bluuebunny/crossref_metadata_2025 huggingface dataset:
The Ontario nuclear power dispute: a strategic analysis
Authors: Armin Motahareh , Hipel Keith W , De Mitali
Published: October 2012

Background

The Graph Model for Conflict Resolution methodology is used to formally investigate the nuclear power dispute that took place in the Canadian province of Ontario in order to obtain strategic insights into its resolution. This flexible systems methodology is used to study the nuclear conflict at two key points in time, 2008 and 2010.

Results

The results of the 2008 analysis show that the only decision makers involved in the conflict who hold real power are the Federal and Ontario governments, although at the beginning of the investigation other organizations had also been considered as participating decision makers. According to a strategic analysis carried out for the conflict as it existed in 2010, the equilibria or potential resolutions of the 2008 analysis are found to be transitional states leading to the 2010 resolution. Moreover, a negative attitude by the Federal Government can cause an outcome to occur that is not highly preferred by either the Federal Government or the province of Ontario.

Conclusions

By closely following the decision makers’ actions, a detailed analysis of the nuclear dispute in Ontario is carried out. Stability, sensitivity, and attitude analyses are performed, and the results are closely correlated with what happened in reality.
Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study
Authors: Ringman John M , Frautschy Sally A , Teng Edmond , Begum Aynun N , Bardens Jenny , Beigi Maryam , Gylys Karen H , Badmaev Vladimir , Heath Dennis D , Apostolova Liana G , Porter Verna , Vanek Zeba , Marshall Gad A , Hellemann Gerhard , Sugar Catherine , Masterman Donna L , Montine Thomas J , Cummings Jeffrey L , Cole Greg M
Published: October 2012

Introduction

Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.

Methods

We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.

Results

Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).

Conclusions

Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.

Trial registration

ClinicalTrials.gov Identifier: NCT00099710.
Impact of emergency medical helicopter transport directly to a university hospital trauma center on mortality of severe blunt trauma patients until discharge
Authors: Desmettre Thibaut , Yeguiayan Jean-Michel , Coadou Hervé , Jacquot Claude , Raux Mathieu , Vivien Benoit , Martin Claude , Bonithon-Kopp Claire , Freysz Marc ,   the French Intensive Care Recorded in Severe Trauma
Published: October 2012

Introduction

The benefits of transporting severely injured patients by helicopter remain controversial. This study aimed to analyze the impact on mortality of helicopter compared to ground transport directly from the scene to a University hospital trauma center.

Methods

The French Intensive Care Research for Severe Trauma cohort study enrolled 2,703 patients with severe blunt trauma requiring admission to University hospital intensive care units within 72 hours. Pre-hospital and hospital clinical data, including the mode of transport, (helicopter (HMICU) versus ground (GMICU), both with medical teams), were recorded. The analysis was restricted to patients admitted directly from the scene to a University hospital trauma center. The main endpoint was mortality until ICU discharge.

Results

Of the 1,958 patients analyzed, 74% were transported by GMICU, 26% by HMICU. Median injury severity score (ISS) was 26 (interquartile range (IQR) 19 to 34) for HMICU patients and 25 (IQR 18 to 34) for GMICU patients. Compared to GMICU, HMICU patients had a higher median time frame before hospital admission and were more intensively treated in the pre-hospital phase. Crude mortality until hospital discharge was the same regardless of pre-hospital mode of transport. After adjustment for initial status, the risk of death was significantly lower (odds ratio (OR): 0.68, 95% confidence interval (CI) 0.47 to 0.98, P = 0.035) for HMICU compared with GMICU. This result did not change after further adjustment for ISS and overall surgical procedures.

Conclusions

This study suggests a beneficial impact of helicopter transport on mortality in severe blunt trauma. Whether this association could be due to better management in the pre-hospital phase needs to be more thoroughly assessed.
Novel splenic antigen-presenting cells derive from a Lin−c-kitlo progenitor
Authors: Periasamy Pravin , Tan Jonathan K H , OˈNeill Helen C
Published: October 2012

The spleen contains a novel antigen presenting a cell type which develops from endogenous hematopoietic progenitors.

The main DC subsets in murine spleen arise from BM-derived precursors. Recently, a novel APC type was described in spleen. To determine if spleen contains the progenitors of this subset, a stromal coculture system was used to assess candidate progenitors for their hematopoietic potential. Here, the progenitor of that subset is identified as a spleen endogenous Lin−c-kitlo hematopoietic progenitor and is most highly enriched among the Lin−c-kitloCD34+ subset. Dendritic-like cells produced in vitro functionally resemble the previously described in vivo equivalent subset with high endocytic capacity and capability for antigen-specific activation of CD8+ T cells but not CD4+ T cells.
Activation of the liver X receptor-β potently inhibits osteoclastogenesis from lipopolysaccharide-exposed bone marrow-derived macrophages
Authors: Robertson Remen Kirsten M , Lerner Ulf H , Gustafsson Jan-Åke , Andersson Göran
Published: October 2012

LXR, an important inflammatory regulator, potently inhibits the formation of osteoclasts in a bacterial LPS environment.

