India has a great wealth of various naturally occurring plant drugs which have potential pharmacological activities. The troublesome weed, Datura stramonium (Jimsonweed) is a plant with both poisonous and medicinal properties and has been proven to have great pharmacological potential with a great utility and usage in folklore medicine. The present investigation was therefore undertaken to determine the microscopic or anatomical studies analysis were reported and also encourages cultivation of the highly valuable plant in large scale to increase the economic status of the cultivators and provide a support to use of the plant in traditional medicine.


Since the collapse of the Bretton Woods system, countries have been able to choose from a variety of exchange-rate arrangements. We argue that politicians' incentives condition the choice of an exchange-rate arrangement. These incentives reflect the configuration of domestic political institutions, particularly electoral and legislative institutions. In systems where the cost of electoral defeat is high and electoral timing is exogenous, politicians will be less willing to forgo their discretion over monetary policy with a fixed exchange rate. In systems where the costs of electoral defeat are low and electoral timing is endogenous, politicians are more likely to adopt a fixed exchange-rate regime. Consequently, differences in domestic political systems can help account for variations in the choice of exchange-rate arrangements. We test this argument using constrained multinomial logit and binomial logit on a sample of twenty democracies over the period 1974–95. Domestic political institutions have a significant effect on exchange-rate regime choice, even after controlling for systemic, macroeconomic, and other political variables.


The purpose of this paper is to investigate the effect of ablation parameters on the ablation characteristics for the fixed diamond multi-wire sawing by using Taguchi method. Meanwhile, using the optimal ablation parameters, we accomplish the cutting dynamic analysis and controller design of the diamond multi-wire sawing system. In this paper, we apply the Chemical Mechanical Polishing (CMP) theorem to derive the ingot profile and cutting rate equations of the diamond multi-wire sawing system. The characteristics discussed in this paper include ingot profile variance, cutting rate. The ablation parameters are tension force, wire velocity, cutting force, width of the kerf. The orthogonal array, signal-to-noise (S/N) ratio and analysis of variance (ANOVA) are employed to analyze the effect of these ablation parameters. In the meantime, we use the optimal ablation parameters to accomplish the controller design of the diamond multi-wire sawing system, include diamond high-speed control of the main roller in the cutting system, cutting rate control and the moving wire bow angle holding.


Deletions and/or mutations of p53 are relatively rare and late events in the natural history of B-cell chronic lymphocytic leukemia (B-CLL). However, it is unknown whether p53 signaling is functional in B-CLL and if targeted nongenotoxic activation of the p53 pathway by using nutlin-3, a small molecule inhibitor of the p53/MDM2 interaction, is sufficient to kill B-CLL cells. In vitro treatment with nutlin-3 induced a significant cytotoxicity on primary CD19(+) B-CLL cells, but not on normal CD19(+) B lymphocytes, peripheral-blood mononuclear cells, or bone marrow hematopoietic progenitors. Among 29 B-CLL samples examined, only one was resistant to nutlin-3-mediated cytotoxicity. The induction of p53 by nutlin-3 in B-CLL samples was accompanied by alterations of the mitochondrial potential and activation of the caspase-dependent apoptotic pathway. Among several genes related to the p53 pathway, nutlin-3 up-regulated the steady-state mRNA levels of PCNA, CDKN1A/p21, GDF15, TNFRSF10B/TRAIL-R2, TP53I3/PIG3, and GADD45. This profile of gene activation showed a partial overlapping with that induced by the genotoxic drug fludarabine. Moreover, nutlin-3 synergized with both fludarabine and chlorambucil in inducing B-CLL apoptosis. Our data strongly suggest that nutlin-3 should be further investigated for clinical applications in the treatment of B-CLL.


OBJECTIVE
To review published evidence regarding the effectiveness of trauma systems by using population-based data.

DESIGN
A systematic review of peer-reviewed literature assessing the influence of trauma system implementation on the outcome of all injured patients.

MATERIALS AND METHODS
Literature available in MEDLINE, HealthSTAR, and CINHAL was reviewed for studies that use population-based data to assess the benefit of trauma system development. Studies were included that assessed trauma systems in North America and used a comparison or control group in the analysis.

MAIN RESULTS
Published evidence, reported for eight of the nine trauma systems evaluated, demonstrates improved outcomes, principally measured as hospital survival. Improvement occurred after the trauma system or some component of a trauma system (e.g., sophisticated prehospital care) was established.

CONCLUSION
Population-based evidence supports a 15 to 20% improved survival rate among seriously injured patients with trauma system implementation. Future study is required to determine whether trauma systems improve the outcome of all injured patients, not just high-risk subsets of the population.


This study proposes a track condition monitoring technique using car-body acceleration that can be easily measured by an in-service vehicle for the sake of an increase in safety of railway transportation. This paper demonstrates the possibility of estimating track irregularities of conventional railway tracks using car-body acceleration only. The methodology proposed uses inverse dynamics to estimate track irregularity from car-body acceleration, applying a Kalman filter to solve this problem. This technique estimates the track irregularity in the longitudinal plane (track geometry and 10m-chord versine). The Kalman filter is able to apply to inverse analysis by expressing track geometry as a random walk model, and incorporating the model in an equation of state. The estimation technique can support a change of the vehicle velocity by selecting an appropriate impulse response in the measurement equation for the vehicle velocity. Estimation results in simulation and full scale tests revealed that the proposed estimation technique is effective for track condition monitoring with acceptable accuracy for conventional railways.


Nek7 is a serine/threonine kinase of the mammalian NIMA-related kinases (Neks) family, which members are involved in the regulation of the progression of the cell cycle. Although several Nek members have been associated with a range of cell cycle-related tasks, including DNA repair, a possible role of Nek7 in the DNA-damage response is so far unknown. Here, we employed in vitro and in vivo interaction assays to identify Mat1 as a specific Nek7 binding partner and substrate. In addition, we showed that Nek7 pulled down both CDK7 and cyclin H and directly phosphorylated Mat1, indicating that Nek7 may play a role in the regulation of the CAK complex. Furthermore, we showed that both Nek7 and Mat1 depletion led to an accumulation of cells in the S-phase, decreased cell proliferation and increased apoptosis . Notably, the mutational ablation of kinase Nek7 activity also induced increased apoptosis upon DNA damage. Collectively, our findings support the notion that Nek7 may cooperate with Mat1 in signal pathways that govern the cell cycle machinery including DDR, S-phase progression and apoptosis, and thereby can constitute an important novel player for in the context of cellular transformation and tumorigenesis.


The impact of nonpoint-source pollution on surface waters in agricultural watersheds is an emerging environmental issue. As part of the U.S. Geological Survey National Water Quality Assessment program in the Hudson River Basin, Canajoharie Creek was monitored for seasonal and spatial patterns of nutrient chemistry from March 1993 to January 1996. Nitrate and silica concentrations in Canajoharie Creek suggest that seasonal and spatial variations of these nutrients are dominated by hiological processes, particularly uptake by phytoplankton. Observed concentration patterns were more typical of those observed in much larger, low-gradient streams. The median nitrate and silica concentrations in Canajoharie Creek were significantly lower from April through November than during winter. Concentrations of hoth constituents declined downstream from the headwaters during base-flow conditions in June 1995. Groundwater and surface water chemistry data support biological causes for downstream decreases in silica. The strong correlation between nitrate and silica in samples collected along the mainstem suggests that most of the nitrate decrease is due to uptake by diatoms. Downstream patterns of chlorophyll-a in phytoplankton strongly suggest the conversion of in-stream nutrients to algal biomass. Data collected from Canajoharie Creek outlet during the northeast drought of 1995 indicate that silica concentrations in May had possibly declined to a level that adversely affected the diatom community. This decline in the diatom population and suhsequent resurgence is inferred from a sharp rise in silica concentrations hetween May and July and a reversal of this trend from mid-July through October without associated changes in hydrology.


The aim of the current study was to investigate the effect of the use of olive oil and L-Carnitine on the function of the immune system, microbial population and the quality of Japanese quail meat tested in a completely randomized design with factorial arrangement of 8 treatments, 5 replications and 11 birds for 35 days with levels (zero, 0.5, 1, 1.5) of olive oil and the level (zero and 250 mg per kg), L-Carnitine. The interaction between the consumption of olive oil and L-Carnitine have significant effect on feed intake and weight gain. So that all treatments during the period of breeding, feed intake and weight gain increased more than the control group. The treatments ranged from 7 to 21 days. It had significant effect on the feed conversion ratio. But the interaction between treatments in other intervals had no significant effect on the feed conversion ratio. The interaction of treatments on carcass characteristics showed that the interaction between the consumption of olive oil and L-Carnitine had significant effect on the weight of the breast, life, and gizzard. But it has no significant effect on carcass weight, Leg, heart, spleen, intestine, and bursa of Fabricius. The results showed that the interaction between the consumption of olive oil and L-Carnitine has significant effect on the population of coliforms (Escherichia coli and Salmonella). Also all treatments had a significant increase compared to the control group. But the total microbial population and the intestinal lactic acid had no significant effect. The treatments had a significant effect on blood albumin and triglycerides. But there was no significant effect on the glucose and cholesterol. Experimental treatments significantly increased titers primary challenge by producing sheep red blood cells. But the second challenge by producing the sheep red blood cell antibody against Newcastle disease virus, not significant in number, in all the treatments showed higher antibody levels compared to the control group. The interaction of treatments with PH has significant impact on the quality of meat and meat MDA3.


