bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the structural model for ferrihydrite derived from real-space modelling of high-energy X-ray diffraction data
Authors: Manceau A.
Published: May 2009

A new structural model for ferrihydrite that challenges the standard ferrihydrite model established by X-ray diffraction and confirmed by neutron diffraction and single-crystal electron nanodiffraction was recently proposed by Michel et al. (2007a) from the simulation of the pair distribution function obtained by Fourier transformation of diffraction data measured at λ = 0.137 Å. The new ferrihydrite model is isostructural to akdalaite (Al10O14(OH)2), a mineral having the Baker-Figgis δ-isomer of the Al13-Keggin structure as its structural motif. The new model is unrealistic because: (1) it is completely periodic (i.e. defect-free); (2), it has 20% tetravalent octahedral iron (VIFe4+), 20% divalent tetrahedral iron (IVFe2+), and some IVFe–O distances equal to or larger than the VIFe3+–O distances, thus violating Pauling's 2nd rule; (3) it does not describe X-ray diffraction and EXAFS spectroscopic data; and, (4) it is inconsistent with electron microscopy results and contradicts previous X-ray scattering studies.
Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia
Authors: Fang Hsin-Yu , Hughes Russell , Murdoch Craig , Coffelt Seth B. , Biswas Subhra K. , Harris Adrian L. , Johnson Randall S. , Imityaz Hongxia Z. , Simon M. Celeste , Fredlund Erik , Greten Florian R. , Rius Jordi , Lewis Claire E.
Published: May 2009

Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1β and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-κB (NF-κB) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1α and 2α or NF-κB in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-κB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors.
A plant MinD homologue rescues Escherichia coli HL1 mutant (ΔMinDE) in the absence of MinE
Authors: Zhang Min , Hu Yong , Jia Jingjing , Gao Hongbo , He Yikun
Published: May 2009

Background

In E. coli, the Min operon (MinCDE) plays a key role in determining the site of cell division. MinE oscillates from the middle to one pole or another to drive the MinCD complex to the end of the cell. The MinCD complex prevents FtsZ ring formation and the subsequent cell division at cell ends. In Arabidopsis thaliana, a homologue of MinD has been shown to be involved in the positioning of chloroplast division site.

Results

To learn whether the MinD homologue in plants is functional in bacteria, AtMinD was expressed in E. coli. Surprisingly, AtMinD can rescue the minicell phenotype of E. coli HL1 mutant (ΔMinDE) in the absence of EcMinE. This rescue requires EcMinC. AtMinD was localized to puncta at the poles of E. coli cells and puncta in chloroplasts without oscillation. AtMinD expressed in the HL1 mutant can cause a punctate localization pattern of GFP-EcMinC at cell ends. Yeast two hybrid and BiFC analysis showed that AtMinD can interact with EcMinC.

Conclusion

Similar to the MinD in Bacillus subtilis, AtMinD is localized to the polar region in E. coli and interacts with EcMinC to confine EcFtsZ polymerization and cell division at the midpoint of the cell.
Economic burden of asthma: a systematic review
Authors: Bahadori Katayoun , Doyle-Waters Mary M , Marra Carlo , Lynd Larry , Alasaly Kadria , Swiston John , FitzGerald Js Mark
Published: May 2009

Background

Asthma is associated with enormous healthcare expenditures that include both direct and indirect costs. It is also associated with the loss of future potential earnings related to both morbidity and mortality. The objective of the study is to determine the burden of disease costs associated with asthma.

Methods

We performed a systematic search of MEDLINE, EMBASE, CINAHL, CDSR, OHE-HEED, and Web of Science Databases between 1966 and 2008.

Results

Sixty-eight studies met the inclusion criteria. Hospitalization and medications were found to be the most important cost driver of direct costs. Work and school loss accounted for the greatest percentage of indirect costs. The cost of asthma was correlated with comorbidities, age, and disease severity.

Conclusion

Despite the availability of effective preventive therapy, costs associated with asthma are increasing. Strategies including education of patients and physicians, and regular follow-up are required to reduce the economic burden of asthma.
CTLA4 blockade increases Th17 cells in patients with metastatic melanoma
Authors: von Euw Erika , Chodon Thinle , Attar Narsis , Jalil Jason , Koya Richard C , Comin-Anduix Begonya , Ribas Antoni
Published: May 2009

Background

Th17 cells are CD4+ cells that produce interleukin 17 (IL-17) and are potent inducers of tissue inflammation and autoimmunity. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature.

Methods

Peripheral blood mononuclear cells (PBMC) were collected before and after receiving tremelimumab within two clinical trials, one with tremelimumab alone (21 patients) and another together with autologous dendritic cells (DC) pulsed with the melanoma epitope MART-126–35 (6 patients). Cytokines were quantified directly in plasma from patients and after in vitro stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by intracellular cytokine staining (ICS).

