, without palmitate, Wingless fails to reach the surface of imaginal disc cells and, as electron microscopy (EM) analysis suggests, appears to accumulate in the endoplasmic reticulum (ER). Artificial targeting of palmitate-deficient Wingless to the plasma membrane does not rescue signalling activity. Therefore, palmitate at C93 has a dual role: in secretion and signalling. From our analysis of [S239A]Wingless, which lacks a conserved residue shown to be acylated in Wnt3a, we infer that palmitoleic acid is not, as previously suggested, absolutely required for secretion. Nevertheless, this mutant has poor signalling activity, suggesting that palmitoleic acid contributes significantly to signalling. We suggest that the overall level of lipidation affects signalling activity.
Static model for flexure-based compliant mechanism driven by piezo stacks
Authors: Choi K-B , Lee J J
Published: April 2008

Flexure-based compliant mechanisms have been used in ultra-precision stages, stages for nano-imprint machines, AFM scanners, and MEMS structures, etc. In this paper, a mathematical static model for flexure-based compliant mechanism driven by piezo stacks is derived. The force vector generated from piezo stacks was linearized in terms of displacement and applied voltage vectors. Then, the piezo force vector was substituted into the static model of a compliant mechanism. Finally, the force and the displacement vectors of input bodies, and the block force and the displacement vectors of output bodies were derived. The derived mathematical model was verified by FEM analyses and experiments. The derived mathematical model can well describe the static performance of a flexure-based compliant mechanism driven by piezo stacks.
Design of a new mechanism for jetting dispenser featuring piezoactuator
Authors: Nguyen Q H , Han Y M , Choi S B , Hong S M
Published: April 2008

This work presents both the static and dynamic models for a new type of jetting dispenser featuring a piezostack actuator, which is applicable to electronic packaging assembly. After describing the configuration of the dispensing mechanism and operational principle of the proposed piezostack-driven jetting dispenser, a static modelling for mechanical part is analysed by considering the piezostack behaviour, fluid compressibility, and structural deflection. Both linear and non-linear behaviours of the structural plate are analysed and incorporated. The dynamic modelling of the mechanical part is also performed by considering the dynamic behaviour of the piston and needle. After optimizing the design parameters, such as piston radius and so on, the behaviour of the needle motion is obtained and checked for adhesive dispensing applicability. In order to demonstrate the effectiveness of the proposed static and dynamic models, an experimental test is undertaken by showing needle displacement.
Singular properties of flow separation as a real cause of cavitation inception
Authors: Washio S , Takahashi S , Uemura K , Iwamoto T , Ogata T
Published: April 2008

At the very beginning stage of cavitation an infinitesimal cavity suddenly emerges and rapidly grows on the wall close to the point of flow separation. The present paper intends to make clear the mechanism of this peculiar phenomenon previously discovered by the present authors in oil flows, by experimentally examining the characteristics of a separating flow. First, pressure and temperature distributions along a cylindrical smooth wall in an oil flow were measured across the point of separation, which has proved that both tensile stress and heat are really generated near the separation point. Second, a laminar air flow passing over a sharp edge was inspected by particle image velocimetry (PIV). The inspection of the separating flow based on the PIV data has revealed that fluid particle near the separation point is not only drastically stretched but also intensely sheared along the separation streamline. With all the results integrated, it has been concluded that the singular structure of a separating flow is the real cause of both tensile stress and heat generation. When thus generated tension exceeds a threshold, it possibly breaks the adhesion between the liquid and the wall, leaving a microscopic rift on the interface that would grow to a visible cavity.
Non-linear dynamic behaviour of rotor—bearing system trained by bevel gears
Authors: Li M
Published: April 2008

