bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Notch to Target Cancer Stem Cells
Authors: Pannuti Antonio , Foreman Kimberly , Rizzo Paola , Osipo Clodia , Golde Todd , Osborne Barbara , Miele Lucio
Published: June 2010

The cellular heterogeneity of neoplasms has been at the center of considerable interest since the “cancer stem cell hypothesis”, originally formulated for hematologic malignancies, was extended to solid tumors. The origins of cancer “stem” cells (CSC) or tumor-initiating cells (TIC; henceforth referred to as CSCs) and the methods to identify them are hotly debated topics. Nevertheless, the existence of subpopulations of tumor cells with stem-like characteristics has significant therapeutic implications. The stem-like phenotype includes indefinite self-replication, pluripotency, and, importantly, resistance to chemotherapeutics. Thus, it is plausible that CSCs, regardless of their origin, may escape standard therapies and cause disease recurrences and/or metastasis after apparently complete remissions. Consequently, the idea of selectively targeting CSCs with novel therapeutics is gaining considerable interest. The Notch pathway is one of the most intensively studied putative therapeutic targets in CSC, and several investigational Notch inhibitors are being developed. However, successful targeting of Notch signaling in CSC will require a thorough understanding of Notch regulation and the context-dependent interactions between Notch and other therapeutically relevant pathways. Understanding these interactions will increase our ability to design rational combination regimens that are more likely to prove safe and effective. Additionally, to determine which patients are most likely to benefit from treatment with Notch-targeting therapeutics, reliable biomarkers to measure pathway activity in CSC from specific tumors will have to be identified and validated. This article summarizes the most recent developments in the field of Notch-targeted cancer therapeutics, with emphasis on CSC. Clin Cancer Res; 16(12); 3141–52. ©2010 AACR.
Targeting Hedgehog — a Cancer Stem Cell Pathway
Authors: Merchant Akil A. , Matsui William
Published: June 2010

The Hedgehog (Hh) pathway has been implicated in a wide variety of human tumors, and early clinical trials with pathway antagonists have validated Hh signaling as a bona fide anticancer target. Despite these encouraging results, several issues surrounding the basic biology of the Hh pathway in human cancers remain unclear. These include the influence of specific oncogenic events on Hh signal transduction, the precise mode of Hh signaling (i.e., autocrine or paracrine) that occurs within human tumors, and the best means to inhibit aberrant pathway activity in the clinical setting. The cancer stem cell (CSC) hypothesis may explain a number of clinical phenomena, such as unchecked self-renewal and the development of metastatic disease, and to some extent, the Hh signaling pathway has been implicated in all of these processes. Therefore, Hh pathway inhibitors may also represent some of the first agents to formally examine the CSC hypothesis in the clinical setting. The diverse nature of Hh signaling in human cancers suggests that disease-specific factors must be carefully considered to identify the optimal use of novel pathway inhibitors. Clin Cancer Res; 16(12); 3130–40. ©2010 AACR.
Enhanced Anticancer Effect of the Combination of BIBW2992 and Thymidylate Synthase–Targeted Agents in Non–Small Cell Lung Cancer with the T790M Mutation of Epidermal Growth Factor Receptor
Authors: Takezawa Ken , Okamoto Isamu , Tanizaki Junko , Kuwata Kiyoko , Yamaguchi Haruka , Fukuoka Masahiro , Nishio Kazuto , Nakagawa Kazuhiko
Published: June 2010

Most non–small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)–targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR. Mol Cancer Ther; 9(6); 1647–56. ©2010 AACR.
Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice
Authors: Fritz Vanessa , Benfodda Zohra , Rodier Geneviève , Henriquet Corinne , Iborra François , Avancès Christophe , Allory Yves , de la Taille Alexandre , Culine Stéphane , Blancou Hubert , Cristol Jean Paul , Michel Françoise , Sardet Claude , Fajas Lluis
Published: June 2010

Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3α/β, the latter on being consistent with a decrease in β-catenin activity and mRNA levels of various β-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression. Mol Cancer Ther; 9(6); 1740–54. ©2010 AACR.
Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design
Authors: Wei Ping , Walls Marlena , Qiu Ming , Ding Richard , Denlinger Robert H. , Wong Anthony , Tsaparikos Kosta , Jani Jitesh P. , Hosea Natilie , Sands Michelle , Randolph Sophia , Smeal Tod
Published: June 2010