A compact and power-efficient serial I/O targeting dense silicon carrier interconnects is reported. Based on expected channel characteristics, the proposed I/O features low-impedance transmitter termination, high-impedance receiver termination, and a receiver with modified DFE with IIR filter feedback (DFE-IIR). The DFE-IIR receiver uses a single additional IIR filter feedback tap to compensate many post cursors without paying the power and area penalty that would be incurred with a conventional high tap-count DFE. Equalization capabilities of the compact I/O at 10 Gb/s are demonstrated over various channels including conventional chip-to-chip and backplane links with half-baud losses of up to 27 dB. Finally, a transmitter-receiver pair operating over a 40-mm on-chip emulated silicon carrier channel was demonstrated to 8.9 Gb/s, at a link power efficiency of 1.9 mW/Gb/s.


The pathophysiology of idiopathic Parkinson disease (PD) is traditionally characterized as substantia nigra degeneration, but careful examination of the widespread neuropathologic changes suggests individual differences in neuronal vulnerability. A major limitation to studies of disease progression in PD has been that conventional magnetic resonance imaging (MRI) techniques provide relatively poor contrast for the structures that are affected by the disease, and thus are not typically used in experimental or clinical studies. Here, we review the current state of structural MRI as applied to the analysis of the PD brain. We also describe a new multispectral MRI method that provides improved contrast for the substantia nigra and basal forebrain, which we recently used to show that these structures display different trajectories of volume loss early in the disease.


The maintenance and management of railway infrastructure plays a central role in ensuring the reliability and availability of rail transport. In a highly competitive transport market, the rail industry is required to employ new and innovative maintenance strategies that will position rail transport as an affordable and reliable transportation alternative. This can be realised through implementing maintenance strategies that prioritise efficient resource allocation. Application of reliability-based techniques to make informed decisions in maintenance management, with an overall aim of reducing operational expenditure while maintaining safety and efficiency, has been increasing. This paper presents a framework for the application of a reliability-based technique to evaluate the reliability of railway infrastructure systems.


As both wireless and optical communications systems move towards high-data-rate applications, high-frequency low-phase-noise oscillators are important building blocks in the receiver and transmitter design. CMOS oscillators with integrated inductors are therefore well suited for such applications. This paper describes two integrated CMOS LC oscillators designed for operation over 10 GHz. The first one is based on the ring-coupled quadrature VCO configuration with wide tuning range, while the other is a 4-stage ring oscillator using inductive load. Fabricated in a 0.25-/spl mu/m CMOS technology, both oscillators can operate from a single supply voltage as low as 1.5 V. The highest operating frequencies for the quadrature VCO and ring oscillator are 11 and 12.55 GHz, respectively.


Abstract Palaeoenvironmental investigations were carried out in the Siedlungskammer (prehistoric settlement area) Burgweinting (Regensburg, Bavaria, Germany) to reveal past settlement conditions and human impact on the environment. Two sequences were obtained from the Islinger Mühlbach Fen, in close proximity to the archaeological excavation site in Burgweinting, which documents an almost continuous settlement history since the Neolithic Period. The analyses of the sequences comprise stratigraphic, geochemical and microscopic charcoal analyses. For chronological information, radiocarbon dating was conducted on a total of 10 samples. Thus, the first long-term fire record was reconstructed for the investigation area, and the results were correlated, based on radiocarbon dating, with the available environmental information and settlement history in the Siedlungskammer Burgweinting. The fire record reveals an almost continuous, but alternating fire history. Furthermore, it shows that fire played an important role in the Siedlungskammer Burgweinting and that most probably as early as the Mesolithic hunterer–gatherers deliberately used fire.


The energy transition from fossil fuels to renewable or cleaner energy sources is upon us. There is also a global focus on reducing atmospheric carbon dioxide emissions. Several major companies are placing an emphasis on solutions such as hydrogen and carbon capture and sequestration or reuse. While this will provide new business opportunities for the pipeline industry, there are inherent risks, especially as they are scaled up to meet societal demand. Therefore, there is a need to assess the potential for harm to people and the environment.
 Hydrogen is a flammable gas with the potential for both fire and explosion. Carbon dioxide is an asphyxiant at high concentrations and can dissolve in water, having unintended environmental effects. Traditional oil dispersion models have been used by the oil and gas sector and pipeline industry for decades to investigate overland, downstream, and in water movement, behavior, and potential effects of hypothetical and real-world releases. Atmospheric dispersion models have been used to assess vapor transport, resulting potential impacts (e.g., asphyxiation and or toxic effects) to humans and the environment, and risk of fire and explosion.
 Based upon our experience with the current regulatory environment, the scrutiny placed upon operators by regulators and intervenors (especially with other products such as oil), and the large amount of time required to plan, permit, construct, and operate pipelines, we believe these comprehensive and quantitative assessments will be at the forefront of decision making. The use and potential adaptation of these existing modeling tools will be crucial in assessing risk from transport, storage, and use to ensure safety of each project through all phases of its life cycle (e.g., prior to permitting, construction, operation, and decommissioning) during this energy transition.


OBJECTIVE--To investigate general practitioners' attendance at and views on child protection conferences and their confidence in dealing with sexual abuse in children. DESIGN--Anonymous postal questionnaire sent to all general practitioners in Tower Hamlets and review of consecutive case conferences held by social services for three months in 1989. SETTING--Tower Hamlets health district. SUBJECTS--91 general practitioners, 56 of whom (62%) responded. MAIN OUTCOME MEASURES--Number of conferences attended, reasons for non-attendance, and reported confidence in dealing with sexual abuse. RESULTS--General practitioners estimated that 202 child protection conferences had been held in 1989 on their patients and that they had attended 85 of these. Information from social services for three months suggested that general practitioners had attended only nine of the 114 conferences reviewed. Timing of the conference was the most important reason for non-attendance. All respondents wanted access to the minutes of these conferences irrespective of their own attendance. Most general practitioners were very or moderately confident of their ability to detect child sexual abuse and non-accidental injury and to communicate with the family. CONCLUSION--More effort should be made to ensure that general practitioners are notified of case conferences and that the timing and location of conferences is compatible with their other commitments.


Purpose
The purpose of this paper is to present the framework of a fourth paradigm since the existing three paradigms in quality management are not sufficient anymore to understand what happened in the past and surely fail to understand what is happening at the moment and needed in future.

Design/methodology/approach
A literature review has been undertaken on different visions on quality management that are used. The underlying principles have led to three quality paradigms. Literature on quadrant models is studied to place the three existing paradigms and identify the possible characteristics of the fourth.

Findings
One can discern four quality paradigms in quality management: the Empirical Paradigm, the Reference Paradigm, the Reflective Paradigm and the Emergence Paradigm. The use of these paradigms differs according to the context. Together they form a concept of Total Quality Management. At the moment the Emergence Paradigm has not had enough attention although it might be the best equipped to find new ways of working for the organisations in the current context.

Research limitations/implications
In the literature review the authors selected seven journals in the Business Source Premier database: Total Quality Management (Total Quality Management & Business Excellence); the Academy of Management Review; Product and Operations Management; Organisational Dynamics; the Harvard Business Review; the Sloan Management Review and Organisational Behavior and Performance. In the advanced search mode the authors entered two subjects: "quality management" and "paradigm". The selected results (in total 289 articles) were examined for its fitness for answering the questions above. That resulted in a selection of 26 articles that are being used in the literature review.

Practical implications
The Emergence Paradigm can be further investigated on its use for quality management in organisations in times of emergent change. Some first insights have been presented here.

Social implications
The Emergence Paradigm can have impact beyond the field of quality management.

Originality/value
The paper provides new insights in the essence of quality management in times of change and clarity on the usability of the thoughts and tools of four different paradigms in the twenty-first century.


us with underlying criteria. Instead, they rest their case saying there was "no uniformity as to practice or opinion" (p. 15), so the text becomes a collection of data related more by rhetoric than logic. Ostensibly, Part II of the study by Dr. Sherbini co~ plements the first by dealing with three "methodologies for use in organizing international data" (p. xii) to classify or group countries. Thus confined to methodology, it is not related to applications for planning and control discussed in Part I. The three methods of classification are designated as "Development Approach Through Cluster Analysis," "Regional Typological Approach," and "Two Dimensional Direct Score Approach." The first clusters countries according to attributes of environmental and social nature. The Regional . Typological Approach involves analysis of countries on the basis of 25 socioeconomic factors. The "Two Dimensional Direct Score Approach" measures the standing of countries on two dimensions: economic-demographic on the X-axis, and internal stability and cohesion on the Y-axis. As a study in methodology, this work lacks essential criteria for judging the alternative techniques; therefore, we have no way of evaluating them. Failing this, one can evaluate each methodology separately in terms of its effectiveness in developing relatively homogeneous groupings, as an example "cluster analysis" since, in our opinion, it is the most elegant of the three. Cluster analysis was used to group countries "to express approximate degrees of similarity, determined by the number of attributes shared between them" (p. 63). The analysis showed that in the "most highly developed" group (with 16 nations) five attributes were shared by two-thirds of the countries at this level. However, the ability of this method to develop mutually exclusive clusters is considerably reduced at the next lower level ·(i.e., "developed"), that is, "no universally common attribute appears at this level" (p. 75). The story is much the same at subsequent levels-there is little difference between the "under-developed" and "most under-developed" groups. A better approach might have been for the author to experiment with different criteria for dividing a given attribute into different ranks to create clusters with the maximum possible distance between them.1 This is not to deny the usefulness of Dr. Sherbini's work. It is an indication that methods to develop empirical typologies may be applied to the field of international marketing. s. PRAKASH SETHI AND RICHARD H. HOLTON University of California, Berkeley


In the following study the relation between the public debt and the inflation will be analysed. The transmission from the public debt to the inflation through the money supply and long term interest rate will be shown. Based on these theoretical thoughts the variables public debt, consumer price index, money supply m3 and the long term interest rate will be analysed within a vector error correction model. In the empirical part of this paper we will evaluate the timeperiod from the first quarter in 1991 until the fourth quarter in 2010 for Germany. In a vector error correction model every variable can be taken as endogenous. The variables in the model will be tested for cointegrated relationships and estimated with the Johansen-Approach.


