bluuebunny/crossref_metadata_2025 huggingface dataset:
Skip the Age of Playback
Authors: Kirschner Sebastian
Published: July 2012

Kathleen Higgins (2012) claims that emotional responses to music are mostly social constructs, derived from the cultural transmission of musical knowledge. I agree with this general idea, but question Higgins’ ethnocentric and narrow view, which reduces music mainly to the art of combining sounds to produce beauty of form and expression of emotion. Instead, I propose that the distinctive and unique behavior of active music-making evolved culturally to serve a range of adaptive functions in the social environments humans used to live in before the age of playback. Consequently, emotions perceived and induced via music should be studied in such “original” contexts.
Emotions as Transformational Structures
Authors: de Rivera Joseph
Published: July 2012

Emotions involve transformations of the relationships that exist in the “natural” world as well as in social worlds. Thus, the emotions that humans construct are based on affective processes that exist independently from human society and are not necessarily constituted by the interplay of culture and genetic or physiological processes.
The Sciences of the Artificial Emotions: Comment on Aylett and Paiva
Authors: Gratch Jonathan
Published: July 2012

This article offers a critical perspective on efforts to build computational models of human emotional processes. I argue that current computational scientists are missing an opportunity to bring simplicity and clarity to emotion research by adopting an overly literal interpretation of psychological theory. Rather, hearkening back to arguments from the early days of cognitive science, I suggest an approach of reinterpreting psychological phenomena through the lens of computation. I illustrate this approach through models of emotional dynamics and cultural differences.
Balancing Emotions between Constraints and Construction: Comment on Boiger and Mesquita
Authors: Semin Gün R.
Published: July 2012

Emotion events are undoubtedly socially constructed and emerge in interactions that take place in relationships; they are dynamic and situated in social-cultural contexts as Boiger and Mesquita (2012) argue. However, such constructions evolve within important limiting conditions set to human functioning. Our understanding of how emotional events are constructed can only be complete by assigning a central role to body, brain, and the social-physical conditions in the construction process, since these are critical constraints to human functioning.
Ur-Emotions: The Common Feature of Animal Emotions and Socially Constructed Emotions
Authors: Parrott W. Gerrod
Published: July 2012

Comparison of human and animal emotions reveals a fuzzy yet discernible boundary. Their undeniable similarities are more aptly described as ur-emotions than as basic emotions. This article describes how the concept of ur-emotion can be useful to animal researchers as well as to social constructionists by making sense of emotional variation both across species and across cultures.
Emotion Science Needs to Account for the Social World
Authors: Boiger Michael , Mesquita Batja
Published: July 2012

Emotions are complex processes that are constrained by biology, but not fully explained without taking into account the social context in which they develop. Mapping these contexts, and understanding how and under which conditions they shape emotions, is an essential task for the science of emotions; a task that—at least in psychology—has been neglected. The three commentaries each offer some interesting reflections on exactly this task.
Reply to Comments by Bainbridge, Gratch, and Nishida
Authors: Aylett Ruth , Paiva Ana
Published: July 2012

We respond to two themes in the comments by Bainbridge, Gratch, and Nishida: first, the importance of embodiment, and second the issue of what should be explicitly modelled as against what should be dynamically generated. Finally, we briefly respond to the ethical questions raised by Bainbridge.
Current Emotion Research in Sociology: Advances in the Discipline
Authors: Stets Jan E.
Published: July 2012

This article provides a survey and analysis of recent research in the sociology of emotions. I address theoretical advances by discussing three theories that have been making some inroads into the study of emotions: identity theory, exchange theory, and justice theory. I also address substantive advances including an analysis of specific emotions and emotions as they relate to economic activity and labor. Finally, I discuss some innovative developments that show promise for future research in the area. Overall, the sociology of emotions remains an active area of research; however, there is still work that needs to be done. Throughout this article, I suggest avenues for further research.
Safety and efficacy of iron chelation therapy with deferiprone in patients with transfusion-dependent thalassemia
Authors: Jamuar Saumya S. , Lai Angeline H.M.
Published: July 2012

Deferiprone is an orally active iron-chelating agent used in the management of transfusion-related hemosiderosis. It has been in clinical use for over 20 years and has been shown to be effective in reducing cardiac iron load and improving cardiac function. As cardiac siderosis is the leading cause of death in patients with transfusion-dependent thalassemia, deferiprone helps to improve the overall prognosis of these patients. It is relatively well tolerated with gastrointestinal symptoms being the commonest side effects. Agranulocytosis (0.5%), neutropenia (9%), thrombocytopenia (up to 45%) and arthropathy (20%) are the most important side effects and may require discontinuation of therapy. Regular monitoring of blood counts is recommended for patients on deferiprone therapy.
Utilising friction spot joining for dissimilar joint between aluminium alloy (A5052) and polyethylene terephthalate
Authors: Yusof F , Miyashita Y , Seo N , Mutoh Y , Moshwan R
Published: July 2012