Results

There were no significant changes in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained from patients before and after administration of tremelimumab. However, when PBMC were activated in vitro, IL-17 cytokine in cell culture supernatant and Th17 cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in post-dosing samples. There were no differences in the levels of Th17 cells between patients with or without an objective tumor response, but samples from patients with inflammatory and autoimmune toxicities during the first cycle of therapy had a significant increase in Th17 cells.

Conclusion

The anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities.

Trial Registration

Clinical trial registration numbers: NCT0090896 and NCT00471887
Gene expression in the prefrontal cortex during adolescence: implications for the onset of schizophrenia
Authors: Harris Laura W , Lockstone Helen E , Khaitovich Phillipp , Weickert Cynthia Shannon , Webster Maree J , Bahn Sabine
Published: May 2009

Background

Many critical maturational processes take place in the human brain during postnatal development. In particular, the prefrontal cortex does not reach maturation until late adolescence and this stage is associated with substantial white matter volume increases. Patients with schizophrenia and other major psychiatric disorders tend to first present with overt symptoms during late adolescence/early adulthood and it has been proposed that this developmental stage represents a "window of vulnerability".

Methods

In this study we used whole genome microarrays to measure gene expression in post mortem prefrontal cortex tissue from human individuals ranging in age from 0 to 49 years. To identify genes specifically altered in the late adolescent period, we applied a template matching procedure. Genes were identified which showed a significant correlation to a template showing a peak of expression between ages 15 and 25.

Results

Approximately 2000 genes displayed an expression pattern that was significantly correlated (positively or negatively) with the template. In the majority of cases, these genes in fact reached a plateau during adolescence with only subtle changes thereafter. These include a number of genes previously associated with schizophrenia including the susceptibility gene neuregulin 1 (NRG1). Functional profiling revealed peak expression in late adolescence for genes associated with energy metabolism and protein and lipid synthesis, together with decreases for genes involved in glutamate and neuropeptide signalling and neuronal development/plasticity. Strikingly, eight myelin-related genes previously found decreased in schizophrenia brain tissue showed a peak in their expression levels in late adolescence, while the single myelin gene reported increased in patients with schizophrenia was decreased in late adolescence.

Conclusion

The observed changes imply that molecular mechanisms critical for adolescent brain development are disturbed in schizophrenia patients.
Association of MICA with rheumatoid arthritis independent of known HLA-DRB1risk alleles in a family-based and a case control study
Authors: Kirsten Holger , Petit-Teixeira Elisabeth , Scholz Markus , Hasenclever Dirk , Hantmann Helene , Heider Dirk , Wagner Ulf , Sack Ulrich , Hugo Teixeira Vitor , Prum Bernard , Burkhardt Jana , Pierlot Céline , Emmrich Frank , Cornelis François , Ahnert Peter
Published: May 2009

Introduction

The gene MICA encodes the protein major histocompatibility complex class I polypeptide-related sequence A. It is expressed in synovium of patients with rheumatoid arthritis (RA) and its implication in autoimmunity is discussed. We analyzed the association of genetic variants of MICA with susceptibility to RA.

Methods

Initially, 300 French Caucasian individuals belonging to 100 RA trio families were studied. An additional 100 independent RA trio families and a German Caucasian case-control cohort (90/182 individuals) were available for replication. As MICA is situated in proximity to known risk alleles of the HLA-DRB1 locus, our analysis accounted for linkage disequilibrium either by analyzing the subgroup consisting of parents not carrying HLA-DRB1 risk alleles with transmission disequilibrium test (TDT) or by implementing a regression model including all available data. Analysis included a microsatellite polymorphism (GCT)n and single-nucleotide polymorphisms (SNPs) rs3763288 and rs1051794.

Results

In contrast to the other investigated polymorphisms, the non-synonymously coding SNP MICA-250 (rs1051794, Lys196Glu) was strongly associated in the first family cohort (TDT: P = 0.014; regression model: odds ratio [OR] 0.46, 95% confidence interval [CI] 0.25 to 0.82, P = 0.007). Although the replication family sample showed only a trend, combined family data remained consistent with the hypothesis of MICA-250 association independent from shared epitope (SE) alleles (TDT: P = 0.027; regression model: OR 0.56, 95% CI 0.38 to 0.83, P = 0.003). We also replicated the protective association of MICA-250A within a German Caucasian cohort (OR 0.31, 95% CI 0.1 to 0.7, P = 0.005; regression model: OR 0.6, 95% CI 0.37 to 0.96, P = 0.032). We showed complete linkage disequilibrium of MICA-250 (D' = 1, r
2
= 1) with the functional MICA variant rs1051792 (D' = 1, r
2
= 1). As rs1051792 confers differential allelic affinity of MICA to the receptor NKG2D, this provides a possible functional explanation for the observed association.