Bacterial-induced bone diseases, such as periodontitis and osteomyelitis, are chronic inflammatory diseases characterized by increased bone destruction as a result of enhanced osteoclastogenesis. The LXRα and -β are important modulators of inflammatory signaling and can potently inhibit RANKL-induced osteoclast differentiation. Here, we investigated the effects of the LXR agonist GW3965 on LPS-induced osteoclast differentiation. Mouse BMMs primed with RANKL for 24 h, then exposed to LPS in the presence of GW3965 for 4 days, formed significantly fewer and smaller TRAP+-multinucleated osteoclasts with reduced expression of osteoclast markers (Acp5, Ctsk, Mmp-9, Dc-stamp, and Itgβ3), along with inhibition of actin ring development. GW3965 was able to repress proinflammatory cytokine (TNF-α, IL-1β, IL-6, and IL-12p40) expression in BMMs exposed to LPS alone; however, once BMMs entered the osteoclast lineage following RANKL priming, GW3965 no longer inhibited cytokine expression. The inhibitory action of GW3965 involved the Akt pathway but seemed to be independent of MAPKs (p38, ERK, JNK) and NF-κB signaling. GW3965 acted in a LXRβ-dependent mechanism, as osteoclast differentiation was not inhibited in BMMs derived from LXRβ−/− mice. Finally, activation of LXR also inhibited differentiation in LPS-exposed mouse RAW264.7 cells. In conclusion, GW3965 acts through LXRβ to potently inhibit osteoclast differentiation from RANKL-primed BMMs in a LPS environment. In this respect, activation of the LXR could have a beneficial, therapeutic effect in the prevention of bacterial-induced bone erosion.
MicroRNA miR-308 regulates dMyc through a negative feedback loop in Drosophila
Authors: Daneshvar Kaveh , Nath Sritama , Khan Abid , Shover Wesley , Richardson Christine , Goodliffe Julie M.
Published: October 2012

The abundance of Myc protein must be exquisitely controlled to avoid growth abnormalities caused by too much or too little Myc. An intriguing mode of regulation exists in which Myc protein itself leads to reduction in its abundance. We show here that dMyc binds to the miR-308 locus and increases its expression. Using our gain-of-function approach, we show that an increase in miR-308 causes a destabilization of dMyc mRNA and reduced dMyc protein levels. In vivo knockdown of miR-308 confirmed the regulation of dMyc levels in embryos. This regulatory loop is crucial for maintaining appropriate dMyc levels and normal development. Perturbation of the loop, either by elevated miR-308 or elevated dMyc, caused lethality. Combining elevated levels of both, therefore restoring balance between miR-308 and dMyc levels, resulted in lower apoptotic activity and suppression of lethality. These results reveal a sensitive feedback mechanism that is crucial to prevent the pathologies caused by abnormal levels of dMyc.
Epizoic acoelomorph flatworms impair zooplankton feeding by the scleractinian coral Galaxea fascicularis
Authors: Wijgerde Tim , Schots Pauke , Van Onselen Eline , Janse Max , Karruppannan Eric , Verreth Johan A. J. , Osinga Ronald
Published: October 2012

Many scleractinian coral species host epizoic acoelomorph flatworms, both in aquaculture and in situ. These symbiotic flatworms may impair coral growth and health through light-shading, mucus removal and disruption of heterotrophic feeding. To quantify the effect of epizoic flatworms on zooplankton feeding, we conducted video analyses of single polyps of Galaxea fascicularis (Linnaeus 1767) grazing on Artemia nauplii in the presence and absence of symbiotic flatworms. 18S DNA analysis revealed that flatworms inhabiting G. fascicularis belonged to the genus Waminoa (Convolutidae), which were hosted at a density of 3.6±0.4 individuals polyp−1. Polyps hosting flatworms exhibited prey capture rates of 2.2±2.5, 3.4±4.5 and 2.7±3.4 nauplii polyp−1 30 min−1 at prey concentrations of 250, 500 and 1,000 nauplii L−1, respectively. Polyps that had their flatworms removed displayed prey capture rates of 2.7±1.6, 4.8±4.1 and 16.9±10.3 nauplii polyp−1 30 min−1. Significant main and interactive effects of flatworm presence and ambient prey concentration were found, reflected by the fact that flatworms significantly impaired host feeding rates at the highest prey density of 1,000 nauplii L−1. In addition, flatworms displayed kleptoparasitism, removing between 0.1±0.3 and 0.6±1.1 nauplii 30 min−1 from the oral disc of their host, or 5.3±3.3 to 50.0±2.1% of prey acquired by the coral. We suggest classifying the coral-associated Waminoa sp. as an epizoic parasite, as its presence may negatively affect growth and health of the host.
Homeotic functions of the Teashirt transcription factor during adult Drosophila development
Authors: Wang Wei , Tindell Neil , Yan Shun , Yoder John H.
Published: October 2012