This paper describes the design and tests of an all-reflection two-beam interferometer. The unique feature of this interferometer is the use of a combination of three diffraction gratings as a beam splitter. The use of reflection-type diffraction gratings as a beam splitter eliminates the need for transmission elements and thereby extends the applicability of two-beam interferometry to regions of the electromagnetic spectrum such as the vacuum ultraviolet where transmitting beam splitters are not available. A preliminary type of grating beam splitter using a single grating is discussed, and its disadvantages are described. Finally, an interferometer that uses three gratings as a beam splitter and which can function as an all-reflection Fourier-transform spectrometer is described. Interferograms of simple spectra taken with this instrument are presented.


Large enrollment undergraduate science courses are often seen as "gatekeepers" and tend to support less-than-ideal pedagogical approaches. Student satisfaction with teaching and learning and gains in student conceptual understanding in these courses is often limited at best. At University of Colorado Denver, the Learning Assistant (LA) Program supports the transformation of these large-enrollment science courses to include more interactive teaching strategies and learning opportunities. We find that students in these LA-supported courses are satisfied with these courses in part because of their use of LAs, primarily during the lecture meeting time. Students do not report using LA support as much outside of course lecture meetings. Further, students in an LA-supported General Biology course also exhibited much larger gains in conceptual understanding. We suggest that future work should investigate cross-group comparisons of cognitive and affective gains by factors such as ethnicity; class; gender; and interactions among students, LAs, and faculty. Transforming Undergraduate Science Education With Learning Assistants: Student Satisfaction in Large Enrollment Courses


Purpose - This paper seeks to examine the relationships between working conditions, innovation activities and industrial relations in two local production systems located in the northern Italy, exploiting data collected through Design/methodology/approach - The paper follows a recent stream of literature, which is still quite scanty, that addresses the issue of the implication for workers derived from the introduction of organizational changes. This topic is addressed and extended, taking into consideration both the role of firm level industrial relations and the role of other innovation activities that may influence working conditions. Findings - The results seem to support the position maintained by the advocates of organizational changes. Job empowerment is spurred by the form of organizational changes usually defined as high performance workplace practices. However, such typology of changes in the organization does not seem to be linked with positive trends in safety/security and stress. At the same time the positive role of cooperative industrial relations on the working condition emerges, also as complementary elements to innovation activities. Originality/value - This work confirms some relevant empirical results obtained in international literature about the linkages between organizational changes and working conditions. At the same time it provides an original perspective of analysis taking into account other influencing factors of workers' well being: good quality industrial relations at firm level and innovation activities such as technological innovation and ICT.


Interleukin-12 (IL-12) has shown significant antitumor activity in several preclinical animal tumor models. Our previous studies showed that IL-12 inhibited tumor growth in human osteosarcoma and Ewing's sarcoma animal model. Decreased Fas expression in osteosarcoma increased the lung metastatic potential. In this study, we further examined the mechanism of IL-12 antitumor activity and showed that IL-12 significantly increased Fas expression in both human osteosarcoma cells LM7 and Ewing's sarcoma cells TC71. Up-regulation of Fas expression increased their sensitivity to Fas-induced cell apoptosis. Constructs of the Fas promoter linked to a luciferase reporter gene were used to determine the promoter activity. IL-12 increased Fas promoter activity 4.2- and 4.9-fold in TC71 and LM7 cells, respectively. Time course studies have shown that recombinant IL-12 stimulated Fas promoter activity at 2 hours, reached the peak level at 4 hours, and then declined at 24 hours. To investigate whether IL-12 specifically enhanced Fas promoter activity, we determined whether another gene (E1A) was able to stimulate Fas promoter activity. We also evaluated effect of IL-12 on the topoisomerase IIα promoter. The results indicated that E1A but not IL-12 stimulated topoisomerase IIα promoter activity. E1A failed to increase Fas promoter activity. We also found that κB-Sp1 element at position −295 to −286 in Fas promoter was essential for IL-12-induced activation, and nuclear factor-κB transcription factor was activated after IL-12 treatment in TC71 cells. These results indicate that IL-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma by enhancing Fas promoter activity. Understanding this mechanism may lead to new therapeutic approaches for the treatment of sarcoma involving the use of IL-12. (Mol Cancer Res 2005;3(12):685–91)


Four types of biomass (chicken waste, wood pellets, coffee residue, and tobacco stalks) were cofired at 30 wt % with a U.S. sub-bituminous coal (Powder River Basin Coal) in a laboratory-scale fluidized bed combustor. A cyclone, followed by a quartz filter, was used for fly ash removal during tests. The temperatures of the cyclone and filter were controlled at 250 and 150 degrees C, respectively. Mercury speciation and emissions during cofiring were investigated using a semicontinuous mercury monitor, which was certified using ASTM standard Ontario Hydra Method. Test results indicated mercury emissions were strongly correlative to the gaseous chlorine concentrations, but not necessarily correlative to the chlorine contents in cofiring fuels. Mercury emissions could be reduced by 35% during firing of sub-bituminous coal using only a quartz filter. Cofiring high-chlorine fuel, such as chicken waste (Cl = 22340 wppm), could largely reduce mercury emissions by over 80%. When low-chlorine biomass, such as wood pellets (Cl = 132 wppm) and coffee residue (Cl = 134 wppm), is cofired, mercury emissions could only be reduced by about 50%. Cofiring tobacco stalks with higher chlorine content (Cl = 4237 wppm) did not significantly reduce mercury emissions. This was also true when limestone was added while cofiring coal and chicken waste because the gaseous chlorine was reduced in the freeboard of the fluidized bed combustor, where the temperature was generally below 650 degrees C without addition of the secondary air. Gaseous speciated mercury in flue gas after a quartz filter indicated the occurrence of about 50% of total gaseous mercury to be the elemental mercury for cofiring chicken waste, but occurrence of above 90% of the elemental mercury for all other cases. Both the higher content of alkali metal oxides or alkali earth metal oxides in tested biomass and the occurrence of temperatures lower than 650 degrees C in the upper part of the fluidized bed combustor seemed to be responsible for the reduction of gaseous chlorine and, consequently, limited mercury emissions reduction during cofiring. This study identified the important impacts of temperature profile and oxides of alkali metal (alkali earth metal) on mercury emissions during cofiring in the fluidized bed combustor.


Anode-respiring bacteria (ARB) perform an unusual form of respiration in which their electron acceptor is a solid anode. The focus of this study was to characterize the electrical stress direct evolution of biocatalysts as a way of enriching the community with ARB for microbial fuel cell. The original microbial consortium was sampled from a sodic-saline bottom soil (Texcoco Lake). Interestingly, iron (III) reducing bacteria consortium in the sodic-saline bottom soil was 8500 ± 15 MPN/100 mL by the most probable number method, since microbial reduction of iron (III) is reported to be associated to anode-respiring capabilities. Cyclic voltammetry studies of electrochemical stressed biofilm-ARB were conducted at 28 th and 135 th days, and an irreversible electron transfer reaction was found possibly related to electron transfer reaction of the cytochrome. The electrochemical impedance spectroscopy results revealed that the resistance of the biofilm-ARB decreased with time (28 th day-11.11Ω and 135 th day- 5.5Ω), possibly associated to the adaptability of electroactive biofilm on the graphite electrode surface. Confocal microscopy showed that the biofilms are active in nature and the biofilm-ARB attained ~40 μm thickness at the 136 th day. Electrical stressed-ARB gave a maximum power density of 79.4mW/m 2 , and unstressed-ARB gave a maximum power density of 41.0mW/m 2 in a single-chamber microbial fuel cell (SCMFC). All these electrochemical experiments and evaluation sug- gest that the electrical-stress directed evolution of ARB community was associated to a more efficient extracellular electron transfer proc- ess in SCMFC.


Angiopoietin-1 (Ang1) regulates both vascular quiescence and angiogenesis through the receptor tyrosine kinase Tie2. We and another group previously showed that Ang1 and Tie2 form distinct signaling complexes at cell-cell and cell-matrix contacts. We further demonstrated that the former up-regulates Notch ligand delta-like 4 (Dll4) only in the presence of cell-cell contacts. Because Dll4/Notch signal restricts sprouting angiogenesis and promotes vascular stabilization, we investigated the mechanism of how the Ang1/Tie2 signal induces Dll4 expression to clarify the role of the Dll4/Notch signal in Ang1/Tie2 signal-mediated vascular quiescence. Under confluent endothelial cells, the basal Notch signal was observed. Ang1, moreover, induced Dll4 expression and production of the Notch intracellular domain (NICD). Ang1 stimulated transcriptional activity of β-catenin through phosphoinositide 3-kinase (PI3K)/AKT-mediated phosphorylation of glycogen synthase kinase 3β (GSK3β). Correspondingly, the GSK3β inhibitor up-regulated Dll4, whereas depletion of β-catenin by siRNA blocked Ang1-induced Dll4 expression, indicating the indispensability of β-catenin in Ang1-mediated up-regulation of Dll4. In addition, Dll4 expression by the GSK3β inhibitor was only observed in confluent cells, and was impeded by DAPT, a γ-secretase inhibitor, implying requirement of the Notch signal in β-catenin-dependent Dll4 expression. Consistently, we found that either Ang1 or NICD up-regulates Dll4 through the RBP-J binding site within intron 3 of the DLL4 gene and that β-catenin forms a complex with NICD/RBP-J to enhance Dll4 expression. Ang1 induced the deposition of extracellular matrix that is preferable for basement membrane formation through Dll4/Notch signaling. Collectively, the Ang1/Tie2 signal potentiates basal Notch signal controlling vascular quiescence by up-regulating Dll4 through AKT-mediated activation of β-catenin.