Conclusions

We present evidence for linkage and association of MICA-250 (rs1051794) with RA independent of known HLA-DRB1 risk alleles, suggesting MICA as an RA susceptibility gene. However, more studies within other populations are necessary to prove the general relevance of this polymorphism for RA.
PI-3 kinase activity is necessary for ERK1/2-induced disruption of mammary epithelial architecture
Authors: Pearson Gray W , Hunter Tony
Published: May 2009

Introduction

Epithelial tumors, including breast cancer, are being identified and treated at earlier stages of tumor development because of technological advances in screening and detection methods. It is likely that early-stage epithelial tumors, such as mammary ductal carcinoma in situ (DCIS), will be amenable to new and more efficacious diagnostic tests and forms of therapy. However, our limited understanding of the underlying molecular mechanisms of early-stage epithelial tumor growth has hampered the development of new forms treatment and preventative therapy.

Methods

The Raf–MEK1/2–ERK1/2 mitogen-activated protein kinase module is activated by stimuli complicit in mammary neoplastic progression. We have recently demonstrated that the activation of ERK1/2 induces a non-invasive form of motility, where cells can track along the basement membrane and adjacent epithelial cells, but do not become invasive over time, using real-time imaging of a mammary epithelial organotypic culture model. Using this novel approach combined with traditional biochemical techniques, we have analyzed at the molecular level how ERK1/2 induces this new non-invasive form of motility as well as proliferation and cell survival.

Results

We find that the activation of Raf:ER in the differentiated epithelium of fully formed acini promotes proliferation and cell survival, which are characteristic features of pre-invasive DCIS lesions. The activation of ERK1/2 correlated with induction of c-Fos, a transcriptional regulator of proliferation and reduced expression of the pro-apoptotic BH3-only protein BIM. Both ERK1/2 and PI-3 kinase-dependent effector pathways were required for activated Raf:ER to reduce expression of p27 and promote proliferation. In addition, PI-3K activity was necessary for the induction of non-invasive motility induced by ERK1/2.

Conclusions

ERK1/2 activation is sufficient to induce cell behaviors in organotypic culture that could promote recurrent and invasive growth in DCIS patients. Interestingly, PI-3K activity is necessary for two of these behaviors, proliferation and cell motility. Collectively, our results suggest that the relationship between the activity state of the ERK1/2 and PI-3K signaling pathways and recurrent growth in DCIS patients should be investigated.
B-type natriuretic peptide release and left ventricular filling pressure assessed by echocardiographic study after subarachnoid hemorrhage: a prospective study in non-cardiac patients
Authors: Meaudre Eric , Jego Christophe , Kenane Nadia , Montcriol Ambroise , Boret Henry , Goutorbe Philippe , Habib Gilbert , Palmier Bruno
Published: May 2009

Introduction

Serum B-type natriuretic peptide (BNP) is frequently elevated after subarachnoid hemorrhage (SAH), but whether this high BNP level is related to transient elevation of left ventricular filling pressure (LVFP) is unknown. However, in patients with preexistent cardiac pathologies, it is impossible to differentiate between BNP elevation caused by chronic cardiac abnormalities and BNP related to acute neurocardiac injury.

Methods

All adult patients with SAH admitted to our intensive care unit were eligible. Patients were excluded for the following reasons: admission >48 hours after aneurysm rupture, pre-existing hypertension, or cardiac disease. Levels of BNP and cardiac troponin Ic were measured daily for 7 days. Echocardiography was performed by a blinded cardiologist on days 1, 2, and 7. Doppler signals from the mitral inflow, tissue Doppler, and the color M-mode–derived flow propagation velocity (FPV) were obtained to assess echo-estimated LVFP.

Results

During a 3-year period, sixty-six consecutive patients with SAH were admitted. Thirty one patients were studied. The BNP level was >100 ng/L in 25 patients (80%) during the first 3 days, with a peak on day 2 (median, 126 ng/L) followed by a gradual decrease (median variation days 1 to 7, 70%). All patients had an ejection fraction >50%. Early transmitral velocity/tissue Doppler mitral annular early diastolic velocity was low: 5.4 (± 1.5) on day 1, 5.8 (± 1.2) on day 2, and 5.1 (± 0.9) on day 7. Early transmitral velocity/FPV was also low: 1.27 (± 0.4), 1.25 (± 0.3), and 1.1 (± 0.2) on days 1, 2, and 7, respectively. Cardiac troponin Ic levels ranged from 0 to 3.67 μg/L and were correlated with BNP (r = 0.63, P < 0.01).

Conclusions

BNP rises gradually over two days and return to normal within a week after SAH. Its release is associated with myocardial necrosis, but is unrelated to elevated LVFP assessed by echocardiography.
Whole genome sequencing of a natural recombinant Toxoplasma gondiistrain reveals chromosome sorting and local allelic variants
Authors: Bontell Irene Lindström , Hall Neil , Ashelford Kevin E , Dubey JP , Boyle Jon P , Lindh Johan , Smith Judith E
Published: May 2009

Background

Toxoplasma gondii is a zoonotic parasite of global importance. In common with many protozoan parasites it has the capacity for sexual recombination, but current evidence suggests this is rarely employed. The global population structure is dominated by a small number of clonal genotypes, which exhibit biallelic variation and limited intralineage divergence. Little is known of the genotypes present in Africa despite the importance of AIDS-associated toxoplasmosis.