During Drosophila development region-specific regulation of target genes by Hox proteins is modulated by genetic interactions with various cofactors and genetic collaborators. During embryogenesis one such modulator of Hox target specificity is the zinc-finger transcription factor Teashirt (Tsh) that is expressed in the developing trunk and cooperatively functions with trunk-specific Hox proteins to promote appropriate segment fate. This embryonic function of Tsh is characterized as homeotic since loss of embryonic Tsh activity leads to transformation of trunk segments toward head identity. In addition to this embryonic homeotic role, Tsh also performs vital Hox-independent functions through patterning numerous embryonic, larval and adult structures. Here we address whether the homeotic function of Tsh is maintained throughout development by investigating its contribution to patterning the adult abdomen. We show that Tsh is expressed throughout the developing abdomen and that this expression is dependent on the three Bithorax Hox proteins Ultrabithorax, Abdominal-A and Abdominal-B. Conditional reduction of Tsh activity during pupation reveals broad homeotic roles for this transcription factor throughout the adult abdomen. Additionally we show that, as during embryogenesis, the tsh paralog tiptop (tio) plays a partially redundant role in this homeotic activity.
Toxoplasma gondii infection induces dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion
Authors: Mitra Rupshi , Sapolsky Robert Morris , Vyas Ajai
Published: October 2012

Pathological anxiety is thought to reflect a maladaptive state characterized by exaggerated fear. Naturally occurring perturbations that reduce fear can be crucial in the search for new treatments. The protozoan parasite Toxoplasma gondii invades rat brain and removes fear of rats for cat odors, a change believed to be parasitic manipulation of host behavior aimed at increasing parasite transmission. It is likely that mechanisms employed by Toxoplasma gondii can be used as a heuristic tool to understand possible means of fear reduction in clinical settings. Male Long-Evans rats were infected with Toxoplasma gondii and compared with sham-infected animals 8 weeks post-infection. Amount of circulating plasma corticosterone and dendritic arborization of basolateral amygdala principal neurons were quantified. Previous studies have shown that corticosterone, acting within the basolateral amygdala, enhances the fear response to environmental stimuli. Here we show that Toxoplasma gondii infection causes a dendritic retraction in basolateral amygdala neurons. Such dendritic retraction is accompanied by lower amount of circulating corticosterone both at baseline and when induced by an aversive cat odor. The concerted effects of parasitism on two pivotal physiological nodes of fear response provide an animal model relevant to stress hormones interaction with amygdalar plasticity.
Phenotypic overlap in the contribution of individual genes to CNV pathogenicity revealed by cross-species computational analysis of single-gene mutations in humans, mice and zebrafish
Authors: Doelken Sandra C. , Köhler Sebastian , Mungall Christopher J. , Gkoutos Georgios V. , Ruef Barbara J. , Smith Cynthia , Smedley Damian , Bauer Sebastian , Klopocki Eva , Schofield Paul N. , Westerfield Monte , Robinson Peter N. , Lewis Suzanna E.
Published: October 2012

Numerous disease syndromes are associated with regions of copy number variation (CNV) in the human genome and, in most cases, the pathogenicity of the CNV is thought to be related to altered dosage of the genes contained within the affected segment. However, establishing the contribution of individual genes to the overall pathogenicity of CNV syndromes is difficult and often relies on the identification of potential candidates through manual searches of the literature and online resources. We describe here the development of a computational framework to comprehensively search phenotypic information from model organisms and single-gene human hereditary disorders, and thus speed the interpretation of the complex phenotypes of CNV disorders. There are currently more than 5000 human genes about which nothing is known phenotypically but for which detailed phenotypic information for the mouse and/or zebrafish orthologs is available. Here, we present an ontology-based approach to identify similarities between human disease manifestations and the mutational phenotypes in characterized model organism genes; this approach can therefore be used even in cases where there is little or no information about the function of the human genes. We applied this algorithm to detect candidate genes for 27 recurrent CNV disorders and identified 802 gene-phenotype associations, approximately half of which involved genes that were previously reported to be associated with the individual phenotypic features and half of which were novel candidates. A total of 431 associations were made solely on the basis of model organism phenotype data. Additionally, we observed a striking, statistically significant tendency for individual disease phenotypes to be associated with multiple genes located within a single CNV region, a phenomenon that we denote as pheno-clustering. Many of the clusters also display statistically significant similarities in protein function or vicinity within the protein-protein interaction network. Our results provide a basis for understanding previously un-interpretable genotype-phenotype correlations in pathogenic CNVs and for mobilizing the large amount of model organism phenotype data to provide insights into human genetic disorders.
Inflammation drives wound hyperpigmentation in zebrafish by recruiting pigment cells to sites of tissue damage
Authors: Lévesque Mathieu , Feng Yi , Jones Rebecca , Martin Paul
Published: October 2012