The weld strength of thermoplastics with aluminium alloy, such as high density polyethylene and polypropylene sheets, is influenced by friction stir welding parameters. This paper focuses on the preliminary investigation of joining parameter at various levels as well as the mechanical properties of friction spot joining (FSJ) of aluminium alloy (A5052) to polyethylene terephthalate (PET). A number of FSJ experiments were carried out to obtain optimum mechanical properties by adjusting the plunge speed and plunge depth in the ranges of 5–40 mm min−1 and 0·4–0·7 mm respectively, while spindle speed remains constant at 3000 rev min−1. The results indicated that A5052 and PET successfully joined with the aid of frictional heat energy originated from the friction spot welding process. The effect of plunge speed on the joined area and the effect of formation of bubbles at the interface of joints on the shear strength of joint are discussed.
Effect of Sc and Zr alloying on microstructure and precipitation evolution of as cast Al–B4C metal matrix composites
Authors: Lai J , Zhang Z , Chen X-G
Published: July 2012

Additions of Sc and Zr were introduced into Al–15 vol.-B4C composites, and eight experimental composites with different Sc and Zr levels were prepared via a conventional cast process. Optical microscopy, SEM and TEM were applied for observing the as cast microstructures, including the interfaces between the Al matrix and the B4C as well as the evolution of the precipitates. It was found that Sc involved the interfacial reactions with B4C that partially consumed the Sc. On the other hand, no major Zr reaction products were found in the interfaces, and the major part of Zr remained in the matrix for precipitation strengthening. The Sc addition yielded considerable precipitation strengthening in the as cast and peak aged conditions. The combination of Sc and Zr significantly enhanced the precipitation strengthening. Nanoscale precipitates Al3Sc and Al3(Sc,Zr) were found in the as cast microstructure and contributed to the significant increase of matrix hardness.
Nanostructured martensite–austenite dual phase steels
Authors: Hu F , Wu K M , Misra R D K
Published: July 2012

Nanostructured martensite–austenite microstructure was achieved by a quenching–partitioning–tempering (Q–P–T) treatment of high carbon low temperature bainitic steel. Microstructure observations showed that the nanostructured steel consisted of fine martensite (about 25 nm in thickness), retained austenite and carbides. X-ray diffraction analysis indicated that carbon was partitioned into austenite after martensite transformation. High hardness (about 655 HV1) and relatively high retained austenite fraction (0·36–0·41) was attained. The heat treatment times were greatly reduced, nearly equal or higher hardness and retained austensite fraction were achieved by Q–P–T treatment, compared with low temperature super bainite process.
Chevkinite-group minerals from Russia and Mongolia: new compositional data from metasomatites and ore deposits
Authors: Macdonald R. , Bagiński B. , Kartashov P. , Zozulya D. , Dzierżanowski P.
Published: July 2012

Electron-microprobe analyses of Russian and Mongolian chevkinite-group minerals from little-known host lithologies, including various metasomatic rocks, quartzolites and an apatite deposit, are presented. The mineral species analysed include chevkinite-(Ce), perrierite-(Ce), polyakovite-(Ce) and Sr- and Zr-rich perrierite-(Ce). Compositional variation in the Sr-rich members of the group is broadly represented by the exchange vector (Fe + Mn + Al + REE) ↔ (Ca + Sr + Ti + Zr). Despite the varied parageneses, the chevkinite-(Ce) compositions are similar to previously published data. Many crystals have strong internal compositional variations, partly produced during primary crystallization and partly during low-temperature hydrothermal alteration.
Comments on the eruption of basaltic magma at Tor Zawar, Balochistan, Pakistan on 27 January 2010, with a discussion of the geochemical and petrological constraints on its petrogenesis
Authors: Kassi A. M. , Kasi A. K. , Khan A. Tawab , Khan A. Salam
Published: July 2012

An article by A. C. Kerr and coworkers published in 2010 in Mineralogical Magazine (74, 1027–1036), reviewed an event that was interpreted as the eruption of a basaltic flow on 27th January 2010, at Tor Zawar, Ziarat, Pakistan. The regional and local geology, volcanological aspects, petrography and major-element and trace-element analyses of two samples were presented. On the basis of these data it was proposed that this was a magmatic event and that the lava was derived from the mantle. On the basis of our extensive field work in the this area, and observations at the site of another similar incident that happened almost a year later (in January 2011) ∼300 m north of the first locality, we wish to clarify the geological context and propose an alternative origin.