Results

We here present extensive sequence analysis of eight isolates from Uganda, including the whole genome sequencing of a type II/III recombinant isolate, TgCkUg2. 454 sequencing gave 84% coverage across the approximate 61 Mb genome and over 70,000 single nucleotide polymorphisms (SNPs) were mapped against reference strains. TgCkUg2 was shown to contain entire chromosomes of either type II or type III origin, demonstrating chromosome sorting rather than intrachromosomal recombination. We mapped 1,252 novel polymorphisms and clusters of new SNPs within coding sequence implied selective pressure on a number of genes, including surface antigens and rhoptry proteins. Further sequencing of the remaining isolates, six type II and one type III strain, confirmed the presence of novel SNPs, suggesting these are local allelic variants within Ugandan type II strains. In mice, the type III isolate had parasite burdens at least 30-fold higher than type II isolates, while the recombinant strain had an intermediate burden.

Conclusions

Our data demonstrate that recombination between clonal lineages does occur in nature but there is nevertheless close homology between African and North American isolates. The quantity of high confidence SNP data generated in this study and the availability of the putative parental strains to this natural recombinant provide an excellent basis for future studies of the genetic divergence and of genotype-phenotype relationships.
Pivotal Advance: CEACAM1 is a negative coreceptor for the B cell receptor and promotes CD19-mediated adhesion of B cells in a PI3K-dependent manner
Authors: Lobo Elizabeth O , Zhang Zhifang , Shively John E
Published: May 2009

CEACAM1 coreceptor for the B-cell receptor inhibits activated B-cells by recruiting SHP-1 to its phosphorylated ITIMs, preventing phosphorylation of the large subunit of PI-3K.

Upon antigen binding, the BCR transduces a signal culminating in proliferation or in AICD of the B cell. Coreceptor engagement and subsequent modification of the BCR signal pathway are mechanisms that guide the B cell to its appropriate fate. For example, in the absence of coreceptor engagement, anti-sIgM antibodies induce apoptosis in the human Daudi B cell lymphoma cell line. ITIM-bearing B cell coreceptors that potentially may act as negative coreceptors include FcRγIIb, CD22, CD72, and CEACAM1 (CD66a). Although the role of CEACAM1 as an inhibitory coreceptor in T cells has been established, its role in B cells is poorly defined. We show that anti-sIgM antibody and PI3K inhibitor LY294002-induced apoptosis are reduced significantly in CEACAM1 knock-down clones compared with WT Daudi cells and that anti-sIgM treatment induced CEACAM1 tyrosine phosphorylation and association with SHP-1 in WT cells. In contrast, treatment of WT Daudi cells with anti-CD19 antibodies does not induce apoptosis and has reduced tyrosine phosphorylation and SHP-1 recruitment to CEACAM1. Thus, similar to its function in T cells, CEACAM1 may act as an inhibitory B cell coreceptor, most likely through recruitment of SHP-1 and inhibition of a PI3K-promoted activation pathway. Activation of B cells by anti-sIgM or anti-CD19 antibodies also leads to cell aggregation that is promoted by CEACAM1, also in a PI3K-dependent manner.
Resistin Is More Abundant in Liver Than Adipose Tissue and Is Not Up-Regulated by Lipopolysaccharide
Authors: Szalowska Ewa , Elferink Marieke G. L. , Hoek Annemiek , Groothuis Geny M. M. , Vonk Roel J.
Published: May 2009

Context: Resistin is an adipokine correlated with inflammatory markers and is predictive for cardiovascular diseases. There is evidence that serum resistin levels are elevated in obese patients; however, the role of resistin in insulin resistance and type 2 diabetes remains controversial.

Objective: We addressed the question of whether inflammation may induce expression of resistin in organs involved in regulation of total body energy metabolism, such as liver and adipose tissue (AT).

Methods: Human liver tissue, sc AT, and omentum were cultured in the absence/presence of lipopolysaccharide (LPS). The resistin and cytokine mRNA and protein expression levels were determined by real-time PCR, ELISA, and Multiplex Technology, respectively. The localization of resistin in human liver was analyzed by immunohistochemistry.

Results: Resistin gene and protein expression was significantly higher in liver than in AT. Exposure of human AT and liver tissue in culture to LPS did not alter resistin concentration; however, concentrations of IL-1β, IL-6, and TNFα were significantly increased in these tissues. In liver, resistin colocalizes with markers for Kupffer cells, for a subset of endothelial and fibroblast-like cells.