In humans, skin is the largest organ serving as a barrier between our body and the outside world. Skin protects our internal organs from external pathogens and other contaminants, and melanocytes within the skin protect the body from damage by ultraviolet light. These same pigment cells also determine our skin colour and complexion. Skin wounding triggers a repair response that includes a robust recruitment of inflammatory cells, which function to kill invading microbes and clear away cell and matrix debris. Once at the wound site, these innate immune cells release a barrage of cytokines that direct the activities of other cells during the repair process. Tissue damage and repair also frequently lead to alterations in skin pigmentation, in particular to wound hyperpigmentation. In this study, we describe a model of wound hyperpigmentation in the translucent zebrafish larva, where we can live-image the recruitment of melanocytes and their precursors, melanoblasts, to the wound site. We show that these pigment cells are drawn in after the initial recruitment of innate immune cells and that the inflammatory response is essential for wound hyperpigmentation. This new model will allow us to uncover the molecular link between immune and pigment cells during tissue repair and to screen for potential therapeutics to dampen wound hyperpigmentation.
The emerging role of Polycomb repressors in the response to DNA damage
Authors: Vissers Joseph H. A. , van Lohuizen Maarten , Citterio Elisabetta
Published: October 2012

Polycomb group (PcG) genes encode chromatin modifiers that are involved in the maintenance of cell identity and in proliferation, processes that are often deregulated in cancer. Interestingly, besides a role in epigenetic gene silencing, recent studies have begun to uncover a function for PcG proteins in the cellular response to DNA damage. In particular, PcG proteins have been shown to accumulate at sites of DNA double-strand breaks (DSBs). Several signaling pathways contribute to the recruitment of PcG proteins to DSBs, where they catalyze the ubiquitylation of histone H2A. The relevance of these findings is supported by the fact that loss of PcG genes decreases the efficiency of cells to repair DSBs and renders them sensitive to ionizing radiation. The recruitment of PcG proteins to DNA breaks suggests that they have a function in coordinating gene silencing and DNA repair at the chromatin flanking DNA lesions. In this Commentary, we discuss the current knowledge of the mechanisms that allow PcG proteins to exert their positive functions in genome maintenance.
Does the MRI or MRI contrast medium gadopentetate dimeglumine change the oxidant and antioxidant status in humans?
Authors: Olmaz Refik , Turgutalp Kenan , Oguz Ebru Gok , Horoz M , Ozhan Onur , Muslu Necati , Sungur Mehmet A , Kiykim Ahmet
Published: October 2012

Background

It has become evident that gadolinium-based contrast agents (GBCA) may have nephrotoxic potential. Oxidative stress is one of the most important pathways in the pathogenesis of iodinated contrast-induced nephropathy.

Purpose

To investigate the effects of static magnetic fields and gadopentetate dimeglumine (Magnevist®) on oxidant/antioxidant status via measurement of total antioxidant capacity (TAC), total oxidant status (TOS), and serum malondialdehide (MDA).

Material and Methods

Two age- and sex-matched groups of patients not under oxidative stress conditions that underwent magnetic resonance imaging (MRI) were recruited to this study. While contrast-enhanced (Magnevist®, 0.2 mmol/kg) MRI was performed in group 1, MRI without GBCA was performed in group 2. Fasting blood glucose, C-reactive protein, serum creatinine, liver enzymes, uric acid, and lipid parameters were examined in all patients. Peripheral venous blood samples in order to determine TAC, TOS, and MDA were collected before and 6, 24, and 72 h after the MRI procedures. The TOS:TAC ratio was used as the oxidative stress index (OSI). Patients were followed up to 72 h.

Results

There were no significant changes in serum TAC, TOS, and MDA levels (Δserum TAC, Δserum TOS, and ΔMDA) in either group 6, 24, or 72 h after the procedures (P > 0.05). Furthermore, OSI did not change after the procedures in either group (P > 0.05).

Conclusion

Magnetic field and gadopentetate dimeglumine (Magnevist®) do not change the oxidant or antioxidant status at a dose of 0.2 mmol/kg.
Effects of a cocoa diet on an intestinal inflammation model in rats
Authors: Pérez-Berezo Teresa , Ramírez-Santana Carolina , Franch Angels , Ramos-Romero Sara , Castellote Cristina , Pérez-Cano Francisco J , Castell Margarida
Published: October 2012

Cocoa is a rich source of fiber and flavonoids with recognized antioxidant and anti-inflammatory potential. The aim of this study was to evaluate the effects of a cocoa-enriched diet on rats with dextran sulfate sodium (DSS)-induced colitis. Wistar rats were fed with either a 5% cocoa diet or standard diet. Colon inflammation was induced by DSS in the drinking water: 5% for six days and 2% over the following nine days. Colitis was assessed by body weight loss, stool consistency and blood presence in stools. A group of animals fed standard diet was treated with quercitrin (1 mg/kg) after colitis establishment. After two weeks of DSS treatment, the colon oxidative and inflammatory status and lymphocyte composition from blood and mesenteric lymph nodes (MLNs) were assessed. The cocoa-fed group did not exhibit amelioration of clinical colitis but displayed higher antioxidant activity than the colitic reference group by the restoration of colon glutathione content and prevention of lipid peroxidation. The cocoa diet showed anti-inflammatory potential because it down-regulated serum tumor necrosis factor-α, colon inducible nitric oxide synthase activity and decreased colon cell infiltration. The lymphocyte composition in MLNs was not modified by drinking DSS, but there was an increase in the proportion of natural killer and regulatory T-cells in the blood. These changes were not modified by cocoa. In conclusion, cocoa intake may help to inhibit the negative oxidative effects consequent to colitis, although this action is not enough to abrogate the intestinal inflammation significantly.
Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency
Authors: Marcus Nancy Y , Blomenkamp Keith , Ahmad Muneeb , Teckman Jeffrey H
Published: October 2012