The vibrations of parallel geared rotor—bearing system have been intensively discussed; however, little attention has been paid to the dynamic analysis of angled bevel-geared system supported on journals. In the present work, the non-linear dynamics of a bevel-geared rotor system on oil film bearings is studied. First, the dynamic model is developed under some assumptions, such as rigid rotors, short-bearings, small teeth errors, and so forth. Then, the non-linear dynamic behaviours of both the balanced and unbalanced rotor system are analysed, respectively, in which the equilibrium points, limit cycles, their stability, and bifurcations are paid more attention. Numerical results show that in the bevel-geared rotor system under the action of non-linear oil film forces there exists a series of complex non-linear dynamic phenomena of rotor orbits, such as Hopf bifurcation, torus-doubling bifurcation, and jump phenomenon. All these features can help us to understand the dynamic characteristics of bevel-geared rotor—bearing system at design stage and during running period. Finally, some concerned problems during the investigation are also present.
Study on the method for 6-SPS Gough—Stewart platforms to pass through type-II singular points with its original configuration
Authors: Wang Yu-X , Li Y-T , Guo R-Q
Published: April 2008

It is well known that there exist many more singularities in parallel manipulators. At the singular point, the motion of the parallel manipulator is uncertain. In order to make parallel manipulators produce concrete output at singular points, and go away from singular points with the desired configuration, the method for the manipulator to pass through type-II singularities with its original configuration has been investigated in the paper. First, the semi-regular hexagon Gough—Stewart manipulator is taken as an example to analyse the configuration bifurcation characteristics at the vicinities of the type-II singularities going with the input parameters. The studies show that on different configuration branches, the singularity-free moving region is different, and there are two or four assembly configurations in the space above the base for the same group of input parameters. By researching transition behaviours of the configuration bifurcation curves under the disturbances applied to the other input parameters, it is found that under a suitable disturbance the perturbed persistent configuration will go away from the non-persistent configuration. Based on this kind of character, a novel method for the manipulator to pass through the turning point with its original configuration has been presented.
Research Note—Channel Structure with Knowledge Spillovers
Authors: Gupta Sudheer
Published: April 2008

We study two main questions in this paper: (1) How do spillovers of knowledge created by manufacturers' investments in process innovation affect channel structure and effort investment incentives? (2) What are the interactions between organizational incentives to form joint ventures and strategic alliances with competitors, and coordinate decisions vertically with downstream channel members? We focus on situations where spillovers are involuntary, firms' innovative activities are nonoverlapping, and firms benefit directly from the results of competitors' innovations. Under these conditions, we find that spillovers in process knowledge increase the likelihood of observing decentralized channel structures. Surprisingly, decentralized manufacturers invest more in process innovation than perfectly coordinated manufacturers do when spillovers are large. Moreover, in industries where large spillovers exist, horizontal cooperation among manufacturers induces higher levels of process innovation investments than channel coordination does. From a public policy perspective, however, the desirability of such cooperative arrangements among competitors depends on channel structure: joint ventures among decentralized manufacturers are more likely to meet the regulators' criteria of raising effort investments than cooperation among integrated manufacturers would be. Investment incentives are best provided when firms share their process knowledge and are buffered from subsequent price competition by independent retailers.
Research Note—Attention Arousal Through Price Partitioning
Authors: Bertini Marco , Wathieu Luc
Published: April 2008

Existing evidence suggests that preferences are affected by whether a price is presented as one all-inclusive expense or partitioned into a set of mandatory charges. To explain this phenomenon, we introduce a new mechanism whereby price partitioning affects a consumer's perception of the secondary (i.e., nonfocal) benefits derived from a transaction. Four experiments support the hypothesis that a partitioned price increases the amount of attention paid to secondary attributes tagged with distinct price components. Characteristics of the offered secondary attributes such as their perceived value, relative importance, and evaluability can therefore determine whether price partitioning stimulates or hinders demand. Beyond its descriptive and prescriptive implications, this theory contributes to the emerging notion that pricing can transform, as well as capture, the utility of an offer.
Research Note—Improving the Efficiency of Course Bidding at Business Schools: Field and Laboratory Studies
Authors: Krishna Aradhna , Ünver M. Utku
Published: April 2008