Our field observations suggest that both events were the result of localized surface melting at the base of metal electricity pylons, and their associated steel cable supports. The metal pylons and cable supports provided a path to earth for lightning discharges into the volcanic conglomerate of the Late Cretaceous Bibai Formation. We propose that this transmitted sufficient energy to melt the outcrop. We disagree with the proposal that the 'lava flows' at Tor Zawar were magmatic events and that the rocks formed are derived from the mantle. Alternatively, we propose that these 'lavas' were produced in a manner similar to fulgurites.
Xenotime-(Y) and Sn-rich thortveitite in miarolitic pegmatites from Baveno, Southern Alps, Italy
Authors: Guastoni A. , Nestola F. , Ferraris C. , Parodi G.
Published: July 2012

Xenotime-(Y), (Y,REE)PO4, and thortveitite, (Sc, Y)2Si2O7, in a miarolitic cavity in a niobium, yttrium, fluorine (NYF) granitic pegmatite at Baveno, Verbania, Southern Alps, Italy, were investigated by electron microprobe analysis and single-crystal X-ray diffraction. Fluorine has an important role as a complexing agent for Y and REEs in supercritical pegmatitic fluids; annitesiderophyllite and chamosite are the most likely sources of the Y and REEs. The thortveitite from Baveno contains up to 3.20 wt.% SnO2, an unusually high Sn content. Xenotime-(Y) is enriched in Gd in comparison to other Alpine xenotimes. Quantitative chemical data and measurements of the lattice parameters show that a higher scandium content results in a smaller unit-cell volume in thortveitite. The substitution of REEs for Y up to ∼20 mol.% has little effect on the unit cell of xenotime-(Y). The textures of xenotime-(Y) and thortveitite provide information about the dissolution and crystallization processes in the miarolitic cavity.
Microbial effects on mineral–radionuclide interactions and radionuclide solid-phase capture processes
Authors: Brookshaw D. R. , Pattrick R. A. D. , Lloyd J. R. , Vaughan D. J.
Published: July 2012

Understanding the environmental and biogeochemical behaviour of radionuclides is essential for managing our nuclear legacy safely. Remediation efforts and the concept of geological disposal of nuclear waste focus on immobilizing radionuclides within the subsurface. Here we review recent developments in the understanding of solid-phase capture processes of Cs, Sr, Tc, U, Pu and Np. Abiotic interactions between minerals and these radionuclides (including sorption, reductive precipitation and co-precipitation) have been studied in various conditions. Microbially driven processes are much less well characterized, for example the effects of microbial reduction on the structure and reactivity of existing minerals, or their role in the formation of new minerals. Metabolites released by bacteria can play a role in both mineral dissolution and formation, and better understanding their release and role in mineralization has great potential in the development of solid-phase capture processes for radionuclides.

With the aid of a map of the research landscape covered by this review (created using a cluster-analysis tool, a self-organizing map), we highlight the most promising sequestration processes for specific radionuclides. However, radionuclides exhibit highly species-specific behaviour in their interactions with minerals and microorganisms. More research is required to characterize the role mineral surfaces play in bioreductive immobilization of Pu and Np, the reduction products formed, and their relative stability. Further studies should concentrate on more environmentally relevant experiments that include bacteria, minerals and radionuclides.
Minimalist ensemble algorithms for genome-wide protein localization prediction
Authors: Lin Jhih-Rong , Mondal Ananda Mohan , Liu Rong , Hu Jianjun
Published: July 2012

Background

Computational prediction of protein subcellular localization can greatly help to elucidate its functions. Despite the existence of dozens of protein localization prediction algorithms, the prediction accuracy and coverage are still low. Several ensemble algorithms have been proposed to improve the prediction performance, which usually include as many as 10 or more individual localization algorithms. However, their performance is still limited by the running complexity and redundancy among individual prediction algorithms.

Results

This paper proposed a novel method for rational design of minimalist ensemble algorithms for practical genome-wide protein subcellular localization prediction. The algorithm is based on combining a feature selection based filter and a logistic regression classifier. Using a novel concept of contribution scores, we analyzed issues of algorithm redundancy, consensus mistakes, and algorithm complementarity in designing ensemble algorithms. We applied the proposed minimalist logistic regression (LR) ensemble algorithm to two genome-wide datasets of Yeast and Human and compared its performance with current ensemble algorithms. Experimental results showed that the minimalist ensemble algorithm can achieve high prediction accuracy with only 1/3 to 1/2 of individual predictors of current ensemble algorithms, which greatly reduces computational complexity and running time. It was found that the high performance ensemble algorithms are usually composed of the predictors that together cover most of available features. Compared to the best individual predictor, our ensemble algorithm improved the prediction accuracy from AUC score of 0.558 to 0.707 for the Yeast dataset and from 0.628 to 0.646 for the Human dataset. Compared with popular weighted voting based ensemble algorithms, our classifier-based ensemble algorithms achieved much better performance without suffering from inclusion of too many individual predictors.

Conclusions

We proposed a method for rational design of minimalist ensemble algorithms using feature selection and classifiers. The proposed minimalist ensemble algorithm based on logistic regression can achieve equal or better prediction performance while using only half or one-third of individual predictors compared to other ensemble algorithms. The results also suggested that meta-predictors that take advantage of a variety of features by combining individual predictors tend to achieve the best performance. The LR ensemble server and related benchmark datasets are available at http://mleg.cse.sc.edu/LRensemble/cgi-bin/predict.cgi.
Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea
Authors: Dayyat Ehab A , Zhang Shelley X , Wang Yang , Cheng Zixi Jack , Gozal David
Published: July 2012

Background

In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Such findings are markedly attenuated in rodents exposed to sustained hypoxia 9SH) of similar magnitude. The hypoxia-sensitive gene erythropoietin (EPO) has emerged as a major endogenous neuroprotectant, and could be involved in IH-induced neuronal dysfunction.