Alpha-1-antitrypsin deficiency is a genetic disorder resulting in the expression of misfolded mutant protein that can polymerize and accumulate in hepatocytes, leading to liver disease in some individuals. Transgenic PiZ mice are a well-characterized model, which express human alpha-1-antitrypsin mutant Z protein (ATZ protein) and faithfully recapitulate the human liver disease. Liver tissue expressing alpha-1-antitrypsin mutant Z protein exhibits inflammation, injury and replacement of damaged cells. Fibrosis and hepatocellular carcinoma (HCC) develop in aging PiZ mice. In this study, microarray analysis was performed comparing young PiZ (ZY) mice to wild-type (WY), and indicated that there were alterations in gene expression levels that could influence a number of pathways leading to liver disease. Redox-regulating genes were up-regulated in ZY tissue, including carbonyl reductase 3 (CBR3), glutathione S-transferase alpha 1 + 2 (GSTA(1 + 2)) and glutathione S-transferase mu 3 (GSTM3). We hypothesized that oxidative stress could develop in Z mouse liver, contributing to tissue damage and disease progression with age. The results of biochemical analysis of PiZ mouse liver revealed that higher levels of reactive oxygen species (ROS) and a more oxidized, cellular redox state occurred in liver tissue from ZY mice than WY. ZY mice showed little evidence of oxidative cellular damage as assessed by protein carbonylation levels, malondialdehyde levels and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8oxodG) staining. Aging liver tissue from PiZ older mice (ZO) had elevated ROS, generally lower levels of antioxidant enzymes than younger mice and evidence of cellular damage. These data indicate that oxidative stress is a contributing factor in the development of liver disease in this model of alpha-1-antitrypsin deficiency.
The periprosthetic capsule and connective tissue diseases: a piece in the puzzle of autoimmune/autoinflammatory syndrome induced by adjuvants
Authors: Bassetto Franco , Scarpa Carlotta , Vindigni Vincenzo , Doria Andrea
Published: October 2012

Breast prostheses have been criticized for being responsible for triggering systemic autoimmune disease. The presence of breast implants causes a natural foreign body reaction characterized by the infiltration of macrophages and T-cells. Using PubMed, Medline and eMedicine, we performed a systematic literature review on the stages of periprosthetic capsule formation and cells involved in order to understand which immunological pathways could be responsible for giving rise to, and the development of, connective tissue disease such as systemic sclerosis. We focused on the relationship between tissue growth factor- β, interleukin (IL)-1, IL-6 and T helper 17 or T regulatory cells, as well as on their effects on the different steps of capsular tissue formation. A disturbance in the modulation of these key cytokines may be responsible, in susceptible individuals, for a perpetuation of the inflammatory reaction which can locally lead to capsular contracture and at the systemic level may contribute to triggering autoimmune diseases.
Novel insights into the architecture and protein interaction network of yeast eIF3
Authors: Khoshnevis Sohail , Hauer Florian , Milón Pohl , Stark Holger , Ficner Ralf
Published: October 2012

Translation initiation in eukaryotes is a multistep process requiring the orchestrated interaction of several eukaryotic initiation factors (eIFs). The largest of these factors, eIF3, forms the scaffold for other initiation factors, promoting their binding to the 40S ribosomal subunit. Biochemical and structural studies on eIF3 need highly pure eIF3. However, natively purified eIF3 comprise complexes containing other proteins such as eIF5. Therefore we have established in vitro reconstitution protocols for Saccharomyces cerevisiae eIF3 using its five recombinantly expressed and purified subunits. This reconstituted eIF3 complex (eIF3rec) exhibits the same size and activity as the natively purified eIF3 (eIF3nat). The homogeneity and stoichiometry of eIF3rec and eIF3nat were confirmed by analytical size exclusion chromatography, mass spectrometry, and multi-angle light scattering, demonstrating the presence of one copy of each subunit in the eIF3 complex. The reconstituted and native eIF3 complexes were compared by single-particle electron microscopy showing a high degree of structural conservation. The interaction network between eIF3 proteins was studied by means of limited proteolysis, analytical size exclusion chromatography, in vitro binding assays, and isothermal titration calorimetry, unveiling distinct protein domains and subcomplexes that are critical for the integrity of the protein network in yeast eIF3. Taken together, the data presented here provide a novel procedure to obtain highly pure yeast eIF3, suitable for biochemical and structural analysis, in addition to a detailed picture of the network of protein interactions within this complex.
Activation of PKR by RNA misfolding: HDV ribozyme dimers activate PKR
Authors: Heinicke Laurie A. , Bevilacqua Philip C.
Published: October 2012

