julilili42/papers huggingface dataset:
William H. A. Williams . Tourism, Landscape, and the Irish Character: British Travel Writers in Pre‐Famine Ireland.(History of Ireland and the Irish Diaspora.)Madison : University of Wisconsin Press . 2008 . Pp. xi, 267. $65.00.
2009-12-01

Much early modern tourism was affected by two or perhaps three Irishmen. One was Frederick Hervey, fourth earl of Bristol, bishop of Derry (1730–1803), dilettante and traveller, whose name came to be connected with the continent's classiest hotels. Another was Arthur Wellesley, duke of Wellington, whose campaigns and their commemoration generated much of the “battle tourism” made possible by the coming railway age. The third was Charles Maturin, whose Melmoth the Wanderer (1820) created the tourist from hell. The sublime as horror is never far from the eye-witness accounts discussed in William H. A. Williams's fascinating work. The marks of a growing specialism can be seen in the book's bibliography. Of eight anthologies of tourist writing on Ireland cited, all but one stem from the post-1990 period that witnessed the postmodern disaggregation of history, away from Staatsräson and toward boutique studies of varying relevance to humanist survival in the penumbra of finance capital. It is no coincidence that more print is (or in the last couple of decades was) devoted to genteel writing about the cabins and crosses of Ireland than to the far more infective socio-economic history of Liechtenstein or the Cayman Islands.
Lapatinib Can Be Safely Given Concomitantly to EC-Doc as Neoadjuvant Chemotherapy for Breast Cancer. First Planned Safety Analysis of the Geparquinto Study (GBG 44).
2009-12-01

Abstract Background:Trastuzumab has significantly improved pathological complete response rates of neoadjuvant treatment in HER2 positive breast cancer (HER2+BC). The tyrosine-kinase inhibitor lapatinib (L) has shown efficacy in metastatic breast cancer. Previous data in metastatic breast cancer suggested increased hematologic toxicity of docetaxel (Doc) combined with L. As the dose and safety of L in combination with epirubicin (E), cyclophosphamide (C), and Doc has not yet been adequately tested, an integrated safety phase was conducted.Patients and Methods:The GeparQuinto trial, a neoadjuvant phase III study, planned to include 2500 patients (pts) in total and 594 HER2+BC pts for comparing L versus trastuzumab (H) given concomitantly to anthracycline-taxane based chemotherapy. Female pts with untreated, histologically confirmed uni- or bilateral, cT3/4a-d, HER2+BC and no clinically relevant cardiovascular co-morbidities received 4 cycles of E (90mg/m2) + C (600 mg/m2) q3w followed by Doc 100mg/ m2 q3w. Pts were randomized to receive either H (6 mg/kg; 8mg/kg loading dose; q3w) or L given concomitantly to all cycles. The 1st cohort in the L arm received 1000 mg/d L during the 1st cycle EC and the 1st cycle Doc and 1250 mg/d L through all other cycles and received prophylactic treatment with pegfilgrastim (6 mg on day 2) and loperamide (2x2mg daily). The 2nd cohort received no loperamide, if &amp;lt;=1 diarrhea grade 3 and no pegfilgrastim if &amp;lt;=3 events of grade 4 neutropenia and &amp;lt;=1 febrile neutropenia (FN) occurred during cycles 1+2 of the 1st 10 pts of the 1st cohort. The remaining pts received 1250 mg/d L in the first cycle and no prophylaxis with loperamide if &amp;lt;=2 diarrhea grade 3 and &amp;lt;= 1 diarrhea grade 4 and no pegfilgrastim if &amp;lt;=4 events of grade 4 neutropenia and &amp;lt;=2 FN occurred during cycles 1+2 of the 1st 10 pts of the 2nd cohort. An interim safety analysis was planned when 60 pts completed all cycles.Results:As of June 1 2009 918 (178 HER+BC) pts have been recruited. 31 pts received ECH-DocH and 29 pts ECL-DocL. In the 1st cohort no grade 3 diarrhea and 2 grade 4 neutropenias occurred. In the 2nd cohort again, no grade diarrhea 3, but 8 grade 4 neutropenias (1 FN) occurred in 4 pts. L was, when compared to H, associated with less grade 1/2 anemia (27.6% vs. 51.6.%) but more grade 1/2 skin rash (27.6% vs. 6.5%) during cycle 1 (data on all cycles will be presented). No significant differences for other toxicities were seen.Conclusion:L at a dose of 1250 mg/d is feasible and well tolerated when given concomitantly to EC-Doc if G-CSF is given prophylactically during DocL. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1094.
Redistributing Gains from Globalisation*
2009-12-01