Methods and Results

IH induced only transiently increased expression of EPO mRNA in hippocampus, which was continued in (SH)-exposed mice. IH, but not SH, adversely affected two forms of spatial learning in the water maze, and increased markers of oxidative stress. However, on a standard place training task, mice treated with exogenously administered EPO displayed normal learning, and were protected from the spatial learning deficits observed in vehicle-treated (C) littermates exposed to IH. Moreover, anxiety levels were increased in IH as compared to normoxia, while no changes in anxiety emerged in EPO-treated mice. Additionally, C mice, but not EPO-treated IH-exposed mice had significantly elevated levels of NADPH oxidase expression, as well as increased MDA and 8-OHDG levels in cortical and hippocampal lysates.

Conclusions

The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by imbalances between EPO expression and increased NADPH oxidase activity, and thus pharmacological agents targeting EPO expression in CNS may provide a therapeutic strategy in sleep-disordered breathing.
Phosphorylation of transglutaminase 2 (TG2) at serine-216 has a role in TG2 mediated activation of nuclear factor-kappa B and in the downregulation of PTEN
Authors: Wang Yi , Ande Sudharsana R , Mishra Suresh
Published: July 2012

Background

Transglutaminase 2 (TG2) and its phosphorylation have been consistently found to be upregulated in a number of cancer cell types. At the molecular level, TG2 has been associated with the activation of nuclear factor-kappa B (NF-κB), protein kinase B (PKB/Akt) and in the downregulation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). However, the underlying mechanism involved is not known. We have reported that protein kinase A (PKA) induced phosphorylation of TG2 at serine-216 (Ser216) regulates TG2 function and facilitates protein-protein interaction. However, the role of TG2 phosphorylation in the modulation of NF-κB, Akt and PTEN is not explored.

Methods

In this study we have investigated the effect of TG2 phosphorylation on NF-κB, Akt and PTEN using embryonic fibroblasts derived from TG2 null mice (MEF
tg2-/-
) overexpressing native TG2 or mutant-TG2 (m-TG2) lacking Ser216 phosphorylation site with and without dibutyryl cyclic-AMP (db-cAMP) stimulation. Functional consequences on cell cycle and cell motility were determined by fluorescence activated cell sorting (FACS) analysis and cell migration assay respectively.

Results

PKA activation in TG2 overexpressing MEF
tg2-/-
cells resulted in an increased activation of NF-κB and Akt phosphorylation in comparison to empty vector transfected control cells as determined by the reporter-gene assay and immunoblot analysis respectively. These effects were not observed in MEF
tg2-/-
cells overexpressing m-TG2. Similarly, a significant downregulation of PTEN at both, the mRNA and protein levels were found in cells overexpressing TG2 in comparison to empty vector control and m-TG2 transfected cells. Furthermore, Akt activation correlated with the simultaneous activation of NF-κB and a decrease in PTEN suggesting that the facilitatory effect of TG2 on Akt activation occurs in a PTEN-dependent manner. Similar results were found with MCF-7 and T-47D breast cancer cells overexpressing TG2 and m-TG2 further supporting the role of TG2 phosphorylation in NF-κB activation and in the downregulation of PTEN.

Conclusions

Collectively, these data suggest that phosphorylation of TG2 at Ser216 plays a role in TG2 mediated activation of NF-κB, Akt and in the downregulation of PTEN. Blocking TG2 phosphorylation may provide a novel strategy to attenuate NF-κB activation and downregulation of PTEN in TG2 overexpressing cancers.
Effect of physical activity and sun exposure on vitamin D status of Saudi children and adolescents
Authors: Al-Othman Abdulaziz , Al-Musharaf Sara , Al-Daghri Nasser M , Krishnaswamy Soundararajan , Yusuf Deqa S , Alkharfy Khalid M , Al-Saleh Yousef , Al-Attas Omar S , Alokail Majed S , Moharram Osama , Sabico Shaun , Chrousos George P
Published: July 2012

Background

Accumulating evidence suggests an increased prevalence of vitamin D deficiency in the Middle East. In this context, we aimed to determine whether the prevalence of vitamin D deficiency is related to degree of physical activity and sun exposure among apparently healthy Saudi children and adolescents, a little studied population.

Methods

A total of 331 Saudi children aged 6–17 years (153 boys and 178 girls) were included in this cross sectional study. Levels of physical activity and sun exposure were determined using a standard questionnaire. Anthropometry, serum calcium and 25-(OH) vitamin D were analyzed.

Results

All subjects were vitamin D deficient, the majority being moderately deficient (71.6%). Age was the single most significant predictor affecting 25 (OH) Vitamin D levels, explaining 21% of the variance perceived (p = 1.68 x 10-14). Age-matched comparisons revealed that for groups having the same amount of sun exposure, those with moderate or are physically active will have higher levels of vitamin D status, though levels in across groups remained deficient.

