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Abstract: Background: Evidence of benefits of laparoscopic and laparoscopic-assisted colectomies (LAC) over open procedures in gastrointestinal surgery has continued to accumulate. With its wide implementation, technical difficulties and limitations of LAC have become clear. Hand-assisted laparoscopic surgery (HALS) was introduced in an attempt to facilitate the transition from open techniques to minimally invasive procedures. Continuing debate exists about which approach is to be preferred, HALS or LAC. Several studies have compared these two techniques in colorectal surgery, but no single study provided evidence which procedure is superior. Therefore, a systematic review was carried out comparing HALS with LAC colorectal resection. Methods: Eligible studies were identified from electronic databases (Medline, Embase Cochrane) and cross-reference search. The database search, quality assessment, and data extraction were independently performed by two reviewers. Minimal outcome criteria for inclusion were operating time, conversion rate, hospital stay, and morbidity. Results: Out of 468 studies a total of 13 studies were selected for comprehensive review. Two randomized controlled trials (RCT) and 11 non-RCTs, comprising 1017 patients, met the inclusion criteria. Because of possible clinical heterogeneity two groups of procedures were created: segmental colectomies and total (procto)colectomies. In the segmental colectomy group significant differences in favor of the HALS group were seen in operating time (WMD 19 min) and conversion rate (OR of 0.3 conversions). In the total (procto)colectomy group a significant difference in favor of the HALS group was seen in operating time (WMD 61 min). Conclusions: This systematic review indicates that HALS provides a more efficient segmental colectomy regarding operating time and conversion rate, particularly accounting for diverticulitis. A significant operating time advantage exists for HALS total (procto)colectomy. HALS must therefore be considered a valuable addition to the laparoscopic armamentarium to avoid conversion and speed up complicated colectomies.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGSwas developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N= 2367) and replicated in the combined PsyCourse (N= 89) and BipoLife (N= 102) studies. The associations of Li+PGSand lithium treatment response —defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P< 0.05. Li+PGSwas positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P= 9.8 × 10−12, R2= 1.9%) and continuous (P= 6.4 × 10−9, R2= 2.6%) outcomes. Compared to bipolar patients in the 1stdecile of the risk distribution, individuals in the 10thdecile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P= 3.9 × 10−4, R2= 0.9%), but not for the continuous outcome (P= 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGSmay be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

It is important to determine the presence of different radionuclides in the environment at all times in order to control and assess the risk level they pose to the environment. Laboratory and in-situ gamma-ray spectrometry can be used for detecting, monitoring, and assessing levels of radioactivity and radiation dose rates in the environment due to both natural and artificial sources. In this study, the greatest challenge in the calibration of detectors for in-situ gamma spectrometry has been solved. Calibration factors that can be used to convert the net count rates of collected spectrum's photopeak using a portable gamma-ray spectrometer, to quantitative specific activities have been derived. Calibration pads were simulated using standard materials RGU, RGK, and RGTh from International Atomic Energy Agency (IAEA). Region of interest (ROI) were carefully determined around these photopeaks in order to obtain count rates due to each radionuclide under its reference peak. The conversion factors obtained are reliable.

Polymer membranes are widely used in separation processes including desalination1, organic solvent nanofiltration2,3and crude oil fractionation4,5. Nevertheless, direct evidence of subnanometre pores and a feasible method of manipulating their size is still challenging because of the molecular fluctuations of poorly defined voids in polymers6. Macrocycles with intrinsic cavities could potentially tackle this challenge. However, unfunctionalized macrocycles with indistinguishable reactivities tend towards disordered packing in films hundreds of nanometres thick7–9, hindering cavity interconnection and formation of through-pores. Here, we synthesized selectively functionalized macrocycles with differentiated reactivities that preferentially aligned to create well-defined pores across an ultrathin nanofilm. The ordered structure was enhanced by reducing the nanofilm thickness down to several nanometres. This orientated architecture enabled direct visualization of subnanometre macrocycle pores in the nanofilm surfaces, with the size tailored to ångström precision by varying the macrocycle identity. Aligned macrocycle membranes provided twice the methanol permeance and higher selectivity compared to disordered counterparts. Used in high-value separations, exemplified here by enriching cannabidiol oil, they achieved one order of magnitude faster ethanol transport and threefold higher enrichment than commercial state-of-the-art membranes. This approach offers a feasible strategy for creating subnanometre channels in polymer membranes, and demonstrates their potential for accurate molecular separations.

Consumer demand for new and non-traditional food items is discussed.