Abstract This paper analyses the effects of redistribution in a model of international trade with heterogeneous firms in which a fair‐wage effort mechanism leads to firm‐specific wage payments and involuntary unemployment. The redistribution scheme is financed by profit taxes and gives the same absolute lump‐sum transfer to all workers. International trade increases aggregate income and income inequality, ceteris paribus . If, however, trade is accompanied by a suitably chosen increase in the profit tax rate, it is possible to achieve higher aggregate income and a more equal income distribution than in autarky, provided that the share of exporters is sufficiently high.
The Tumor Suppressor p53 Transcriptionally Regulates cGKI Expression during Neuronal Maturation and Is Required for cGMP-Dependent Growth Cone Collapse
2009-12-02

The cGMP-dependent protein kinase type I (cGKI) has multiple functions including a role in axonal growth and pathfinding of sensory neurons, and counteracts Semaphorin 3A (Sema3A)-induced growth cone collapse. Within the nervous system, however, the transcriptional regulation of cGKI is still obscure. Recently, the transcription factor and tumor suppressor p53 has been reported to promote neurite outgrowth by regulating the gene expression of factors that promote growth cone extension, but specific p53 targets genes that may counteract growth cone collapse have not been identified so far. Here, we show that p53 promotes cGKI expression in neuronal-like PC-12 cells and primary neurons by occupying specific regulatory elements in a chromatin environment during neuronal maturation. Importantly, we demonstrate that p53-dependent expression of cGKI is required for the ability of cGMP to counteract growth cone collapse. Growth cone retraction mediated by Sema3A is overcome by cGMP only in wild-type, but not in p53-null dorsal root ganglia. Reconstitution of p53 levels is sufficient to recover both cGKI expression and the ability of cGMP to counteract growth cone collapse, while cGKI overexpression rescues growth cone collapse in p53-null primary neurons. In conclusion, this study identifies p53 as a transcription factor that regulates the expression of cGKI during neuronal maturation and cGMP-dependent inhibition of growth cone collapse.
Visual Motion Perception Deficits Due to Cerebellar Lesions Are Paralleled by Specific Changes in Cerebro-Cortical Activity
2009-12-02

Recent anatomical studies have revealed strong cerebellar projections into parietal and prefrontal cortex. These findings suggest that the cerebellum might not only play a functional role in motor control but also cognitive domains, an idea also supported by neuropsychological testing of patients with cerebellar lesions that has revealed specific deficits. The goal of the present study was to test whether or not cognitive impairments after cerebellar damage are resulting from changes in cerebro-cortical signal processing. The detection of global visual motion embedded in noise, a faculty compromised after cerebellar lesions, was chosen as a model system. Using magnetoencephalography, cortical responses were recorded in a group of patients with cerebellar lesions ( n = 8) and controls ( n = 13) who observed visual motion of varied coherence, i.e., motion strength, presented in the peripheral visual field during controlled stationary fixation. Corroborating earlier results, the patients showed a significant impairment in global motion discrimination despite normal fixation behavior. This deficit was paralleled by qualitative differences in responses recorded from parieto-temporal cortex, including a reduced responsiveness to coherent visual motion and a striking loss of bilateral representations of motion coherence. Moreover, the perceptual thresholds correlated with the cortical representation of motion strength on single subject basis. These results demonstrate that visual motion processing in cerebral cortex critically depends on an intact cerebellum and establish a correlation between cortical activity and impaired visual perception resulting from cerebellar damage.
Cellular pharmacology of multi- and duplex drugsconsisting of ethynylcytidine and 5-fluoro-2′-deoxyuridine
2009-12-02