Aberrant regulation of Notch signaling has been implicated in tumorigenesis. Proteolytic release of the Notch intracellular domain (NICD) by γ-secretase plays a key role in Notch-dependent nuclear signaling. γ-Secretase is an attractive pharmaceutical target for therapeutic intervention in cancer. We describe the potent antitumor effects of PF-03084014, a small molecule that is a reversible, noncompetitive, and selective γ-secretase inhibitor. The ability of PF-03084014 to inhibit γ-secretase activity was shown by the reduction of endogenous NICD levels and by the downregulation of Notch target genes Hes-1 and cMyc in the T-cell acute lymphoblastic leukemia (T-ALL) cell line HPB-ALL. PF-03084014 caused cell growth inhibition of several T-ALL cell lines via cell cycle arrest and induction of apoptosis. PF-03084014 treatment also resulted in robust NICD reduction in HBP-ALL xenograft models. Broad antitumor efficacy at well-tolerated dose levels was observed in six Notch-dependent models. Additional mechanism-of-action studies showed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the antitumor activity of PF-03084014 may be mediated by its direct effects on tumor cell growth or survival. Further studies on PF-03084014–induced gastrointestinal toxicity identified an intermittent dosing schedule that displayed reduced body weight loss and sustained antitumor efficacy. We also showed that glucocorticoids abrogated PF-03084014–induced gastrointestinal toxicity and delayed administration of glucocorticoids did not compromise its protection effect. Collectively, the results show that inhibition of Notch signaling by PF-03084014 while minimizing gastrointestinal toxicity presents a promising approach for development of therapies for Notch receptor–dependent cancers. This compound is being investigated for the treatment of T-ALL and advanced solid tumors in phase I clinical trials. Mol Cancer Ther; 9(6); 1618–28. ©2010 AACR.
Zinc Protoporphyrin IX Stimulates Tumor Immunity by Disrupting the Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase
Authors: Metz Richard , DuHadaway James B. , Rust Sonja , Munn David H. , Muller Alexander J. , Mautino Mario , Prendergast George C.
Published: June 2010

The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) has emerged as an important driver of immune escape in a growing number of cancers and cancer-associated chronic infections. In this study, we define novel immunotherapeutic applications for the heme precursor compound zinc protoporphyrin IX (ZnPP) based on our discovery that it is a potent small-molecule inhibitor of IDO. Inhibitory activity was determined using in vitro and in-cell enzyme assays as well as a novel in vivo pharmacodynamic system. An irreversible mechanism of inhibition was documented, consistent with competition for heme binding in newly synthesized cellular protein. siRNA methodology and an IDO-deficient mouse strain were used to verify the specificity of ZnPP as an IDO inhibitor. In a preclinical model of melanoma, ZnPP displayed antitumor properties that relied on T-cell function and IDO integrity. ZnPP also phenocopied the known antitumor properties of IDO inhibitors in preclinical models of skin and breast carcinoma. Our results suggest clinical evaluation of ZnPP as an adjuvant immunochemotherapy in chronic infections and cancers in which there is emerging recognition of a pathophysiologic role for IDO dysregulation. Mol Cancer Ther; 9(6); 1864–71. ©2010 AACR.
Autophagy Regulates Keratin 8 Homeostasis in Mammary Epithelial Cells and in Breast Tumors
Authors: Kongara Sameera , Kravchuk Olga , Teplova Irina , Lozy Fred , Schulte Jennifer , Moore Dirk , Barnard Nicola , Neumann Carola A. , White Eileen , Karantza Vassiliki
Published: June 2010

Autophagy is activated in response to cellular stressors and mediates lysosomal degradation and recycling of cytoplasmic material and organelles as a temporary cell survival mechanism. Defective autophagy is implicated in human pathology, as disruption of protein and organelle homeostasis enables disease-promoting mechanisms such as toxic protein aggregation, oxidative stress, genomic damage, and inflammation. We previously showed that autophagy-defective immortalized mouse mammary epithelial cells are susceptible to metabolic stress, DNA damage, and genomic instability. We now report that autophagy deficiency is associated with endoplasmic reticulum (ER) and oxidative stress, and with deregulation of p62-mediated keratin homeostasis in mammary cells, allograft tumors, and mammary tissues from genetically engineered mice. In human breast tumors, high phospho(Ser73)-K8 levels are inversely correlated with Beclin 1 expression. Thus, autophagy preserves cellular fitness by limiting ER and oxidative stress, a function potentially important in autophagy-mediated suppression of mammary tumorigenesis. Furthermore, autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism. High phospho(Ser73)-K8 expression may be a marker of autophagy functional status in breast tumors and, as such, could have therapeutic implications for breast cancer patients. Mol Cancer Res; 8(6); 873–84. ©2010 AACR.
Overexpression of KLF13 and FGFR3 in Oral Cancer Cells
Authors: Henson B.J. , Gollin S.M.
Published: June 2010

KLF13 and FGFR3 have important cellular functions and each is believed to play a role in cancer. KLF13 is a transcription factor required for the expression of several oncogenes. FGFR3 is a fibroblast growth factor receptor that initiates a signaling cascade leading to the activation of numerous cellular pathways. Here we show that KLF13 and FGFR3 are overexpressed in oral cancer cells. We also show that artificially reducing cellular levels of KLF13 and FGFR3 decreases cell proliferation and increases sensitivity to ionizing radiation. These data suggest that KLF13 and FGFR3 contribute to malignancy in oral cancer cells and may be useful biomarkers for early detection and possible targets for therapy.
On the Social and Legal Status of Slaves in the North Caucasus
Authors: Inozemtseva Elena
Published: June 2010