Protein Kinase R (PKR), the double-stranded RNA (dsRNA)-activated protein kinase, plays important roles in innate immunity. Previous studies have shown that PKR is activated by long stretches of dsRNA, RNA pseudoknots, and certain single-stranded RNAs; however, regulation of PKR by RNAs with globular tertiary structure has not been reported. In this study, the HDV ribozyme is used as a model of a mostly globular RNA. In addition to a catalytic core, the ribozyme contains a peripheral 13-bp pairing region (P4), which, upon shortening, affects neither the catalytic activity of the ribozyme nor its ability to crystallize. We report that the HDV ribozyme sequence alone can activate PKR. To elucidate the RNA structural basis for this, we prepared a number of HDV variants, including those with shortened or lengthened P4 pairing regions, with the anticipation that lengthening the P4 extension would yield a more potent activator since it would offer more base pairs of dsRNA. Surprisingly, the variant with a shortened P4 was the most potent activator. Through native gel mobility and enzymatic structure mapping experiments we implicate misfolded HDV ribozyme dimers as the PKR-activating species, and show that the shortened P4 leads to enhanced occupancy of the RNA dimer. These observations have implications for how RNA misfolding relates to innate immune response and human disease.
Alternative transcription start site selection leads to large differences in translation activity in yeast
Authors: Rojas-Duran Maria F. , Gilbert Wendy V.
Published: October 2012

mRNA levels do not accurately predict protein levels in eukaryotic cells. To investigate contributions of 5′ untranslated regions (5′ UTRs) to mRNA-specific differences in translation, we determined the 5′ UTR boundaries of 96 yeast genes for which in vivo translational efficiency varied by 80-fold. A total of 25% of genes showed substantial 5′ UTR heterogeneity. We compared the capacity of these genes' alternative 5′ UTR isoforms for cap-dependent and cap-independent translation using quantitative in vitro and in vivo translation assays. Six out of nine genes showed mRNA isoform-specific translation activity differences of greater than threefold in at least one condition. For three genes, in vivo translation activities of alternative 5′ UTR isoforms differed by more than 100-fold. These results show that changing genes' 5′ UTR boundaries can produce large changes in protein output without changing the overall amount of mRNA. Because transcription start site (TSS) heterogeneity is common, we suggest that TSS choice is greatly under-appreciated as a quantitatively significant mechanism for regulating protein production.
A Simulation-Based Approach to Decision Making with Partial Information
Authors: Montiel Luis V. , Bickel J. Eric
Published: October 2012

The construction of a probabilistic model is a key step in most decision and risk analyses. Typically this is done by defining a single joint distribution in terms of marginal and conditional distributions. The difficulty of this approach is that often the joint distribution is underspecified. For example, we may lack knowledge of the marginal distributions or the underlying dependence structure. In this paper, we suggest an approach to analyzing decisions with partial information. Specifically, we propose a simulation procedure to create a collection of joint distributions that match the known information. This collection of distributions can then be used to analyze the decision problem. We demonstrate our method by applying it to the Eagle Airlines case study used in previous studies.
Optimizing Inventory Levels Within Intel's Channel Supply Demand Operations
Authors: Wieland Brian , Mastrantonio Pat , Willems Sean P. , Kempf Karl G.
Published: October 2012

Intel's Channel Supply Demand Operations (CSDO) organization is responsible for satisfying the boxed processor demands of Intel's vast customer network of distributors, resellers, dealers, and system integrators. In 2005, CSDO began a multiechelon inventory optimization (MEIO) project to improve its efficiency and effectiveness by optimizing inventory levels and locations across CSDO's end-to-end supply chain. This paper describes the project plan, workflows, and results. One year after implementation, total inventory levels were reduced by more than 11 percent; in addition, service levels of products modeled using the MEIO process were eight points higher than products not modeled using this process. The MEIO process continues to be in place at Intel and has resulted in sustained reductions in inventory levels, average service levels exceeding 90 percent, and more than an order-of-magnitude reduction in the number of expedites.
IBM Blends Heuristics and Optimization to Plan Its Semiconductor Supply Chain
Authors: Degbotse Alfred , Denton Brian T. , Fordyce Kenneth , Milne R. John , Orzell Robert , Wang Chi-Tai
Published: October 2012

IBM uses operations research techniques to plan its enterprise semiconductor supply chain. The scale and complexity of this planning problem make developing robust supply chain optimization tools a challenge. Pure optimization methods are computationally infeasible, and fast heuristic methods alone generate poor results. Consequently, we developed a method that decomposes the problem by dividing the bills of materials product structure horizontally and vertically into complex and simple portions that are based on the major stages in semiconductor manufacturing and the choices of supply chain paths for building parts. The method then solves the complex portions with a mixed-integer program and the simple portions with fast heuristics that contain small embedded linear programs. A unique pegging algorithm, an explosion heuristic, and an implosion linear program enable coordination among these portions. The result is a unified production, shipping, and distribution plan with no evidence of the original decomposition. This method has helped IBM to improve its asset utilization, customer service, and inventory levels.
Editorial: The First Rothkopf Rankings of Nonacademic Organizations
Authors: Fricker Ronald D.
Published: October 2012