Prodrugs can have the advantage over parent drugs in increased activation and cellular uptake. The multidrug ETC-L-FdUrd and the duplex drug ETC-FdUrd are composed of two different monophosphate-nucleosides, 5-fluoro-2'deoxyuridine (FdUrd) and ethynylcytidine (ETC), coupled via a glycerolipid or phosphodiester, respectively. The aim of the study was to determine cytotoxicity levels and mode of drug cleavage. Moreover, we determined whether a liposomal formulation of ETC-L-FdUrd would improve cytotoxic activity and/or cleavage. Drug effects/cleavage were studied with standard radioactivity assays, HPLC and LC-MS/MS in FM3A/0 mammary cancer cells and their FdUrd resistant variants FM3A/TK(-). ETC-FdUrd was active (IC(50) of 2.2 and 79 nM) in FM3A/0 and TK(-) cells, respectively. ETC-L-FdUrd was less active (IC(50): 7 nM in FM3A/0 vs 4500 nM in FM3A/TK(-)). Although the liposomal formulation was less active than ETC-L-FdUrd in FM3A/0 cells (IC(50):19.3 nM), resistance due to thymidine kinase (TK) deficiency was greatly reduced. The prodrugs inhibited thymidylate synthase (TS) in FM3A/0 cells (80-90%), but to a lower extent in FM3A/TK(-) (10-50%). FdUMP was hardly detected in FM3A/TK(-) cells. Inhibition of the transporters and nucleotidases/phosphatases resulted in a reduction of cytotoxicity of ETC-FdUrd, indicating that this drug was cleaved outside the cells to the monophosphates, which was verified by the presence of FdUrd and ETC in the medium. ETC-L-FdUrd and the liposomal formulation were neither affected by transporter nor nucleotidase/phosphatase inhibition, indicating circumvention of active transporters. In vivo, ETC-FdUrd and ETC-L-FdURd were orally active. ETC nucleotides accumulated in both tumor and liver tissues. These formulations seem to be effective when a lipophilic linker is used combined with a liposomal formulation.
The Mitochondrial Porin, VDAC, Has Retained the Ability to Be Assembled in the Bacterial Outer Membrane
2009-12-03

Beta-barrel proteins are present in the outer membranes (OMs) of Gram-negative bacteria, mitochondria, and chloroplasts. Their assembly requires a machinery of which the central component, called Omp85 (BamA) in bacteria and Tob55 (Sam50) in mitochondria, is evolutionarily conserved. An open question is whether the signals in beta-barrel OM proteins required for assembly via this multicomponent machinery are also conserved. To address this question, we have expressed in Escherichia coli the mitochondrial porin voltage-dependent anion channel (VDAC) from Neurospora crassa fused to a bacterial signal sequence for transport across the bacterial inner membrane. The protein was assembled in the bacterial OM where it formed pores. Assembly of VDAC was dependent on its beta-signal, which is required for assembly in the mitochondrial OM, and on the bacterial Omp85 assembly machinery. These results demonstrate that the basic mechanism of beta-barrel assembly in the OMs of bacteria and mitochondria is conserved.
Losing the lead: the patenting decision in the light of the disclosure requirement
2009-12-03

Empirical findings state that the disclosure requirement might be a reason for firms to rely on secrecy rather than patents to protect their inventions. We choose a dynamic framework in which we can explicitly analyze the patenting decision reflecting the tradeoff between a positive protective effect and a negative effect due to the required disclosure of the protected invention. In spite of a patent, the inventor's rival may still enter the market with a non-infringing product. Measuring the technological lead of the inventor by a time advantage he has compared with his rival, we show that if his headstart exceeds a critical threshold, he will not patent and rather rely on secrecy.
High plasma levels of adipocytokines are associated with platelet activation in patients with coronary artery disease
2009-12-03

Previous studies suggested that the adipocytokines, adiponectin and leptin, are associated with the progression and prognosis of coronary artery disease (CAD). The aim of this study was to differentially evaluate plasma levels of adiponectin and leptin in patients with CAD and their association with conventional laboratory parameters and markers of platelet activation. We consecutively evaluated 220 patients, who presented with a symptomatic CAD. Among these 83 (37.7%) presented with an acute coronary syndrome (ACS) and 137 (62.3%) with a stable angina pectoris (SAP). All patients have received coronary angiography. Baseline concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Lower detection limits of the assay were 0.079 ng/mL for total adiponectin and 15.6 pg/mL for leptin. Patients with ACS showed significantly enhanced plasma levels of adiponectin and leptin compared with SAP (ACS vs. SAP (mean +/- SD): adiponectin: 9.9 +/- 7.6 microg/mL vs. 7.2 +/- 5.7 microg/mL; P = 0.008; leptin: 20.9 +/- 16.4 ng/mL vs. 15.2 +/- 10.9 ng/mL; P = 0.012). However, a correlation between plasma total adiponectin and leptin levels has not been observed (r = 0.038; P = 0.706). Plasma levels of total adiponectin and leptin positively correlated with C-reactive protein (adiponectin: r = 0.277; P = 0.001; leptin: r = 0.248; P = 0.007) and troponin-I (adiponectin: r = 0.219; P = 0.001; leptin: r = 0.190; P = 0.025). Plasma levels of both adipocytokines have shown an inverse correlation with markers of platelet activation such as platelet glycoprotein VI (adiponectin: r = -0.120; P = 0.048; leptin:r = -0.205; P = 0.036), and in a negative trend with P-selectin (adiponectin: r = -0.116; P = 0.073; leptin: r = -0.172; P = 0.078). To support our findings, we determined high-molecular-weight adiponectin in a subgroup of 37 patients, which showed similar results. Increased concentrations of total adiponectin and leptin were associated with ACS. Intriguingly, high plasma levels of both adipocytokines seem to modulate platelet activation. Further studies should elucidate the adipocytokine regulation in CAD.
A Doubly Labeled Penetratin Analogue as a Ratiometric Sensor for Intracellular Proteolytic Stability
2009-12-03