The transport of nucleic acids from the nucleus to the cytoplasm is a potential site for modification of normal cellular processes by drugs and hormones. In this study the effect of phenobarbitone on nucleocytoplasmic transport of ribosomes was measured in an assay system in vitro. The transport of radioactive ribosomes from isolated rat hepatic nuclei to unlabelled post-microsomal supernatant was measured in rats treated with 80 mg of phenobarbitone/kg body wt. or saline 3h before death. With either treatment, transport was linear with time, and dependent on temperature and the presence of ATP. However, phenobarbitone treatment increased transport of ribonucleoproteins over saline-treated animals nearly twofold. The effect of phenobarbitone was mediated through the cytosol, but was not the result of altered stability of the RNA transported to the cytosol. Cycloheximide (5 mg/kg body wt.) given 3.5 h before death inhibited the stimulation of transport by phenobarbitone. The data indicate that phenobarbitone increased the transport of RNA by stimulating the synthesis of cytosol factors that regulate transport of RNA from the nucleus.


The experience of loneliness varies across cultures. This study explored loneliness among students in two metropolitan senior high schools in Ghana. A sample of 244 students (40.5% males, 59.5% females; mean age =18.4 years) completed Revised University of California Los Angeles (R-UCLA) Loneliness Scale developed by Russell (1982). A series of one-way analysis of variance tests (ANOVA) were used to determine the existence of any significant differences among variables. The results of the findings indicate that the mean RUCLA scores among the senior high school students fell in the lower range (N=244; M=45.81; SD=10.001). There were significant differences in gender F (1, 240) = 7.858, p = .005. ; In age, F (1, 240) = 4.958, p = .0027, and religious affiliation F (1, 240) = 9.030, p = .003. The results of this study indicate that varying degrees of loneliness is felt in different cultures because the way people live and approach problem solving in their social context are different. This paper explains why this new knowledge can be used to inform parents, school administrators and counselors appreciate the effect of other demographic variables on loneliness in the life of Ghanaian adolescents.


In Luke-Acts the social codes and concepts associated with food and meals replicate and support the contrasting social codes, interests, and ideologies associated with the Jerusalem Temple, on the one hand, and the Christian household, on the other. In this study the thesis is advanced that in contrast to the Temple and the exclusivist purity and legal system it represents, Luke has used occasions of domestic dining and hospitality to depict an inclusive form of social relations which transcends previous Jewish purity regulations and which gives concrete social expression to the inclusive character of the gospel, the kingdom of God, and the Christian community.


ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are a family of multidomain extracellular protease enzymes with 19 members. A growing number of ADAMTS family gene variants have been identified in patients with various hereditary diseases. To understand the genomic landscape and mutational spectrum of ADAMTS family genes, we evaluated all reported variants in the ClinVar database and Human Gene Mutation Database (HGMD), as well as recent literature on Mendelian hereditary disorders associated with ADAMTS family genes. Among 1089 variants in 14 genes reported in public databases, 307 variants previously suggested for pathogenicity in Mendelian diseases were comprehensively re-evaluated using the American College of Medical Genetics and Genomics (ACMG) 2015 guideline. A total of eight autosomal recessive genes were annotated as being strongly associated with specific Mendelian diseases, including two recently discovered genes (ADAMTS9 and ADAMTS19) for their causality in congenital diseases (nephronophthisis-related ciliopathy and nonsyndromic heart valve disease, respectively). Clinical symptoms and affected organs were extremely heterogeneous among hereditary diseases caused by ADAMTS family genes, indicating phenotypic heterogeneity despite their structural and functional similarity. ADAMTS6 was suggested as presenting undiscovered pathogenic mutations responsible for novel Mendelian disorders. Our study is the first to highlight the genomic landscape of ADAMTS family genes, providing an appropriate genetic approach for clinical use.


ABSTRACT Ma, H.; Zhang, W.; Cui, X.; An, B.; Jin, Y., and Cheng, K., 2015. Substation electromagnetic environment of electric power communication equipment and characteristic parameters. The steady and transient electromagnetic environment near electrical equipment in substations and converter stations is measured in different voltage levels and different positions. After analyzing and counting a large number of measurement samples, mathematics character parameters of steady electromagnetic disturbance in substations are gained, which provide the theoretical basis for protective measures.


BACKGROUND
Cerebral malaria (CM) accounts for nearly 400,000 deaths annually in African children. Current dogma suggests that CM results from infected RBC (iRBC) sequestration in the brain microvasculature and resulting sequelae. Therapies targeting these events have been unsuccessful; findings in experimental models suggest that CD8+ T cells drive disease pathogenesis. However, these data have largely been ignored because corroborating evidence in humans is lacking. This work fills a critical gap in our understanding of CM pathogenesis that is impeding development of therapeutics.

METHODS
Using multiplex immunohistochemistry, we characterized cerebrovascular immune cells in brain sections from 34 children who died from CM or other causes. Children were grouped by clinical diagnosis (CM+ or -), iRBC sequestration (Seqhi, lo, or 0) and HIV status (HIV+ or -).

RESULTS
We identified effector CD3+CD8+ T cells engaged on the cerebrovasculature in 69% of CM+ HIV- children. The number of intravascular CD3+CD8+ T cells was influenced by CM status (CM+ vs -, P = 0.004) and sequestration level (Seqhi > lo, P = 0.010). HIV co-infection significantly increased T cell numbers and shifted cells from an intravascular (P = 0.004) to perivascular (P < 0.0001) distribution.

CONCLUSION
Within the studied cohort, CM is associated with cerebrovascular engagement of CD3+CD8+ T cells, which is exacerbated by HIV coinfection. Thus, CD3+CD8+ T cells are highly promising targets for CM adjunctive therapy, opening new avenues for the treatment of this deadly disease.

FUNDING
This research was supported by the Intramural Research Program of the National Institutes of Health.


AIMS
To use simulation to estimate the impact of alcohol taxation on drinking, non-fatal violent victimization and homicide in New York City (NYC). We simulate the heterogeneous effects of alcohol price elasticities by income, level of consumption and beverage preferences, and examine whether taxation can reduce income inequalities in alcohol-related violence.

DESIGN
Agent-based modeling simulation.

SETTING
NYC, USA.

PARTICIPANTS
Adult population aged 18-64 years in the year 2000 in the 59 community districts of NYC. The population of 256 500 agents approximates a 5% sample of the NYC population.

MEASUREMENTS
Agents were parameterized through a series of rules that governed alcohol consumption and engagement in violence. Six taxation interventions were implemented based on extensive reviews and meta-analyses, increasing universal alcohol tax by 1, 5 and 10%, and beer tax by 1, 5 and 10%.

FINDINGS
Under no tax increase, approximately 12.2% [95% credible interval (prediction interval, PI) = 12.1-12.3%] were heavy drinkers. Taxation decreased the proportion of heavy drinkers; a 10% tax decreased heavy drinking to 9.6% (95% PI = 9.4-9.8). Beer taxes had the strongest effect on population consumption. Taxation influenced those in the lowest income groups more than the highest income groups. Alcohol-related homicide decreased from 3.22 per 100 000 (95% PI = 2.50-3.73) to 2.40 per 100 000 under a 10% universal tax (95% PI = 1.92-2.94). This translates into an anticipated benefit of ~1200 lives/year.

CONCLUSION
Reductions in alcohol consumption in a large urban environment such as New York City can be sustained with modest increases in universal taxation. Alcohol tax increases also have a modest effect on alcohol-related violent victimization. Taxation policies reduce income inequalities in alcohol-related violence.


According to Wlodkowski (2003), "accelerated learning programs are one of the fastest growing transformations in higher education" (p. 5). The Center for the Study of Accelerated Learning at Regis University has documented at least 250 colleges or universities that offer accelerated learning programs for working adults. By definition, accelerated learning programs are structured to enable students to take courses and earn credits in a shorter period of time, versus a traditional 16-week semester. Thus, how one teaches adults in an accelerated program must differ from how one teaches in a traditional semester format. The purpose of this article is to review the current research and theory on accelerated learning and to offer practical suggestions as to how educators in accelerated learning programs can provide an effective learning experience. In the early 1960s, a Bulgarian psychiatrist named Georgi Lozanov taught English to 60 students using a variety of non-traditional teaching techniques, including the use of music, meditation, and a variety of visual and auditory techniques. Referring to his teaching approach as "suggestopedia," Lozanov was interested in students' ability to recall past experiences and to utilize both left-brain and right-brain abilities. For Lozanov, "suggestopedia" was not just a method of learning faster, but rather learning in a more holistic way by employing a "multi-sensory, brain-compatible teaching and learning methodology" (McKeon, 1995, pp. 64-65). In the 1970s, corporate training specialists in the United States adopted his ideas, and developed what is known today as "accelerated learning" (McKeon, 1995). It is a way of saving time and money on training, while at the same time realizing more positive results (Zemke, 1995). These same accelerated teaching methods can be used in higher education, particularly with adult students in accelerated degree completion and graduate programs. The Amazing Brain Accelerated learning theory is built on the findings of recent research on the structure and processes of the human brain and seeks to access all aspects of the tripartite structure of the brain. The brain stem, or reptilian brain, controls the basic bodily functions, such as heart rate and breathing. The limbic system or mammalian brain controls the emotions, desires, sexual appetites, and long-term memory The neocortex or thinking brain handles the higher cognitive functions such as seeing, hearing, thinking, and talking (Rose & Nicholl, 1997). These different "brains" are interlinked and serve as "clearing houses for specialized functions" (Meier, 2000, p. 35) in the brain's overall operation. The key to effective accelerated learning is to use the whole brain in the learning process. The reptilian brain connects to automatic bodily functions and thus utilizes the physical body in the learning process. The limbic brain is the center for the emotional dimensions of learning, and the neocortex helps create meaning and value out of information learned. Brain research indicates that learning involves body and mind. The body and brain interact in two distinct ways. First, the vast systems of nerves throughout the body keep the brain appraised of what is happening in the body at any moment. Second, the hypothalamus (a part of the reptilian brain) sends chemical messages through the blood stream that are experienced as a variety of emotions, ranging from exhilaration to depression (Zull, 2002). Maxfield (1990) suggests that consciousness (and by extension thinking and learning) is active throughout the body and not restricted to the brain, causing attitudes, beliefs, and expectations to be lodged in the body. Learners must be aware of physical feelings and reactions that can either enhance or inhibit learning. He thus proposes a holistic paradigm that incorporates both rational and non-rational types of learning, as well as the use of various mind-body techniques such as biofeedback, meditation, hypnosis, and relaxation training. …