Conclusion

Vitamin D deficiency is common among Saudi children and adolescents, and is influenced by both sun exposure and physical activity. Promotion of an active outdoor lifestyle among Saudi children in both homes and schools may counteract the vitamin D deficiency epidemic in this vulnerable population. Vitamin D supplementation is suggested in all groups, including those with the highest sun exposure and physical activity.
Glycoside Hydrolases from a targeted Compost Metagenome, activity-screening and functional characterization
Authors: Dougherty Michael J , D’haeseleer Patrik , Hazen Terry C , Simmons Blake A , Adams Paul D , Hadi Masood Z
Published: July 2012

Background

Metagenomics approaches provide access to environmental genetic diversity for biotechnology applications, enabling the discovery of new enzymes and pathways for numerous catalytic processes. Discovery of new glycoside hydrolases with improved biocatalytic properties for the efficient conversion of lignocellulosic material to biofuels is a critical challenge in the development of economically viable routes from biomass to fuels and chemicals.

Results

Twenty-two putative ORFs (open reading frames) were identified from a switchgrass-adapted compost community based on sequence homology to related gene families. These ORFs were expressed in E. coli and assayed for predicted activities. Seven of the ORFs were demonstrated to encode active enzymes, encompassing five classes of hemicellulases. Four enzymes were over expressed in vivo, purified to homogeneity and subjected to detailed biochemical characterization. Their pH optima ranged between 5.5 - 7.5 and they exhibit moderate thermostability up to ~60-70°C.

Conclusions

Seven active enzymes were identified from this set of ORFs comprising five different hemicellulose activities. These enzymes have been shown to have useful properties, such as moderate thermal stability and broad pH optima, and may serve as the starting points for future protein engineering towards the goal of developing efficient enzyme cocktails for biomass degradation under diverse process conditions.
An inverse metabolic engineering approach for the design of an improved host platform for over-expression of recombinant proteins in Escherichia coli
Authors: Ghosh Chaitali , Gupta Rashmi , Mukherjee Krishna Jyoti
Published: July 2012

Background

A useful goal for metabolic engineering would be to generate non-growing but metabolically active quiescent cells which would divert the metabolic fluxes towards product formation rather than growth. However, for products like recombinant proteins, which are intricately coupled to the growth process it is difficult to identify the genes that need to be knocked-out/knocked-in to get this desired phenotype. To circumvent this we adopted an inverse metabolic engineering strategy which would screen for the desired phenotype and thus help in the identification of genetic targets which need to be modified to get overproducers of recombinant protein. Such quiescent cells would obviate the need for high cell density cultures and increase the operational life span of bioprocesses.

Results

A novel strategy for generating a library, consisting of randomly down regulated metabolic pathways in E. coli was designed by cloning small genomic DNA fragments in expression vectors. Some of these DNA fragments got inserted in the reverse orientation thereby generating anti-sense RNA upon induction. These anti-sense fragments would hybridize to the sense mRNA of specific genes leading to gene ‘silencing’. This library was first screened for slow growth phenotype and subsequently for enhanced over-expression ability. Using Green Fluorescent Protein (GFP) as a reporter protein on second plasmid, we were able to identify metabolic blocks which led to significant increase in expression levels. Thus down-regulating the ribB gene (3, 4 dihydroxy-2-butanone-4-phosphate synthase) led to a 7 fold increase in specific product yields while down regulating the gene kdpD (histidine kinase) led to 3.2 fold increase in specific yields.

Conclusion

We have designed a high throughput screening approach which is a useful tool in the repertoire of reverse metabolic engineering strategies for the generation of improved hosts for recombinant protein expression.
Diesel exhaust increases EGFR and phosphorylated C-terminal Tyr 1173 in the bronchial epithelium
Authors: Pourazar Jamshid , Blomberg Anders , Kelly Frank J , Davies Donna E , Wilson Susan J , Holgate Stephen T , Sandström Thomas
Published: July 2012

Background

Epidemiological studies have demonstrated adverse health effects of environmental pollution. Diesel exhaust (DE) is a major contributor to particulate matter pollution. DE exposure has been shown to induce a pronounced inflammatory response in the airways, together with an enhanced epithelial expression of cytokines such as IL-8, Gro-α, IL-13 and activation of redox sensitive transcription factors (NFκB, AP-1), and MAP kinases (p38, JNK). The aim of the present investigation was to elucidate the involvement of the epidermal growth factor receptor (EGFR) signalling pathway in the epithelial response to DEin-vivo.

Results

Immunohistochemical staining was used to quantify the expression of the EGFR, phosphorylated Tyrosine residues, MEK and ERK in the bronchial epithelium of archived biopsies from 15 healthy subjects following exposure to DE (PM10, 300 μg/m3) and air. DE induced a significant increases in the expression of EGFR (p = 0.004) and phosphorylated C-terminal Tyr 1173 (p = 0.02). Other investigated EGFR tyrosine residues, Src related tyrosine (Tyr 416), MEK and ERK pathway were not changed significantly by DE.