The present paper is an attempt to elucidate some aspects of the social and legal status of slaves and, generally, the dependent populace in the North-Eastern Caucasus. The material introduced here allows to reveal some characteristic features of slavery and servitude, as well as several forms of deprivation of rights and social harrasment of the people belonging to lower classes in the mentioned area during the late mediaeval period.
The Rise of the Russian Khalifat: The View from the Jihadist Side
Authors: Shlapentokh Dmitry
Published: June 2010

Russia, similar to many other parts of the globe, continues to be affected by terrorism, mostly since the beginning of the conflicts in the Caucasus. While started by the Chechens after the beginning of the First Chechen War (1994-1996), terrorism and resistance to Moscow in general soon moved outside Chechen borders, absorbing representatives from other ethnic groups of the Caucasus and beyond. As a result, what originally had been mostly a Chechen nationalist movement finally transformed itself into a multi-ethnic force where the liberation of Chechnya from Russian rule became just one aspect of the struggle. Moreover, nationalist-minded Chechens seemed to have moved to the margins of the resistance, for increasing numbers of the resistance members could well go to the official Chechen leadership. While nationalistic and, in a way, a moderate model of the Chechen resistance became increasingly unworkable, jihadism provided an increasingly acceptable modus operandi. To start with, jihadism emphasises an ideological, Muslim identity and discards any sense of ethnicity, nationalism in general, that separates Muslims from each other. Secondly, jihadism promulgates the creation of a universal Khalifat as the final goal. Khalifat is seen as the ideal society, in a way similar to that of the “thousand-year rule of Christ” and/or communism, each of which actually transcends history as it is known. All of this has led to the increasing influence of jihadists among the members of the Chechen resistance, and a final split between them and the nationalist-minded members of the resistance. This paper presents a detailed analytic account of the recent developments within the Chechen resistance, as well as the jihadist ideology, and terrorism in the North Caucasus and Russia in general.
FimB Regulates FimA Fimbriation in Porphyromonas gingivalis
Authors: Nagano K. , Hasegawa Y. , Murakami Y. , Nishiyama S. , Yoshimura F.
Published: June 2010

The periodontitis-associated pathogen Porphyromonas gingivalis colonizes and forms a biofilm in gingival crevices through fimbriae. It is known that the often-used strains ATCC 33277 and 381 produce long FimA fimbriae. We found a possible nonsense mutation within fimB, immediately downstream from fimA, coding a major subunit of FimA fimbriae of the strains. Indeed, P. gingivalis strains, except for ATCC 33277 and 381, universally expressed FimB, the gene product of fimB. Electron micrographs revealed that a FimB-restored strain had short and dense, “toothbrush”-like, FimA fimbriae. FimA overexpression elongated the fimbriae, whereas FimB overexpression shortened them. FimB restoration increased production of FimA and its accessory proteins. Thus, FimB regulates the length and expression of FimA fimbriae. Additionally, FimB restoration significantly reduced the release of FimA fimbriae from the cell surface, suggesting that FimB functions as an anchor of the fimbriae. The restoration enhanced adherent activity as well.
β-catenin Initiates Tooth Neogenesis in Adult Rodent Incisors
Authors: Liu F. , Dangaria S. , Andl T. , Zhang Y. , Wright A.C. , Damek-Poprawa M. , Piccolo S. , Nagy A. , Taketo M.M. , Diekwisch T.G.H. , Akintoye S.O. , Millar S.E.
Published: June 2010

β-catenin signaling is required for embryonic tooth morphogenesis and promotes continuous tooth development when activated in embryos. To determine whether activation of this pathway in the adult oral cavity could promote tooth development, we induced mutation of epithelial β-catenin to a stabilized form in adult mice. This caused increased proliferation of the incisor tooth cervical loop, outpouching of incisor epithelium, abnormal morphology of the epithelial-mesenchymal junction, and enhanced expression of genes associated with embryonic tooth development. Ectopic dental-like structures were formed from the incisor region following implantation into immunodeficient mice. Thus, forced activation of β-catenin signaling can initiate an embryonic-like program of tooth development in adult rodent incisor teeth.
Locating Chinese Urban Housing Policy in an International Context
Authors: Stephens Mark
Published: June 2010

China’s economic development has often been contrasted with that of other transition economies in Europe, but academics have fought shy of making direct comparisons of urban housing reform in the two systems. This paper fills this gap by making such direct comparisons. Adopting the market—housing model advocated by the World Bank as an analytical framework it finds that extensive housing privatisation in China is supported by a system of urban housing property rights and a growing residential mortgage market. Although China has a distinctive institutional framework, there is also much variety among the European transition countries, and a distinctive Chinese model was not identified; so this micro-level analysis did not support the contention that China represents a form of ‘contested modernity’. Nonetheless, a crucial point arises from China’s hybrid status as a developing as well as a transition country. The bulk of the urban migrant population remains excluded from formal housing policy and enabling strategies that form an element of the market—housing model especially in developing countries are not so much replaced by a distinctive Chinese model as by a yawning gap.
Housing Supply and Residential Segregation in Ireland
Authors: Vang Zoua M.
Published: June 2010

