Purpose

The purpose of this paper is to identify the factors which are instrumental to poverty reduction opposed to many factors that are considered as impediments to poverty reduction in a poor country like Bangladesh.

Design/methodology/approach

This paper is an outcome of review of literature covered wide range of issues including sectoral contribution to economic growth but none has exclusively dealt with the instrumental role of the poverty reduction factors, insider's view, long-term observations (1960-2014), and reviews of secondary data.

Findings

In order to reduce poverty, rather than attempting to change the "culture of poverty," remove the "structural trap," or "kin system as poverty trap" it can be achieved through harnessing the enabling factors of poverty reduction. Study argues that rather than focusing on "barriers" to poverty reduction, a country needs to identify and focus on its "potential" factors of poverty reduction. The dominant enabling factors for Bangladesh were agricultural development and remittance. The utilization of land and labor could bring a transformation in the rural economy of Bangladesh which was essential to poverty reduction.

Practical implications

The study shows that the individuals can escape poverty largely through their own effort where a proper policy support from the government is needed. The state needs to play the facilitating role rather than the instrumental in the case of poverty reduction.

Originality/value

The paper reveals instruments to poverty reduction where usual practice was to identify the barrier to development and to suggest the means of overcoming those barriers. It suggests how to look into the matter from other way round where instead of identifying the barrier attempt should be made to identify the enabling factors and to harness those enabling factors. The findings are based on the country-specific literatures but not generalized in the form as attempted here. The study shows a means of poverty reduction where country-specific strategy or home-grown model can be drawn out based on the identification of potential factors.


Recent RF applications and research require thousands of accurate
measurements to be performed within a practical time. For instance,
the global model extraction of a DUT requires thousands of accurate
measurements, which would take a very long time when using the
traditional RF measurement systems because they are relatively slow.
Moreover, the inaccessible software that is used by the traditional systems
has made them a vendor-defined system, where their application
cannot be extended or amended. This is contrary to the need for a
flexible RF system that can be extended and modified according to
user preferences. Furthermore, the traditional load-pull measurement
strategies are time-consuming thanks to the iteration process and the
need for the user interaction. Therefore, developing a new high-speed
measurement is essential.
This work demonstrates a high-speed load-pull measurement system
that maintains flexibility, accuracy, speed, and high dynamic range.
The system's architecture is based on PXIe modules, where the signal
Thoalfukar Husseini
detection is achieved through the use of vector signal analysers (VSA)
that can operate over 50 MHz frequency bandwidth. The RF signal
generation employs vector signal generators (VSG) using continuous
wave (CW) mode generation. The system is calibratable over a 100 dB
dynamic range and the measurement speed approaches 200 measurements/
sec at 10K samples/average. Due to the accessibility of the raw
measured data and the customisable written software, statistical information
has been employed to monitor the quality of the measurements
and the status of the system. Moreover, an automated active load-pull
measurement has been implemented on this measurement system.
The automated process has been achieved by exploiting the load-based
Cardiff behavioural model. This model is used to predict the required
injected signals a21 to emulate a load impedance at the DUT reference
plane, wherein the results show the ability of the model to achieve
a load-target with an error less than -35 dB. The prediction of the
DUT's response by the model combined with customised software
has allowed for an automated fundamental active load-pull process
that requires minimum user interaction to automatically identify the
optimum load conditions for the design-relevant parameters (e.g. gain,
efficiency or output power over one or multi-power levels) within a
few seconds. Two methods have been used to take the impact of the
test-set on the generated signal into account: descriptive function and
ix
Thoalfukar Husseini
simple look-up table. These two approaches have been implemented
and verified. The results show that each model can achieve the power
target with a residual error of less than 0.1 dB.
The automation process has not only covered the definition of the
optimum impedances over different power levels but has also identified,
in a time efficient manner, the appropriate load-pull impedance
space. This ensures that the model's coefficients, which are required
for predicting the DUT's response b21 and efficiency, are accurately
extracted. This approach significantly reduces the number of required
measurements, and hence reduces the measurement time when compared
to the traditional approach. It takes less than 42 sec to perform
1282 load-pull measurements, that define the appropriate design
space (-3dB power contours) for 16 power levels while ensuring that
the a- wave based Cardiff behavioural model is simultaneously and
accurately extracted.
For the sake of an efficient utilization of the measurement system
and further reduction in the required number of measurements required
to generate a global behavioural model that is compatible for
CAD-tool design, a linear interpolation approach over the extracted
coefficients was employed and verified. This approach has allowed
x
Thoalfukar Husseini
further reduction in the number of measurements because there is no
need to perform the load-pull measurement over a high dense grid of
input drive power levels (a11), which is essential for the global model
generation.


Coherent noise may be removed from seismic data by first making an approximate model of the noise, then producing an even better estimation of the noise by adaptively matching the modeled noise to the data. This modified model of the noise may then be subtracted from the data, eliminating most coherent noise. The success of this approach depends both on how well the initial model matches the true noise and the success of the adaptive matching in modifying the initial noise prediction to match the true noise. The adaptive matching step is complicated by the presence of the signal and other noise in the data. In this article, the noise of interest is surface-related multiples, although other types of coherent noise may be removed with this approach.


The goal of many railgun investigations is to arrive at a railgun design that is capable of launching projectiles to extremely high velocities (10 to 100 km/s). Often a second goal is for the railgun design to allow for repetitive launches without a total rebuild of the railgun. These two goals are the objectives the Center for Electromechanics at The University of Texas at Austin (CEM-UT) has pursued over the past several years. As part of the investigation, a serious study of coaxial railguns was conducted. Coaxial railguns were studied because the coaxial geometry offers two attractive features. One feature is the simplified construction, and the other is an inherent lower L' value. Studies were conducted on 0.5-and 5.0-m long coaxial railguns. Results were mixed in that high velocities were obtained (37 km/s), and several shots were done on one gun without cleanup or rebuild, but plasma mass amounts were small and not tightly patterned. Experiments are still underway, on a limited basis, to attempt to focus and bunch the plasma during launch and as it exists the muzzle.


Among four AZ91 samples, two were once anodized and the others were twice anodized in two electrolytic baths. After twice anodization, two coatings coexist on the base metal. Surface morphology showed that for one of twice anodic coatings (sample 2), the second coating only existed on some places and sealed some pores of the first coating after short time on the second anodizing. However, for another twice anodic coating (namely sample 4), the second anodization spent very long time and the coating was thick and loose. Salt spray testing showed that sample 2 had the most excellent corrosion resistance and the reason is discussed.


: Incubation of normal rat cortical or brain stem tissue with 3H-NE or 3H-5-HT and subsequent exposure to amphetamine produced a concentration-related release of the transmitters from tissue stores into the incubation media. Although pretreatment with the catecholamine neurotoxin in 6-hydroxydopamine (6-OHDA) reduced the retention of 3H-NE in both of these tissues, the proportion of 3H-NE released by amphetamine was attenuated only in cortical tissue. Pretreatment with the serotonergic neurotoxin, 5,6-dihydroxytryptamine (5,6-DHT) had no effect on the retention or release of 3H-NE in cortical or brain stem tissue. Pretreatment with 5,6-DHT reduced the retention of 3H-5-HT in the cortex and brain stem, but the release of 3H-5-HT was significantly attenuated only in the latter tissue. 6-OHDA pretreatment increased the retention and proportion of cortical 3H-5-HT released by amphetamine but reduced the release of brain stem 3H-5-HT in the absence of an effect on retention. It appears that the in vitro release of 3H-NE from the cerebral cortex occurs primarily from catecholamine and not serotonergic neurons whereas the cortical release of 3H-5-HT is not an event specific to serotonergic nerve terminals. The release of 3H-5-HT from brain stem does not appear to be restricted to the serotonergic cell bodies since its release was attenuated by 5,6-DHT and 6-OHDA.


The adaptation of software applications is a critical need in ubiquitous computing. This adaptation should be done at runtime as a response to changes in software infrastructure. Each adaptation occurs correctly when it is separated but it may interact with other adaptations when they are composed. These interactions can affect the target behavior after adaptation. We call this interference. In this paper, we present an original approach to resolve interference. We represent applications and their adaptations by graphs; then we apply graph transformation rules on these graphs to resolve interferences.


There is an increasing concern over the cyber security of Critical Infrastructures (CI) due to the increasing ability of cyber attackers to cause even catastrophic failures. It is mainly due to the pervasiveness of ICT (Information and Communication Technologies) and to the consequent de isolation of SCADA (Supervision, Control and Data Acquisition) system, which represents the nervous system of most CIs. Cyber attacks could block the connection between SCADA Control Centre and its remote devices or insert fake commands/measurements in the equipment communications. With reference to an actual case study, constituted by a SCADA system controlling a portion of a medium voltage power grid and a corporate network, we discuss how cyber threats, vulnerabilities and attacks might degrade the functionalities of SCADA and corporate network, which, in turn, might lead to outages of the electrical grid. We represent SCADA and corporate network under malware propagation, Denial of Service and Man In The Middle attacks and predict their consequent performance degradation. Particularly, we use NetLogo to identify possible malware propagation in relation to SCADA & corporate security policies adopted from the utility and NS2 simulator to compute the consequences of the attacks on SCADA and in turn on power grid.


The emphasis of portfolio decision-making is placed on how to obtain the optimal solution of portfolio allocation in recent years. The objective for most of programming models, so called either the return model or the risk model, is to maximize the profit or to minimize the cost for portfolio selection based on mean-variance (MV) theorem proposed by Markowitz. However, both two objectives must be taken into consideration at the same time instead of trade-off between risk and return in the real situations. In general, these two objectives are not crisp under uncertainty environment from the point of view of the investors. In this paper, a method of portfolio selection is proposed to arrive at dealing with optimizing risk-return structure of a portfolio simultaneously in fuzzy terms, named fuzzy multi-goal portfolio (FMGP) decision-making model. The FMGP decision making model here is applied to analyze the weighting for the underlying of a portfolio with the aspiration-level using fuzzy membership functions (FMFs) to obtain feasible solutions. Genetic algorithm (GA) is also employed here to tackle the curse of computation for a large-scale portfolio. The evidence from Morgan Stanley country indices (MSCI) portfolios shows the viability and effectiveness for the investment decision-making under uncertainty environment.