Banks and other financial institutions can utilize mystery shopping as an effective marketing medium. The key is to develop clear objectives for the mystery shopping program and to establish standards for evaluating personnel. It is also important to evaluate past measurement programs in terms of success, failure and method as part of program design. Other factors to consider in launching a mystery shopping program are the evaluators, survey design, evaluation schedule, program launch and presentation of results., It's an old truism: You never see yourself the way others see you - and, if you're a bank, the way others experience you. Mystery shopping puts you in your [...]

Customer service plays an essential role in meeting banking institutions' goals. With the increasing competition in the banking industry, this is an area where banks should focus on if they aim to increase their share of the market. Implementing an effective measurement program is essential to determine how customer demands can be efficiently met. Customer feedback is also important for banks to identify problem areas and develop ways to solve them., The dollar bills I get from your bank look just like the ones I can get from the bank across the street. It's the service I get from your employees [...]

The evolution of banking technology should not shift the bank management's focus away from its customers. A balance should be developed between services offered by high-tech equipment and those provided by bank employees. This balance can be achieved by considering factors such as the corporate vision, the environment, sustainable quality customer service and product exposure., Following the lead of retailers, banking has become progressively driven by technology. But despite the benefits derived from computers and telecommunications, they are only means to an end - connecting [...]

The use of specialty grains to enhance the quality of crops will continue to grow. The trend towards the use of such grains will stimulate integration among agricultural marketing firms and farms. The most significant factor that will hinder the entry of more integrated production-marketing firms will most likely be product differentiation. Existing producers of specialty grains can differentiate their products by exercising their property rights.

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Hydrogeological assessment of groundwater resources was carried out with a view to evaluate the potential of the aquifers to provide portable water supply and access the distribution of electrical parameters of hydrogeologic units in some areas in Odeda, Ogun State, Nigeria. A geophysical survey using vertical electrical sounding (VES) with the Schlumberger electrode array, with half-current electrode spacing (AB/2) varying from 1 to 132 m was carried out at 30 different stations in the study area. The VES data were interpreted qualitatively and quantitatively. Three-to-five sub-surface layers consisting of topsoil, weathered layer consisting of clay, sandy clay, clayey sand and sand layers, and fractured/fresh basement were delineated. Layer resistivities and thicknesses obtained on the curves within the study area showed one main aquifer type, which is the fractured basement. The longitudinal unit conductance (ranging from 0.049720 to 1.4520000 mhos) of the study area aided the protective capacity to be rated into good, moderate and weak. About 33% of the study area falls within the weak protective capacity, 57% falls within the moderate protective capacity and 10% falls within the good protective capacity.

In the rapidly evolving biopharmaceuticals industry, technical developments frequently outpace regulatory developments. One such area is in current good manufacturing practice (cGMP) guidelines for the manufacture of excipient sugars used [...]

In einem Gespräch blickt der Sozialarbeiter Axel Biere auf seine langjährige Tätigkeit in verschiedenen Positionen im Jugendamt Berlin zurück und skizziert dabei die Entwicklung der vergangenen rd. 35 Jahre, vor allem im ASD.

The local work function is an invaluable feature for the specific analysis of the influences of atomic and molecular nanostructures on each other as well as the underlying surface. Adsorbate molecules can modify this parameter by introducing an electrical dipole moment, which affects the local contact potential. This can be accessed by Kelvin probe force microscopy (KPFM). In this paper, we demonstrate, by combining highly resolved topographic atomic force microscopy (AFM) data with the simultaneously acquired local work function signal, how each of these channels yield one angular coordinate, resulting in the three-dimensional determination of surface molecular dipole orientations. We studied the adsorption of terphenylthiol (TPT) self-assembled monolayers on Au(111) and Ag(111), as it is relevant in the light of electron radiation-induced transformation to carbon nanomembranes. We present noncontact AFM data combined with frequency-modulated KPFM in ultrahigh vacuum at room temperature without any kind of deliberate tip functionalization. Our results show a surface coverage-dependent Langmuir-like evolution of phases with domains of flat lying as well as with upright molecular arrangements. Whereas we found an almost complete vertical orientation on silver, the orientation on gold was found to be tilted, corresponding to sp- and sp3-hybridized bond angles, respectively.