The article examines the role of housing supply in ethnic diversity and the residential segregation of Asian, African and eastern European immigrants from Irish nationals in Ireland. Housing supply is defined as the proportions of new housing, private rental accommodation and social housing among all housing units in an electoral district. Multivariate regressions reveal that, among all three housing supply variables, the proportion of private rentals had the largest effect on ethnic diversity and immigrant— Irish segregation. Areas with higher proportions of private rental units were more ethnically diverse, had greater presences of Africans, Asians and eastern Europeans (as opposed to high concentrations of Irish nationals) and exhibited greater integration between each of the three immigrant groups and Irish nationals. The article concludes with a discussion of immigrant assimilation and questions whether the patterns of residential integration observed would further facilitate other forms of social inclusion for immigrants in Irish society.
Relationshopping: Investigating the market metaphor in online dating
Authors: Heino Rebecca D. , Ellison Nicole B. , Gibbs Jennifer L.
Published: June 2010

In this manuscript we explore the ways in which the marketplace metaphor resonates with online dating participants and how this conceptual framework influences how they assess themselves, assess others, and make decisions about whom to pursue. Taking a metaphor approach enables us to highlight the ways in which participants’ language shapes their self-concept and interactions with potential partners. Qualitative analysis of in-depth interviews with 34 participants from a large online dating site revealed that the marketplace metaphor was salient for participants, who employed several strategies that reflected the assumptions underlying the marketplace perspective (including resisting the metaphor). We explore the implications of this metaphor for romantic relationship development, such as the objectification of potential partners.
Effects of a scapula-oriented shoulder exercise programme on upper limb dysfunction in breast cancer survivors: a randomized controlled pilot trial
Authors: Seung Ah Lee  , Kang Ji-Young , Yong Duck Kim  , Ah Ra An  , Kim Sung-Won , Kim Yeon-Soo , Lim Jae-Young
Published: June 2010

Objective: To examine the effects of a scapula-oriented exercise on upper limb dysfunction in breast cancer survivors.

Study design: A prospective randomized, controlled pilot trial with historical control.

Setting: Rehabilitation department at a university hospital.

Subjects: Thirty-two women with breast cancer were randomly assigned to scapula-oriented exercise group (n = 16) and general exercise group (n = 16). An historical control group (n = 18) without exercise was enrolled from breast cancer survivors.

Interventions: The scapula-oriented exercises were designed focusing on scapulothoracic movement. The general exercise group performed body conditioning exercise. Exercise therapies were performed for one session per week for eight weeks.

Main outcome measures: Pain and physical disabilities related to upper limb dysfunction, quality of life and depression were used as subjective outcomes. Objective outcome measures included shoulder range of motion and strength. Outcomes were assessed at baseline and post exercise.

Results: At baseline, no significant difference was observed among the three groups. The scapula-oriented exercise group showed improvements in pain, physical function, social function, and global quality of life compared with baseline, whereas the general exercise group showed improved fatigue and range of motion. The change in global quality of life (P = 0.067; effect size, 0.33) and strength of external rotation (P = 0.001; effect size, 0.55) were significantly greater in the scapula-oriented exercise group than in the general exercise and control group.

Conclusion: Scapula-oriented exercise had beneficial effects on pain, quality of life and aspects of strength. The sample size required in a larger definitive study is 32 subjects per group.
Interprofessional teamwork in medical rehabilitation: a comparison of multidisciplinary and interdisciplinary team approach
Authors: Körner Mirjam
Published: June 2010

Objective: To compare multi- and interdisciplinary team approaches concerning team process (teamwork) and team effectiveness (team performance and staff satisfaction) in German medical rehabilitation clinics.

Design: A cross-sectional study with a descriptive—explorative design.

Setting: Eighteen medical rehabilitation clinics divided into two groups (somatic and psychosomatic indication fields).

Subjects: The 18 head physicians or psychotherapists in the clinics and their complete rehabilitation teams (n = 824).

Main measures: An interview guide was designed to determine the team approach in a telephone interview. A staff questionnaire for team members measured teamwork and team effectiveness with psychometrically validated questionnaires and self-administered items.

Results: All 18 head physicians took part in the telephone interview. The response rate of the employee attitude survey averaged 46% (n = 378). Eight teams were categorized as multidisciplinary and seven teams as interdisciplinary. In three cases the results were ambiguous. These teams were not considered in the further study. As expected, the interdisciplinary team approach showed significantly better results for nearly all aspects of teamwork and team effectiveness in comparison with the multidisciplinary team approach. The differences between multi- and interdisciplinary approach concerning teamwork and team effectiveness were higher in the somatic (8 teams, n = 183) than in the psychosomatic indication fields (7 teams, n = 195).