Conclusion

Exposure to DE (PM10, 300 μg/m3) caused enhanced EGFR expression and phosphorylation of the tyrosine residue (Tyr 1173) which is in accordance with the previously demonstrated activation of the JNK, AP-1, p38 MAPK and NFkB pathways and associated downstream signalling and cytokine production. No effects were seen on the MEK and ERK pathway suggesting that at the investigated time point (6 hours post exposure) there was no proliferative/differentiation signalling in the bronchial epithelium. The present findings suggest a key role for EGFR in the bronchial response to diesel exhaust.
Cutaneous Tactile Allodynia Associated with Microvascular Dysfunction in Muscle
Authors: Laferrière Andre , Millecamps Magali , Xanthos Dimitris N , Xiao Wen Hua , Siau Chiang , de Mos Marissa , Sachot Christelle , Ragavendran J Vaigunda , Huygen Frank JPM , Bennett Gary J , Coderre Terence J
Published: July 2012

Background:

Cutaneous tactile allodynia, or painful hypersensitivity to mechanical stimulation of the skin, is typically associated with neuropathic pain, although also present in chronic pain patients who do not have evidence of nerve injury. We examine whether deep tissue microvascular dysfunction, a feature common in chronic non-neuropathic pain, contributes to allodynia.

Results:

Persistent cutaneous allodynia is produced in rats following a hind paw ischemia-reperfusion injury that induces microvascular dysfunction, including arterial vasospasms and capillary slow flow/no-reflow, in muscle. Microvascular dysfunction leads to persistent muscle ischemia, a reduction of intraepidermal nerve fibers, and allodynia correlated with muscle ischemia, but not with skin nerve loss. The affected hind paw muscle shows lipid peroxidation, an upregulation of nuclear factor kappa B, and enhanced pro-inflammatory cytokines, while allodynia is relieved by agents that inhibit these alterations. Allodynia is increased, along with hind paw muscle lactate, when these rats exercise, and is reduced by an acid sensing ion channel antagonist.

Conclusion:

Our results demonstrate how microvascular dysfunction and ischemia in muscle can play a critical role in the development of cutaneous allodynia, and encourage the study of how these mechanisms contribute to chronic pain. We anticipate that focus on the pain mechanisms associated with microvascular dysfunction in muscle will provide new effective treatments for chronic pain patients with cutaneous tactile allodynia.
Pathway-based classification of cancer subtypes
Authors: Kim Shinuk , Kon Mark , DeLisi Charles
Published: July 2012

Background

Molecular markers based on gene expression profiles have been used in experimental and clinical settings to distinguish cancerous tumors in stage, grade, survival time, metastasis, and drug sensitivity. However, most significant gene markers are unstable (not reproducible) among data sets. We introduce a standardized method for representing cancer markers as 2-level hierarchical feature vectors, with a basic gene level as well as a second level of (more stable) pathway markers, for the purpose of discriminating cancer subtypes. This extends standard gene expression arrays with new pathway-level activation features obtained directly from off-the-shelf gene set enrichment algorithms such as GSEA. Such so-called pathway-based expression arrays are significantly more reproducible across datasets. Such reproducibility will be important for clinical usefulness of genomic markers, and augment currently accepted cancer classification protocols.

Results

The present method produced more stable (reproducible) pathway-based markers for discriminating breast cancer metastasis and ovarian cancer survival time. Between two datasets for breast cancer metastasis, the intersection of standard significant gene biomarkers totaled 7.47% of selected genes, compared to 17.65% using pathway-based markers; the corresponding percentages for ovarian cancer datasets were 20.65% and 33.33% respectively. Three pathways, consisting of Type_1_diabetes mellitus, Cytokine-cytokine_receptor_interaction and Hedgehog_signaling (all previously implicated in cancer), are enriched in both the ovarian long survival and breast non-metastasis groups. In addition, integrating pathway and gene information, we identified five (ID4, ANXA4, CXCL9, MYLK, FBXL7) and six (SQLE, E2F1, PTTG1, TSTA3, BUB1B, MAD2L1) known cancer genes significant for ovarian and breast cancer respectively.

Conclusions

Standardizing the analysis of genomic data in the process of cancer staging, classification and analysis is important as it has implications for both pre-clinical as well as clinical studies. The paradigm of diagnosis and prediction using pathway-based biomarkers as features can be an important part of the process of biomarker-based cancer analysis, and the resulting canonical (clinically reproducible) biomarkers can be important in standardizing genomic data. We expect that identification of such canonical biomarkers will improve clinical utility of high-throughput datasets for diagnostic and prognostic applications.