Registrars' offices at most universities face the daunting task of allocating course seats to students. Because demand exceeds supply for many courses, course allocation needs to be done equitably and efficiently. Many schools use bidding systems in which student bids are used both to infer preferences over courses and to determine student priorities for courses. However, this dual role of bids can result in course allocations not being market outcomes, and in unnecessary efficiency loss, which can potentially be avoided with the use of an appropriate market mechanism. We report the result of field and laboratory studies that compare a typical course-bidding mechanism with the alternate Gale-Shapley Pareto-dominant market mechanism. Results from the field study (conducted at the Ross School of Business, University of Michigan) suggest that using the latter could vastly improve efficiency of course allocation systems while facilitating market outcomes. Laboratory experiments with greater design control confirm the superior efficiency of the Gale-Shapley mechanism. The paper tests theory that has important practical implications because it has the potential to affect the learning experience of very large numbers of students enrolled in educational institutions.
A No-Arbitrage Analysis of Macroeconomic Determinants of the Credit Spread Term Structure
Authors: Wu Liuren , Zhang Frank Xiaoling
Published: April 2008

From a large array of economic and financial data series, this paper identifies three fundamental risk dimensions underlying an economy: inflation, real output growth, and financial market volatility. Furthermore, through a no-arbitrage model, the paper links the dynamics and market pricing of the three risk dimensions to the term structure of U.S. Treasury yields and corporate bond credit spreads. Model estimation shows that positive inflation shocks increase Treasury yields and widen credit spreads on corporate bonds across all maturities and credit-rating classes. Positive real output growth shocks also increase Treasury yields, but they suppress the credit spreads at low credit-rating classes, thus generating negative correlations between interest rates and credit spreads. The financial market volatility factor has a small and transient effect on the Treasury yield curve, but it exerts a strongly positive and persistent effect on the credit spread term structure. The paper provides a robust and internally consistent method for extracting systematic economic information from a large array of noisy observations and establishing how different risk dimensions of the fundamental economy interact with interest rate and credit risk.
Confirmed β16 Arg/Arg Polymorphism in a Patient with Uncontrolled Asthma
Authors: Metzger Nicole L , Kockler Denise R , Hylton Gravatt Leigh Anne
Published: April 2008

Objective:

To report a case of confirmed β16 Arg/Arg polymorphism (Arg/Arg) in a patient with uncontrolled asthma.

Case Summary:

A 49-year-old black female presented to the emergency department with acute shortness of breath with subsequent intubation. After extubation, she reported multiple hospitalizations for asthma with one prior intubation, adherence to asthma medications, and very frequent use of her short-acting β2-agonist (SABA). Because of her asthma history, self-reported adherence, and race, she was tested for β2-adrenoreceptor genotype, which revealed Arg/Arg. Based on these findings, β2-agonists were discontinued and tiotropium (maintenance) and ipratropium (primary rescue) were initiated as part of her asthma regimen. Application of the Naranjo probability scale revealed probable causality between uncontrolled asthma in our patient and SABA use. The patient is followed in our outpatient pulmonary clinic and, at time of writing, had not been admitted to our hospital for asthma-related events.

Discussion:

Approximately 15% of Americans with asthma are Arg/Arg, with an increased prevalence in black and Asian populations. It is hypothesized that changes in the degree of sensitivity or desensitization to the bronchodilator effect of β2-agonists may occur in these individuals. Data exist, although they are conflicting, suggesting that inhaled β2-agonists may worsen clinical outcomes. Trials have reported declines in peak expiratory flow rates plus increases in asthma symptoms and exacerbations when SABAs have been used regularly in patients with Arg/Arg. Studies evaluating long-acting β2-agonists (LABAs) have inconsistent results. Preliminary data suggest that anticholinergics may serve as a beneficial primary rescue medication instead of β2-agonists in patients with Arg/Arg.

Conclusions:

Clinicians should be aware of factors (eg, race and polymorphisms) that may predict unfavorable outcomes with regular SABA and possibly LABA use. Patients with poor asthma control despite adherence to asthma therapy may benefit from β2-adrenoreceptor genotyping and, possibly, from anticholinergics.
Cowhage-Evoked Itch Is Mediated by a Novel Cysteine Protease: A Ligand of Protease-Activated Receptors
Authors: Reddy Vemuri B. , Iuga Aurel O. , Shimada Steve G. , LaMotte Robert H. , Lerner Ethan A.
Published: April 2008

Cowhage spicules provide an important model for histamine-independent itch. We determined that the active component of cowhage, termed mucunain, is a novel cysteine protease. We isolated mucunain and demonstrate that both native and recombinant mucunain evoke the same quality of itch in humans. We also show that mucunain is a ligand for protease-activated receptors two and four. These results support and expand the relationship between proteases, protease-activated receptors, and itch.
Imaging of an Early Memory Trace in theDrosophilaMushroom Body
Authors: Wang Yalin , Mamiya Akira , Chiang Ann-shyn , Zhong Yi
Published: April 2008