Wireless sensor networks (WSNs) are event-based systems that rely on the collective effort of several microsensor nodes. Reliable event detection at the sink is based on collective information provided by source nodes and not on any individual report. However, conventional end-to-end reliability definitions and solutions are inapplicable in the WSN regime and would only lead to a waste of scarce sensor resources. Hence, the WSN paradigm necessitates a collective event-to-sink reliability notion rather than the traditional end-to-end notion. To the best of our knowledge, reliable transport in WSN has not been studied from this perspective before. In order to address this need, a new reliable transport scheme for WSN, the event-to-sink reliable transport (ESRT) protocol, is presented in this paper. ESRT is a novel transport solution developed to achieve reliable event detection in WSN with minimum energy expenditure. It includes a congestion control component that serves the dual purpose of achieving reliability and conserving energy. Importantly, the algorithms of ESRT mainly run on the sink, with minimal functionality required at resource constrained sensor nodes. ESRT protocol operation is determined by the current network state based on the reliability achieved and congestion condition in the network. This self-configuring nature of ESRT makes it robust to random, dynamic topology in WSN. Furthermore, ESRT can also accommodate multiple concurrent event occurrences in a wireless sensor field. Analytical performance evaluation and simulation results show that ESRT converges to the desired reliability with minimum energy expenditure, starting from any initial network state.


Road transport is the dominant mode of transport in sub-Saharan Africa, carrying close to 90 percent of the region's passenger and freight transport, and providing the only access to rural communities where over 70 percent of Africans live. Despite their importance, most of the region's nearly 2 million km of roads are poorly managed and badly maintained. By 1990, nearly a third of the $150 billion invested in roads had been eroded through lack of maintenance. To restore only those roads that are economically justified and prevent further deteriorations will require annual expenditures of at least $1.5 billion over the next ten years, or more than double the requirements of regular maintenance. To find sustainable solutions to these problems, the United Nations Economic Commission for Africa (UNECA) and the World Bank launched the Road Maintenance Initiative (RMI) as part of the sub-Saharan Africa Transport Policy Program (SSATP). With support from a number of bilateral donors, the Initiative has spent the last six years working with African countries to identify the causes of poor road maintenance policies and to develop an agency for reforming them. The key concept to emerge from the debate on how to strengthen financing and management of roads is commercialization; bring roads into the marketplace and put them on a fee for service basis. However, since roads are and will largely remain a public monopoly, commercialization requires complementary reforms in four important areas called the four basic building blocks; 1) create ownership by involving road users in management to win public support for adequate funding and control of the agencies; 2) secure an adequate and stable flow of funds; 3) clarify who is responsible for what; and 4) strengthen management by adoption of private sector management practices. A number of sub-Saharan African countries are in the process of implementing reforms towards the commercial management of their roads. These reforms include involving road users in management through road management boards, securing an adequate and stable flow of funds through road tariffs/road funds, and increasingly commercializing/privatizing the execution of engineering services and road works.


Wireless sensor networks have been a big promise during the last few years, but a lack of real applications makes difficult the establishment of this technology. In this paper a real monitoring application in an instant coffee factory is presented. This application belongs to the group of environmental solutions based on wireless sensor networks, and it is focused on the impact of the instant coffee production processes in one of the largest instant coffee factories in Europe. The paper includes the entire application scenario, from the hardware of the WSN nodes to the software that will evaluate the impact and will close the loop.


Wheat (Triticum aestivum L.) cultivar LZ953 is one of a type of large-spike and large-grain cultivars with delayed leaf senescence and slow grain filling. Its grain filling is adversely affected by the dry hot winds that generally occur during the late stages of the crop in northern China. This study investigated the possible reasons for the slow grain filling and compared LZ953 with an early ripening cultivar, LM14, cultivated at high and low nitrogen (N) levels. The results showed greater photosynthetic rate, carbon (14C) accumulation, leaf area, and soluble sugar accumulation in stems and sheaths at grain filling in LZ953 than LM14. However, export of soluble sugar from the stem and sheaths, as well as starch accumulation in the grains, were smaller in LZ953. As a result, grain filling was slow during the first 14 days after anthesis (DAA). Nitrogen level had no significant effect on the grain-filling rate of either cultivar. Under high N, LZ953 absorbed more N after anthesis than LM14. In LZ953 soluble sugar storage in the stems and sheaths and starch accumulation were greatly reduced under high N. Nevertheless, the soluble sugar contents of the stem and leaf sheaths of LZ953 were greater than those of LM14. At 15 DAA, the 14CO2 assimilation of LZ953 was significantly greater than that of LM14, while the percentage of assimilated 14C in the grains of LM14 was greater than that of LZ953. The proportion of 14C partitioned to the grains of LZ953 was reduced by increased N application. Our results suggest that carbohydrate utilization, starch synthesis, or both limit the rate of early grain filling in LZ953. This would lead to a negative feedback on the export of soluble sugar from vegetative organs.


As energy is one of most important aspects for evaluating algorithms' performance, it's crucial to provide a tool to measure the energy consumed. There still was not satisfying solution to monitor energy consumption of every sensor node in large-scale wireless sensor network. In this paper, we propose a new real-time energy monitoring schema as a function component of WSN testbed sensor network assistant platform, SNAP. Our monitoring schema has the following advantages: real-time accurate energy measurement, the ability to cope with large-scale WSN, side effect free to the monitored nodes, highly adaptive to different kinds of sensor nodes and supporting further energy efficiency analysis on nodes. Noted that all of these advantages are based on SNAP, we introduce the architecture and implementation of our proposed schema together with the counterpart of SNAP. Then we use experimental results to evaluate and demonstrate the performance of this energy consumption monitoring schema.


Back in the early 1990s when a section of the American foreign policy think tank and the intelligentsia were euphorically forecasting scenarios for the consolidation of western victory in the Cold War, James Woolsey, then head of the US Central Intelligence Agency forewarned that the widely celebrated victory and transition to the post-Cold War era was akin to the West, having slain the dragon (of Soviet threat), now living in a jungle full of poisonous snakes (Woolsey 1993). There can hardly be a better metaphoric representation of the post-9/11 projection of American power in the postcolonial world, especially in Africa. This article argues that the US-led war on terror tends to reinforce the crisis of postcoloniality in Africa by deliberately producing metaphors, images, discourses, doctrines and policies aimed at magnifying and mainstreaming terrorism scares on the turbulent politico-economic landscape of Africa, as a means to justify imperial governance and supervision. It is a project that ideologically feeds into influential transhistorical discourses and portrayal of Africa as a timespace of infantilism, requiring endless western propping and chaperoning. Evidently, African political regimes serve as satellite collaborators in the enterprise in a trajectory that the author captures within the discursive framework of postcoloniality.


Abstract: An interview with Thomas Pickering, US Undersecretary of State for Political Affairs, is presented. Text: Before becoming Undersecretary of State for Political Affairs in 1997, Thomas R. Pickering served in some of the United States' most important diplomatic posts around the world. He has been US Ambassador to Russia, India, Israel, El Salvador, Nigeria, and Jordan, as well as President Bush's Permanent Representative to the United Nations. During his time in Russia (1993-1996), he oversaw US involvement in the critical early years of that country's postcommunist transformation. In his current post, Undersecretary Pickering oversees the State Department's regional bureaus and has played a decisive role in major recent events ranging from Kosovo to East Timor. Senior Editor Andor Meszaros spoke with Undersecretary Pickering in early October about US-Russian relations, NATO, and the UN. HARVARD INTERNATIONAL REVIEW: You were the Ambassador to Russia for several years. How would you characterize the US-Russian relationship today? The US-Russian relationship has been through some hard times, but I would say we also have developed a keen sense of how each of us sees the other and about how each thinks and operates. On the Russian side there is a clear sense of concern about the United States and what its goals and objectives are, as well as feelings of hurt that somehow they were not automatically rescued from the difficulties brought about by the fall of communism. On the US side, there are concerns about the commitment of Russia to a future in which political systems and economic arrangements are going to produce the best results for the people in Russia. There are also deep concerns about the Russian government's ability to deal with problems such as corruption and criminality. "Active engagement" may be the best way to describe our relationship that spans international cooperation, security issues, and reform. Do you think that US foreign policy toward Russia since 1991 could or should have been conducted any differently? In many cases I think tactical details might possibly have been slightly different, but the fundamentals we are committed to with respect to Russia, the political reform and economic change and integration of Russia into the international community, remain very much the same. The strategies for dealing with these goals-the combination of high-level diplomatic contacts, the development of a cooperative working style, and the involvement of the United States in critical assistance programs in key areas-would have clearly remained the preferred ways of doing business with Russia. But should we have done a particular thing X, Y, or Z at a particular time? Was a specific economic policy recommendation wise or not? These in my mind are tactical issues open to question. On the other hand, I do not think they fundamentally affected the outcome. If I had a sense of nostalgic regret, I would say that perhaps we didn't move fast enough with some of our programs of support or assistance, particularly with regard to the judiciary and similar areas. On the other hand, I cannot tell you that the Russians were ready to absorb much faster programs that we might have been able to provide them. Turning to the effectiveness of US policy, given the anti-Western sentiment that exists at least within the Russian government if not with the Russian people, how do you think the United States can effectively promote its point of view through its foreign policy? We have to do a number of things all at the same time. We have to be able to encourage the Russians that principles are very important both for them and for us, and that we have to maintain a commitment to them in order to be able to have any kind of a relationship at all. Yeltsin, despite occasional differences in view, has remained basically committed to a lot of these principles and increasingly his governments have as well. …


This paper introduces the design of a transformer load management (TLM) application program based on an automated mapping/facilities management/geographic information system (AM/FM/GIS). The data required for this application is mainly extracted from the databases of the AM/FM/GIS system and customer information system (CIS) and combined with customer daily load patterns obtained by load surveys over a long-term period. This integration environment including graphic and nongraphic databases enhances the TLM program by taking full advantages of AM/FM/GIS capabilities. The program provides a general system information inspection function as well as a load analysis and inquiry function which allow engineers to examine in detail the distribution system facilities or to perceive the loading conditions of a specified distribution device. In addition, the program provides a load distribution map overview function for easily investigating a feeder-wide load distribution through a full-color graphic screen. This application program can be applied to keep the distribution transformers from being damaged due to overloading or to prevent inefficient operation by reason of very light-loading conditions.