Endocytosis has been shown to play a major role in the cellular import of cationic cell-penetrating peptides (CPPs) and CPP conjugates. Considering the presence of proteolytic activities inside the endolysosomal compartment, it is necessary to assess the consequences of the import mechanism on the intracellular integrity of the vector and the cargo. In this work, a penetratin analogue terminally labeled with two different fluorophores was synthesized and used as a sensor to quantitatively dissect the contribution of intracellular proteolytic activities on the breakdown of this specific CPP. Using a panel of lysosomal protease inhibitors, the endocytic compartment was identified as the major site of degradation. In contrast, an inhibitor of the proteasome had little effect on intracellular peptide integrity. Very remarkably, inhibitors of endolysosomal proteolysis also affected the intracellular distribution of fluorescence, leading to a reduction of fluorescein fluorescence in the cytoplasm. This change in fluorescence distribution was very similar to the one observed after incubation of cells with inhibitors of endosomal acidification. These results indicate that cytoplasmic fluorescence, typically interpreted as CPP entering the cytosol, may originate from proteolytic breakdown products.
Ready to analyze genetically modified human platelets
2009-12-03

Platelets play a critical role in hemostasis and thrombosis. In this issue of Blood , a new study presented by Salles and colleagues demonstrates that functional human platelets can be generated in mice after transplantation of human hematopoietic stem cell progenitors. 1 This method opens up new avenues to study thrombopoiesis and platelet function in vivo, and the effect of distinct genetic modifications.
ChemInform Abstract: The Many Faces of Rare Earth Carbodiimide Compounds.
2009-12-03

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Analysis of differential DNA damage in the mitochondrial genome employing a semi-long run real-time PCR approach
2009-12-04

The maintenance of the mitochondrial genomic integrity is a prerequisite for proper mitochondrial function. Due to the high concentration of reactive oxygen species (ROS) generated by the oxidative phosphorylation pathway, the mitochondrial genome is highly exposed to oxidative stress leading to mitochondrial DNA injury. Accordingly, mitochondrial DNA damage was shown to be associated with ageing as well as with numerous human diseases including neurodegenerative disorders and cancer. To date, several methods have been described to detect damaged mitochondrial DNA, but those techniques are semi-quantitative and often require high amounts of genomic input DNA. We developed a rapid and quantitative method to evaluate the relative levels of damage in mitochondrial DNA by using the real time-PCR amplification of mitochondrial DNA fragments of different lengths. We investigated mitochondrial DNA damage in SH-SY5Y human neuroblastoma cells exposed to hydrogen peroxide or stressed by over-expression of the tyrosinase gene. In the past, there has been speculation about a variable vulnerability to oxidative stress along the mitochondrial genome. Our results indicate the existence of at least one mitochondrial DNA hot spot, namely the D-Loop, being more prone to ROS-derived damage.
A Crystal Structure of the Bifunctional Antibiotic Simocyclinone D8, Bound to DNA Gyrase
2009-12-04

Targeting DNA Gyrase DNA gyrase, an enzyme that unwinds double-stranded DNA, is essential in bacteria, but missing in humans, and is thus an important antibiotic target. DNA gyrase is inhibited by the well-known fluoroquinolines and aminocoumarins antibiotics, as well as by symocyclinones—bifunctional antibiotics comprising an aminocoumarin and a polyketide group. Surprisingly, symocyclinones, unlike aminocoumarin inhibitors, do not inhibit DNA gyrase GTPase activity, but instead inhibit binding to DNA. Now Edwards et al. (p. 1415 ) use biochemical and structural studies to show that the two functional groups of the antibiotic bind in separate pockets on the gyrase. Each group is a relatively weak inhibitor that together potently inhibit DNA binding.
Soluble CD70: a novel immunotherapeutic agent for experimental glioblastoma
2009-12-04