This paper presents the first rankings of nonacademic organizations according to their contributions to the INFORMS practice literature. Two rankings are given, each based on a different metric: visibility is the number of authors who list an organization as their primary affiliation; yield is the equivalent number of INFORMS practice papers attributable to each organization based on author primary affiliation. For the visibility rankings, IBM comes in first place, followed by Hewlett-Packard in second, the US Government in third, and General Electric in fourth place. These are followed by Sasol, Procter & Gamble, and Merrill Lynch. For the yield rankings, the US Government comes in first place, followed by General Electric and IBM tied for second, and Hewlett-Packard in fourth place. They are followed by Intel in fifth, Procter & Gamble in sixth, and Merrill Lynch in seventh place.
Restoring shoulder abduction in children with Erb’s palsy
Authors: Abdelaziz T. H. , Samir S. , Magdy W.
Published: October 2012

A total of 35 children with Erb’s palsy and shoulder abduction of < 90° underwent transfer of teres major. In 18 cases (group 1) a trapezius transfer was added (combined procedure). In 17 cases (group 2) teres major transfer was carried out in isolation (single procedure). The mean gain in abduction was 67.2° (60° to 80°) in group 1 and 37.6° (20° to 70°) in group 2, which reached statistical significance (p < 0.001).

Group 2 was further divided into those who had deltoid power of < M3 (group 2a) and those with deltoid power ≥ M3 (group 2b). The difference in improvement of abduction between groups 2a and group 2b was statistically significant (p < 0.001) but the difference between group 2b and group 1 was not (p = 0.07).

We recommend the following protocol of management: in children with abduction ≥ 90° a single procedure is indicated. In children with abduction < 90°: a combined procedure is indicated if deltoid power is < M3 and a single procedure is indicated if deltoid power is ≥ M3. If no satisfactory improvement is achieved, the trapezius can be transferred at a later stage.
The radiological parameters correlated with the alignment of the femoral component after Oxford Phase 3 unicompartmental knee replacement
Authors: Kim J-G. , Kasat N. S. , Bae J-H. , Kim S-J. , Oh S-M. , Lim H-C.
Published: October 2012

The purpose of this study was to measure the radiological parameters of femoral component alignment of the Oxford Phase 3 unicompartmental knee replacement (UKR), and evaluate their effect on clinical outcome. Multiple regression analysis was used to examine the relative contributions of the radiological assessment of femoral component alignment in 189 consecutive UKRs performed by a single surgeon. The American Knee Society scores were compared between groups, defined as being within or outside recommended tolerances of the position of the femoral component. For the flexion/extension position 21 UKRs (11.1%) lay outside the recommended limits, and for posterior overhang of the femoral component nine (4.8%) lay outside the range. The pre-operative hip/knee/ankle (HKA) angle, narrowest canal distance from the distal femoral entry point of the alignment jig and coronal entry-point position had significant effects on the flexion/extension position. Pre-operative HKA angle had a significant influence on posterior overhang of the femoral component. However, there was no significant difference in American Knee Society scores relative to the position of the femoral component.
Survivorship of high tibial osteotomy in the treatment of osteoarthritis of the knee
Authors: Niinimäki T. T. , Eskelinen A. , Mann B. S. , Junnila M. , Ohtonen P. , Leppilahti J.
Published: October 2012

Previous studies from single centres or single-surgeon series report good early and mid-term results for high tibial osteotomy (HTO) in the treatment of osteoarthritis of the knee. However, the survivorship of HTO at a national level is unknown. This registry-based study included 3195 high HTOs performed between 1987 and 2008. Kaplan-Meier analysis revealed an overall survivorship of 89% (95% confidence interval (CI) 88 to 90) at five years and 73% (95% CI 72 to 75) at ten years, when conversion to total knee replacement was taken as the endpoint. Females and patients aged > 50 years had worse survivorship than males or patients aged ≤ 50 years (hazard ratio (HR) 1.26 (95% CI 1.11 to 1.43) and HR 1.41 (95% CI 1.23 to 1.64), respectively). The survivorship of HTOs performed between 1998 to 2008 was worse than for those performed between 1987 and 1997.
The use of non-vascularised osteochondral autograft for reconstruction of articular surfaces in the hand and wrist
Authors: Ng C. Y. , Watts A. C.
Published: October 2012

Bone loss involving articular surface is a challenging problem faced by the orthopaedic surgeon. In the hand and wrist, there are articular defects that are amenable to autograft reconstruction when primary fixation is not possible. In this article, the surgical techniques and clinical outcomes of articular reconstructions in the hand and wrist using non-vascularised osteochondral autografts are reviewed.
Defining peri-prosthetic infection
Authors: Oussedik S. , Gould K. , Stockley I. , Haddad F. S.
Published: October 2012