In 2013, National Museums Scotland collected Cybraphon, an interactive autonomous internet-connected robot band, created in 2009 by artists' collective and musicians FOUND. Cybraphon obsessively Googles itself every 15 seconds to see how popular it is. All Cybraphon activity rests in the hands of the online community and as such provides a means of displaying online social interaction in a unique way, manifested through an object. It captures its makers' interest in social media interaction at a point in time, 2009, when the phenomenon was still relatively new. This case study will provide background on the making of Cybraphon and then explore the Museum's approach and the audience reaction to this experimental foray into social media 'collecting'.


Pico et al present an interesting manuscript that tackles two outstanding questions in Quaternary glacial geology and paleoclimatology: what were the dimensions of the Laurentide Ice Sheet during Marine Isotope Stage (MIS) 3 and what triggered Heinrich events? Pico et al suggest that the formation and sudden discharge of a proglacial icedammed lake in the Torngat Mountains (Labrador, Canada) sometime during MIS 3 could have served as a triggering mechanism for a MIS 3 Heinrich event(s). Indeed, the authors present an impressive reconstruction of the region's paleotopography and potential paleolake dimensions and volume that hypothetically acted as a trigger for a MIS 3 Henrich event. This argument relies heavily on 1) field evidence for the existence of a paleo ice-dammed lake with wave action eroding bedrock platforms, and 2) the age of the lake dating to MIS 3 based on interpretation of two Be ages from a bedrock surface near the proposed shoreline. Based on our experience measuring Be in glaciated landscapes exhibiting weathering zones and spatial patterns of ice-sheet erosion, we think there are more likely, alternative interpretations of an ice-margin history that would result in the apparent Be ages reported by Pico et al.


Regulatory regions of the mouse muscle creatine kinase (MCK) gene, previously discovered by analysis in cultured muscle cells, were analyzed in transgenic mice. The 206-bp MCK enhancer at nt-1256 was required for high-level expression of MCK-chloramphenicol acetyltransferase fusion genes in skeletal and cardiac muscle; however, unlike its behavior in cell culture, inclusion of the 1-kb region of DNA between the enhancer and the basal promoter produced a 100-fold increase in skeletal muscle activity. Analysis of enhancer control elements also indicated major differences between their properties in transgenic muscles and in cultured muscle cells. Transgenes in which the enhancer right E box or CArG element were mutated exhibited expression levels that were indistinguishable from the wild-type transgene. Mutation of three conserved E boxes in the MCK 1,256-bp 5' region also had no effect on transgene expression in thigh skeletal muscle expression. All these mutations significantly reduced activity in cultured skeletal myocytes. However, the enhancer AT-rich element at nt - 1195 was critical for expression in transgenic skeletal muscle. Mutation of this site reduced skeletal muscle expression to the same level as transgenes lacking the 206-bp enhancer, although mutation of the AT-rich site did not affect cardiac muscle expression. These results demonstrate clear differences between the activity of MCK regulatory regions in cultured muscles cells and in whole adult transgenic muscle. This suggests that there are alternative mechanism of regulating the MCK gene in skeletal and cardiac muscle under different physiological states.


Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an unfavorable prognosis, increasing the risk of stroke and death. Although traditionally associated with cardiovascular diseases, there is increasing evidence of high incidence of AF in patients with highly prevalent noncardiovascular diseases, such as cancer, sepsis, chronic obstructive pulmonary disease, obstructive sleep apnea and chronic kidney disease. Therefore, considerable number of patients has been affected by these comorbidities, leading to an increased risk of adverse outcomes. The authors performed a systematic review of the literature aiming to better elucidate the interaction between these conditions. Several mechanisms seem to contribute to the concomitant presence of AF and noncardiovascular diseases. Comorbidities, advanced age, autonomic dysfunction, electrolyte disturbance and inflammation are common to these conditions and may predispose to AF. The treatment of AF in these patients represents a clinical challenge, especially in terms of antithrombotic therapy, since the scores for stratification of thromboembolic risk, such as the CHADS2 and CHA2DS2VASc scores, and the scores for hemorrhagic risk, like the HAS-BLED score have limitations when applied in these conditions. The evidence in this area is still scarce and further investigations to elucidate aspects like epidemiology, pathogenesis, prevention and treatment of AF in noncardiovascular diseases are still needed.


Allergy to bumblebee venom is a rare form of Hymenoptera venom allergy. Because bumblebees are increasingly used for the pollination of greenhouse plants, the prevalence of this Hymenoptera allergy has increased during the past decade. The clinical presentation, diagnosis and therapy of bumblebee venom allergy are similar to other Hymenoptera venom allergies. There is a significant immunological cross-reactivity between bumblebee and honeybee venom. It has been claimed that immunotherapy with honeybee venom can protect patients with bumblebee venom allergy. This concept, however, has been called into question after the finding of bumblebee venom-specific IgE lacking cross-reactivity to honeybee venom, and three cases of bumblebee venom-allergic patients in whom immunotherapy with honeybee venom was unsuccessful. Immunotherapy with pure bumblebee venom has been shown to be effective and safe, and is currently the treatment of choice in individuals who cannot avoid contact with bumblebees. Immunotherapy with honeybee venom, however, should be considered in patients with severe reactions to bumblebee stings and concurrent sensitization to honeybee venom.


Security experts generally believe that, "security cannot be added on, it must be designed from the beginning."
This dissertation shows that retrofitting security does not need to be a massive reengineering effort, nor does it need to be ad hoc. Security solutions can be added through systematic, general purpose security-oriented program transformations. We describe a catalog of security-oriented program transformations; so far the catalog contains thirty seven transformations. These security-oriented program transformations improve the traditional approaches of security engineering and keep software secure in the face of new security threats. Security-oriented program transformations are not silver bullets; using them requires skill and knowledge of the program being transformed. They are instead power tools that make it easier to add security to existing systems replacing the point solution of a typical patch with a more systematic removal of a vulnerability. When appropriate tools are built and the program transformations are easy enough to apply, then they will allow a software developer to add 'security on demand'.


BACKGROUND AND OBJECTIVES
In Italy, the prevalence of C282Y is lower than in Northern European countries. We hypothesized a higher prevalence of C282Y in Northern than in Southern Italian populations. We previously identified a nonsense mutation (E168X) in hemochromatosis probands originating from a region in the north-west of Italy. We aimed to define the prevalence of C282Y and E168X in that region and the origin of the E168X mutation by haplotype analysis.

DESIGN AND METHODS
Six-hundred and six blood donors were investigated for C282Y, H63D, S65C and E168X mutations by polymerase chain reaction (PCR)-restriction assays. Three hundred were also tested for rare HFE and TFR2 mutations by reverse-hybridization test strips. D6S265, D6S105 and D6S1281 microsatellites were analyzed to define E168X 6p-associated haplotypes.

RESULTS
One C282Y homozygote, thirteen C282Y/ H63D compound heterozygotes, four E168X heterozygotes and three E168X/H63D compound heterozygotes were found. The allele frequencies of C282Y, H63D, S65C, and E168X were 4.7%, 14.9%, 0.74% and 0.58%, respectively.

INTERPRETATION AND CONCLUSIONS
The prevalence of C282Y in the region investigated was much higher than that previously reported in Italy. This finding is probably due to the heavy Celtic component of this north-western population and suggests that in populations of Northern Italian descent screening studies for hemochromatosis could be cost-effective. The prevalence of E168X in this region, although low, suggests that the mutation probably originated here many years ago and its frequency increased as a result of a local founder effect. Given its severity, we suggest that the E168X mutation should be searched for in all hemochromatosis patients of Northern ancestry with an incomplete HFE genotype.


Polymers with thermally activated delayed fluorescence (TADF) are very suitable and promising emitters for use in solution-processed organic light-emitting diodes (OLEDs). However, only a few efficient TADF polymers have been reported to date. In this work, a series of polymers with acridine/carbazole donor backbones and triphenyltriazine acceptor pendant are synthesized. The polymers show remarkable TADF due to the intrinsic twisted donor/acceptor structure derived from the copolymerization monomer and have a high photoluminescence quantum yield of up to 90%, in neat films, through management of the monomer ratios. Non-doped OLEDs based on the polymers display a yellow emission and achieve maximum external quantum and power efficiencies of up to 15.5% and 50.5 lm W−1. More importantly, the non-doped devices possess low turn-on and driving voltages of 2.53 V and 4.05 V (1000 cd m−2) with an extremely small efficiency roll-off of as low as 0.5%. Compared with doped devices, non-doped devices exhibit superior electroluminescent performances, with similar efficiencies but a lower efficiency roll-off and driving voltage, verifying that the designed conjugated polymers are superior emitters for non-doped TADF OLEDs by simple solution-processing.