Object Given the overall poor outcome with current treatment strategies in malignant gliomas, immunotherapy has been considered a promising experimental approach to glioblastoma for more than 2 decades. A cell surface molecule, CD70, may induce potent antitumor immune responses via activation of the costimulatory receptor CD27 expressed on immune effector cells. There is evidence that a soluble form of CD70 (sCD70) may exhibit biological activity, too. A soluble costimulatory ligand is attractive because it may facilitate immune activation and may achieve a superior tissue distribution. Methods To test the antiglioma effect of sCD70, the authors genetically modified SMA-560 mouse glioma cells to secrete the extracellular domain of CD70. They assessed the immunogenicity of the transfected cells in cocultures with immune effector cells by the determination of immune cell proliferation and the release of interferon-γ. Syngeneic VM/Dk mice were implanted orthotopically with control or sCD70-releasing glioma cells to determine a survival benefit mediated by sCD70. Depletion studies were performed to identify the cellular mediators of prolonged survival of sCD70-releasing glioma-bearing mice. Results The authors found that ectopic expression of sCD70 enhanced the proliferation and interferon-γ release of syngeneic splenocytes in vitro. More importantly, sCD70 prolonged the survival of syngeneic VM/Dk mice bearing intracranial SMA-560 gliomas. The survival rate at 60 days increased from 5 to 45%. Antibody-mediated depletion of CD8-positive T cells abrogates the survival advantage conferred by sCD70. Conclusions These data suggest that sCD70 is a potent stimulator of antiglioma immune responses that depend critically on CD8-positive T cells. Soluble CD70 could be a powerful adjuvant for future immunotherapy trials for glioblastoma.
Fasting plasma glucose and Type 2 diabetes risk: a non‐linear relationship
2009-12-04

Diabet. Med. 27, 473–476 (2010) Abstract Aims The current definition of impaired fasting glucose (IFG, ≥ 100 mg/dl) has been criticized as being too low for selective identification of individuals at risk for Type 2 diabetes. Furthermore, it is unclear whether any cut‐off is justifiable from the shape of association between fasting plasma glucose (FPG) and diabetes. We therefore evaluated the association between FPG and incidence of Type 2 diabetes in a prospective, population‐based study. Methods A case–cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)‐Potsdam cohort study involved 589 fasted participants in a randomly selected subcohort and 153 incident cases. Restricted cubic spline regression was used to examine non‐linearity of associations and we calculated pairs of sensitivities and specificities for different cut‐offs of FPG. Results Spline regression with adjustment for age, sex, body mass index, waist circumference, education, physical activity, alcohol consumption, and plasma levels of triglycerides, high‐density lipoprotein cholesterol and γ‐glutamyltransferase indicated that FPG was associated with risk in a non‐linear fashion. Risk with higher FPG increased only above ∼84 mg/dl. FPG ≥ 84 mg/dl yielded a sensitivity of 95.4% at a false‐positive rate of 86.8%. In comparison, FPG ≥ 100 and ≥ 110 mg/dl yielded sensitivities of 78.4 and 42.5% and false‐positive rates of 27.8 and 6.8%, respectively. The optimal cut‐off of FPG was at ∼102 mg/dl (sensitivity: 75.8%, false‐positive rate: 20.7%). Conclusions Although our study suggests a threshold for increasing diabetes risk at 84 mg/dl, this cut‐off would classify the vast majority of the population as at risk. The statistically optimal cut‐off supports the current definition of IFG (≥ 100 mg/dl).
Refereed digital publication to support online communities
2009-12-04

In this article, we examine how the international computer graphics (CG) community can be empowered by disseminating and recognising peer-reviewed educational work. Over the past years, we have developed a technical platform to support these activities. However, to move forward, we need to gather and rally the online community around it. Indeed, we require providing the social scaffolding for personal involvement and ownership to enhance the growth of the community tool. To this end, we conducted a survey in late 2005, the results of which are presented here and we discuss the actions derived and directions entailed by our latest findings. Apart from removing barriers to participation, we concentrate our efforts on adding peer-recognition through member profiles ('who's who in CG education') and on disseminating the different, community-borne, views on CG curricula.