Peri-prosthetic infection remains a leading cause of revision surgery. Recent publications from the American Musculoskeletal Infection Society have sought to establish a definition of peri-prosthetic infection based on clinical findings and laboratory investigations. The limitations of their approach are discussed and an alternative definition is proposed, which it is felt may better reflect the uncertainties encountered in clinical practice.
Exam Corner – November 2012
Authors: Khanduja V.
Published: October 2012

The FRCS (Tr & Orth) examination has three components: MCQs, Vivas and Clinical Examination. The Vivas are further divided into four sections comprising Basic Science, Adult Pathology, Hands and Children’s Orthopaedics and Trauma. The Clinical Examination section is divided into Upper and Lower limb cases. The aim of this section in the Journal is to focus specifically on the trainees preparing for the exam and to cater to all the sections of the exam. The vision is to complete the cycle of all relevant exam topics (as per the syllabus) in four years.
Drawing Identity from Change: Planning for Haverford College
Authors: Trainer Nancy Rogo
Published: October 2012

American collegiate campuses are studies in adaptation. By considering the campus as a whole, planning can suggest ways to accommodate significant change while reinforcing the physical qualities most closely and positively linked to the college—without nostalgically invoking the architecture of past eras. Urban design mapping and diagramming methods can help discern the overlaid patterns, systems, and relationships that form the unitary campus and suggest potential frameworks for future development. This article considers the relationship between these drawing methods and the planning process, using as an example Venturi, Scott Brown and Associates' recent plan for Haverford College.
A Note on Adaptation in Gardens
Authors: Hunt John Dixon
Published: October 2012

Adaptation in gardens is often different than adaption to buildings. Materials decay, ownership changes or new patrons have different ideas of how a landscape should look, private gardens are opened to the public, and even gardens may—without obvious formal alterations—be subjected to new interpretations. Examples adduced are the Tuileries, Rousham, Blenheim and Longleat.
Preservation by Adaptation: Is It Sustainable?
Authors: Donofrio Gregory
Published: October 2012

The historic preservation field is aggressively promoting itself as "green." Adaptive reuse of historic buildings is now widely considered a sustainable development practice. As with architecture in general, however, sustainability in preservation is too often narrowly framed around environmental issues such as the conservation of materials, energy, and water. Commonly accepted definitions of sustainability recognize two other components: economics and culture. Rarely does the preservation field consider sustainability as an entire system of interrelated environmental, economic, and social relationships, as envisioned by the Brundtland Report of 1987. This article offers several reasons for the preservation field to engage in the full spectrum of sustainability concerns, including economic and social issues. It then reexamines one of most famous case studies in the canon of historic preservation in the United States—Faneuil Hall Marketplace in Boston—to consider the extent to which sustainability was addressed as a system of interrelated relationships. In conclusion, it suggests that preservation could be made more sustainable by drawing connections among several existing concepts, findings, and methods developed by Randall Mason, Setha Low, and others.
Women and Property in Early Louisiana: Legal Systems at Odds
Authors: Sundberg Sara Brooks
Published: October 2012

This study examines the intersection between gender, law and ethnicity in female property holding in Louisiana between 1811–1835. The civilian legal tradition, operative in Louisiana during this time period, offered married women considerable economic benefits compared to the common law legal tradition utilized in most other states. Women under Louisiana civil law retained their legal identity and they inherited half of the property accrued during marriage. They might also own and manage their separate property. A comparison of women’s probated wealth, in a contiguous transect of counties and parishes in Mississippi and Louisiana demonstrates that Louisiana women accrued economic benefits from these provisions and fared better economically than their common law counterparts in Mississippi. Some women actively managed their property. For others, there is evidence to suggest that their property allowed them a kind of “bargaining power” within marriage. Yet, Louisiana women reaped economic benefits from civil law only if their families adhered to the law. Ethnicity influenced whether that happened. French-speaking families, more familiar with the civil law tradition, were more likely to adhere to the letter and spirit of the law. As a result, French-speaking women in Louisiana were more likely to reap economic benefits from the law than their Anglo counterparts. Female property holding in Louisiana exposes a legal borderland where civilian and common law legal traditions were at still at odds.
On the Work of Things: Musical Production, Theatrical Labor, and the “General Intellect”
Authors: Ridout Nicholas
Published: October 2012

Heiner Goebbels’s music theatre installation Stifters Dinge , a “no-man show” dominated by five automated pianos, provides the starting point for a consideration of the piano and the theatre as machines for the production of social relations. This essay traces the history of the piano as an instrument of bourgeois revolution, in which a historically distinctive relation between people and things is constructed. It builds on autonomist theorizations of “general intellect” and “virtuosity” to suggest that, in addition to thing theory’s restoration of “thingness” to the concept of the commodity, it may also be possible to recuperate from the theatre and the piano’s animation of dead labor a fragmentary experience of the possibility of alternative relations between people and things, people and people.