Publicly-traded debt securities differ on a number of dimensions, including quality, maturity, seniority, security, and convertibility. Finance research has provided a number of theories as to why firms should issue debt with different features; yet, there is very little empirical work testing these theories. We consider a sample of 14,867 debt issues in the U.S. between 1971 and 2004. Our goal is to test the implications of these theories, and, more generally, to establish a set of stylized facts regarding the circumstances under which firms issue different types of debt. Our results suggest that there are three main types of factors that affect the structure of debt issues: First, firm-specific factors such as leverage, growth opportunities and cash holdings are related with the convertibility, maturity and security structure of issued bonds. Second, economy-wide factors, in particular the state of the macroeconomy, affect the quality distribution of securities offered; in particular, during recessions, firms issue fewer poor quality bonds than in good times but similar numbers of high-quality bonds. Finally, controlling for firm characteristics and economy-wide factors, project specific factors appear to influence the types of securities that are issued. Consistent with commonly stated 'maturity-matching' arguments, long-term, nonconvertible bonds are more likely to be issued by firms investing in fixed assets, while convertible and short-term bonds are more likely to finance investment in R&D.


The world has begun the third millennium while the different activities of humans have been affected by water stress and the scarcity of water in the world. This problem will result, in the not very distant future, in water conflicts and war among nations in most regions of the world particularly those in arid and semiarid regions. Iran, a country in the Middle East, in addition to aridity and water stress, has also been involved in problems of water management. In recent years, government interference in water management has caused the people to distance themselves from their principal participatory role in water management. The withdrawal of water users from their responsibility has made the problems more complicated in Iran, particularly in the North Eastern part of Iran. This research has been undertaken using a descriptive and analytical method with documents and field studies on problems resulting from government involvement in water management to find the key solutions from native knowledge to reduce the problems. The result of our investigation shows that, despite the half century government involvement in water resource management without acknowledging the role of creative cooperation of people, there is still an acceptable social investment that could be used in water resource management. The other result of this research is that native knowledge, if used, could now solve the problems that sustainability could be achieved in the management of soil and water resources.


The change in electrical characteristics of a-Si:H thin-film transistors (TFTs) was determined in the presence of electrical gate bias stress, gamma radiation, and both simultaneously, simulating the harsh environment of space. Multiple TFTs were tested under each condition, and the current-voltage characteristics were measured. The results show the gate bias stress increasing the threshold voltage (VT) with power law time dependence while the gamma irradiation decreases threshold voltage for all working transistors. When both the irradiation and gate bias stress were applied simultaneously, the VT initially increased with electrical stress and then decreased as the gamma radiation dominated. Changes in effective mobility were also extracted and detailed analysis of the current-voltage characteristics indicated that the gamma radiation creates interface traps and electron-hole pairs whereas the gate stress produces defect states in the amorphous silicon.


1-Hydroxyquinolones were recently described as effective inhibitors of Toxoplasma gondii replication. These compounds (e.g. HDQ and compound B) were previously shown to inhibit the alternative NADH dehydrogenase (NADH2-I) activity and thus the respiratory chain of T. gondii. However, the phenotype of ndh2-I knock-out mutants suggested the presence of additional target(s).

In this study, the fourth enzyme of de novo pyrimidine biosynthesis, the T. gondii dihydroorotate dehydrogenase (TgDHODH), was identified as a novel 1-hydroxyquinolone target. T. gondii mutants with a partial resistance phenotype towards 1-hydroxyquinolones were used to analyze the expression profile and the coding sequence of all ubiquinone reducing mitochondrial dehydrogenases, which are the likely targets of 1-hydroxyquinolones. Quantitative RT-PCR analysis revealed no significant differences in the mRNA expression level of these enzymes. However, DNA-sequencing identified a single point mutation in codon 302 of the TgDHODH coding sequence that changes a conserved asparagine into serine in the vicinity of the dihydroorotate binding site. This mutation is sufficient to confer the partial drug resistance phenotype, as shown by replacement of the wild type allele with the N302S allele, using a "knock-in" strategy. Enzyme kinetics of E. coli expressed and purified wild type and N302S TgDHODH revealed an inhibition of the wild type enzyme activity by nanomolar concentrations of 1-hydroxyquinolones, while the IC50s for the N302S mutant were significantly increased. Furthermore, inhibition kinetics demonstrated that 1-hydroxyquinolones act as competitive inhibitors for the electron acceptor QD, but as uncompetitive inhibitors for dihydroorotate.

TgDHODH is localized in the inner mitochondrial membrane, and is linking the pyrimidine de novo pathway to the mitochondrial respiratory chain by transferring electrons from dihydroorotate to ubiquinone. To distinguish whether the lack of TgDHODH-mediated electron transfer or the inhibition of de novo pyrimidine biosynthesis is responsible for growth inhibition, both pathways were uncoupled by expression of the ubiquinone independent Saccharomyces cerevisiae DHODH (ScDHODH). Heterologous expression of the 1-hydroxyquinolone-insensitive ScDHODH in T. gondii should lead to a restoration of de novo pyrimidine biosynthesis in the presence of HDQ and compound B. These parasites showed a strongly increased resistance towards 1-hydroxyquinolones, demonstrating that inhibition of pyrimidine de novo synthesis significantly contributes to the growth inhibitory potential of 1-hydroxyquinolones in T. gondii. 1-Hydroxyquinolones thus directly inhibit two important metabolic pathways: oxidative phosphorylation and pyrimidine de novo synthesis.

The growth kinetics of drug treated parasites is characterized by a biphasic pattern, with an initial phase (~ 0 to 24 hours) in which the parasites - independent of their resistance or sensitivity to 1-hydroxyquinolones - show an almost complete growth inhibition. In the later phase of treatment, drug-resistant mutants - and to a much lower extent also wild type parasites - start replicating again. This growth recovery is occurring in the absence of a detectable mitochondrial membrane potential. However, parasites possess a strong dependency on glucose metabolism. A decrease of glucose in the tissue culture medium, and a treatment with a glycolytic inhibitor both prevented the growth recovery. Thus, 1-hydroxyquinolone treatment seems to induce a metabolic shift from oxidative phosphorylation towards glycolysis, which can partly restore the energy production.


Marine energy devices must be attached to the seafloor by their foundations, pilings, or anchors, and will have other parts in the water column like the devices themselves, mooring lines, and power export cables running along the seafloor. The installation and presence of these artificial structures will create physical changes that can disrupt or create new habitats, and potentially alter the behavior of mobile organisms such as fish around a device by attracting them to these new artificial reefs and fish aggregating devices. In this study, we tested a new approach for monitoring fish activity around a marine energy device anchor: a 360-degree underwater camera to keep the target (a wave energy converter's anchor) in the field of view of the camera. The camera was deployed in three configurations (hand-held, tripod, video lander) at sites with different hydrodynamics and underwater visibilities. The video lander was the best configuration: very stable, versatile, and easy to handle. The 360-degree field of view enabled observing and counting fishes, which were more abundant at dusk than dawn or noon, around the anchor. Despite remaining challenges, 360-degree cameras are useful tools for monitoring animal interactions with marine energy devices.


This Renewable Energy Data Book for 2008 provides facts and figures on energy in general, renewable electricity in the United States, global renewable energy development, wind power, solar energy, geothermal power, biopower, hydropower, advanced waterpower, hydrogen, renewable fuels, and clean energy investments.


Triazine herbicides are effective herbicides, which are widely used all over the world, but their residues pose a great threat to the environment and human health. Thus, it is crucial to develop a rapid and sensitive method for monitoring the triazine concentrations in the environment. The present study establishes a simple, sensitive and reliable method for determination of four triazine herbicides including atrazine, prometryn, propazine and simazine in water samples. Ordered titanium dioxide (TiO2) nanotube arrays were prepared using an anodization method and were then used as the adsorbent in the development of a micro-solid phase extraction for the enrichment of triazine herbicides before analysis using high performance liquid chromatography. The experimental results demonstrated that TiO2 nanotube arrays showed good adsorption of triazine herbicides, and the proposed method had satisfactory sensitivity with limits of detection in the range of 0.19–0.50 μg L−1. The proposed method was validated using four real environmental water samples and spiked recoveries were in the range of 84.3–101.9%. All the results demonstrated that the proposed method was an effective analytical tool and would be a useful method for the determination of such pollutants.


This chapter provides a principled introduction to uncertainty relations underlying sparse signal recovery. We start with the seminal work by Donoho and Stark, 1989, which defines uncertainty relations as upper bounds on the operator norm of the band-limitation operator followed by the time-limitation operator, generalize this theory to arbitrary pairs of operators, and then develop—out of this generalization—the coherence-based uncertainty relations due to Elad and Bruckstein, 2002, as well as uncertainty relations in terms of concentration of 1-norm or 2-norm. The theory is completed with the recently discovered settheoretic uncertainty relations which lead to best possible recovery thresholds in terms of a general measure of parsimony, namely Minkowski dimension. We also elaborate on the remarkable connection between uncertainty relations and the "large sieve", a family of inequalities developed in analytic number theory. It is finally shown how uncertainty relations allow to establish fundamental limits of practical signal recovery problems such as inpainting, declipping, superresolution, and denoising of signals corrupted by impulse noise or narrowband interference. Detailed proofs are provided throughout the chapter.


Obstructive sleep apnea syndrome (OSAS) is a phenomenon of repeated, episodic reduction, or cessation of airflow (hypopnea/apnea) as a result of upper airways obstruction. First-line treatment in younger children is adenotonsillectomy, although other available treatment options in middle-aged adults include continuous positive airways pressure (CPAP) and airway adjuncts. Oral appliances (OA) are a viable treatment alternative in patients with OSAS. The objective of this study was to assess, in a 1-year follow-up study, an OA in OSAS patients. The participants were subjected to polysomnographic examination with a validated device (MicroMESAM). Eight participants were fitted with a Thornton Adjustable Positioner (TAP). The participants were asked to wear the test appliance for 7 nights, and in case of compliance, for 6 months. The selected patients record their usage of the appliance and any adverse effects in a treatment journal. The research focused on the following outcomes: sleep apnea (i.e. reduction in the apnea/hypopnea index) and the effect of oral appliances on daytime function. In conclusion, the results suggest that OA have a definite role in the treatment of snoring and sleep apnea.