Conclusions: High level of resistin gene and protein expression in liver compared to AT implies that resistin should not be considered only as an adipokine in humans. LPS-induced inflammation does not affect resistin protein synthesis in human liver and AT. This suggests that elevated serum resistin levels are not indicative for inflammation of AT or liver in a manner similar to known inflammatory markers such as IL-1β, IL-6, or TNFα.
On Jevons's Handling of Differential Equations in the Context of His Principle of Exchange, and the Early Reactions
Authors: Grattan-Guinness I.
Published: May 2009

An important part of Jevons's economic theory was his theory of exchange of commodities. For justification he drew upon several aspects of differential equations and their applications, especially a principle in mechanics associated with equilibrium. Unfortunately his use of the principle was faulty. The error is analyzed here, along with his handling of differential equations in general, and the reactions to these aspects of his economic theory made by contemporaries, especially Marshall, Walras, and Edgeworth. These were often critical, though not over his misuse of the mechanical principle!
Adam Smith and the Labor Theory of (Real) Value: A Reconsideration
Authors: Peach Terry
Published: May 2009

This article questions the widely held opinion that Adam Smith confined his use of a labor theory of exchangeable value to an “early and rude state of society” in which independent laborers exchange the surplus products of their labor. It is argued that Smith did not explicitly disavow a more general application for the theory; that he continued to invoke (changes in) quantities of labor as principal determinants of (changes in) exchangeable value in all states of society; and that he had, in his own terms, some theoretical justification for his position. Moreover, it is argued that the lengths to which he went to obtain an association between the concepts of real price/real value and expended labor, ultimately to the point of abandoning his own declared choice of “real measure,” is compelling evidence of his commitment to an albeit rudimentary labor theory of exchangeable value.
Capitalism and Global Queering
Authors: Jackson Peter A.
Published: May 2009

This essay considers the role of market economies in global queering, the transnational proliferation of new male homosexual and male-to-female transgender identities and cultures. Early accounts of global queering highlighted the culturally homogenizing effects of transnational capitalism, representing new queer sexualities beyond the West as cultural imports from the United States. But international similarities among queer cultures also emerge from parallel processes of sex-cultural change produced by national-level forms of capitalism. Case studies from Thai queer history trace market-induced cultural parallels to earlier decades of the twentieth century, before the post-Cold War intensification of globalizing processes. These studies confirm the importance of the market in global queering. They also reveal that international commonalities reflect emergent parallels among multiple queer modernities and result as much from local responses to similar economic conditions as from foreign cultural influences. The alternative narrative of queer histories beyond the West presented here decouples the spread of capitalism from cultural Westernization. It highlights moments where queer subjects have enhanced their autonomy vis-à-vis local heteronormative traditions by creative engagements that take advantage of opportunities provided by the growth of the market economy.
Queer Kinship and Ambivalence
Authors: Pidduck Julianne
Published: May 2009

This article explores the relationship between queer thought and kinship through a study of video autoethnographies by Jean Carlomusto and Richard Fung. I propose the concept of ambivalence as a useful point of departure for grappling with the conflicted political, affective, and conceptual terrain of LGBT kinship. Through close textual analysis of four video autoethnographies, I extend existing sociological, anthropological, and philosophical scholarship on LGBT family and kinship to consider audiovisual production as a specific and productive kinship practice. Queer film and video autoethnography offers unexpected and insightful accounts of queer relationality. In contrast with dominant North American family narratives and imagery concerned with continuity, heredity, and the closed white, heteronormative North American intimate sphere, Carlomusto's and Fung's works probe the moments where kinship breaks down: illness and death, migrant experience, and family secrets. Through a doubled formal and thematic emphasis on fragmentation, discontinuity, and affective ambivalence, these extraordinary works help us understand kinship otherwise, or queerly.
γ-Tubulin-containing abnormal centrioles are induced by insufficient Plk4 in human HCT116 colorectal cancer cells
Authors: Kuriyama Ryoko , Bettencourt-Dias Monica , Hoffmann Ingrid , Arnold Marc , Sandvig Lisa
Published: May 2009

Cancer cells frequently induce aberrant centrosomes, which have been implicated in cancer initiation and progression. Human colorectal cancer cells, HCT116, contain aberrant centrioles composed of disorganized cylindrical microtubules and displaced appendages. These cells also express unique centrosome-related structures associated with a subset of centrosomal components, including γ-tubulin, centrin and PCM1. During hydroxyurea treatment, these abnormal structures become more abundant and undergo a change in shape from small dots to elongated fibers. Although γ-tubulin seems to exist as a ring complex, the abnormal structures do not support microtubule nucleation. Several lines of evidence suggest that the fibers correspond to a disorganized form of centriolar microtubules. Plk4, a mammalian homolog of ZYG-1 essential for initiation of centriole biogenesis, is not associated with the γ-tubulin-specific abnormal centrosomes. The amount of Plk4 at each centrosome was less in cells with abnormal centrosomes than cells without γ-tubulin-specific abnormal centrosomes. In addition, the formation of abnormal structures was abolished by expression of exogenous Plk4, but not SAS6 and Cep135/Bld10p, which are downstream regulators required for the organization of nine-triplet microtubules. These results suggest that HCT116 cells fail to organize the ninefold symmetry of centrioles due to insufficient Plk4.
Syntaxin 3 and SNAP-25 pairing, regulated by omega-3 docosahexaenoic acid, controls the delivery of rhodopsin for the biogenesis of cilia-derived sensory organelles, the rod outer segments
Authors: Mazelova Jana , Ransom Nancy , Astuto-Gribble Lisa , Wilson Michael C. , Deretic Dusanka
Published: May 2009