Conclusions: Teamwork and team effectiveness are higher in teams working with the interdisciplinary team approach. Therefore the interdisciplinary approach can be recommended, particularly for clinics in the somatic indication field. Team development can help to move from the multidisciplinary to the interdisciplinary approach.
The role of central noradrenergic dysregulation in anxiety disorders: evidence from clinical studies
Authors: Kalk NJ , Nutt DJ , Lingford-Hughes AR
Published: June 2010

The nature of the noradrenergic dysregulation in clinical anxiety disorders remains unclear. In panic disorder, the predominant view has been that central noradrenergic neuronal networks and/or the sympathetic nervous system was normal in patients at rest, but hyper-reactive to specific stimuli, for example carbon dioxide. These ideas have been extended to other anxiety disorders, which share with panic disorder characteristic subjective anxiety and physiological symptoms of excess sympathetic activity. For example, Generalized Anxiety Disorder is characterized by chronic free-floating anxiety, muscle tension, palpitation and insomnia. It has been proposed that there is chronic central hypersecretion of noradrenaline in Generalized Anxiety Disorder, with consequent hyporesponsiveness of central post-synaptic receptors. With regards to other disorders, it has been suggested that there is noradrenergic involvement or derangement, but a more specific hypothesis has not been enunciated. This paper reviews the evidence for noradrenergic dysfunction in anxiety disorders, derived from indirect measures of noradrenergic function in clinical populations.
Efficacy markers in depression
Authors: Harmer Catherine J , Cowen Philip J , Goodwin Guy M
Published: June 2010

Current antidepressant agents are similar in efficacy to the original drugs discovered in the 1950s. The development of new treatments for depression is, however, limited by the absence of validated human biomarker models to predict efficacy, clinical profile and dosing. Such models need to meet key criteria for biomarkers including sensitivity, specificity and relevance to depression. Here we review studies exploring whether early changes in emotional processing with antidepressant drug administration meet these criteria. A large body of evidence suggests that changes in emotional memory are particularly relevant to depression and to antidepressant drug action whereas changes in attentional processing are sensitive to anxiolytic drugs. These tasks are not consistently affected by agents which have failed in clinical trials in depression, but do show changes in the predicted direction with agents associated either with amelioration or induction of symptoms. Hence, early assessment of novel drugs on emotional processing may predict likely clinical effects and dosing prior to randomized controlled trials. Greater validation is required to assess whether these effects are an obligatory component of effective treatment of depression and whether use of these models can improve the accuracy of go/no-go decisions in drug development.
Three Gorges Project: Efforts and challenges for the environment
Authors: Fu Bo-Jie , Wu Bing-Fang , Lü Yi-He , Xu Zhi-Hong , Cao Jing-Hua , Dong Niu  , Yang Gui-Shan , Zhou Yue-Min
Published: June 2010

The Three Gorges Project has been subject to intense debates regarding its benefits and costs. The environmental impacts of this huge project have been an important focus of these debates since the project planning stage. After the operation of the Three Gorges Dam at full capacity at the end of 2008, new environmental and ecological issues are emerging. This paper gives a brief description of the Three Gorges Project and its environmental impact assessment process, as well as major efforts to control environmental problems brought about by the project. From the long and complicated evaluation process, it is clear that there are large uncertainties and competing opinions regarding the benefits and costs, especially the ecological and environmental ones, of the project even after great research effort. Emphasis here is given to the environmental challenges including: (1) water quality control; (2) water and sediment regulation; (3) biodiversity conservation in the riparian and aquatic ecosystems; (4) environmentally friendly dam operation and regional sustainable development. Opportunities often grow out of the challenges. The Three Gorges Project provides opportunities for grand-scale experiments on the environmental, ecological, and socio-economic impacts of large dams. Local, national, and international concerted efforts and concrete actions should be directed to the mitigation and control of the negative impacts as well as securing the positive contributions of the project across scales.
Dendrochronological evidence for a lower water-table on peatland around 3200-3000 BC from subfossil pine in northern Scotland
Authors: Moir A.K. , Leroy S.A.G. , Brown D. , Collins P.E.F.
Published: June 2010

Tree-ring analysis of subfossil Pinus sylvestris L., from nine new peatland sites located beyond the species’ current northern limit in Scotland, established a regional chronology called WRATH-9. The chronology has been provisionally dated against Irish pine chronologies and provides the first annual resolution picture of Scots pine expansion from c. 3200 BC and subsequent demise from c. 3000 BC. Pine germination and growth is suggested to be associated with a widespread fall in bog water-tables that indicates a regional climatic control. Bog pines progressively declined in number, rather than died out in a single event, reflecting their growth in a marginal habitat, close to a critical ecological threshold. The use of tree-ring sequences from in situ bog pine macrofossils provides a higher resolution insight into past conditions than possible with existing radiocarbon and pollen-based chronologies.
Interleukin 4 and STAT6 gene polymorphisms are associated with systemic lupus erythematosus in Chinese patients
Authors: Yu H-H. , Liu P-H. , Lin Y-C. , Chen WJ , Lee J-H. , Wang L-C. , Yang Y-H. , Chiang B-L.
Published: June 2010