Autotransplantation of teeth is one of the possibilities to
substitute the missing teeth in the dental arch. In comparison
with prosthetic dentistry and implantology, autogenous
transplantation is the most natural way of tooth replacement.
Although success and advantages are prevailing, there are some
complications like ankylosis or inflammation, which have to be
solved. To understand regenerative processes after
autotransplantations, several animal models and
histological/molecular methods have been established. We review
recent achievements in autotransplantation techniques with
using animal models and the evaluation of advantages and
disadvantages of their using as showed also in our experiments.
The most common laboratory animals used in autotransplantation
research are mice and rats. Despite the monophyodont dentition
and reduced dental formula together with hypsodont incisors and
toothless diastema, numerous findings can be successfully
extrapolated from rodents to humans. Various parameters of
successful autotransplantation such as periodontal tissue
regeneration, reinnervation or revascularisation have already
been proved in the mouse. The autotransplantation of teeth
currently has a firm place in the field of dentistry because of
preserving the physiological properties of teeth, periodontal
and alveolar bone.


During endochondral bone formation, hypertrophic chondrocytes initiate synthesis of type X collagen. Previous studies have shown that regulation of this molecule is at the level of transcription. To further explore this regulation, we have studied a segment of the type X collagen gene extending from 562 base pairs (bp) upstream to 86 bp downstream of the transcriptional start site. We have studied this "proximal promoter region" by both structural analysis by DNase I in vivo footprinting and functional analysis by transient transfections. In type X collagen-expressing, hypertrophic chondrocytes, in vivo footprinting detected a fully protected TATA region flanked by hypersensitive sites but no other major protection. Type X collagen-negative cells (nonhypertrophic chondrocytes and tendon fibroblasts) showed major protection at a number of other sites, most notably an 8-bp region overlapping an AP2 site and a 9-bp region including the sequence CACACA. The importance of the proximal promoter region in restricting expression of type X collagen to hypertrophic chondrocytes was supported by transfection studies. A chloramphenicol acetyltransferase construct containing this region directed 5-10-fold higher chloramphenicol acetyltransferase expression in hypertrophic chondrocytes than in the other cell types. A 2.6-kilobase upstream fragment produced no additional effect. Thus, the proximal promoter region contains at least some regulatory elements for the cell-specific expression of type X collagen.


In this paper, we concentrate on the problem of finding the viewpoint that best satisfies a set of visual composition properties, often referred to as Virtual Camera or Viewpoint Composition. Previous approaches in the literature, which are based on general optimization solvers, are limited in their practical applicability because of unsuitable computation times and limited experimental analysis. To bring performances much closer to the needs of interactive applications, we introduce novel ways to define visual properties, evaluate their satisfaction, and initialize the search for optimal viewpoints, and test them in several problems under various time budgets, quantifying also, for the first time in the domain, the importance of tuning the parameters that control the behavior of the solving process. While our solver, as others in the literature, is based on Particle Swarm Optimization, our contributions could be applied to any stochastic search process that solves through many viewpoint evaluations, such as the genetic algorithms employed by other papers in the literature. The complete source code of our approach, together with the scenes and problems we have employed, can be downloaded from https://bitbucket.org/rranon/smart-viewpoint-computation-lib.


The pervasiveness of cell phones among young people has made them an ideal platform to cater educational content informally (anywhere, anytime). Although there are a large number of mobile learning tools, educational games provide an adequate compromise between educational content and games that makes the informal educational exploration more enjoyable and engaging. However, most educational games for cell phones are created by software developers as complex software packages which require software engineering knowledge to be modified or customized as needed. In this paper, we propose a system where games are created by game designers and educational contents by teachers, and both are brought together in a seamless manner. This novel approach facilitates the use of educational games without the need of programming skills and guarantees that teachers can easily create the educational contents that go into the mobile games.


Vibrio cholerae serogroup O1 and O139 cause cholera outbreaks globally. The O1 serogroup consists of classical and El Tor biotypes, which cause the fifth, sixth and seventh cholera pandemic. More recently, the sporadic Matlab variant of O1 strain that possess both the classical and El Tor biotype characteristics was found to be emerging. The hybrid and variant strains have been reported to cause cholera outbreaks in India, Pakistan, and Bangladesh, then recently in Kelantan, Malaysia. These hybrid and variant biotypes could be misidentified as El Tor biotype due to their combined characteristics of both the El Tor and classical biotypes. Therefore, this study aimed to characterise and re-identify the biotypes of forty-four V. cholerae O1 El Tor clinical isolates from different outbreaks in Sabah(n=27), Sarawak (n=15) and Klang (n=2) from year 2009 to 2012. The isolates were subjected to phenotypic and genotypic tests for determination of their biotype and genetic characteristics. In order to identify the phenotypic characteristics of these clinical V. cholerae O1 isolates, polymyxin B susceptibility test, Voges-Proskauer test, haemolysis test, and chicken blood cell agglutination test were performed. The presence of genes of tcpA, ctxA, ctxB, hlyA, rtxC, and rstC in the isolates were detected using PCR approach. The results showed that 42 out of the 44 (95%) V. cholerae O1 clinical isolates tested in this study possess all the six genes tested. Both of the isolates from Klang lacked the rstC gene. Notably, based on the phenotypic characteristics and ctxB gene sequence, all of the V. cholerae O1 outbreak clinical isolates examined in this study, which were previously identified as El Tor biotype, was re-identified as either belongs to hybrid or variant biotype. Of the 44 isolates examined, 13 (30%) isolates were classified as the hybrid biotype; while 31 (70%) isolates were identified to be the variant biotype. DNA fingerprinting using REP-PCR was also carried out to determine the relationship among the V. cholerae O1 clinical isolates in this study. Based on the results, four REP profiles (REP 1, REP 2, REP 3 and REP 4) were observed based on the dendrogram generated. REP 1 and REP 2 groups were predominant while the two strains of O139 serogroup demonstrated a distinct profile (REP 4). In conclusion, all of the forty-four V. cholerae clinical isolates from cholera outbreaks occurred in Sarawak, Sabah and Klang in year 2009 to 2012 were not of the typical 7th pandemic El Tor biotype but demonstrated the characteristics of the variant or hybrid biotype, which were reported to be emerging. The isolates causing cholera outbreaks in Sarawak and Sabah were found to be genetically close and demonstrated limited genetic variation based on the REP-PCR genotyping.


Introduction: Recently, analyses of large heterogeneous databases have suggested
that there are no differences whether "lipid panels" are drawn in the fed or
fasted state, even in diabetic individuals. Whether this is true for individual
diabetic patients is unknown. Methods: We studied eight type 2 diabetic individuals and measured serial lipid panels
to determine the effect of a large lunch meal. A "Big Mac" equivalent meal was
fed to each volunteer and blood for lipid assays was obtained at baseline and
hourly for five hours following the meal. Results: The meal induced a significant elevation of glucose, insulin, and c-peptide
in each volunteer. In addition, the following lipid parameters significantly
changed from baseline concentration during the meal: total cholesterol, non-HDL
cholesterol, LDL-cholesterol and triglycerides. Furthermore, the timing of the
blood draw post meal also was a determinant of the lipid concentration. No
significant concentration change occurred in HDL-cholesterol. Conclusions: In type 2 diabetic
patients, lipid panels should be drawn in the fasting state unless the only
lipid parameter of interest is HDL-cholesterol.


Climate change creates challenges for wild species, but plants have survived and adapted to similar changes in their evolutionary past. Most plants were originally outcrossing, one theoretical genetic reason being that self-fertilization does not create novel recombinants that allow adaptation. Thus selfing seems an evolutionary "dead end". Nevertheless, self-fertilizing plants make up 14% of seed plant species. We offer a new interpretation of a response by self-fertilizing wild species to extreme existential threats, which creates novel recombinant progeny. This proposed mechanism goes beyond reproductive assurance, the usual explanation of selfing. Extreme stress, such as excessive heat within a specific window, first makes plants male-sterile, while female organs remain functional and can receive wind-borne pollen from any of the few nearby stress-tolerant individuals. Thus stress-induced male sterility enables and/or enhances outcrossing in selfing plants. Although in practice this proposed mechanism requires very special circumstances and operates only in certain species with conducive floral traits, we posit that over evolutionary time even such rare events can make a significant lasting impact on a species' survival in changing conditions. This proposed mechanism, which we call Diversity Assurance, allows a population subject to severe stress to sample preferentially those genes that underpin tolerance to that specific stress. These genes are then recombined in subsequent generations, along with the male-sterility-under-stress trait of the female parent. This contributes in part to explain the effective evolution and hence persistence of self-fertilizing species. Diversity Assurance, we propose, is an adaptive mechanism that has been selected under extreme stress, underpinned by a simple loss-of-function of the male reproductive system. It may be triggered not only by heat, but also by other stressors. This proposed mechanism helps to explain why even highly self-fertilizing plant species remain able to respond to environmental changes through triggered outcrossing.


1. Choline- and inositol-labelled phospholipids of human cultured lymphocytes turn over in a biphasic manner; phytohaemagglutinin activation stimulates turnover. 2. Choline-labelled phospholipids of rat liver and kidney, but not of blood, turn over in vivo as fast as those of duodenum, ileum or colon. Turnover in the intestinal tissues is greater in fed than in starved or vitamin A-deficient rats. In each case phosphatidylcholine turns over relatively faster than sphingomyelin or lyso-phosphatidylcholine. 3. It is concluded that phospholipid turnover of the type described is a common feature of viable cells, and that metabolically favourable conditions increase, rather than decrease, turnover.