Reviewers

This article was reviewed by John McDonald (nominated by I. King Jordon), Eugene Koonin, Nathan Bowen (nominated by I. King Jordon), and Ekaterina Kotelnikova (nominated by Mikhail Gelfand).
Designing a strategy to implement cost-effective blood transfusion management in elective hip and knee arthroplasties: A study protocol
Authors: Voorn Veronique MA , Marang-van de Mheen Perla J , So-Osman Cynthia , Vliet Vlieland Thea PM , Koopman-van Gemert Ankie WMM , Nelissen Rob GHH , van Bodegom-Vos Leti ,   for the LISBOA study group
Published: June 2012

Background

Total hip and knee arthroplasties are two of the most commonly performed procedures in orthopedic surgery. Different blood-saving measures (BSMs) are used to reduce the often-needed allogenic blood transfusions in these procedures. A recent large randomized controlled trial showed it is not cost effective to use the BSMs of erythropoietin and perioperative autologous blood salvage in elective primary hip and knee arthroplasties. Despite dissemination of these study results, medical professionals keep using these BSMs. To actually change practice, an implementation strategy is needed that is based on a good understanding of target groups and settings and the psychological constructs that predict behavior of medical professionals. However, detailed insight into these issuses is lacking. Therefore, this study aims to explore which groups of professionals should be targeted at which settings, as well as relevant barriers and facilitators that should be taken into acount in the strategy to implement evidence-based, cost-effective blood transfusion management and to de-implement BSMs.

Methods

The study consists of three phases. First, a questionnaire survey among all Dutch orthopedic hospital departments and independent treatment centers (n = 99) will be conducted to analyze current blood management practice. Second, semistructured interviews will be held among 10 orthopedic surgeons and 10 anesthesiologists to identify barriers and facilitators that are relevant for the uptake of cost-effective blood transfusion management. Interview questions will be based on the Theoretical Domains Interview framework. The interviews will be followed by a questionnaire survey among 800 medical professionals in orthopedics and anesthesiology (400 professionals per discipline) in which the identified barriers and facilitators will be ranked by frequency and importance. Finally, an implementation strategy will be developed based on the results from the previous phases, using principles of intervention mapping and an expert panel.

Discussion

The developed strategy for cost-effective blood transfusion management by de-implementing BSMs is likely to reduce costs for elective hip and knee arthroplasties. In addition, this study will lead to generalized knowledge regarding relevant factors for the de-implementation of non-cost-effective interventions and insight in the differences between implementation and de-implementation strategies.
Biochemical and cellular implications of a dual lipase-GEF function of phospholipase D2 (PLD2)
Authors: Gomez-Cambronero Julian
Published: July 2012

Review of GEF, a key for leukocyte chemotaxis, described as a new role of phospholipase D in cellular functions.

PLD2 plays a key role in cell membrane lipid reorganization and as a key cell signaling protein in leukocyte chemotaxis and phagocytosis. Adding to the large role for a lipase in cellular functions, recently, our lab has identified a PLD2-Rac2 binding through two CRIB domains in PLD2 and has defined PLD2 as having a new function, that of a GEF for Rac2. PLD2 joins other major GEFs, such as P-Rex1 and Vav, which operate mainly in leukocytes. We explain the biochemical and cellular implications of a lipase-GEF duality. Under normal conditions, GEFs are not constitutively active; instead, their activation is highly regulated. Activation of PLD2 leads to its localization at the plasma membrane, where it can access its substrate GTPases. We propose that PLD2 can act as a “scaffold” protein to increase efficiency of signaling and compartmentalization at a phagocytic cup or the leading edge of a leukocyte lamellipodium. This new concept will help our understanding of leukocyte crucial functions, such as cell migration and adhesion, and how their deregulation impacts chronic inflammation.
The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity
Authors: Chang Tammy T , Walther Isabelle , Li Chai-Fei , Boonyaratanakornkit Jim , Galleri Grazia , Meloni Maria Antonia , Pippia Proto , Cogoli Augusto , Hughes-Fulford Millie
Published: July 2012

Transactivation of immediate early genes, especially targets of the Rel/NFκB pathway, is disrupted in T cells activated in microgravity.

This study tested the hypothesis that transcription of immediate early genes is inhibited in T cells activated in μg. Immunosuppression during spaceflight is a major barrier to safe, long-term human space habitation and travel. The goals of these experiments were to prove that μg was the cause of impaired T cell activation during spaceflight, as well as understand the mechanisms controlling early T cell activation. T cells from four human donors were stimulated with Con A and anti-CD28 on board the ISS. An on-board centrifuge was used to generate a 1g simultaneous control to isolate the effects of μg from other variables of spaceflight. Microarray expression analysis after 1.5 h of activation demonstrated that μg- and 1g-activated T cells had distinct patterns of global gene expression and identified 47 genes that were significantly, differentially down-regulated in μg. Importantly, several key immediate early genes were inhibited in μg. In particular, transactivation of Rel/NF-κB, CREB, and SRF gene targets were down-regulated. Expression of cREL gene targets were significantly inhibited, and transcription of cREL itself was reduced significantly in μg and upon anti-CD3/anti-CD28 stimulation in simulated μg. Analysis of gene connectivity indicated that the TNF pathway is a major early downstream effector pathway inhibited in μg and may lead to ineffective proinflammatory host defenses against infectious pathogens during spaceflight. Results from these experiments indicate that μg was the causative factor for impaired T cell activation during spaceflight by inhibiting transactivation of key immediate early genes.
poly(I:C) costimulation induces a stronger antiviral chemokine and granzyme B release in human CD4 T cells than CD28 costimulation
Authors: Meyer Tim , Oberg Hans-Heinrich , Peters Christian , Martens Ina , Adam-Klages Sabine , Kabelitz Dieter , Wesch Daniela
Published: July 2012