An imbalance between T Helper 1 (TH1) and T Helper 2 (TH2) cytokine production is important for the pathogenesis of systemic lupus erythematosus (SLE). We aimed to investigate gene—gene associations of TH1 and T H2 cytokines genes in Chinese patients with SLE. Twenty single nucleotide polymorphisms (SNPs) in eight cytokines genes were genotyped in 110 SLE patients and 138 healthy controls in a case—control association study. The minor allelic frequencies of interleukin4(IL4) -590 T/C, -33 T/C, 9241C/G, and IL10 -592 A/C were significantly increased in SLE patients compared with those in controls (p < 0.05). None of the separate 20 SNPs showed significant association with SLE after Bonferroni correction. An IL4 haplotype -590C/-33C/9241G/14965C was significantly associated with SLE (odds ratio 3.7, 95% confidence interval [CI] 1.5—8.9, p = 0.004, Bonferroni-corrected p = 0.024). A borderline significant three-locus gene—gene interaction among IL4 9241 C/G, IL4 -33 T/C, signal transducer and activator of transcription 6, IL4-induced (STAT6) 2892 C/T was detected by a multifactor dimensionality reduction test (p = 0.051). However, the presence of two at-risk genotypes lead to increased risk of SLE for two-locus interaction using logistic regression method. The risk of SLE increased significantly when a subject has two at-risk genotypes for IL4 -590C and STAT6 2892C (odds ratio, 3.24, 95% CI 1.5—7.0, p = 0.003, Bonferroni-corrected p = 0.009), IL4 -33C and STAT6 2892C (odds ratio 3.06, 95% CI 1.4— 6.7, p = 0.005, Bonferroni-corrected p = 0.015), as well as IL4 9241G and STAT6 2892C (odds ratio 3.34, 95% CI 1.6—7.1, p = 0.002, Bonferroni-corrected p = 0.006). Further, plasma IL-4 concentrations were significantly lower in SLE patients than in healthy controls (1.59 + 3.53 versus 5.67 + 11.28 pg/ml, p = 0.042). These results indicated that IL4 and STAT6 genes might be involved in the etiology of SLE and potentially increased SLE risk through their interaction effect in Chinese patients.
Deadline: Ethics and the Ethnographic Divorce
Authors: Tillmann Lisa M.
Published: June 2010

In the summer of 2009, the author receives a call from a New York Times reporter about her book Between Gay and Straight. The book portrays her (now-ex) husband’s and her integration into a network of gay male friends. “Deadline” explores tensions between private and public as the private turmoil of divorce clashes with the public construction of the author’s marriage and with her determination to continue the social justice work of Between Gay and Straight.
Community Organizing Goes to College: A Practice-Based Model to Implement Environmental Strategies to Reduce High-Risk Drinking on College Campuses
Authors: Wagoner Kimberly G. , Rhodes Scott D. , Lentz Ashley W. , Wolfson Mark
Published: June 2010

Community organizing is a successful method to leverage resources and build community capacity to identify and intervene on health issues. However, published accounts documenting the systematic facilitation of the process are limited. This qualitative analysis explored community organizing using data collected as part of the Study to Prevent Alcohol Related Consequences (SPARC), a randomized community trial of 10 North Carolina colleges focused on reducing consequences of high-risk drinking among college students. The authors sought to develop and confirm use of a community-organizing model, based in practice, illustrating an authentic process of organizing campus and community stakeholders for public health change. Using the grounded theory approach, they analyzed and interpreted data from three waves of individual interviews with full-time community organizers on five SPARC intervention campuses. A five-phase community-organizing model was developed and its use was confirmed. This model may serve as a practical guide for public health interventions using community-organizing approaches.
Effect of initial grain size on evolved ferrite grain size during high Z large strain deformation
Authors: Murty S. V. S. , Torizuka S. , Nagai K. , Kitai T. , Kogo Y.
Published: June 2010

The effect of initial grain size on the evolved ferrite grain size during high Z large strain deformation was studied in ultralow carbon steel with two widely varying initial microstructures: a coarse grained (200 μm) and an ultrafine grained (0·7 μm) microstructures. Plane strain compression was used for imposing large strain in the test specimen and a thermomechanical simulator was used for varying the strain rate and temperature precisely. Electron backscattered diffraction was used for the analysis of deformed microstructure and for grain size measurements. Deformation conditions were varied to cover wide range of Zener–Hollomon parameters. It was noted that the evolved ferrite grain size solely depends on the Zener–Hollomon parameter and does not depend on the initial grain size. The relation d=10 Z–0·12 ( Qgb=155 kJ mol–1) was obtained for two initial microstructures with grain sizes varying by three orders of magnitude.
Soft mechanochemical synthesis of MgFe2O4 nanoparticles from the mixture of α-Fe2O3 with Mg(OH)2 and Fe(OH)3 with Mg(OH)2
Authors: Pavlović M. B. , Jovalekić Č. , Nikolić A. S. , Manojlović D. , Šojić N.
Published: June 2010