The provision of clean water is a global challenge, and membrane filtration is a key technology to address it. Conventional filtration membranes are constrained by a trade-off between permeance and selectivity. Recently, some nanostructured membranes demonstrated the ability to overcome this limitation by utilizing well-defined carbon nanoconduits that allow a coordinated passage of water molecules. The fabrication of these materials is still very challenging, but their performance inspires research toward nanofabricated membranes. This study reports on molecularly thin membranes with sub-nanometer channels that combine high water selectivity with an exceptionally high permeance. Carbon nanomembranes (CNMs) of ∼1.2 nm thickness are fabricated from terphenylthiol (TPT) monolayers. Scanning probe microscopy and transport measurements reveal that TPT CNMs consist of a dense network of sub-nanometer channels that efficiently block the passage of most gases and liquids. However, water passes through with an extremely high permeance of ∼1.1 × 10–4mol·m–2·s–1·Pa–1, as does helium, but with a ∼ 2500 times lower flux. Assuming all channels in a TPT CNM are active in mass transport, we find a single-channel permeation of ∼66 water molecules·s–1·Pa–1. This suggests that water molecules translocate fast and cooperatively through the sub-nanometer channels, similar to carbon nanotubes and membrane proteins (aquaporins). CNMs are thus scalable two-dimensional sieves that can be utilized toward energy-efficient water purification.

REIGNING BLANCPAIN ENDURANCE champion Maxi Buhk kicked off his pursuit of this year's Sprint Series crown by winning the main event in the Nogaro opener with Maxi Gotz in their [...]

Heart failure- (HF) and arrhythmia-related complications are the main causes of morbidity and mortality in patients with nonischemic dilated cardiomyopathy (NIDCM). Cardiovascular magnetic resonance (CMR) imaging is a noninvasive tool for risk stratification based on fibrosis assessment. Diffuse interstitial fibrosis in NIDCM may be a limitation for fibrosis assessment through late gadolinium enhancement (LGE), which might be overcome through quantitative T1 and extracellular volume (ECV) assessment. T1 and ECV prognostic value for arrhythmia-related events remain poorly investigated. We asked whether T1 and ECV have a prognostic value in NIDCM patients.

Model checkers and sequential equivalence checkers have become essential tools for the semiconductor industry in recent years. The Hardware Model Checking Competition (HWMCC) was founded in 2006 with the purpose of intensifying research interest in these technologies, and establishing more of a science behind them. For example, the competition provided a standardized benchmark format, a challenging and diverse set of industrially-relevant public benchmarks, and, as a consequence, a significant motivation for additional research to advance the state-of-the-art in model checkers for these verification problems. This paper provides a historical perspective, and an analysis of the tools and benchmarks submitted to the competition. It also presents a detailed analysis of the results collected in the 2014 edition of the contest, showing relations among tools, and among tools and benchmarks. It finally proposes a list of considerations, lessons learned, and hints for both future organizers and competitors.

In this paper, we discuss the most important changes and new features introduced with version 2.0 of our SMT solver Boolector, which placed first in the QF_BV and QF_ABV tracks of the SMT competition 2014. We further outline some features and techniques that were not yet described in the context of Boolector.

Banking institutions as service-oriented organizations need to put customers on top of their priority lists. It is important for banks to assess the level of their customer service performance to determine how they fare in the face of stiff market competition. Customer service measurement systems should be put in place as essential elements of banking strategies and business marketing plans. Implementing this system requires a thorough analysis of service objectives and performance based on established customer service standards., We are not an airline with great customer service; we are a great customer-service organization that happens to be in the airline business.' That comment by one Southwest Airlines employee [...]

Abstract: Background: Minimally invasive Ivor Lewis esophagectomy is one of the approaches used worldwide for treating esophageal cancer. Optimization of this approach and especially identifying the ideal intrathoracic anastomosis technique is needed. To date, different types of anastomosis have been described. A literature search on the current techniques and approaches for intrathoracic anastomosis was held. The studies were evaluated on leakage and stenosis rate of the anastomosis. Methods: The PubMed electronic database was used for comprehensive literature search by two independent reviewers.Results: Twelve studies were included in this review. The most frequent applied technique was the stapled anastomosis. Stapled anastomoses can be divided into a transthoracic or a transoral introduction. This stapled approach can be performed with a circular or linear stapler. The reported anastomotic leakage rate ranges from 0 to 10%. The reported anastomotic stenosis rate ranges from 0 to 27.5%. Conclusions: This review has found no important differences between the two most frequently used stapled anastomoses: the transoral introduction of the anvil and the transthoracic. Clinical trials are needed to compare different methods to improve the quality of the intrathoracic anastomosis after esophagectomy.

Surgical resection is regarded as the only curative option for resectable oesophageal cancer, but pulmonary complications occurring in more than half of patients after open oesophagectomy are a great concern. We assessed whether minimally invasive oesophagectomy reduces morbidity compared with open oesophagectomy.

See alsoMakris M, van Veen JJ. Reduced cardiovascular mortality in hemophilia despite normal atherosclerotic load. This issue, pp 20–2; Zwiers M, Lefrandt JD, Mulder DJ, Smit AJ, Gans ROB, Vliegenthart R, Brands‐Nijenhuis AVM, Kluin‐Nelemans JC, Meijer K. Coronary artery calcification score and carotid intima–media thickness in patients with hemophilia. This issue, pp 23–9.