Clinical trials of immunotoxins in cancer patients have been limited in many cases by vascular leak syndrome (VLS). Recently, rats were identified as a model for VLS induced by BR96 sFv-PE40, a carcinoma-reactive single-chain immunotoxin. In this study, the toxin component of this immunotoxin, PE40, was found to be responsible for inducing hydrothorax in rats, thereby demonstrating that direct binding to the BR96 antigen was not essential to the onset of VLS. Mutational analysis of PE40 determined that both ADP ribosylation and proteolytic processing functions innate to Pseudomonas exotoxin A (PE) were necessary for PE40 to induce hydrothorax in rats; however, neither function by itself was sufficient for VLS induction. Additionally, nonsteroidal anti-inflammatory agents were found to block VLS in rats receiving BR96 sFv-PE40. These results demonstrate that the toxin component of PE-based immunotoxins induce VLS and suggest agents for clinical management of the toxicity.


: In tests staged on anesthetized cats the effects of reserpine, isobarine and dopegit upon the resistance of cerebral vessels were studied resistographically. In 60--120 minutes after their introduction these drugs raise the resistance of intracranial vessels, inhibiting their reaction to electric stimulation of sympathic nerves and bringing down at the same time the total arterial pressure. An inference is drawn to the effect that the mounting perfusion pressure in the cerebral vessels following the action of reserpine and isobarine occurs as a result of their alpha-adrenoreceptors stimulation with norepinephrine that is intensively secreted from the nerve endings. Dopegit exerts an analogous action through formation of alpha-methyl-norepinephrine, which produces, like norepinephrine, an effect on the cerebral vessels.


BACKGROUND
The presence of stones in the common bile duct (CBD) may cause complications such as obstructing jaundice or ascending cholangitis, and the stones should be removed.

OBJECTIVES
To assess the efficacy of percutaneous elimination of CBD stones from the gallbladder through the papilla.

METHODS
During a 4 year period, six patients (five men and one woman, mean age 71.5 years) who had CBD stones and an existing gallbladder drain underwent percutaneous stone push into the duodenum after balloon dilatation of the papilla, with a diameter equal to that of the largest stone. Access into the CBD was from the gallbladder, using an already existing percutaneous gallbladder drain (cholecystostomy tube).

RESULTS
Each patient had one to three CBD stones measuring 7-14 mm. Successful CBD stone elimination into the duodenum was achieved in five of the six patients. The single failure occurred in a patient with choledochal diverticulum, who was operated successfully. There were no major or minor complications during or after the procedures.

CONCLUSIONS
Trans-cholecystic CBD stone elimination is a safe and feasible percutaneous technique that utilizes existing tracts, thus obviating the need to create new percutaneous access. This procedure can replace endoscopic or surgical CBD exploration.


Distance education institutions are moving towards adoption and use of Internet learning environment for complementary learning, for which is a reflection of changes in use of teaching/learning technologies. Because of its immediacy of interaction, Internet technology is increasingly being accepted as a good information resource as well as good instructional media. It was for this reason that the Open University of Tanzania (OUT) developed own web site and hoisted the Learning Management Platforms as well as Internet access points for students.This study was aimed at investigating accessibility and use of such Internet learning environments by Distance education students of the Open University of Tanzania. This was a descriptive study, which used purposive sampling procedures to draw a total of 84 respondents: 2 system administrators, 2 OUT Directors and 80 OUT students from the three Dar es Salaam regional centers. The same sample was used to draw 27 Focus Group Discussion participants. The study sought to discuss students' perceptions on their competence level in using Internet facilities, availability of Internet services, training and perceived major barriers in using same services. The study used the following data collection methods: observations, a questionnaire, interview and focus group discussions. Results revealed: lack of computer skills, which was found to be most significant, demographic factors and information processing skills. Among demographic influences, gender was the most leading influences while distance was the fourth most significant influence. However, age and income were found to have no significant influence as expected.
The study provides the following recommendations: There should be provision of further training for students in computer use and information processing skills, Information Technology experts should be trained and there have to be Internet rooms appropriate to students' needs. Further studies should asses use of various Internet services for students learning through distance education; ascertain faculty acceptance including use of Internet Integrated teaching; investigate in detail accessibility as well as use of Internet learning environments for different courses.
Policy issues should enhance ways on how OUT could collaborate with other universities in East Africa to purchase a greater volume of bandwidth, which will lower marginal costs of that bandwidth. Other measures include introducing computer courses in schools and institute modalities for OUT students to acquire their personal computers.


Chris Frith's target chapters contain a wealth of interesting experiments and striking theoretical claims. In these comments I begin by drawing out some of the key themes in his discussion of action and the sense of agency. Frith's central claim about conscious action is that what we are primarily conscious of in acting is our own agency. I will review some of the experimental evidence that he interprets in support of this claim and then explore the following three questions about the awareness of agency:(1) Should we locate the phenomena that Frith describes as awareness of agency at the personal level or at the subpersonal level?(2) If we are indeed operating at the personal level, then should we think about awareness of agency as something we experience, or as something that we believe?(3) If awareness of agency is to be understood experientially, is there what some authors have called "a sense of agency", where this is understood to be a distinctive type of experience that accompanies agentive behaviors but is absent in behaviors that are not under the control of the agent?In what follows I argue that awareness of agency should be located at the personal level, and that we should think of it as something we experience . But I will reject the claim that there is a distinctive sense of agency.


: This paper explains the role and the main objectives of the GSE Forest Monitoring (GSE FM) Service Portfolio Evolution. This task supports the cardinal requirements of sustainability of the GMES (Global Monitoring for Environment and Security) services. In order to satisfy the needs of the stakeholder the requests for better and more complete information on environment and security the GMES services must continuously improved. The Service Portfolio Evolution is one of the key inputs for improved service provision. Throughout the entire services of the GSE FM Service Portfolio the interactive involvement within the process of production (in-situ measurements, data pre-processing, data classification, product accuracy assessment etc.) is the most cost and time efficient factor and is therefore be treated with high priority to research activities. The continuous identification of new RD therefore supports the sustainability of the GMES services and establishes common standards for all Service Providers and users. ABSTRACT This paper explains the role and the main objectives of the GSE Forest Monitoring (GSE FM) Service Portfolio Evolution. This task supports the cardinal requirements of sustainability of the GMES (Global Monitoring for Environment and Security) services. In order to satisfy the needs of the stakeholder the requests for better and more complete information on environment and security the GMES services must continuously improved. The Service Portfolio Evolution is one of the key inputs for improved service provision. Throughout the entire services of the GSE FM Service Portfolio the interactive involvement within the process of production (in-situ measurements, data pre-processing, data classification, product accuracy assessment etc.) is the most cost and time efficient factor and is therefore be treated with high priority to research activities. The continuous identification of new R&D therefore supports the sustainability of the GMES services and establishes common standards for all Service Providers and users.


: Microbiological monitoring of the circulation of Vibro cholerae remains one of the key factors contributing to optimization of epidemiological surveillance in a specific area and the laboratory diagnosis of cholera is a basic applied tool for the detection and characterization of isolated cultures. The quality of etiological identification of the pathogen, the competent use of procedures, and the observance of a laboratory diagnosis scheme increases the likelihood of the cholera pathogen being detected in the samples taken from human beings and environmental objects, which allows to timely notify the disease and to prevent it. The current goals of investigations include the development of more accessible and rapid methods that would further find their place in the scheme for the laboratory diagnosis of cholera.


A fusion gene that results from a translocation t(9;22)(q34;q11) that fuses the 5' part of the BCR gene to the 5' side of exon 2 of a mutated form of the ABL1 gene. In this fusion gene there is a point mutation where guanine has been substituted with cytosine at nucleotide position 895 of the ABL1 gene. This mutation is associated with imatinib- and dasatinib-resistant leukemias.


The effect of phenibut on the locomotor and orientation-research activity, as well as on the alcohol and food motivation, was studied on experimental animals under conditions of voluntary chronic alcoholism. Phenibut decreased the manifestations of alcohol-induced behavioral disorders and reduced alcohol motivation.


Now diagnostic methods with the help of machine learning have been able to help doctors in this field. One of the most important of these methods is deep learning, which has gotten good answers in images containing cancer. Increasing the accuracy of deep neural network classifiers can increase the diagnosis of breast cancer. In this paper, we have tried to achieve higher accuracy than non-parallel models with the help of a parallel model of a deep neural network. The proposed method is a parallel hybrid method combining AlexNet and VGGNet networks applied in parallel to mammographic images. The database used in this article is INBreast. The results obtained from this method show a 4% increase compared to some other classification models so that in the type of density 1, it has achieved about 99.7%. In the case of other densities, an accuracy of nearly 99% has been obtained.