The influence of long term soft milling of a mixture of (1) Mg(OH)2 and α-Fe2O3 and (2) Mg(OH)2 and Fe(OH)3 powders in a planetary ball mill on the reaction synthesis of nanosized MgFe2O4 ferrites was studied. Soft mechanochemical reaction leading to formation of the MgFe2O4 spinel phase was followed by scanning electron microscopy, transmission electron microscopy, X-ray diffraction and magnetisation measurements. The spinel phase formation was first observed after 5 h of milling and its formation was completed after 15 h in case (2). The synthesised MgFe2O4 ferrite had a nanocrystalline structure with a crystallite size of about 10 and 15 nm respectively for cases (1) and (2). Measurements after 15 h of milling show magnetisation values of 15·23 and 10·14 J T–1 kg–1 respectively for cases (1) and (2).
Diamond formation in the deep mantle: the record of mineral inclusions and their distribution in relation to mantle dehydration zones
Authors: Harte B.
Published: June 2010

Studies of the inclusions contained in natural diamonds have shown the occurrence of minerals which must have formed at depths below the lithosphere and which may be closely matched with the silicate mineral assemblages determined by high pressure and temperature experimental studies for depths of 300 to 800 km in the Earth's mantle. The inclusions come principally from two main depth zones: (1) the lower asthenosphere and upper transition zone; (2) the Upper Mantle/Lower Mantle (UM/LM) boundary region and the uppermost LM. The inclusions from zone 1 are very largely majoritic garnets (with or without clinopyroxene) which indicate bulk compositions of eclogitic/metabasic affinity. The minerals from zone 2 include Ca-Si and Mg-Si perovskites and ferropericlase and are dominantly of metaperidotitic bulk composition, but include some possible metabasite assemblages. In many of these natural assemblages, the tetragonal almandine pyrope phase occurs rather than the garnet found in experiments.

As natural diamonds are believed to crystallize in fluids/melts, the hypothesis is developed that the restriction of diamonds and inclusions of particular compositions to the above two depth intervals is because they are controlled by loci of fluid/melt occurrence. Attention is focused on subduction zones because both suites of inclusions show some evidence of subducted protoliths. The lower zone (600–800 km) coincides with the region where dehydration may be expected for hydrous ringwoodite and dense hydrous Mg-silicates formed in subducted peridotites. The dehydration of lawsonite in subducted metabasites provides a particular location for melt formation and the inclusion of the shallower (~ 300 km) majoritic inclusions. For the deeper majoritic inclusions in the region of the upper transition zone, melt development may occur as a consequence of the hydrous wadsleyite-to-olivine transformation, and such melt may then interact with the upper crustal portion of a subducting slab. These suggestions offer an explanation of the depth restrictions and the compositional restrictions of the inclusions. The differences in δ13C values in the host diamonds for the two suites of inclusions may also be explained on this basis.
Boron and lithium isotopic compositions as provenance indicators of Cu-bearing tourmalines
Authors: Shabaga B. M. , Fayek M. , Hawthorne F. C.
Published: June 2010

The Li and B isotopic compositions of gem-quality Cu-bearing tourmalines were used (1) to distinguish among Paraiba tourmalines from Brazil and Cu-bearing tourmalines from Nigeria and Mozambique; and (2) to identify the likely source of Li and B for these gem-quality tourmalines. The δ11B values of tourmaline from Paraiba, Brazil, range from –42.4‰ to –32.9‰, whereas the δ11B values of Cu-bearing tourmaline from Nigeria and Mozambique range from –30.5‰ to –22.7‰ and –20.8‰ to –19.1‰ respectively. Tourmalines from each locality have relatively homogeneous δ11B values and display no overlap. There is slight overlap between δ7Li values of Paraiba tourmaline (+24.5‰ to +32.9‰) and Cu-bearing tourmaline from Nigeria (+32.4‰ to +35.4‰), and δ7Li values of Cu-bearing tourmaline from Nigeria and Mozambique (+31.5‰ to +46.8‰). Nevertheless, Cu-bearing tourmalines from each locality can be fingerprinted using a combination of their δ11B and δ7Li values. The very small δ11B values are consistent with a non-marine evaporite source, and are among the smallest reported for magmatic systems, expanding the global range of B isotopicc omposition for tourmaline by 12‰. The corresponding large δ7Li values are among the largest reported, although they are less diagnostic of the source of the Li. The large δ7Li values in conjunction with the small δ11B values suggest a non-marine evaporite or brine as a source for Li and B, either as constituent(s) of the magma source region or, by assimilation during magma ascent. The large range in δ11B and δ7Li values suggests that B and Li isotope fractionation occurred during magmatic degassing and late-stage magmatic-hydrothermal evolution of the granite-pegmatite system.
Inhibition of lipid antigen presentation in dendritic cells by HIV-1 Vpu interference with CD1d recycling from endosomal compartments
Authors: Moll Markus , Andersson Sofia K. , Smed-Sörensen Anna , Sandberg Johan K.
Published: June 2010