The biogenesis of cilia-derived sensory organelles, the photoreceptor rod outer segments (ROS), is mediated by rhodopsin transport carriers (RTCs). The small GTPase Rab8 regulates ciliary targeting of RTCs, but their specific fusion sites have not been characterized. Here, we report that the Sec6/8 complex, or exocyst, is a candidate effector for Rab8. We also show that the Qa-SNARE syntaxin 3 is present in the rod inner segment (RIS) plasma membrane at the base of the cilium and displays a microtubule-dependent concentration gradient, whereas the Qbc-SNARE SNAP-25 is uniformly distributed in the RIS plasma membrane and the synapse. Treatment with omega-3 docosahexaenoic acid [DHA, 22:6(n-3)] causes increased co-immunoprecipitation and colocalization of SNAP-25 and syntaxin 3 at the base of the cilium, which results in the increased delivery of membrane to the ROS. This is particularly evident in propranolol-treated retinas, in which the DHA-mediated increase in SNARE pairing overcomes the tethering block, including dissociation of Sec8 into the cytosol. Together, our data indicate that the Sec6/8 complex, syntaxin 3 and SNAP-25 regulate rhodopsin delivery, probably by mediating docking and fusion of RTCs. We show further that DHA, an essential polyunsaturated fatty acid of the ROS, increases pairing of syntaxin 3 and SNAP-25 to regulate expansion of the ciliary membrane and ROS biogenesis.
The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins
Authors: Abu-Hamad Salah , Arbel Nir , Calo Doron , Arzoine Laetitia , Israelson Adrian , Keinan Nurit , Ben-Romano Ronit , Friedman Orr , Shoshan-Barmatz Varda
Published: May 2009

The release of mitochondrial-intermembrane-space pro-apoptotic proteins, such as cytochrome c, is a key step in initiating apoptosis. Our study addresses two major questions in apoptosis: how are mitochondrial pro-apoptotic proteins released and how is this process regulated? Accumulating evidence indicates that the voltage-dependent anion channel (VDAC) plays a central role in mitochondria-mediated apoptosis. Here, we demonstrate that the N-terminal domain of VDAC1 controls the release of cytochrome c, apoptosis and the regulation of apoptosis by anti-apoptotic proteins such as hexokinase and Bcl2. Cells expressing N-terminal truncated VDAC1 do not release cytochrome c and are resistant to apoptosis, induced by various stimuli. Employing a variety of experimental approaches, we show that hexokinase and Bcl2 confer protection against apoptosis through interaction with the VDAC1 N-terminal region. We also demonstrate that apoptosis induction is associated with VDAC oligomerization. These results show VDAC1 to be a component of the apoptosis machinery and offer new insight into the mechanism of cytochrome c release and how anti-apoptotic proteins regulate apoptosis and promote tumor cell survival.
IQGAP1 regulates cell proliferation through a novel CDC42-mTOR pathway
Authors: Wang Jian-Bin , Sonn Robert , Tekletsadik Yemmsrach K. , Samorodnitsky Daniel , Osman Mahasin A.
Published: May 2009

Cell proliferation requires close coordination of cell growth and division to ensure constant cell size through the division cycles. IQGAP1, an effector of CDC42 GTPase has been implicated in the modulation of cell architecture, regulation of exocytosis and in human cancers. The precise mechanism underlying these activities is unclear. Here, we show that IQGAP1 regulates cell proliferation, which requires phosphorylation of IQGAP1 and binding to CDC42. Expression of the C-terminal region of IQGAP1 enhanced cellular transformation and migration, but reduced the cell size, whereas expression of the N-terminus increased the cell size, but inhibited cell transformation and migration. The N-terminus of IQGAP1 interacts with mTOR, which is required for IQGAP1-mediated cell proliferation. These findings are consistent with a model where IQGAP1 serves as a phosphorylation-sensitive conformation switch to regulate the coupling of cell growth and division through a novel CDC42-mTOR pathway, dysregulation of which generates cellular transformation.
Serial increased cardiac troponin T predicts mortality in asymptomatic patients treated with chronic haemodialysis
Authors: Roberts Matthew A , Hare David L , Macmillan Neil , Ratnaike Sujiva , Sikaris Ken , Ierino Francesco L
Published: May 2009

Background

A single detectable cardiac troponin predicts mortality in patients treated with dialysis. There are limited data on changes in troponin concentration over time and the clinical implications of serial troponin measurement.

Methods

Serial cardiac troponin T (cTnT) was assayed five times over 12 months in a prospective cohort study of patients with end-stage kidney disease treated with haemodialysis. A concentration of cTnT ≥0.04 μg/L was considered increased. Mortality and cardiovascular events were analysed by survival analysis, according to the serial troponin results.