Poly(I:C) mediated NFκB - and IRF7-activation is stronger than co-stimulatory anti-CD28 mAb, thereby increasing antiviral chemokine and granzyme B release in CD4 T cells.

dsRNA is frequently associated with viral replication. Here, we compared the costimulatory effect of the synthetic analog of dsRNA, poly(I:C), and the agonistic anti-CD28 mAb on anti-CD3 mAb-activated, freshly isolated human CD4 T cells. We tested the hyphothesis that poly(I:C) and anti-CD28 mAb costimulation differ in their effect on the CD4 T cell immune response. Our study shows that costimulation of CD4 T cells by poly(I:C) enhanced CD3-induced production of IP-10, MIP1-α/β, RANTES, and granzyme B involved in antiviral activity more than anti-CD28 mAb. poly(I:C) stimulation, on its own, activated the transcription of IRF7 in human CD4 T cells. Combined CD3 and poly(I:C) stimulation significantly enhanced the transcription of IRF7 and additionally, NF-κBp65 phosphorylation, which might be involved in the induction of antiviral chemokines and the enhanced cytotoxic activity of poly(I:C)-treated CD4 T cells. In comparison with poly(I:C), anti-CD28 mAb as a costimulus induced a stronger proinflammatory response, as indicated by enhanced TNF-α secretion. poly(I:C) had a costimulatory effect on Akt phosphorylation, whereas anti-CD28 mAb only slightly enhanced Akt phosphorylation. In contrast to poly(I:C), anti-CD28 mAb was essential for proliferation of anti-CD3-stimulated CD4 T cells; however, poly(I:C) further increased the anti-CD28/anti-CD3-mediated proliferation. These results indicate that poly(I:C)- and anti-CD28 mAb-induced signaling differ in their costimulatory effect on the CD3-driven, antiviral chemokine release and proinflammatory cytokine secretion in freshly isolated human CD4 T cells.
Activation of type I interferon-dependent genes characterizes the “core response” induced by CpG DNA
Authors: Steinhagen Folkert , Meyer Corinna , Tross Debra , Gursel Mayda , Maeda Takahiro , Klaschik Sven , Klinman Dennis M
Published: July 2012

Structurally diverse CpG oligonucleotides have a shared ability to activate IFN-dependent ‘core genes’ with antiviral activity while maintaining sequence-specific effects on human pDC.

Synthetic ODNs expressing CpG motifs trigger an innate immune response via TLR9. pDCs are major effectors of this response. Two structurally distinct classes of CpG ODNs have been identified that differentially activate pDCs. “K” ODNs trigger the production of TNF-α and IL-6, whereas “D” ODNs preferentially induce the secretion of IFN-α. As K and D ODNs have distinct therapeutic effects, knowledge of their shared and sequence-specific activity is of considerable importance. This work uses the CAL-1 human pDC line to analyze the effect of CpG stimulation on gene expression. Genes up-regulated by both K and D ODNs (n=92) were largely dependent on type I IFN signaling and characterized functionally by antiviral activity. K ODNs induced a short-term increase in IFN-α/β production and uniquely up-regulated genes that supported antibacterial responses. In contrast, D ODNs triggered a persistent increase in IFN-α/β production and uniquely up-regulated genes associated with metabolic functions. Thus, the core functionality of human pDCs mediated by TLR9 ligation rests on a type I IFN response that differs from the response induced by the structural elements unique to specific classes of ODNs.
Randomized Phase II Study of Dacomitinib (PF-00299804), an Irreversible Pan–Human Epidermal Growth Factor Receptor Inhibitor, Versus Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Ramalingam Suresh S. , Blackhall Fiona , Krzakowski Maciej , Barrios Carlos H. , Park Keunchil , Bover Isabel , Seog Heo Dae , Rosell Rafael , Talbot Denis C. , Frank Richard , Letrent Stephen P. , Ruiz-Garcia Ana , Taylor Ian , Liang Jane Q. , Campbell Alicyn K. , O'Connell Joseph , Boyer Michael
Published: July 2012

Purpose

This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily.

Results

One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib.

Conclusion

Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.
Lymphatic Mapping and Sentinel Lymph Node Biopsy in Women With Squamous Cell Carcinoma of the Vulva: A Gynecologic Oncology Group Study
Authors: Levenback Charles F. , Ali Shamshad , Coleman Robert L. , Gold Michael A. , Fowler Jeffrey M. , Judson Patricia L. , Bell Maria C. , De Geest Koen , Spirtos Nick M. , Potkul Ronald K. , Leitao Mario M. , Bakkum-Gamez Jamie N. , Rossi Emma C. , Lentz Samuel S. , Burke James J. , Van Le Linda , Trimble Cornelia L.
Published: July 2012

Purpose

To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer.

Patients and Methods

Eligible women had squamous cell carcinoma, at least 1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed.

Results

In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%).

Conclusion

Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.