Dendritic cells (DCs) play an important role in viral infections both as initiators of immunity and as viral targets. Interaction between DCs and the innate-like CD1d-restricted natural killer T (NKT) cells results in the mutual activation of both cells and the subsequent initiation of cellular immune responses. Here, we show that HIV-1 inhibits the surface expression of CD1d in productively infected DCs and identify this as a novel activity of the HIV-1 vpu gene product. Interestingly, the viral protein U (Vpu) does not enhance constitutive CD1d endocytosis or induce rapid CD1d degradation. Instead, the Vpu protein interacts with CD1d and suppresses its recycling from endosomal compartments to the cell surface by retaining CD1d in early endosomes. This interference with the CD1d antigen presentation pathway strongly inhibits the ability of infected DCs to activate CD1d-restricted NKT cells. Given that the interaction with CD1d-expressing DCs is central to the ability of NKT cells to regulate immunity, these data suggest that interference with the CD1d antigen presentation pathway represents an HIV-1 strategy to evade innate cellular immune responses and imply a role for the innate-like CD1d-restricted NKT cells in the host defense against HIV-1.
dConsensus: a tool for displaying domain assignments by multiple structure-based algorithms and for construction of a consensus assignment
Authors: Alden Kieran , Veretnik Stella , Bourne Philip E
Published: June 2010

Background

Partitioning of a protein into structural components, known as domains, is an important initial step in protein classification and for functional and evolutionary studies. While the systematic assignments of domains by human experts exist (CATH and SCOP), the introduction of high throughput technologies for structure determination threatens to overwhelm expert approaches. A variety of algorithmic methods have been developed to expedite this process, allowing almost instant structural decomposition into domains. The performance of algorithmic methods can approach 85% agreement on the number of domains with the consensus reached by experts. However, each algorithm takes a somewhat different conceptual approach, each with unique strengths and weaknesses. Currently there is no simple way to automatically compare assignments from different structure-based domain assignment methods, thereby providing a comprehensive understanding of possible structure partitioning as well as providing some insight into the tendencies of particular algorithms. Most importantly, a consensus assignment drawn from multiple assignment methods can provide a singular and presumably more accurate view.

Results

We introduce dConsensus http://pdomains.sdsc.edu/dConsensus; a web resource that displays the results of calculations from multiple algorithmic methods and generates a domain assignment consensus with an associated reliability score. Domain assignments from seven structure-based algorithms - PDP, PUU, DomainParser2, NCBI method, DHcL, DDomains and Dodis are available for analysis and comparison alongside assignments made by expert methods. The assignments are available for all protein chains in the Protein Data Bank (PDB). A consensus domain assignment is built by either allowing each algorithm to contribute equally (simple approach) or by weighting the contribution of each method by its prior performance and observed tendencies. An analysis of secondary structure around domain and fragment boundaries is also available for display and further analysis.

Conclusion

dConsensus provides a comprehensive assignment of protein domains. For the first time, seven algorithmic methods are brought together with no need to access each method separately via a webserver or local copy of the software. This aggregation permits a consensus domain assignment to be computed. Comparison viewing of the consensus and choice methods provides the user with insights into the fundamental units of protein structure so important to the study of evolutionary and functional relationships.
Feasibility and effects of adapted cardiac rehabilitation after stroke: a prospective trial
Authors: Tang Ada , Marzolini Susan , Oh Paul , McIlroy William E , Brooks Dina
Published: June 2010

Background

Despite the cardiovascular etiology of stroke, exercise and risk factor modification programs akin to cardiac rehabilitation (CR) are not available. This study aimed to establish the feasibility of adapting a CR model for individuals with mild to moderate stroke disability. A secondary objective was to determine the program's effects on aerobic and walking capacity, and stroke risk factors.

Methods

A repeated measures design was used with a 3-month baseline period and 6-month adapted CR intervention (n = 43, mean ± SD age 65 ± 12 years, 30 ± 28 months post stroke). Feasibility was determined by the number of participants who completed the study, occurrence of adverse events and frequency, duration and intensity of exercise performed. To determine effectiveness of the program, outcomes measured included aerobic capacity (VO2peak, ventilatory threshold), 6-Minute Walk Test (6MWT) distance, and risk factors. Descriptive statistics characterized the classes attended and number and intensity of exercise sessions. Pairedt-tests, one-factor repeated measures analyses of variance contrasts and chi-square analyses were used to compare changes over time.

Results

Two participants withdrew during the baseline period. Of the remaining 41 participants who commenced the program, 38 (93%) completed all aspects. No serious adverse effects occurred. Post-intervention, VO2peak improved relative to the stable baseline period (P= 0.046) and the increase in ventilatory threshold approached significance (P= 0.062).

Conclusions

CR is feasible after stroke and may be adapted to accommodate for those with a range of post-stroke disability. It is effective in increasing aerobic capacity. CR may be an untapped opportunity for stroke survivors to access programs of exercise and risk factor modification to lower future event risk.

Trial registration

ClinicalTrials.gov registration number: NCT01067495