We present DepQBF0.1, a new search-based solver for quantified boolean formulae (QBF). It integrates compact dependency graphs to overcome the restrictions imposed by linear quantifier prefixes of QBFs in prenex conjunctive normal form (PCNF). DepQBF0.1 was placed first in the main track of QBFEVAL’10 in a score-based ranking. We provide a general system overview and describe selected orthogonal features such as restarts and removal of learnt constraints.

In this work, palladium-loaded smart membranes made by UV cross-linking of thermoresponsive microgels are prepared to obtain a reusable, catalytically active material which can, for example, be implemented in chemical reactors. The membranes are examined with respect to their coverage of a supporting mesh via atomic force microscopy measurements. Force indentation mapping was performed in the dried, collapsed state and in the swollen state in water to determine the Young modulus. Furthermore, we compare the catalytic activity of the membrane with the corresponding suspended colloidal nanoparticle microgel hybrids. For this purpose, the reduction of 4-nitrophenol is an established model reaction to quantify the catalytic activity by UV–vis spectroscopy. The membrane is embedded inside a continuous stirred tank reactor equipped for continuous monitoring of the reaction progress. Although catalysis with membranes shows lower catalytic activity than freely dispersed particles, membranes allow straightforward separation and recycling of the catalyst. The fabricated membranes in this work show no decrease in catalytic activity between several cycles, unlike free particles. The feasible and durable deposition of catalytically active inter-cross-linked microgel particles on commercial nylon meshes as supporting scaffolds, as demonstrated in this work, is promising for up-scaling of continuous industrial processes.

The quantifier-free extensional theory of arrays TAplays an important role in hardware and software verification. In this article we present a novel decision procedure that refines formula abstractions with lemmas on demand. We consider the case where TAis combined with a decidable quantifier-free first-order theory TB. Unlike traditional lazy SMT approaches, where lemmas are added on the boolean abstraction layer, our decision procedure adds lemmas in TB. We discuss our decision procedure in detail. In particular, we prove soundness and completeness, and discuss complexity. We present our decision procedure in a generic context and provide implementation details and optimizations, in particular for bit-vectors. Finally, we report on experiments and discuss related work.

Abstract: Background: Evidence of benefits of laparoscopic and laparoscopic-assisted colectomies (LAC) over open procedures in gastrointestinal surgery has continued to accumulate. With its wide implementation, technical difficulties and limitations of LAC have become clear. Hand-assisted laparoscopic surgery (HALS) was introduced in an attempt to facilitate the transition from open techniques to minimally invasive procedures. Continuing debate exists about which approach is to be preferred, HALS or LAC. Several studies have compared these two techniques in colorectal surgery, but no single study provided evidence which procedure is superior. Therefore, a systematic review was carried out comparing HALS with LAC colorectal resection. Methods: Eligible studies were identified from electronic databases (Medline, Embase Cochrane) and cross-reference search. The database search, quality assessment, and data extraction were independently performed by two reviewers. Minimal outcome criteria for inclusion were operating time, conversion rate, hospital stay, and morbidity. Results: Out of 468 studies a total of 13 studies were selected for comprehensive review. Two randomized controlled trials (RCT) and 11 non-RCTs, comprising 1017 patients, met the inclusion criteria. Because of possible clinical heterogeneity two groups of procedures were created: segmental colectomies and total (procto)colectomies. In the segmental colectomy group significant differences in favor of the HALS group were seen in operating time (WMD 19 min) and conversion rate (OR of 0.3 conversions). In the total (procto)colectomy group a significant difference in favor of the HALS group was seen in operating time (WMD 61 min). Conclusions: This systematic review indicates that HALS provides a more efficient segmental colectomy regarding operating time and conversion rate, particularly accounting for diverticulitis. A significant operating time advantage exists for HALS total (procto)colectomy. HALS must therefore be considered a valuable addition to the laparoscopic armamentarium to avoid conversion and speed up complicated colectomies.

In this article we describe and evaluate optimized compact data structures for watching literals. Experiments with our SAT solver PicoSAT show that this low-level optimization not only saves memory, but also turns out to speed up the SAT solver considerably. We also discuss how to store proof traces compactly in memory and further unique features of PicoSAT including an aggressive restart schedule.

Many SAT instances can be decomposed into connected components either initially after preprocessing or during the solution phase when new unit conflict clauses are learned. This observation allows components to be solved individually. We present a technique to handle components within a GRASP like SAT solver without requiring much change to the solver. Results obtained when applying our implementation in the SAT solver COMPSAT to a number of realistic examples show that components really do occur in practice. We also provide some evidence that component structure can be used to improve performance.