Extensive molecular, genetic, and anatomical analyses have suggested that olfactory memory is stored in the mushroom body (MB), a higher-order olfactory center in the insect brain. The MB comprises three subtypes of neurons with axons that extend into different lobes. A recent functional imaging study has revealed a long-term memory trace manifested as an increase in the Ca2+activity in an axonal branch of a subtype of MB neurons. However, early memory traces in the MB remain elusive. We report here learning-induced changes in Ca2+activities during early memory formation in a different subtype of MB neurons. We used three independentin vivoandin vitropreparations, and all of them showed that Ca2+activities in the axonal branches of α′/β′ neurons in response to a conditioned olfactory stimulus became larger compared with one that was not conditioned. The changes were dependent on proper G-protein signaling in the MB. The importance of these changes in the Ca2+activity of α′/β′ neurons during early memory formation was further tested behaviorally by disrupting G-protein signaling in these neurons or blocking their synaptic outputs during the learning and memory process. Our results suggest that increased Ca2+activity in response to a conditioned olfactory stimulus may be a neural correlate of early memory in the MB.
The 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitor Lovastatin Reduces Severity of l-DOPA-Induced Abnormal Involuntary Movements in Experimental Parkinson's Disease
Authors: Schuster Stefan , Nadjar Agnès , Guo Jun Tang , Li Qin , Ittrich Carina , Hengerer Bastian , Bezard Erwan
Published: April 2008

Chronicl-3,4-dihydroxyphenylalanine (l-DOPA) treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termedl-DOPA-induced dyskinesia (LID), about which the rodent analog, the abnormal involuntary movements (AIMs), has been associated consistently with an activation of the Ras-extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase signaling pathway. Previous studies have shown that lovastatin, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity and subsequently the phosphorylation of ERK1/2 (pERK1/2). We hypothesized that lovastatin treatment-commenced previousl-DOPA exposure could reduce AIM incidence and severity in the 6-hydroxydopamine (6-OHDA) rat model of PD by secondarily preventing thel-DOPA/Benserazide-induced increase in pERK1 levels. The lovastatin-l-DOPA/Benserazide-treated 6-OHDA animals displayed less severe rotational behavior as well as a dramatic reduction in AIM severity than thel-DOPA/Benserazide-treated ones. Such lower AIM severity was associated with a decrease inl-DOPA-induced increase in the following: (1) striatal pERK1 and (2) ΔFosB levels, and (3) theta/α oscillations of substantia nigra pas reticulata (SNr) neurons as well as (4) a normalization of SNr firing frequency. Those results strongly suggest that lovastatin might represent a treatment option for managing LID in PD.
Conditional Loss of Dicer Disrupts Cellular and Tissue Morphogenesis in the Cortex and Hippocampus
Authors: Davis Tigwa H. , Cuellar Trinna L. , Koch Selina M. , Barker Allison J. , Harfe Brian D. , McManus Michael T. , Ullian Erik M.
Published: April 2008

To investigate the role of Dicer and microRNAs in the mammalian CNS, we used mice in which the second RNase III domain of Dicer was conditionally floxed. Conditional Dicer mice were bred with mice expressing an α-calmodulin kinase II Cre to selectively inactivate Dicer in excitatory forebrain neuronsin vivo. Inactivation of Dicer results in an array of phenotypes including microcephaly, reduced dendritic branch elaboration, and large increases in dendritic spine length with no concomitant change in spine density. Microcephaly is likely caused by a 5.5-fold increase in early postnatal apoptosis in these animals as determined by active caspase-3 and TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) staining in the cortex. Loss of Dicer function had no measurable effect on cortical lamination as determined byin situhybridization, suggesting that microcephaly is not caused by defects in neuronal migration. Together, these results illustrate thein vivosignificance of Dicer and miRNAs in the mammalian CNS and provide additional support for previousin vitrostudies indicating that misregulation of this pathway may result in gross abnormalities in cell number and function that may contribute to a variety of neurological disorders.