In the fifty years since the Holocaust, the Jewish People have felt one overriding concern: survival. The ghosts of the murdered six million, along with the living generation of survivors, have called out the unifying chant, "never again." In 1948, this concern found a second focus in the state of Israel, the ultimate refuge of Jews worldwide. But Rabbi Michael Goldberg finds that these twin pillars of Jewish identity are brittle, and have already begun to crumble; they will not be enough to support or sustain the next generation. The time has come to answer the question: Why should Jews survive? In this provocative book, Goldberg launches a bold attack on what he calls the "Holocaust cult," challenging Jews to return to a deeper, richer sense of purpose. He argues that this cult-with shrines like the U.S. Holocaust Museum, high priests such as Elie Wiesel, and rites like UJA death camp pilgrimages-is deeply destructive of Jewish identity. As the current "master story" of Judaism, Goldberg writes, the Holocaust has been used to depict Jews as uniquely victimized in human history-transforming them from God's chosen to those who manage to survive despite God's silent complicity in their persecution. This Holocaust-centered, survival-for-survival's-sake Judaism is already showing its emptiness, Goldberg contends; the generation that survived Hitler and founded Israel is dying, and the new generation seems adrift (for instance, one recent survey predicts that 70% of American Jewish marriages will be intermarriages by the turn of the century). Jews need positive reasons for remaining Jewish, he argues; they need to return to the Exodus as their master story-the story of God leading the Jews out of slavery and making with them an eternal covenant that gave the Jews a unique place in God's plan. The Jews should survive, Goldberg concludes, because they are the linchpin in God's redemption of the world. Rabbi Michael Goldberg has long wrestled with the crisis of identity facing today's Jewish community. In Why Should Jews Survive?, he provides a provocative and powerfully argued challenge to the dominant theme of modern Jewish thought.


Co-occurrence of winter-deciduous and evergreen oaks is common in some Mediterranean-type climate areas. However, whether these species show an overlap in their regeneration niche is still poorly understood. We explored experimentally the changes in survival, growth, biomass partitioning, leaf nitrogen content, and water use efficiency ( δ 13 C) in seedlings of a deciduous oak ( Quercus cerrioides) and an evergreen oak ( Quercus ilex) in response to co-variation in light and water availability. Quercus cerrioides exhibited higher root length, root area, leaf nitrogen content, and less negative δ 13 C, but lower leafiness than Q. ilex. The interaction between species and light in specific leaf area and root-shoot ratio indicated different mechanisms to overcome water stress in the two oaks, with Q. ilex relying on leaf hardening and Q. cerrioides relying on a high root-shoot ratiothe two species showed similar survival and growth in most of the light-water gradient. Ecological inference of these results indicates that seedlings of these species have a similar ability to cope with variations in light and water in spite of their contrasting leaf habit. This similar performance suggests a competi tion for similar micro-sites during establishment, rather than a partitioning of the regeneration niche.


The bursts and multiplicity of Internet advertising have made multichannel attribution an immediate challenge for marketing practitioners. Existing attribution models predominantly focus on analyzing consumers' conversion paths with respect to one focal firm while largely overlooking the impact of their interactions with competing firms, leading to biased estimates of advertising effectiveness. We address this problem by developing an integrated individual-level choice model that considers consumers' online visit and purchase decisions across all competitors within one industry. We specifically analyze the effects of multichannel advertising on (1) consumer choice of entry site, (2) consumer search decisions concerning the remaining competing websites, and (3) subsequent purchase at one of the searched websites. We quantify the impact of different digital advertising channels on consumers' decisions at different purchase funnel stages based on individual-level click stream data from the online air ticket booking industry. We find that information stock of all online channels considered—search, display/referral, email, direct—contributes significantly to consumers' visit and purchase decisions, among which search is the most effective advertising channel in driving all three decisions. We map the estimates to the conversion attribution of different channels. The result reveals that the relative contribution of the display/referral channel was underestimated under the popular single-firm attribution models by a factor of two on average. In terms of predictive performance, our model consistently outperforms the single-firm model in predicting the occurrences of future purchases.


Christianity has understood the environment as a gift to nurture and steward, a book of divine revelation disclosing the divine mind, a wild garden in need of cultivation and betterment, and as a resource for the creation of a new Eden. This Cambridge Companion details how Christianity, one of the world's most important religions, has shaped one of the existential issues of our age, the environment. Engaging with contemporary issues, including gender, traditional knowledge, and enchantment, it brings together the work of international scholars on the subject of Christianity and the Environment from a diversity of fields. Together, their work offers a comprehensive guide to the complex relationship between Christianity and the environment that moves beyond disciplinary boundaries. To do this, the volume explains the key concepts concerning Christianity and the environment, outlines the historical development of this relationship from antiquity to the present, and explores important contemporary issues.


In this paper, we propose a flexible method for probabilistic modeling with conditional quantile functions using monotonic regression splines. The shape of the spline is parameterized by a neural network whose parameters are learned by minimizing the continuous ranked probability score. Within this framework, we propose a method for probabilistic time series forecasting, which combines the modeling capacity of recurrent neural networks with the flexibility of a spline-based representation of the output distribution. Unlike methods based on parametric probability density functions and maximum likelihood estimation, the proposed method can flexibly adapt to different output distributions without manual intervention.
We empirically demonstrate the effectiveness of the approach
on synthetic and real-world data sets.


This dissertation examines the history of work in the Dutch East India Company (VOC) and the English East India Company (EIC) settlements in Bengal between 1650 and 1757. By 1650, both companies had firmly established trading networks in Bengal, and by the early years of the eighteenth century, the profitability of trade in Bengal had become very clear to both companies. The volume and value of trade grew steadily until 1757, when the EIC defeated the Nawab of Bengal, Siraj-ud-Daulah, at the Battle of Plassey, thereby inaugurating direct colonial conquest of the region. During this period of trade, when neither company had political sway over the region and very little intrusion into the producing hinterland, they employed hundreds, sometimes thousands, of workers each year. How did these corporate entities manage labor in time and place, where their political control over workers was severely challenged? To answer this question, this dissertation specifically looks at workers who were directly employed by the companies. In doing so, it brings to light the lives and work of laboring people–boatmen, cartmen, coolies, silk reelers, slaves, sailors and soldiers—thus far ignored by social and economic historians of South Asia and the Indian Ocean. Most importantly, it reveals a world of work marked by the workers' assertion of their right to mobility and "customary" payments. By emphasizing workers' agency, I argue that the European companies' control over the workers was far from total. Building on the rich body of work on the economic, social and labor histories of Mughal India and the Indian Ocean, this work proposes to shift the focus of eighteenth-century South Asian history from economic histories of trade and the history of both European and Asian mercantile and political elites to the social history of working people. It also brings labor history into the pre-colonial history of South Asia.


PURPOSE
This study's purposes were to: evaluate the antibacterial effect of chemomechanical instrumentation and a calcium hydroxide-based dressing in primary teeth with pulp necrosis secondary to trauma; and detect the presence of Fusobacterium nucleatum and black-pigmented rods in the canals of these teeth.

METHODS
Microbiological sample collections (MSCs) were obtained: after coronal access to the canals of primary incisors (in 18 teeth; MSC 1); after chemomechanical instrumentation (in 10 teeth; MSC 2); and 72 hours after removal of intracanal medication (in 18 teeth; MSC 3). These samples were sent for microbiological processing. The results were analyzed statistically via chi-square, analysis of variance, and Games-Howell tests (P<.05).

RESULTS
Micro-organisms were isolated in approximately 94%, 10%, and 83% of canals, respectively, in MSCs 1, 2, and 3. There was a statistically significant difference only between MSCs 1 and 2 (P<.03). F nucleatum and black-pigmented rods were detected in approximately 56% and 11% of canals in MSC 1, respectively.

CONCLUSION
Chemomechanical instrumentation and calcium hydroxide-based dressing have an anti-bacterial effect by significantly reducing the number of micro-organisms in the main root canal. They showed a limited efficacy, however, and did not prevent bacterial regrowth after endodontic therapy in primary teeth with pulp necrosis secondary to trauma.


In this study, we give special Smarandache curves according to the Sabban frame in hyperbolic space and new Smarandache partners in de Sitter space. The existence of duality between Smarandache curves in hyperbolic and de Sitter spaces is obtained. We also describe how we can draw pictures of Smarandache partners in de Sitter space of a curve in hyperbolic space. Finally, two examples are given to illustrate our main results.


This paper intends to explore the emergence of the Norman ethnicity during the first three generations of their settlement in Francia. Primarily through analysis of the Gesta Normannorum of Dudo of St. Quentin, the paper will track the deliberate measures that the early rulers of Normandy underwent in order to forge an intermediary ethnic identity which embodied both their Scandinavian heritage as well as embracing their Frankish present. By combining elements of both of these ethnic identities, the Normans created an ethnicity uniquely their own and were thus able to survive and thrive in their new homeland.


Approximately one in three adults 65 years and older fall each year and these falls lead to a substantial number of serious injuries and deaths. Numerous interventions have been proposed for fall-prevention but the efficacy can vary, and may be due to the general nature of the interventions. Older adults may be able to improve their ability to recover from a postural perturbation through perturbation-based balance training (PBBT), similar to the way other motor skills can be improved through training. The purpose of the first study was to investigate the effects of age and fall risk on the efficacy of PBBT. Participants (young adults, older adults at low-risk of falling, older adults at high-risk of falling) completed PBBT on a moving platform three times a week for one month. Balance was quantified using the time to stabilization of the COP and normalized to platform displacement (nTTS), where a decrease in nTTS can be interpreted as an improvement in balance. A significant main effect of group revealed high-risk fallers had a significantly higher nTTS than young adults and a significan main effect of session revealed nTTS was significantly lower one week and one month posttraining than before training. The purpose of the second study was to investigate the effect of training amount on the efficacy of PBBT in older adults. Ten healthy older adults completed PBBT either three times a week or five times a week for four weeks. Both training amounts were sufficient for significant improvements in nTTS one week after training. However, training five times a week was necessary for older adults to maintain improvements in nTTS one month post training.