Abstract Studies in crop species show that the effect of plant allelochemicals is not necessarily restricted to herbivores, but can extend to (positive as well as negative) effects on performance at higher trophic levels, including the predators and parasitoids of herbivores. We examined how quantitative variation in allelochemicals (iridoid glycosides) in ribwort plantain, Plantago lanceolata, affects the development of a specialist and a generalist herbivore and their respective specialist and generalist endoparasitoids. Plants were grown from two selection lines that differed ca. 5-fold in the concentration of leaf iridoid glycosides. Development time of the specialist herbivore, Melitaea cinxia, and its solitary endoparasitoid, Hyposoter horticola, proceeded most rapidly when reared on the high iridoid line, whereas pupal mass in M. cinxia and adult mass in H. horticola were unaffected by plant line. Cotesia melitaearum, a gregarious endoparasitoid of M. cinxia, performed equally well on hosts feeding on the two lines of P. lanceolata. In contrast, the pupal mass of the generalist herbivore, Spodoptera exigua, and the emerging adult mass of its solitary endoparasitoid, C. marginiventris, were significantly lower when reared on the high line, whereas development time was unaffected. The results are discussed with regards to (1) differences between specialist and generalist herbivores and their natural enemies to quantitative variation in plant secondary chemistry, and (2) potentially differing selection pressures on plant defense.

Abstract.: This case study contains a formal verification of the IEEE 1394 FireWire tree identify protocol. Crucial properties of finite models of the protocol have been validated with state-of-the-art symbolic model checkers. Various optimisation techniques were applied to verify concrete and generic configurations.

Iridoid glycosides are a group of terpenoid secondary plant compounds known to deter generalist insect herbivores. In ribwort plantain (Plantago lanceolata), the iridoid glycosides aucubin and catalpol can be induced following damage by insect herbivores. In this study, we investigated whether the same compounds can be induced following infection by the fungal pathogen Diaporthe adunca, the causal agent of a stalk disease in P. lanceolata. Significant induction of aucubin and catalpol was observed in two of the three plant genotypes used in this study following inoculation with the pathogen. In one of the genotypes, induction occurred within 6 hr after inoculation, and no decay was observed within 8 days. The highest level of induction was observed in reproductive tissues (spikes and stalks) where infection took place. In these tissues, iridoid glycoside levels in infected plants were, on average, 97% and 37% higher than the constitutive levels in the corresponding control plants, respectively. Significant induction was also observed in leaves (24%) and roots (17%). In addition to significant genotypic variation in the level of induction, we found genetic variation for the tissue-specific pattern of induction, further broadening the scope for evolutionary fine-tuning of induced responses. Recent studies have revealed a negative association between iridoid glycoside levels in P. lanceolatagenotypes and the amount of growth and reproduction of D. aduncathat these genotypes support. However, for the three genotypes used in the present study, differences in resistance were not related to their constitutive or induced levels of iridoid glycosides, suggesting that additional resistance mechanisms are important in this host-pathogen system. We conclude that iridoid glycosides in P. lanceolatacan be induced both by arthropods and pathogenic micro-organisms. Pathogen infection could, therefore, potentially enhance resistance to generalist insect herbivores in this species.

An important mechanism in stabilizing tightly linked host–parasitoid and prey–predator interactions is the presence of refuges that protect organisms from their natural enemies. However, the presence and quality of refuges can be strongly affected by the environment. We show that infection of the host plant Silene latifoliaby its specialist fungal plant pathogen Microbotryum violaceumdramatically alters the enemy–free space of a herbivore, the specialist noctuid seed predator Hadena bicruris, on their shared host plant. The pathogen arrests the development of seed capsules that serve as refuges for the herbivore's offspring against the specialist parasitoid Microplitis tristis, a major source of mortality of H. bicrurisin the field. Pathogen infection resulted both in lower host–plant food quality, causing reduced adult emergence, and in two–fold higher rates of parasitism of the herbivore. We interpret the strong oviposition preference of H. bicrurisfor uninfected plants in the field as an adaptive response, positioning offspring on refuge–rich, high–quality hosts. To our knowledge, this is the first demonstration that plant–inhabiting micro–organisms can affect higher trophic interactions through alteration of host refuge quality. We speculate that such interference can potentially destabilize tightly linked multitrophic interactions.