Results

From 100 patients who provided a baseline sample for cTnT, 81 completed five serial measurements. The analysis of patients who completed serial cTnT measurements demonstrated that 28 patients (35%) had normal cTnT concentrations in all five samples, 20 patients (24%) had between one and four increased cTnT measurements and 33 patients (41%) had increased concentrations of cTnT in all five samples. The 1.7-y patient survival was 100%, 90% and 78% for patients with zero, one to four, or five out of five concentrations of cTnT increased, respectively ( P = 0.037), and the corresponding cardiovascular event-free survival was 100%, 91% and 78%, respectively ( P = 0.027).

Conclusions

Serial measurements of cTnT concentration were frequently increased in patients receiving haemodialysis. The number of abnormal measurements over time predicted mortality and cardiovascular adverse events.
Self-monitoring of blood glucose in diabetes: is it worth it?
Authors: O'Kane Maurice J , Pickup John
Published: May 2009

Self-monitoring of blood glucose (SMBG) is advocated as a valuable aid in the management of diabetes. The volume and cost of monitoring continues to increase. SMBG has a number of theoretical advantages/disadvantages which might impact on treatment, outcome and wellbeing. Investigating and quantifying the effect of self-monitoring in a condition where self-management plays a central role poses major methodological difficulties because of the need to minimize confounding factors. Despite the absence of definitive evidence, some situations where monitoring is generally accepted to be beneficial include patients on insulin, during pregnancy, in patients with hypoglycaemia unawareness and while driving. An area of controversy is the role of monitoring in non-insulin-requiring type-2 diabetes where observational and controlled studies give conflicting results. The available evidence does not support the general use of monitoring by all patients with type-2 diabetes, although further research is needed to identify specific subgroups of patients or specific situations where monitoring might be useful. The best use of SMBG in patients with type-2 diabetes might be for those receiving insulin and those on sulphonylurea drugs. The impact of monitoring on patient wellbeing must also be considered, with some studies suggesting adverse psychological effects. Given the large increase in the prevalence of type-2 diabetes, it will be important to define the role of SMBG so that resources can be used appropriately. Presently, the widespread use of SMBG (particularly in type-2 diabetes patients) is a good example of self-monitoring that was adopted in advance of robust evidence of its clinical efficacy.
Transparent Parallelization of Constraint Programming
Authors: Michel Laurent , See Andrew , Van Hentenryck Pascal
Published: May 2009

The availability of commodity multicore and multiprocessor machines and the inherent parallelism in constraint programming search offer significant opportunities for constraint programming. These opportunities also present a fundamental challenge: how to exploit parallelism transparently to speed up constraint programs. This paper shows how to parallelize constraint programs transparently without changes to the sequential code. The main technical idea consists of automatically lifting a sequential exploration strategy into its parallel counterpart, allowing workers to share and steal subproblems. Experimental results show that the parallel implementation may produce significant speedups on multicore machines.
The Knowledge-Gradient Policy for Correlated Normal Beliefs
Authors: Frazier Peter , Powell Warren , Dayanik Savas
Published: May 2009

We consider a Bayesian ranking and selection problem with independent normal rewards and a correlated multivariate normal belief on the mean values of these rewards. Because this formulation of the ranking and selection problem models dependence between alternatives' mean values, algorithms may use this dependence to perform efficiently even when the number of alternatives is very large. We propose a fully sequential sampling policy called the knowledge-gradient policy, which is provably optimal in some special cases and has bounded suboptimality in all others. We then demonstrate how this policy may be applied to efficiently maximize a continuous function on a continuous domain while constrained to a fixed number of noisy measurements.
Nonconvex Robust Optimization for Problems with Constraints
Authors: Bertsimas Dimitris , Nohadani Omid , Teo Kwong Meng
Published: May 2009

We propose a new robust optimization method for problems with objective functions that may be computed via numerical simulations and incorporate constraints that need to be feasible under perturbations. The proposed method iteratively moves along descent directions for the robust problem with nonconvex constraints and terminates at a robust local minimum. We generalize the algorithm further to model parameter uncertainties. We demonstrate the practicability of the method in a test application on a nonconvex problem with a polynomial cost function as well as in a real-world application to the optimization problem of intensity-modulated radiation therapy for cancer treatment. The method significantly improves the robustness for both designs.
Practice Prize Paper—Marketing-Mix Recommendations to Manage Value Growth at P&G Asia-Pacific
Authors: Kumar V. , Fan Jia , Gulati Rohit , Venkat P.
Published: May 2009