We consider a binary hypothesis testing problem using wireless sensor networks (WSNs). The decision is made by a fusion center and is based on received data from the sensors. We focus on a spectrum and energy efficient transmission scheme used to reduce the spectrum usage and energy consumption during the detection task. We propose a spectrum and energy efficient multiple access (SEEMA) transmission protocol that performs a censoring-type transmission based on the density of observations using multiple access channels (MAC). Specifically, in SEEMA, only sensors with highly informative observations transmit their data in each data collection. The sensors transmit a common shaping waveform and the fusion center receives a superposition of the analog transmitted signals. SEEMA has important advantages for detection tasks in WSNs. First, it is highly energy and bandwidth efficient due to transmission savings and narrowband transmission over MAC. Second, it can be implemented by simple dumb sensors (oblivious to observation statistics, and local data processing is not required), which simplifies the implementation as compared to existing MAC transmission schemes for detection in WSNs. We establish a finite sample analysis and an asymptotic analysis of the error probability with respect to the network size and provide system design conditions to obtain the exponential decay of the error. Specific performance analysis is developed for common non-i.i.d. observation scenarios, including local i.i.d. observations, and Markovian correlated observations. Numerical examples demonstrate SEEMA performance.


【Objectives : To identify the risk factors of dementia among the elderly in a large city. Methods : A cross-sectional study was conducted in July 2001, with potential participants selected by stratified two stage cluster sampling of the elderly population of Keumgog dong, Busan. A total of 452 elderly people aged 65 years and over, underwent a two phase diagnostic procedure. Mini-mental State Examination-Korean (MMSE-K) and Samsung Dementia Questionnaire were used for the 1st stage, and the Clinical Dementia Rating Scale (CDR), the Bartel ADL, and IADL Index, the Korean Geriatric Depression Scale (KGDS), the Modified Hatchinski Ischemic Scale (MHIS), and other laboratory tests were used for the 2nd stage. Results : Of the 446 participants finally chosen, 45 were confirmed with dementia, and 363 as normal, with the rests not confirmed with dementia or as normal, were excluded from the analysis. According to the logistic regression analysis, the risk of dementia was significantly higher In: people aged 80 and above (OR=4.36, 95% CI=1.97-9.62), illiterate (OR=3.58, 95% CI=1.71-7.46), who had a history of strokes (OR=6.35, 95% CI=2.71-14.87), or who had 3 history of hyperlipidemia (OR=4.74, 95% CI=1.65-13.61), compared to their counterparts. Conclusions : These results suggest that efforts to prevent strokes and hyperlipidemia can significantly decrease the risk of dementia.】


Neprilysin (NEP), which degrades amyloid‐β (Aβ), is expressed by neurons and cerebrovascular smooth muscle cells (CVSMCs). NEP immunolabeling is reduced within cerebral blood vessels of Alzheimer's disease (AD) patients with cerebral amyloid angiopathy (CAA). We have now measured NEP enzyme activity in leptomeningeal and purified cerebral cortical blood vessel preparations from control and AD patients with and without CAA. Measurements were adjusted for smooth muscle actin (SMA) to control for variations in CVSMC content. NEP activity was reduced in CAA, in both controls and AD. In leptomeningeal vessels, NEP activity was related to APOE genotype, being highest in ε2‐positive and lowest in ε4‐positive brains. To assess the role of NEP in protecting CVSMCs from Aβ toxicity, we measured cell death in primary human adult CVSMCs exposed to Aβ1‐40, Aβ1‐42 or Aβ1‐40(Dutch variant). Aβ1‐42 was most cytotoxic to CVSMCs. Aβ1‐42‐mediated cell death was increased following siRNA‐mediated knockdown or thiorphan‐mediated inhibition of NEP activity; conversely Aβ1‐42‐mediated cytotoxicity was reduced by the addition of somatostatin and NEP over‐expression following transfection with NEP cDNA. Our findings suggest that NEP protects CVSMCs from Aβ toxicity and protects cerebral blood vessels from the development and complications of CAA.


In 2001, the newly elected government announced a wide reform of corporate taxation: the Dual income tax system enacted in 1997 by the previous government was greatly limited in its beneficial effects and should be abolished in favour of a single tax rate regime. In the meantime, the existing system of temporary incentives to investment was prolonged, but radically changed. A major difference is that the new incentive is not conditional upon the financing behaviour of companies. Under the new policy course the neutrality of the tax system between debt and equity finance does not seem to be considered an important issue. The emphasis is on the reduction of the overall tax burden on profits. This paper uses the micromodel of corporate taxation MATIS, and data from the balance sheets of a panel of manufacturing companies, to evaluate the possible impact of these recent tax reforms on firms' cash flow. The results show that the new tax policy is not so clearly superior to the one followed by the previous government in reducing the overall tax burden on companies, and will even be worse, in perspective, when comparing the Dual income tax system with the announced uniform tax rate of 33%.


Based on the static test of large-scaled prestressed steel concrete frames, the behavior of crack were tested and investigated. In this paper, according to theory of reinforced concrete members, Code for design of concrete structures(GB 50010-2002)and code ACI 318—05, the formulas of cracking moment considering secondary axial forces were deduced and verified by test results. Conclusion can be drawn as follow: the calculation errors of formulas derive from theory of reinforced concrete members is small, generally less than 6%; the errors of formulas referring to Code for design of concrete structures(GB 50010-2002)is about 10%, which is satisfy the needs of engineering and simply to be calculated; Cracking moment calculated by formulas referring to code ACI 318—05 is less than test result, it is unsafe for engineering application.


This paper considers phenomenological descriptions of health in Gadamer, Heidegger, Merleau-Ponty, and Svenaeus. In these phenomenologies of health, health is understood as a tacit, background state that permits not only normal functioning but also philosophical reflection. Nietzsche's model of health as a state of intensity that is intimately connected to illness and suffering is then offered as a rejoinder. Nietzsche's model includes a more complex view of suffering and pain as integrally tied to health, and its language opens up the possibility of many "healths," providing important theoretical support to phenomenological accounts of the diversity and complexity of health and illness.


The Nance palatal arch is considered a useful means of maintaining arch length and reinforcing anchorage control in the orthodontic patient. Difficulty with oral hygiene around the Nance arch and inflammation and bunching of the gingivae under the acrylic fitting surface are common problems associated with this appliance. We present a case of alveolar bone loss and gingival recession around the palatal root surfaces of the upper incisor teeth following use of Nance palatal arch. A possible cause for this is explored and management of the patient after the Nance arch was removed is discussed.


We analyse the evolution of emerging market loan spreads at a more disaggregated level than other current studies, providing statistical support to the assumption of the "speciality" of the international interbank market, to the extent that the pricing of interbank credit is insensitive to the nature (public or private) of the borrower. In sharp contrast, the public or private nature of other borrowers, such as corporates or financial firms, causes significant differences in spreads. These results could be interpreted as evidence of the possible role played by implicit government guarantees in the international interbank market, which lower the incentives for participants to monitor counterpart risk very closely. Furthermore, the specificity of banks is witnessed by the fact that only spreads on loans to emerging market banks clearly declined following the 1995 Mexican bailout, whereas evidence on the pricing of lending to corporates and financial firms is more ambiguous. Although, on the one hand, this might support the view that financial assistance from the IMF gives rise to moral hazard, on the other hand, contrary to expectations, spreads on loans to Asian banks, the major candidates in the current policy debate on moral hazard, have been unaffected by the IMF's response to Mexico's crisis. JEL classification: F21, F20.


The P2X1 receptor-channels activated by extracellular ATP contribute to the neurogenic component of smooth muscle contraction in vascular beds and genitourinary tracts of rodents and humans. In the present study, we investigated the interactions of plasma membrane phosphoinositides with P2X1 ATP receptors and their physiological consequences. In an isolated rat mesenteric artery preparation, we observed a strong inhibition of P2X1-mediated constrictive responses by depletion of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] with the phosphatidylinositol 4-kinase inhibitor wortmannin. Using the Xenopus laevis oocyte expression system, we provided electrophysiological evidence that lowering PI(4,5)P2 levels with wortmannin significantly decreases P2X1 current amplitude and recovery. Previously reported modulation of recovery of desensitized P2X1 currents by phospholipase C-coupled 5-hydroxytryptamine2A metabotropic receptors was also found to be wortmannin-sensitive. Treatment with wortmannin alters the kinetics of P2X1 activation and inactivation without changing its sensitivity to ATP. The functional impact of wortmannin on P2X1 currents could be reversed by addition of intracellular PI(4,5)P2, but not phosphatidylinositol 3,4,5-trisphosphate, and direct application of PI(4,5)P2 to excised inside-out macropatches rescued P2X1 currents from rundown. We showed that the proximal region of the intracellular C terminus of P2X1 subunit directly binds to PI(4,5)P2 and other anionic phospholipids, and we identified the basic residue Lys364 as a critical determinant for phospholipid binding and sensitivity to wortmannin. Overall, these results indicate that PI(4,5)P2 plays a key role in the expression of full native and heterologous P2X1 function by regulating the amplitude, recovery, and kinetics of ionotropic ATP responses through direct receptor-lipid interactions.


This article examines men's use of physical punishment when interacting with their sons or grandsons in rural Vietnam. By drawing on two periods of anthropological fieldwork in a northern Vietnamese commune, the article analyses the ways in which violence is informed by, while also perpetually reinforcing, a masculine discourse. Vietnam has ratified the Convention on the Rights of the Child and in this spirit virtually all men in the local community disapprove of the use of physical punishment when bringing up boys. However, a father or grandfather occasionally beats his son or grandson when it is deemed necessary to instil discipline in a boy. The article elucidates the ways in which the contradictions between ideals of nonviolent behaviour and actual corporal punishment have fed the construction of certain codes regarding men's beating of boys.