Summary.: Many secondary plant compounds are involved in defense against both insect herbivores and pathogens. Two secondary plant compounds of Plantago lanceolata, the iridoid glycosides catalpol and its precursor aucubin, are well known for their deterrent effects on generalist and non-adapted specialist insect herbivores. We tested the effects of these compounds on the in-vitro growth of a specialist and generalist fungal pathogen of this host species. Two chemical forms of these iridoids were tested. The glycosides and their aglycones, the products of enzymatic conversion by specific $/Beta$-glucosidase enzymes. The glycosides enhanced growth of both the specialist fungus Diaporthe adunca and the generalist fungus Fusarium moniliforme var. subglutinans. The positive effect of these glycosides on the generalist fungus is in sharp contrast with the generally negative effects of these glysosides on generalist insect herbivores. The aglycones of aucubin and catalpol reduced the growth of the specialist fungus D. adunca, but, contrary to expectation, enhanced the growth of the generalist fungus F. moniliforme var. subglutinans. Effects of aucubin on D. adunca were stronger than effects of catalpol. This was true both for the growth stimulating effects of the glycosides and for the fungitoxic effects of the aglycones. We therefore expect that the effects of these iridoids in P. lanceolata on the specialist fungus will strongly depend on the ratio between catalpol and its precursor aucubin and the chemical form (glycoside or aglycone) in which these compounds are encountered by the fungus during growth. Our results suggest that iridoid glycosides in P. lanceolata can be used as defense against both herbivores and pathogens, but that their effects are highly specific with respect to the natural enemy species that is encountered.

We present a new technique for verification of complex hardware devices that allows both generality and a high degree of automation. The technique is based on our new way of constructing a “light-weight” completion function together with new encoding of uninterpreted functions called reference file representation. Our technique combines our completion function method and reference file representation with compositional model checking and theorem proving. This extends the state of the art in two directions. First, we obtain a more general verification methodology. Second, it is easier to use, since it has a higher degree of automation. As a benchmark, we take Tomasulo's algorithm for scheduling out-of-order instruction execution used in many modern superscalar processors like the Pentium-II and the PowerPC 604. The algorithm is parameterized by the processor configuration, and our approach allows us to prove its correctness in general, independent of any actual design.

The phrase model checking refers to algorithms for exploring the state space of a transition system to determine if it obeys a specification of its intended behavior. These algorithms can perform exhaustive verification in a highly automatic manner, and, thus, have attracted much interest in industry. Model checking programs are now being commercially marketed. However, model checking has been held back by the state explosion problem, which is the problem that the number of states in a system grows exponentially in the number of system components. Much research has been devoted to ameliorating this problem. In this tutorial, we first give a brief overview of the history of model checking to date, and then focus on recent techniques that combine model checking with satisfiability solving. These techniques, known as bounded model checking, do a very fast exploration of the state space, and for some types of problems seem to offer large performance improvements over previous approaches. We review experiments with bounded model checking on both public domain and industrial designs, and propose a methodology for applying the technique in industry for invariance checking. We then summarize the pros and cons of this new technology and discuss future research efforts to extend its capabilities.

This research compares and contrasts the college and career experiences of graduates of the Agribusiness and Agricultural Economics undergraduate degree programs at Kansas State University. Using survey data, salary models were estimated for both majors. Starting salaries were not statistically different across majors, whereas current salaries were significantly higher for Agricultural Economics graduates. Alumni of both majors were found to be mobile and enjoy a high degree of satisfaction with their college and career experiences. Agribusiness majors were more likely to supervise employees and be more satisfied with working conditions than Agricultural Economics graduates.

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies. Recently, two point mutations in α-synuclein were found to be associated with familial PD, but as of yet no mutations have been described in the homologous genes β- and γ-synuclein. α-Synuclein forms the major fibrillar component of Lewy bodies, but these do not stain for β- or γ-synuclein. This result is very surprising, given the extent of sequence conservation and the high similarity in expression and subcellular localization, in particular between α- and β-synuclein. Here we compare in vitrofibrillogenesis of all three purified synucleins. We show that fresh solutions of α-, β-, and γ- synuclein show the same natively unfolded structure. While over time α-synuclein forms the previously described fibrils, no fibrils could be detected for β- and γ-synuclein under the same conditions. Most importantly, β- and γ-synuclein could not be cross-seeded with α-synuclein fibrils. However, under conditions that drastically accelerate aggregation, γ-synuclein can form fibrils with a lag phase roughly three times longer than α-synuclein. These results indicate that β- and γ-synuclein are intrinsically less fibrillogenic than α-synuclein and cannot form mixed fibrils with α-synuclein, which may explain why they do not appear in the pathological hallmarks of PD, although they are closely related to α-synuclein and are also abundant in brain.