Procter & Gamble (P&G) Asia-Pacific is interested in managing value growth. Only after fully understanding the true effects of the marketing-mix variables can P&G managers make strategic decisions answering questions such as the following: (1) Are the P&G brands in the detergent market inelastic or elastic with respect to price? How has the price elasticity changed over time? Can P&G increase the price of its brands to gain value growth? (2) What are the price, distribution, and sizing combinations needed to achieve the desirable value growth? (3) How can P&G gain market share from its competitors without cannibalizing its own brands? P&G Asia-Pacific approached us to develop a value growth framework to answer these questions. To generate the answers for the above questions, we develop a three-step weighted random coefficient estimator that captures the heterogeneity across cross sections (different stock-keeping units and states) and the endogeneity of distribution. Based on the parameter estimates, we provide strategic recommendations to P&G for a field test to validate our suggestions. We developed a simulator for P&G managers so that they can generate appropriate marketing-mix strategies for achieving the desired value growth. As a result, P&G gained over $39 million in value growth over a one-year period by implementing the recommendations from our modeling approach.
MAD2 as a Key Component of Mitotic Checkpoint
Authors: Wang Li , Yin Fang , Du Yulei , Du Wenqi , Chen Bei , Zhang Yongguo , Wu Kaichun , Ding Jie , Liu Jie , Fan Daiming
Published: May 2009

We studied the subcellular localization of MAD2 in normal human tissues and gastric cancers. MAD2 showed nuclear and cytoplasmic localization in normal tissues such as muscle, testis, thyroid gland, cerebrum, trachea, and skin; blood vessels in some organs were also MAD2+. In normal stomach, MAD2 was expressed mainly in cytoplasm but showed nuclear staining in the majority of gastric cancers. MAD2 was significantly overexpressed in gastric cancer compared with matched adjacent tissues (P < .001), and expression was related to differentiation and other clinical parameters of cancer (P < .001). The cancer/adjacent normal tissue (C/N) ratio of MAD2 expression was higher than 2 and more frequently observed in patients with lymph gland metastasis (P < .05) and related to cancer differentiation. Our findings suggest that the steady-state amount of MAD2 inside cells may serve as a molecular switch in mitotic checkpoint control and that the subcellular localizations of this spindle protein undergo a shift during malignant transformation. The change of MAD2 expression may be involved mainly in gastric carcinogenesis and associated with the prognosis of gastric cancer; a C/N of more than 2 may be associated with the worse prognosis for survival in gastric carcinoma.
Enhancement of dissolution rates of amorphous silica by interaction with amino acids in solution at pH 4
Authors: Kawano Motoharu , Hatta Tamao , Hwang Jinyeon
Published: May 2009

Amino acids are present in various geochemical environments and they interact with mineral surfaces. To evaluate the effects of amino acids on mineral dissolution at pH conditions less than their isoelectric points (pI), dissolution experiments of X-ray amorphous silica in solutions containing 10.0 mmol/L of various amino acids (cysteine, asparagine, serine, tryptophan, alanine, threonine, histidine, lysine, and arginine) at pH 4 were performed. The results confirmed that basic amino acids (histidine, lysine, and arginine) produce an 8- to 8.5-fold enhancement of the rate of dissolution of amorphous silica compared with an amino acid-free control. Neutral amino acids (cysteine, asparagine, serine, tryptophan, alanine, and threonine) enhanced rates of dissolution by a factor of ∼3 to 3.5. The rate-enhancement effects of amino acids are controlled by concentrations of the amino acid’s cationic species which interact with the negatively charged >SiO− sites at the surface of the amorphous silica.
Chemostratigraphic correlation of sediments containing expandable clay minerals based on ion exchange with Cu(II) triethylenetetramine
Authors: Grygar Tomáš , Kadlec Jaroslav , Žigová Anna , Mihaljevič Martin , Nekutová Tereza , Lojka Richard , Světlík Ivo
Published: May 2009

Copper(II) triethylenetetramine [Cu(trien)]2+ is an agent suitable for the 1-step determination of the cation exchange capacity (CEC) of many geomaterials using a procedure much less laborious than other, commonly used methods. It is also suitable for the determination of the composition of original exchangeable cations. In contrast to other common ions used for CEC analysis, the Cu(II) complex with triethylenetetramine, [Cu(trien)]2+, is specific for expandable clay minerals. The robustness of [Cu(trien)]2+ analysis was verified using reference clays, ion-exchanged reference clays, sediments, and soils. The [Cu(trien)]2+-based CEC of expandable clay minerals is not influenced significantly by ferrihydrite, goethite, manganite, birnessite, calcite, and gypsum. Birnessite, calcite, and gypsum admixtures affect the composition of the evolved cations. [Cu(trien)]2+ does not recover the entire CEC of soils (but rather that of the clay minerals only) which contain components other than clays which contribute to the CEC, e.g. soil organic matter. In a series of loess with buried paleosols and recent soils the [Cu(trien)]2+-based CEC ranged from 30 to 110% of total CEC obtained by traditional BaCl2 methods. The relative ratio of Ca to Mg, the prevailing exchangeable cations in soils and sediments in exogenic environments, are similar after [Cu(trien)]2+ and conventional BaCl2 treatments. The Ca/Mg ratio in the exchangeable fraction was used successfully for chemostratigraphic correlation of paleolacustrine sediments from a large lake in the Upper Carboniferous basins of eastern equatorial Pangaea and a series of recent flood plain sediments of the meandering Morava River in the Czech Republic. The Ca/Mg ratio obtained by [Cu(trien)]2+ analysis is proposed as a novel tool for the chemostratigraphic correlation of sediment series containing expandable clay minerals.