This paper discusses the use of subsidies for soil and water conservation (SWC) in the KRIBHCO IndoBritish Rainfed Farming Project being implemented in degraded areas of western India. The rationale for, and effects of, adopting subsidies are summarised. Although both project staff and farmers agree on the importance of SWC measures, few farmers can afford the investment of time and money. This is largely because production in the area is so low that most farmers are obliged to seek off-farm work during the dry season. As this is when most SWC work is undertaken, there is a need to offset the opportunity cost to farmers of forgoing employment opportunities in order to implement SWC activities. Benefits arising from the use of subsidies include priming of savings and credit groups and a temporary reduction in annual migration levels. Disadvantages include possible lack of equity and low levels of sustainability. The paper concludes by discussing alternative funding arrangements including loans, differential subsidies and other incentives. It suggests that for private farmland, farm households are subsidised with fixed land improvement grants (rather than paying those who participate in the SWC work). Farmers and their hamlet members should discuss how the money would best be used. A fixed subsidy per unit area is proposed for communal land improvement and when watershed management is conducted on a village basis. A village work plan, based on the funds available, would be formulated by village groups in consultation with project staff.


Liberalism as a historical phenomenon is closely articulated with the history of modern democracy. If no consensus exists about what is liberal and democratic in liberal democracies, at least there is agreement regarding the fact that liberalism is precisely the criterion which distinguishes liberal democracy from non-liberal democracies. This criterion was used by us as an orientation guide, allowing us to trace the basic assumptions of this trend of political thought and, at the same time, allowing us to identify the close ties between liberalism and democracy. The central issue discussed here concerns the conflict between freedom and power, as presented in the studies on liberal democracy. Considering such inconsistency, it was possible to understand the reasons that led Hannah Arendt to question the representative system and to deny the separation between freedom and power, as advocated by proponents of liberal democracy. Through this study it is also possible to learn, in the light of Arendt's conception, that power is intrinsically linked to public liberty and is not effective outside human action, depending, therefore, on the coexistence among men in public space. By questioning the limits and difficulties experienced by the representative system advocated by liberal democracy, we came to the realization that, as proposed by Arendt, it is possible to expand the meanings of democracy. Thus, if Arendt's fundamental concern is the decline of public space, which is vital for politics and the conduct of human affairs, her critique is the most appropriate, as it faces the apathy and conformism that characterizes mass society. The rescue and rehabilitation of the political public sphere would be the precondition to rethink the foundations of democracy and the liberal principles that sustain it. Key words: liberal democracy, representative system, freedom, power, Hannah Arendt.


Motivated by the recent opening of a public stool bank that enables fecal microbiota transplantation for the treatment of Clostridium difficile infection, we develop and optimize a mathematical model that tracks the flow of stools from donation to sales. To prevent the spread of infectious diseases, donors are periodically tested and donated stools are not released for sale until a donor passes a subsequent test; donors and their recently donated stools are permanently ejected from the system after a failed test. We choose the testing frequency and a policy for introducing new donors into the system to minimize the long-run expected average costs due to paying donors, processing and testing stools, and holding and backordering finished goods inventory. This problem is a variant of a continuous review inventory problem where items (i.e., donors) are continuously producing product and are failure-prone, and lead times are controllable. Instead of using approximate dynamic programming to deal with the unwieldy size of the state space, we apply heavy traffic results for multiclass infinite-server queues to approximately optimize within a specified class of base-stock policies, which maintains the expected inventory position at a constant level. This policy outperforms a policy that maintains a constant number of donors. Key Words— stochastic inventory theory; heavy traffic approximations, controllable lead times, fecal microbiota transplantation


Splicing of pre messenger RNA (pre mRNA) is catalyzed by the spliceosome, a multimegadalton ribonucleoprotein (RNP) comprising several small nuclear (sn) RNPs and numerous proteins. The spliceosome assembles on its pre mRNA substrate in an ordered process that begins with recognition of the 5' end of the intron (5' splice site, 5'SS) by the U1 snRNP. Thereafter the U2 snRNP binds to the pre mRNA's branch point sequence (BPS), forming complex A. Complex A then binds the pre-formed U4/U6•U5 tri snRNP to form complex B, which contains a full set of snRNAs in a pre-catalytic state. Complex B is then activated for catalysis by a major rearrangement of its RNA network and its overall structure; this remodeling includes dissociation of the U1 and U4 snRNAs and the formation of the activated spliceosome Bact. In the catalytically activated complex (termed B*) step 1 catalysis takes place: the adenosine at the BPS attacks the 5'SS, generating a cleaved 5' exon and intron 3' exon intermediate. The resulting complex C then catalyzes step 2 catalysis, in which the intron is cleaved at the 3' splice site (3'SS) with concomitant ligation of the 5' and 3' exons to form mature mRNA. Thus, the spliceosome is a particularly dynamic RNP machine that undergoes many changes in composition and conformation. The structural dynamics of the spliceosome are facilitated by the action of multiple DExD/H box RNA helicases. Among these are Prp5 and Prp2, which are essential ATPase required prior to the first step of pre-mRNA splicing. Prp5 enables stable U2 snRNP association with the branch site and Prp2 promotes a structural rearrangement that transforms the Bact into the catalytically activated B* complex.
The pathway of spliceosome assembly and the main features of its catalytic chemistry appear to be conserved between metazoans and yeast. Thus, I set out to study isolated spliceosomal complexes from the lower eukaryote Saccharomyces cerevisiae as it was already known to possess a basic (constitutive) spliceosomal machinery similar to that of primates. Each new round of splicing generates a catalytic centre de novo during the transitions from complex B to Bact to B* and to the product of step 1 of splicing, complex C. Here, I focused on the isolation and characterization of complex B, the activated complex Bact and complex C. Each complex was stalled via truncation or modification of the actin pre-mRNA used during the splicing reaction or adjustment of the ATP concentration in the splicing reaction. Each complex was then isolated by centrifugation and affinity selection, their proteomes determined by mass spectrometry (in collaboration with Prof. Henning Urlaub) and their structures examined by electron microscopy (in collaboration with Dr. Berthold Kastner and Prof. Holger Stark), for the first time. The analysis of the three stalled yeast spliceosomal "snapshots" isolated here has made it possible to pinpoint the window of function for important spliceosomal proteins. For instance, the number, characteristics and time of recruitment of evolutionarily conserved proteins involved in the formation and stabilization of the U2/U6/pre-mRNA network of the catalytic center in complex Bact remained so far elusive. The data revealed several evolutionarily conserved proteins recruited at the time of pre-catalytic activation (i.e. Cwc2, Cwc24, Yju2, Prp2 and Spp2) and also provided important hints for those proteins involved in promoting step 1 catalysis and the formation of complex C (i.e. Cwc25). Compared to metazoan spliceosomes the number of proteins associated with purified yeast spliceosomes at any stage is less than a half, yet more than 85% of these have evolutionarily conserved counterpart in humans. The less complex protein composition of yeast spliceosomes offers also a significant advantage for three dimensional (3D) structure analyses. The EM analyses show for the first time images of S. cerevisiae spliceosomal complexes at well defined stages of function. These are at an unprecedented quality level, and they are well suited for 3D structure investigations, based on criteria such as their structural integrity and homogeneity.
In this work I have also applied dual-color fluorescence cross-correlation spectroscopy (dcFCCS, in collaboration with Prof. Jorg Enderlein, III. Institute of Physics, University of Gottingen), to measure the binding affinity of splicing factors – which were detected in the first part of this work – to the yeast spliceosome and to follow their binding dynamics during the catalytic activation of the spliceosome promoted by the RNA helicase/ATPase Prp2 and its co-activator Spp2. dcFCCS is a sensitive and versatile optical technique that allows the direct analysis of the dynamic association and dissociation events among proteins and/or RNAs in complex systems in solution at low nanomolar concentrations and in equilibrium, without requiring biochemical or physical perturbation of the sample. For this purpose I have employed a recently described purified splicing system developed in our laboratory which recapitulate catalytic activation and step 1 of splicing in vitro and consists of Bact complexes assembled in extracts where Prp2 is thermo sensitive and can be heat-inactivated. These Bact complexes lacking Prp2 are then purified to near homogeneity and complemented with recombinantly expressed Prp2 and Spp2 splicing factors. To perform dcFCCS, the Bact complexes were assembled on pre mRNA labeled with a red fluorescent dye. In addition, spliceosomal proteins of interest were labeled in vivo by fusing them with the green fluorescent protein EGFP, by genetic modification in yeast. The purified doubly-labelled spliceosomes were then analyzed before and after catalytic activation by Prp2 and the weakening or strengthening of the binding of the EGFP-labeled protein to the spliceosome was analyzed by measuring the cross-correlation between the green label and the red fluorescent dye. The analysis and evaluation of the dcFCCS data in this work was done in collaboration with Prof. Jorg Enderlein and Mira Prior (III. Institute of Physics, University of Gottingen).
 The data revealed that the binding affinity of quite a number of proteins is significantly changed during the Prp2-mediated catalytic activation of the spliceosome. Specifically, the essential zinc finger protein Cwc24, was quantitatively displaced from the B* complex. Consistent with this, we show that Cwc24 is required for step 1 but not for catalysis per se. Interestingly, the U2-associated SF3a and SF3b proteins Prp11 and Cus1 were destabilized during catalytic activation. Indeed, they remained bound to the B* spliceosome under near-physiological conditions (i.e. 75 mM), but their binding was reduced at higher salt. As the U2 SF3a/b proteins bind near the branch point sequence, this indicated that the branch site must be remodeled in complex B* as a prerequisite for step 1 catalysis. On the other hand, high affinity binding sites were created for the step 1 factors Yju2 and Cwc25 during catalytic activation, consistent with their requirement for step 1 catalysis. In conclusion, These results shed light on the nature of the structural remodeling mediated by Prp2 in the spliceosome and suggest that during catalytic activation the spliceosome undergoes significant rearrangements.