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major components of which are filaments consisting of alpha-synuclein. Two recently identified point mutations in alpha-synuclein are the only known genetic causes of PD. alpha-Synuclein fibrils similar to the Lewy body filaments can be formed in vitro, and we have shown recently that both PD-linked mutations accelerate their formation. This study addresses the mechanism of alpha-synuclein aggregation: we show that (i) it is a nucleation-dependent process that can be seeded by aggregated alpha-synuclein functioning as nuclei, (ii) this fibril growth follows first-order kinetics with respect to alpha-synuclein concentration, and (iii) mutant alpha-synuclein can seed the aggregation of wild type alpha-synuclein, which leads us to predict that the Lewy bodies of familial PD patients with alpha-synuclein mutations will contain both, the mutant and the wild type protein. Finally (iv), we show that wild type and mutant forms of alpha-synuclein do not differ in their critical concentrations. These results suggest that differences in aggregation kinetics of alpha-synucleins cannot be explained by differences in solubility but are due to different nucleation rates. Consequently, alpha-synuclein nucleation may be the rate-limiting step for the formation of Lewy body alpha-synuclein fibrils in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major component of which are filaments consisting of alpha-synuclein. Two recently identified point mutations in alpha-synuclein are the only known genetic causes of PD, but their pathogenic mechanism is not understood. Here we show that both wild type and mutant alpha-synuclein form insoluble fibrillar aggregates with antiparallel beta-sheet structure upon incubation at physiological temperature in vitro. Importantly, aggregate formation is accelerated by both PD-linked mutations. Under the experimental conditions, the lag time for the formation of precipitable aggregates is about 280 h for the wild type protein, 180 h for the A30P mutant, and only 100 h for the A53T mutant protein. These data suggest that the formation of alpha-synuclein aggregates could be a critical step in PD pathogenesis, which is accelerated by the PD-linked mutations.

It is often assumed that host specialization is promoted by trade-offs in the performance of parasites on different host species, but experimental evidence for such trade-offs is scant. We studied differences in performance among strains of the anther smut fungus Ustilago violacea from two closely related host plant species, Silene alba and S. dioica, on progeny of (1) the host species from which they originated, (2) the alternative host species, and (3) inter-specific hybrids. Significant intra-specific variation in the pathogen was found for both infection success on a range of host genotypes (virulence) and components of spore production per infected host (aggressiveness) (sensu Burdon 1987). Strains did not have overall higher virulence on conspecifics of their host of origin than on strains from the heterospecific host, but they did have a significantly (c. 3 times) higher spore production per infected male host. This finding suggests that host adaptation may have evolved with respect to aggressiveness rather than virulence. The higher aggressiveness of strains on conspecifics of their host of origin resulted both from higher spore production per infected flower (spores are produced in the anthers), and greater ability to stimulate flower production on infected hosts. The latter indicates the presence of adaptive intraspecific variation in the ability of host manipulation. As transmission of the fungus is mediated by insects that are both pollinators of the host and vectors of the disease, we also assessed the effect of strains on host floral traits. Infection resulted in a reduction of inflorescence height, flower size, and nectar production per flower. Strains did not differ in their effect on nectar production, but infection with strains from S. alba resulted in a stronger reduction of inflorescence height and petal size on both host species. Vectors may therefore in principle discriminate among hosts infected by different strains and affect their efficiency of transmission. Contrary to assumptions of recent hypotheses about the role of host hybrids in the evolution of parasites, hybrids were not generally more susceptible than parental hosts. It is therefore unlikely that the rate of evolution of the pathogen on the parental species is slowed down by selection for specialization on the hybrids.

The amyloid β-peptide (Aβ) is the major constituent of neuritic plaques in Alzheimer's disease and occurs as a soluble 40-42-residue peptide in cerebrospinal fluid and blood of both normal and AD subjects. It is unclear whether Aβ, once it is secreted by cells, remains free in biological fluids or is associated with other proteins and thus transported and metabolized with them. Such knowledge of the normal fate of Aβ is a prerequisite for understanding the changes that may lead to the pathological aggregation of soluble Aβ in vivo, the possible influence of certain extracellular proteins, particularly apolipoprotein E, on plaque formation, and the pharmacology of putative Aβ-lowering drugs. To address the question of Aβ distribution in human biological fluids, we incubated fresh human plasma from 38 subjects with physiological concentrations (0.5-0.7 nM) of radioiodinated Aβ1-40and seven plasma samples with Aβ1-42. Lipoproteins and lipid-free proteins were separated and analyzed for bound iodinated Aβ1-40. We found that up to 5% of Aβ added to plasma is bound to selected lipoproteins: very low density, low density, and high density, but not lipoprotein(a). The large majority (≈89%), however, is bound to albumin, and very little Aβ is free. Aβ distribution in plasma was not significantly influenced by apolipoprotein E genotype. We conclude that Aβ is normally bound to and transported by albumin and specific lipoproteins in human plasma under physiological conditions.