The results on shock phenomena in dusty plas- mas of the Solar System are reviewed. The problems of dust ion acoustic bow shock in interaction of the solar wind with dusty cometary coma and formation of transient atmospheres of atmosphereless cosmic bodies such as Moon, Mercury, asteroids and comets are considered. The latter assumes the evolution of meteoroid impact plumes and production of charged dust grains due to the condensation of both the plume substance and the vapor thrown from the crater and the surrounding regolith layer. Physical phenomena occur- ring during large meteoroid impacts can be modeled with the aid of active rocket experiments, which involve the release of some gaseous substance in near-Earth space. New vistas in investigation of shock processes in natural dusty plasmas are determined.


Visible light communications (VLC) are gaining popularity and may provide an alternative means of communications in indoor settings. However, to date, there is very little research on the deployment or higher layer protocol design for VLC. In this paper, we first perform channel measurements using a physical layer testbed in the visible light band to understand its physical layer characteristics. Our measurements suggest that in order to increase data rates with VLC (1) the beam width of a communicating link can be shrunk, and (2) the transmission beam can be tuned to point towards the target recipient. We then perform Matlab simulations to verify that the human eye is able to accommodate the changes brought by shrinking a beam or by tuning the beam direction appropriately. As our main contribution, we then design a configuration framework for a VLC indoor local area network, which we call VICO; we leverage the above features towards achieving the highest throughput while maintaining fairness. VICO first tunes the beamwidths and pointing angles of the transmitters to configurations that provide the highest throughput for each client. It then tries to schedule transmissions while accounting for conflicts and the VLC PHY characteristics. Finally, it opportunistically tunes the idle LEDs to reinforce existing transmissions to increase throughput to the extent possible. We perform extensive simulations to demonstrate the effectiveness of VICO. We find that VICO provides as much as 5-fold increase in throughput compared to a simple scheduler that does not exploit the possible variations in beamwidth or beam-angle.


In 2009 the Treaty of Lisbon conferred upon the European Union the exclusive competence on foreign direct investments (Article 207 TFEU). Following from this new competence the EU has carried out a comprehensive regulation of trade and investment issues and reforms which include the creation of an International Investment Court, as proposed by the European Commission in both CETA and TTIP negotiations. This article analyses some of the core legal issues of the proposed Court from a European perspective and comes to the conclusion that the same EU constitutional obstacles allegedly posed by ISDS are present in the ICS. As a result, the Commission's proposal weakens the perception of ISDS as a fair and legitimate mechanism to deal with investment-state disputes, whereas it perpetuates the existence of an external and parallel mechanism of dispute resolution outside the European court system.


System protection mechanisms such as access controls can be fooled by authorized but malicious users, masqueraders, and misfeasors. Intrusion detection techniques are therefore used to supplement them. The capacity of these techniques, however is limited: innocent users may be mistaken for malicious ones while malicious users stay at large. Isolation is a method that has been applied to protect systems from damage while investigating further. This paper proposes the use of isolation at an application level to gain its benefits while minimizing loss of resources and productive work in the case of incidents later deemed innocent. We describe our scheme in the database context. It isolates the database transparently from further damage by users suspected to be malicious, while still maintaining continued availability for their transactions. Isolation is complicated by the inconsistencies that may develop between isolated database versions. We present both static and dynamic approaches to identify and resolve conflicts. Finally, we give several examples of applications in which the isolation scheme should be worthwhile and be able to achieve good performance.


OBJECTIVES
The aim of this Systematic Review is to estimate the osteoradionecrosis rate in patients with head and neck cancer due to teeth extraction performed before radiotherapy and to identify possible risk factors.

MATERIAL AND METHODS
PRISMA protocol was used to evaluate and present the results. PubMed, Scopus, and Web of Science were used as search engines: English full-length papers of clinical studies, in peer-reviewed journals, were investigated. Cumulative meta-analysis was performed with a random effects model. PROSPERO registration code: CRD42018079986.

RESULTS
Among 2,020 records screened, 8 were included in this review. Sixteen of 494 patients who underwent tooth extraction before radiotherapy developed osteoradionecrosis, with an osteoradionecrosis incidence of 2.2% (95% Confidence of Interval = 0.6-3.9, p.<0.185, I^2=3044%). All cases were reported in the mandible. No other clinical risk factor for osteoradionecrosis was detected.

CONCLUSIONS
Even if it is generally recommended to remove oral foci before radiotherapy, this systematic review confirmed that teeth extractions before radiotherapy represent a risk factor for osteoradionecrosis; the considerable amount of missing data prevented us from identifying other possible risk factors for osteoradionecrosis onset. Major efforts should be done to perform sounder methodological clinical investigations.


The siliconization of pharmaceutical glass containers, usually for parenteral formulations, is performed in a so-called heat-curing process using diluted aqueous emulsions of medical grade silicone oils. To do this, the emulsion film is spread on the inner container surface, followed by an application of dry heat at temperatures above 300 degrees C. Water and surfactants are removed by degradation and vaporization, while the thermostable poly(dimethylsiloxane) (PDMS) is left on the surface. In the present study, heat-cured siliconized glass containers of two different types were solvent-extracted to obtain material of heat-treated PDMS. These samples were analyzed by size exclusion chromatography (SEC) and high-temperature gas chromatography (GC) with special respect to low molecular-weight siloxanes (LMWS). By comparison with the untreated starting materials, significant changes in the molecular weight distribution (MWD) of the silicone oil were revealed. Almost all of the LMWS present in untreated materials were not detectable in the heat-cured extract of a 100 cSt. Baysilone silicone oil. Small amounts of PDMS-molecules, with chain lengths of 25 up 45 siloxane units, were traceable. The examination of a second product of higher viscosity yielded unexpected results. The heat-treated extract contained none of the siloxanes that were detected in the starting material. Siloxanes of chain lengths of up to 45 units having molecular weights of over 3000 g/mol could not be found after the siliconization process. This led to the conclusion that not only vaporization effects must be responsible for their absence, but also that silicone suffers from a heat-induced degradation. The results of SEC and GC analysis were supported by each other. The whole molecular weight distribution and four distinct fractions were characterized by SEC, while the GC analysis was capable of a high-resolution view into the LMWS fraction below 3500 g/mol. In conclusion, the benefit of the heat treatment is that no LMWS, a source of toxicological concern, remain in the respective containers. On the other hand, an increase in molecular weight and viscosity of the silicone oil, and thus a possible change of the lubricating properties, is likely to happen through removal of LMWS. But these changes probably have no impact on the hydrophobic surface behavior of silicone-treated glass.


Access to computer systems is most often based on the use of alphanumeric passwords. However, users have difficulty remembering a password that is long and random-appearing. Instead, they create short, simple, and insecure passwords. Today, most Internet applications still establish user authentication with traditional text depended passwords. From the long time there is research to design a secure and user-friendly password method for the security reasons. On the other hand, there are password manager programs which facilitate generating site-specific strong passwords from a single user password to eliminate the memory burden due to more than one password. On the other hand, there are studies exploring the operability of graphical passwords as a more secure and good user-friendly alternative. Image Code Password has been designed to try to make passwords more memorable and easier for people to use and, therefore, more secure. Using an image code as password, users selects on image code rather than type alphanumeric characters.


ABSTRACT A patch reef in the platform lagoon off Old Rhodes Key, Florida, was studied to determine the overall contribution of the green algae Halimeda to the local regime of calcium carbonate sedimentation. It was found that whole and fragmented Halimeda segments can be identified to species in the sediments surrounding the reef, and that the distribution of the disarticulated segments can be correlated with the living Halimeda flora. Seven species of Halimeda were found living on and around the reef in two distinct zones separated by a barren sandy zone. The inner zone (patch reef zone) is inhabited by Halimeda discoidea, H. goreauii, H. opuntia and H. tuna. The outer zone (mixed grass zone) is inhabited by Halimeda incrassata, H. lacrimosa, H. monile, H. opuntia, and H. tuna. The distribution of these last two species is controlled by the availability of hard surfaces which occur in both zones. The distribution of the other species appears to be controlled by localized parameters such as water depth, water temperature, and light penetration. Morphological characteristics, life cycles and reproduction rates control the contribution of Halimeda to patch reef sedimentation. In addition to its role as sediment producer, Halimeda indirectly influences sediment accumulation by serving as a substrate for the attachment of other sediment-contributing organisms, binding sediment below the water-sediment interface, and trapping particles in suspension by locally reducing current velocities.


Hardware in the loop is a widely used technique in power electronics, allowing to test and debug in real time (RT) at a low cost. In this context, field-programmable gate arrays (FPGAs) play an important role due to the high-speed requirements of RT simulations, in which area optimization is also crucial. Both characteristics, area and speed, are affected by the numerical formats (NFs) and their rounding modes. Regarding FPGAs, Xilinx is one of the largest manufacturers in the world, offering Vivado as its main design suite, but it was not until the release of Vivado 2020.2 that support for the IEEE NF libraries of VHDL-2008 was included. This work presents an exhaustive evaluation of the performance of Vivado 2020.2 in terms of area and speed using the native IEEE libraries of VHDL-2008 regarding NF. Results show that even though fixed-point NFs optimize area and speed, if a user prefers the use of floating-point NFs, with this new release, it can be synthesized—which could not be done in previous versions of Vivado. Although support for the native IEEE libraries of VHDL-2008 was included in Vivado 2020.2, it still lacks some issues regarding NF conversion during synthesis while support for simulation is not yet included.