The amyloid beta-peptide (Abeta) is the major constituent of neuritic plaques in Alzheimer's disease and occurs as a soluble 40-42-residue peptide in cerebrospinal fluid and blood of both normal and AD subjects. It is unclear whether Abeta, once it is secreted by cells, remains free in biological fluids or is associated with other proteins and thus transported and metabolized with them. Such knowledge of the normal fate of Abeta is a prerequisite for understanding the changes that may lead to the pathological aggregation of soluble Abeta in vivo, the possible influence of certain extracellular proteins, particularly apolipoprotein E, on plaque formation, and the pharmacology of putative Abeta-lowering drugs. To address the question of Abeta distribution in human biological fluids, we incubated fresh human plasma from 38 subjects with physiological concentrations (0.5-0.7 nM) of radioiodinated Abeta1-40 and seven plasma samples with Abeta1-42. Lipoproteins and lipid-free proteins were separated and analyzed for bound iodinated Abeta1-40. We found that up to 5% of Abeta added to plasma is bound to selected lipoproteins: very low density, low density, and high density, but not lipoprotein(a). The large majority ( approximately 89%), however, is bound to albumin, and very little Abeta is free. Abeta distribution in plasma was not significantly influenced by apolipoprotein E genotype. We conclude that Abeta is normally bound to and transported by albumin and specific lipoproteins in human plasma under physiological conditions.

The permeability of normal human, the human Dutch variant, and the rat Aβ 1-40 proteins at the blood–brain barrier (BBB) was determined in the normal adult rat by quantifying the permeability coefficient–surface area (PS) product for each protein after correction for the residual plasma volume (Vp) occupied by the protein in the blood vessels of different brain regions. The PS for normal and Dutch Aβ ranged from 13 × 10−6to 22 × 10−6ml/g/s in different brain regions, which is 130 to 220 times greater than albumin. These high PS values compare to that of insulin, whose uptake is decidedly by a receptor-mediated transport process, and suggest a similar mechanism for Aβ. Remarkably, the PS for rat Aβ was 4 times higher and ranged from 54 × 10−6to 82 × 10−6ml/g/s for different brain regions, suggesting a distinctive species specificity. While theVpvalues of human and rat Aβ were comparable, the Dutch variant was 2 to 3 times higher, indicating adherence to the vessel walls in different brain regions, consistent with the heavy Aβ deposition that has been described in intracerebral vessel walls with this variant. The high PS values observed for Aβ at the BBB suggest that sources outside the nervous system could contribute, at least in part, to the cerebral Aβ deposits seen in Alzheimer's disease. SDS–PAGE of125I-labeled human Aβ after 60 min of uptake revealed intact protein in plasma and in different brain regions. In addition,125I-labeled human Aβ binding to a protein of 67,000 in both plasma and brain tissue regions was observed with SDS–PAGE. This protein was tentatively identified as albumin, and it was not detectable in the brain regions of animals that had undergone intracardiac perfusion; hence, a portion of Aβ binds tightly to and is likely transported by albumin in plasma. The absence of this Aβ–albumin complex in brain regions after perfusion and the low permeability of albumin at the BBB imply that Aβ itself is efficiently transported at the BBB to account for the high PS values, although presentation of Aβ to the capillary endothelial cell by albumin or other plasma proteins cannot be excluded.

Apolipoprotein E (ApoE) is the major genetic risk factor for Alzheimer's disease (AD). The ApoE4 allele is associated with earlier disease onset and greater cerebral deposition of the amyloid beta peptide (Aβ), the major constituent of senile (amyloid) plaques. The molecular mechanism underlying these effects of ApoE4 remains unclear; ApoE alleles could have different influences on Aβ production, extracellular aggregation, or clearance. Because the missense mutations on chromosomes 14 and 21 that cause familial forms of AD appear to lead to increased secretion of Aβ, it is important to determine whether ApoE4 has a similar effect. Here, we have examined the effects of all three ApoE alleles on the processing of βAPP and the secretion of Aβ in intact cells. We established neural (HS683 human glioma) and non-neural (Chinese hamster ovary) cell culture systems that constitutively secrete both ApoE and Aβ at concentrations like those in human cerebrospinal fluid. βAPP metabolites, generated in the presence of each ApoE allele, were analysed and quantified by two methods: immunoprecipitation and phosphorimaging, and ELISA. We detected no consistent allele-specific effects of ApoE on βAPP processing in either cell type. Our data suggest that the higher amyloid burden found in AD subjects expressing ApoE4 is not due to increased amyloidogenic processing of βAPP, in contrast to findings in AD linked to chromosome 14 or 21. These co-expressing cell lines will be useful in the further search for the effects of ApoE on Aβ aggregation or clearance under physiologically relevant conditions.