The correlation between the hydrogen bonding configurations and the energy band structures of hydrogenated nanocrystalline (NC) silicon films has been investiga ted. The samples were prepared by helicon wave plasma chemical vapor deposition technique. Raman scattering, infrared absorption and optical absorption measurem ents were used to analyze the microstructure, hydrogen bonding configurations an d energy band structures of the deposited films. Raman results indicate that dis tinct different structures appear in films deposited at various substrate temper atures and there is a threshold at about 200℃ for the amorphous silicon to be t ransformed to the NC phase. The energy band structures of the films are closely related to their hydrogen bonding configurations. The chemical shift of the vala nce band to the lower state induced by high hydrogen content and the structural disorder related to low substrate temperature makes the films have wide band gap s and large band tail widths. With increasing the substrate temperature, the dec rease trend of optical band and tail width is mainly related to the enrichment o f the hydrogen located in the grain boundary, which perform the function of term inating the dandling bonds at NC silicon grain surface. Further increasing the s ubstrate temperature broadens the band tail width of the films because the hydro gen content is too low to passivate the dangling bonds at the NC silicon grain s urface.


Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.


Each transport mode owns itself technical economy. On the basis of multiple transport mode selection, the paper presents the route optimization model for single-task from one origination to one destination in the fourth party logistics, and gives the solution of Genetic Algorithms. In the algorithms, a length-variant encoding scheme of round number is adopted to represent the selected route, and idea that keeps the best individual is used. The results of experiments show that Genetic Algorithms can solve the route optimization problem based on the selection of multiple transport modes in the fourth party logistics conveniently and effectively.


The international border between Nigeria and her neighboring countries is roughly 4745sq.km. The major border countries with Nigeria are Cameroon (1,690 kilometers) in the east, Niger (1,497 kilometers) in the north, Benin (773 kilometers) in the west, and Chad (87 kilometers) in the north-east. Nigeria also shares maritime boundaries with Equatorial Guinea and Sao Tome and Principle. The current border corresponds to the inter-colonial border between British and French territories that was set up in 1889. Due to the fact that between these countries hardly any natural boundaries exist, in some parts its exact demarcation remains unclear. The border region includes a large surface of lagoonand marshlands in the Ouémé valley, which have traditionally been used as transport and trade routes and which are very difficult to control and monitor by migration and customs authorities. This coupled with the challenges facing African states to manage their borders are compounded by globalization that is tearing down traditional borders through advancement in technology and transformation of international relations. At the moment crimes are committed without crossing borders and huge amounts of goods are sold through cyberspace. The problem of security as a result of these borderless-borders in Nigeria has become one of the most intractable challenges facing the country today. In recent time, the security challenges in Nigeria and its border crime are alarming, especially, the activities of the terrorist group known as ''Boko Haram'' in which lives and property are no longer secure. There are many speculations that the groups may have found their way through our porous borders. Therefore, the study probes into the nature of Nigeria borders using analytical framework of assessment in the emerging trans-border crimes, the causes and sources of insecurity of lives and property in Nigeria. The paper then revealed that the major criminal activities in Nigeria borders are smuggling of contraband goods and illegal immigrants, trafficking in weapons and human parts, drug trafficking, vehicle crime, trafficking of illegally exploited natural resources, including the illicit trade in timber, oil and diamond among others. The paper then suggests that much of the conventional wisdom regarding how best to address Nigeria border crime and security is not only enacting a law but also creating proper national security awareness, involvement of new stakeholders in the security sector and strong institutional framework to checkmate the activities of transborder crime.


A feature of U.S. post-war business cycle experience that is by now widely documented is the tendency of the spread between the respective interest rates on commercial paper and Treasury bills to widen shortly before the onset of recessions. By contrast, the paper- bill spread did not anticipate the 1990-91 recession. Empirical work presented in this paper supports two (not mutually exclusive) explanations for this departure from past experience. First, at least part of the paper-bill spread's predictive content with respect to business cycle fluctuations stems from its role as an indicator of monetary policy, but the 1990-91 recession was unusual in post-war U.S. experience in not being immediately precipitated by tight monetary policy. Second, movements of the spread during the few years just prior to the 1990-91 recession were strongly influenced by changes in the relative quantities of commercial paper, bank CDs and Treasury bills that occurred for reasons unrelated to the business cycle. This latter finding in particular sheds light on the important role of imperfect substitutability of different short-term debt instruments in investors portfolios, and highlights the burdens associated with using relative interest rate relationships as business cycle indicators.


Abstract Objective. Following recent literature which stresses the importance of broadening the conceptualization of mental functioning in youth, this paper aims to investigate structural relations between indicators of anxiety, depressive symptoms, and psychological resources in non-referred Italian adolescents, as captured by the Strengths and Difficulties Questionnaire (SDQ; 26), the Spence Children's Anxiety Scale (SCAS; 44) and the Children Depression Inventory (CDI; 30). Methods. A hierarchical model which considers both the interplays and overlaps between these instruments is tested by means of Confirmatory Factor Analysis, in order to explore the possibility to use the three tools within a meaningful screening battery. First, validity and reliability of SDQ, SCAS, and CDI is successfully controlled thanks to three appropriate preliminary studies, an evidence not already acquired in the Italian context for the adolescent population. Then, the focal study devises and tests a model that merges indicators of the SDQ, SCAS, and CDI scales into four correlated factors, that is, Psychological Resources, Externalized behavior problems, Internalized Fear and Internalized Anxious Misery. Conclusions. Overall, findings corroborate the combined use of SDQ, SCAS, and CDI as a screening battery for the assessment of mental functioning in youth adopting a dimensional rather than a categorical approach.


Abstract Selective estrogen receptor modulators (SERMs) represent a class of drugs that act as agonist or antagonist for estrogen receptor in a tissue-specific manner. The SERMs drugs are initially used for the prevention and treatment of osteoporosis in postmenopausal women. Bone health in prostate cancer patients has become a significant concern, whereby patients undergo androgen deprivation therapy is often associated with deleterious effects on bone. Previous preclinical and epidemiological findings showed that estrogens play a dominant role in improving bone health as compared to testosterone in men. Therefore, this evidence-based review aims to assess the available evidence derived from animal and human studies on the effects of SERMs on the male skeletal system. The effects of SERMs on bone mineral density (BMD)/content (BMC), bone histomorphometry, bone turnover, bone strength and fracture risk have been summarized in this review.


PIV measurements have been carried out to study the effect of exhaust plume and nozzle length on the flow topology and mean pressure distribution of axisymmetric base flows at freestream Mach numbers 0.76 and 2.20. Four different nozzle lengths with and without exhaust plume have been tested. The use of different nozzle lengths leads to flow cases in which the shear layer impinges on the model (solid reattachment), on the flow downstream of the model (fluidic reattachment), and intermittently on the model and on the flow (hybrid reattachment). An increase in nozzle length and the presence of an exhaust plume led to an increase in mean reattachment length at Mach 2.20, whereas no significant change in reattachment length was observed at Mach 0.76. The flow cases with the longest nozzles for which solid reattachment occurred showed significantly higher turbulent kinetic energy levels, at Mach 2.20, but significantly lower levels at Mach 0.76. Comparisons of flow cases with a long nozzle without a plume and flow cases with a short nozzle but with a plume suggest that the presence of the plume cannot accurately be modelled by replacing the plume with a solid geometry. Pressure results showed that the location of the low-pressure region downstream of the base remains rather invariant for different flow cases with and without plume and for different nozzle lengths. An increase in nozzle length leads to higher local pressure at the nozzle exit and therefore results in a less under-expanded or more over-expanded plume.


Several cancer therapeutic agents have been associated with pulmonary toxicity. Herein, we describe the case of a 73-year-old woman with breast cancer metastatic to the liver, who developed noncardiogenic pulmonary edema (NPE) while on treatment with gemcitabine plus docetaxel combination with granulocyte colony-stimulating factor (G-CSF) support. Gemcitabine, a deoxycytidine analogue, is reported to produce mild self-limiting and only occasionally severe pulmonary toxicity. The microtubule stabilizer docetaxel has been associated with water retention complications. The combination of these two agents has shown promising activity in several solid tumors and is in a phase of clinical development with prophylactic G-CSF in most of the trials due to the high rate of dose-limiting neutropenia observed with this combination. In our case pulmonary toxicity resolved rapidly following the administration of corticosteroids. A possible deleterious synergy of the compounds involved in this case is discussed and the medical literature on NPE related to cancer therapy is shortly reviewed. We conclude that NPE should always be considered in patients with respiratory function deterioration while on therapy with the gemcitabine-docetaxel combination and G-CSF. Corticosteroids can provide maximum benefit if started early upon diagnosis coupled with withdrawal of the causative drugs.


PURPOSE OF INVESTIGATION
To show management of patients with breast lobular carcinoma in situ (LCIS).

MATERIALS AND METHODS
This study is the retrospective review of 65 patients, between 1996 and 2012, with isolated LCIS of the breast, evaluated through clinical examination, ultrasound, and mammography at the first examination and follow-up.

RESULTS
In 53 patients (81.54%), clinical examination was negative. In 14/65 (21.54%) cases, ultrasound was positive and led to biopsy. The clusters of tiny calcifications were the predominant mammographic pattern (45 cases, 69.23%). Forty-six patients (70.77%) underwent surgical biopsy after guided stereotactic placement of metallic marker (hook-wire), 12 (18.46%) by stereotactic vacuum biopsy (SVB), 5 (7.69%) by core needle biopsy (CNB) under ultrasound guidance, two (3.08%) patients CNB with clinically palpable nodules. Fourteen (21.54%) women underwent a quadrantectomy or total mastectomy after the first diagnosis; in this latter group follow-up was negative. Among the 51 patients (78.46%) who did not undergo quadrantectomy or total mastectomy, five relapses occurred, respectively, three LCIS and two infiltrating ductal carcinomas (IDC). Follow-up ranged from 12 to 144 months.

CONCLUSION
LCIS is a risk factor for invasive carcinoma and should be managed with careful follow-up, but if there is a discrepancy between pathology and imaging, surgical excision is mandatory.


This guide features some of the resources and materials relevant for students, staff, and faculty in the Department of Chemistry


An analysis for controlling a static-unstable tactical missile using two-loop acceleration autopilot was detailed. The rate feedback loop was firstly presented. The equivalent actuator dynamics was introduced and examined. Thus an overall stabilization condition combined with both low and high frequency cases was proposed. The lever effect led by inertial measurement unit was of benefit to a great controllable range. The results show that the autopilot control capacity is dominated by actuator bandwidth, and a compromise should be determined between the flight performance and the actuator requirement for a static unstable tactical missile.


Climate change science is unequivocal on the link between fossil fuels and climate change. Yet, some governments – including those in Australia – fail to meet agreed targets and continue to invest in the coal industry. Scientists and other scholars have expressed concern that the science is not prompting shifts in policy adequate to address current and future effects of climate change. Many have called for other tools – specifically, the arts and social sciences – to investigate and communicate about the environmental and social changes underway. In this context, this article explores the potential of interdisciplinary collaborative song-writing as research practice. Beginning on a boat on Australia's Great Barrier Reef, the research team adopted singing and song-writing as a method for coming together to reflect upon our research aims and motivations, to explore and express the delight and grief we were experiencing in this climate-changing land and seascape and potentially to reach new audiences and create different affects. Our multidisciplinary expertise offered impetus to pursue a hybrid form: an original song written, professionally recorded and vinyl pressed; scholarly notes to expand on our song lyrics; visual presentation of our music as annotated score; and written reflections on the process and its contribution to knowledge. Here, we present and explore the possibilities of song-writing as creative geographical practice.


Spring water geochemistry is applied here to evaluate the geothermal potential in Rhenohercynian fold and thrust belt around the deepest borehole in Belgium (Havelange borehole: 5648 m MD). Fifty springs and (few) wells around Havelange borehole were chosen according to a multicriteria approach including the hydrothermal source of "Chaudfontaine" (T ≈ 36 °C) taken as a reference for the area. The waters sampled, except Chaudfontaine present an in-situ T range of 3.66–14.04 °C (mean 9.83 °C) and a TDS (dry residue) salinity range of 46–498 mg/L. The processing methods applied to the results are: hierarchical clustering, Piper and Stiff diagrams, TIS, heat map, boxplots, and geothermometry. Seven clusters are found and allow us to define three main water types. The first type, locally called "pouhon", is rich in Fe and Mn. The second type contains an interesting concentration of the geothermal indicators: Li, Sr, Rb. Chaudfontaine and Moressée (≈5 km East from the borehole) belong to this group. This last locality is identified as a geothermal target for further investigations. The third group represents superficial waters with frequently high NO3 concentration. The application of conventional geothermometers in this context indicates very different reservoir temperatures. The field of applications of these geothermometers need to be review in these geological conditions.


This paper uses administrative data to in detail document how the share of youths not in employment, education or training has evolved over time in the Scandinavian countries. We study both first- and second-generation immigrant youths as well as natives to explore whether the pattern differ depending on the region of origin. We show that the NEET rates are higher among youths with an immigrant background compared to youths with a native background in all countries. Even when controlling for youth background characteristics, first- and second-generation immigrant youths have significantly higher probability of being in NEET compared to native youths.


In this paper, the discrete method of eigenvectors of covariance matrix has been used to weight minimization of steel frame structures. Eigenvectors of Covariance Matrix (ECM) algorithm is a robust and iterative method for solving optimization problems and is inspired by the CMA-ES method. Both of these methods use covariance matrix in the optimization process, but the covariance matrix calculation and new population generation in these two methods are completely different. At each stage of the ECM algorithm, successful distributions are identified and the covariance matrix of the successful distributions is formed. Subsequently, by the help of the principal component analysis (PCA), the scattering directions of these distributions will be achieved. The new population is generated by the combination of weighted directions that have a successful distribution and using random normal distribution. In the discrete ECM method, in case of succeeding in a certain number of cycles the step size is increased, otherwise the step size is reduced. In order to determine the efficiency of this method, three benchmark steel frames were optimized due to the resistance and displacement criteria specifications of the AISC-LRFD, and the results were compared to other optimization methods. Considerable outputs of this algorithm show that this method can handle the complex problems of optimizing discrete steel frames.


We measured denitrification and anammox potential rates in homogenized sediments over two annual cycles from two estuarine sites (Providence River estuary and Narragansett Bay) and two continental shelf sites (Block Island and Rhode Island sounds). Denitrification varied both spatially and seasonally, but anammox only varied spatially. Denitrification ranged from 2.5 to 112 nmol N h−1 mL−1 sediment, and anammox from 0 to 8.7 nmol N h−1 mL−1 sediment, with the contribution of anammox to N2 fluxes (ra) ranging from undetectable to 4% in estuarine sites and 8–42% on the shelf. Oxygen microprofiles were analyzed in intact cores and concentrations of nitrate, nitrite, and ammonium were measured in the sediment slice corresponding to the depth layer in which potential rates were measured. Denitrification rates correlated positively with diffusive O2 consumption and temperature and potential anammox rates correlated positively with pore‐water concentrations. Anammox was positively correlated with denitrification in shelf sediments where anammox was regularly detected, but not in estuarine sediments. ra was negatively correlated with diffusive O2 consumption and positively correlated with pore‐water nitrate. Both organic matter and nitrate were important factors regulating the contribution of anammox to N2 production. As a whole, our results demonstrate that incorporating processes that control these two factors into models of N cycling, rather than focusing on organic matter availability alone, may improve predictions of the relative importance of anammox to N2 production in marine sediments.


The aim of this research was to investigate the role of smartphones in teaching the English language to a population of fifteen, visually-impaired Brazilian students. Classroom ethnography was chosen as the methodological design and data generated from classroom observations, didactic materials that were made and posted on apps, and two questionnaires were used. We resorted to descriptive and interpretive analyses as we intended to find linguistic and behavioral patterns regarding the use of information and communications technology (ICT), focusing on smartphones, for communication and learning English. Results show that, at the beginning of the course, students had little to no ability to use smartphones, including apps such as WhatsApp and Facebook mobile. After two years of formal language and smartphone instruction, all students learned how to use their mobile phones, and were able to post and listen to podcasts and written texts on WhatsApp and Facebook mobile in both their native language and in English. The students also engaged in real-life communication events with peers in Brazil and other parts of the world. Mobile-assisted language learning (MALL) helped these students enhance their social and cultural capital.


Apoptosis induction of host macrophages has emerged as a common virulence mechanism among bacterial pathogens. Infection with Campylobacter jejuni is a leading cause of gastroenteritis worldwide and is characterized by an acute inflammatory response in the small intestine. The authors used the human monocytic cell line THP-1 to examine apoptosis induction and pro-inflammatory cytokine production during C. jejuni infection. Flow cytometric analysis revealed that 48 h after inoculation, a C. jejuni wild-type isolate induced apoptosis in 63 % of THP-1 cells while only 34 % of cells inoculated with a ciaB mutant, which does not secrete the Cia (Campylobacter invasion antigens) proteins, underwent apoptosis. Complementation of the ciaB mutant resulted in levels of apoptosis similar to those induced by the C. jejuni wild-type isolate, suggesting that the Cia proteins have a role in apoptosis induction. It was shown that a proteinase K- and heat-stable component of C. jejuni also stimulated THP-1 apoptosis. Inoculation with a C. jejuni gmhD mutant indicated that lipooligosaccharide was not the stimulatory molecule. Immunoblot and ELISA analyses revealed that C. jejuni infection stimulated the synthesis, processing and secretion of interleukin 1 beta (IL-1 beta). Inhibition of caspase 1 activity eliminated IL-1 beta processing and secretion, but did not affect apoptosis induction. In addition, treatment of cells with a caspase-9-specific inhibitor did not affect apoptosis induction, arguing against activation of an apoptotic pathway dependent on either caspase 1 or 9 activation. Collectively, these data suggest that the inoculation of macrophages with C. jejuni results in the processing of IL-1 beta and apoptosis through different regulatory pathways. Furthermore, these data argue that C. jejuni may use a mechanism distinct from Salmonella typhimurium and Shigella flexneri to initiate macrophage apoptosis and release of IL-1 beta.


Although doxorubicin (Dox) is widely used in clinical treatment for solid tumors, it causes many side‐effects such as heart and kidney damage, bone marrow suppression, and drug resistance. Legumain is a lysosomal protease that is elevated and associated with an invasive and metastatic phenotype in a number of solid tumors. In this study, we designed and synthesized a Dox prodrug, N‐benzyloxycarbonyl‐Ala‐Ala‐Asn‐Doxorubicin (CBZ‐AAN‐Dox), with 94% purity. Single substrate kinetic assays demonstrated hLegumain‐specific enzymatic cleavage and activation of the prodrug in vitro, and this enzymatic cleavage of the prodrug substrate was more sensitive in acidic conditions, releasing more than 70% of Dox after 24 h. Treatment of tumor cells with our prodrug demonstrated a much higher IC50 value, significantly enhanced uptake of the prodrug, and considerably less cellular toxicity compared to Dox treatment alone. Our study presents a novel prodrug, CBZ‐AAN‐Dox, to potentially increase both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain.