C-C chemokine receptor type 2 (CCR2) is highly expressed in human breast cancer tissue by both cancer cells and infiltrating immune cells. High expression of CCR2 is correlated with advanced tumor stage, metastasis, and early relapse. Studies in mice have suggested that CCR2 expression on infiltrating inflammatory monocytes promotes primary tumor growth and metastasis. However, the role of CCR2 expression on cancer cells has not been well studied. To determine how CCR2 directly impacts tumor growth and metastasis, we used a murine model of luminal breast cancer, the mouse mammary tumor virus (MMTV) promoter polyoma middle T antigen (PyMT) model. We crossed MMTV-PyMT mice to Ccr2-/- mice and found that loss of CCR2 did not alter tumor onset. However, primary tumors of MMTV-PyMT;Ccr2+/+ mice grew significantly faster than tumors of MMTV-PyMT;Ccr2-/- mice. Lung metastases were also larger in MMTV-PyMT;Ccr2+/+ mice than in MMTV-PyMT;Ccr2-/- mice. We determined by RNA in situ hybridization that CCR2 was indeed expressed by both host cells and cancer cells in MMTV-PyMT tumors. To differentiate between the contributions of CCR2 expression in the tumor and host, we transplanted primary cancer cells derived from MMTV-PyMT;Ccr2+/+ and MMTV-PyMT;Ccr2-/- mice to syngeneic Ccr2+/+ and Ccr2-/- hosts. Surprisingly, CCR2 expression in the host had no significant effect on tumor growth. However, deletion of CCR2 from cancer cells resulted in delayed tumor growth and increased survival. Furthermore, when Ccr2+/+ and Ccr2-/- cancer cells were transplanted to athymic nude mice (lacking T cells), the resulting tumors no longer showed a delayed growth. Consistent with this finding, flow cytometry of infiltrating leukocytes in tumors transplanted to syngeneic mice revealed increased levels of CD8+ cytotoxic T cells and antigen-presenting CD103+ dendritic cells into Ccr2-/- tumors compared to wild type tumors. These data suggest that CCR2 expression on cancer cells regulates an immune response to the tumors. Supporting this conclusion, expression of programmed cell death ligand 1 (PD-L1) on Ccr2-/- cancer cells was reduced to just 30% of the level on wild type cancer cells, indicating that CCR2 expression on cancer cells suppresses the anti-tumor immune response. Together, our results establish a novel role for cancer cell CCR2 expression in breast cancer progression by suppression of cytotoxic T cells through an immune checkpoint. Citation Format: Miriam R. Fein, Ana S. Almeida, Anais Eberhardt, Mikala Egeblad. Cancer cell expression of CCR2 regulates the PD-L1/ PD-1 immune checkpoint in breast cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A063.


Abstract 'Landscape' and 'ritual' have been largely discussed in the social and human sciences, although their inter-relatedness has gained little scholarly attention. Drawing on earlier studies of ritual and landscape, as well as the authors′ own ethnographic works, 'ritual landscape' is suggested here as a useful analytical tool with which to understand how landscapes are produced, and how they, in their turn, produce certain types of being. 'Ritual landscape' recognises different modalities of agency, power-relation, knowledge, emotion, and movement. The article shows how the subjectivity of other-than-human beings such as ancestors, earth formations, land, animals, plants and, in general, materiality of ritual contexts, shape landscapes. We argue that ways of perceiving landscape includes a number of material and immaterial aspects indicated by ways of moving through landscapes and interacting with different human and non-human subjects that come to inhabit the world, creating relations and producing agentive ensembles and complexes.


We present an array evaluation of standard and non-standard arrays over a hydrogeological target. We develop the arrays by linearly combining data from the pole-pole (or 2-pole) array. The first test shows that reconstructed resistances for the standard Schlumberger and dipole-dipole arrays are equivalent or superior to the measured arrays in terms of noise, especially at large geometric factors. The inverse models for the standard arrays also confirm what others have presented in terms of target resolvability, namely the dipole-dipole array has the highest resolution. In the second test, we reconstruct random electrode combinations from the 2-pole data segregated into inner, outer, and overlapping dipoles. The resistance data and inverse models from these randomized arrays show those with inner dipoles to be superior in terms of noise and resolution, and that overlapping dipoles can cause model instability and low resolution. Finally, we use the 2-pole data to create an optimized array that maximizes the model resolution matrix for a given electrode geometry. The optimized array produces the highest resolution and target detail. Thus, the tests demonstrate that high quality data and high model resolution can be achieved by acquiring field data from the pole-pole array.


Numerous diseases are induced by free radicals via lipid peroxidation, protein peroxidation and DNA damage. It has been known that a variety of plant extracts have antioxidant activities to scavenge free radicals. Whether Polygonum cuspidatum Sieb. et Zuce has antioxidant activity is unknown. In this study, dried roots of Polygonum cuspidatum were extracted by ethanol and the extract was lyophilized. Free radical scavenging assays, superoxide radical scavenging assays, lipid peroxidation assays and hydroxyl radical-induced DNA strand scission assays were employed to study antioxidant activities. The results indicate that the IC50 value oí Polygonum cuspidatum extract is 110 microg/ml in free radical scavenging assays, 3.2 microg/ml in superoxide radical scavenging assays, and 8 microg/ml in lipid peroxidation assays, respectively. Furthermore, Polygonum cuspidatum extract has DNA protective effect in hydroxyl radical-induced DNA strand scission assays. The total phenolics and flavonoid content of extract is 641.1 +/- 42.6 mg/g and 62.3 +/- 6.0 mg/g. The results indicate that Polygonum cuspidatum extract clearly has antioxidant effects.


In the all-optical switches using Mach–Zehnder interferometer side-coupled with a ring resonator, the switching power is quadratically reversely proportional to the resonator finesse in the high-finesse case. In order to enhance the resonator finesse, the loss rate a and the coupler reflectivity r should approach 1. Therefore, we propose a new configuration by inserting an amplifier into the ring to compensate for the losses in the ring and using a pumped nonlinear coupler instead of the ordinary coupler. The resonator finesse can be enhanced dramatically and the minimum switching power can be obtained.


An important problem in the area of computer graphics is the visualization of large, complex information spaces. Datasets of this type have grown rapidly in recent years, both in number and in size. Images of the data stored in these collections must support rapid and accurate exploration and analysis. This article presents a method for constructing visualizations that are both effective and aesthetic. Our approach uses techniques from master paintings and human perception to visualize a multidimensional dataset. Individual data elements are drawn with one or more brush strokes that vary their appearance to represent the element's attribute values. The result is a nonphotorealistic visualization of information stored in the dataset. Our research extends existing glyph-based and nonphotorealistic techniques by applying perceptual guidelines to build an effective representation of the underlying data. The nonphotorealistic properties the strokes employ are selected from studies of the history and theory of Impressionist art. We show that these properties are similar to visual features that are detected by the low-level human visual system. This correspondence allows us to manage the strokes to produce perceptually salient visualizations. Psychophysical experiments confirm a strong relationship between the expressive power of our nonphotorealistic properties and previous findings on the use of perceptual color and texture patterns for data display. Results from these studies are used to produce effective nonphotorealistic visualizations. We conclude by applying our techniques to a large, multidimensional weather dataset to demonstrate their viability in a practical, real-world setting.


The effect of pre-irradiation heat treatments on thermal non-equilibrium grain boundary segregation (TNES) and subsequent radiation-induced grain boundary segregation (RIS) is studied in a series of model austenitic stainless steels. The alloys used for this study are based on AISI 316 stainless steel and have the following nominal compositions: Fe-16Cr-13Ni-1.25Mn (base 316), Fe-16Cr-13Ni-1.25Mn-2.0Mo (316 + Mo) and Fe-16Cr-13Ni-1.25Mn-2.0Mo-0.07P (316 + Mo + P). Samples were heat treated at temperatures ranging from 1100 to 1300 C and cooled at 4 different rates (salt brine quench, water quench, air cool and furnace cool) to evaluate the effect of annealing temperature and quench rate on TNES. The alloys were than processed with the treatment (temperature and cooling rate) that resulted in the maximum Cr enrichment. Alloys with and without the heat treatment to enrich the grain boundaries with Cr were characterized following irradiation to 1 dpa at 400 C with high-energy protons in order to understand the influence of alloying additions and pre-irradiation grain boundary chemistry on irradiation-induced elemental enrichment and depletion profiles. Various mechanistic models will be examined to explain the observed behavior.


In this article we study the connection between proximal point methods for nonconvex optimization and the backward Euler method from numerical Ordinary Differential Equations (ODEs). We establish conditions for which these methods are equivalent. In the case of weakly convex functions, for small enough parameters, the implicit steps can be solved using a strongly convex objective function. In practice, this method can be faster than gradient descent. In this paper we find the optimal value of the regularization parameter.


Organometallic complexes containing transition metals, such as Ru(II), Os(II), Ir(III), have been moderately and recently used in medicinal chemistry as anticancer, antimalarial, antimicrobial or diagnostic agents. Current trends have led researchers to explore and define new synthetic methods in the quest for the design of new drugs and reduce the inherit associated toxic side-effects by using metal based compounds. Ferrocene based derivatives have been subjected to study for their biological and medicinal applications. Examples include ferrocenophane polyphenol, ferrocenyl quinone methides, ferrocenyl-aminoquinoline-carboxamide and a ferrocene-substituted hydroxytamoxifen, which has been proved as a potential new breast cancer therapeutic. Ferroquine displays antimalarial activity and ferrocifen is a tamoxifen-ferrocene anticancer agent. During the course of our research, we have focused on synthesizing and studying the biological activity of novel organometallic compounds containing the corresponding ferrocene moiety. We aimed to make, at least, 3 different families of compounds, which were cannabinoid receptor (CB1/CB2 receptor agonists), histone deacetylase (HDAC) selective inhibitors and general kinase inhibitors.

Firstly, a review covering the state-of-the-art in bioorganometallic chemistry will be presented. Secondly, we started with the synthesis of a small library of compounds containing the following groups: ferrocenylamine, 4-oxo-1, 4-dihydropyridine and dihydroquinoline. We used aminoferrocene as a bioisostere of the adamantylamine group where previous studies of compounds containing the latter group had showed it to effectively interact with the cannabinoid receptors, CB1 and CB2. Some of our compounds displayed good to excellent potency in the nM range against the CB1 and CB2 receptors.

Thirdly, we embarked to synthesise HDAC inhibitors knowing their potential as anti-cancer drugs and trying to obtain, wherever possible, enzyme isoform selectivity. One of the well-known HDAC inhibitors is suberoylanilide hydroxamic acid (SAHA). Vorinastat, as it is also known, has received Food and Drug Administration approval for treating patients with cutaneous T-cell lymphoma. The compound developed in our group by replacing ferrocene for the phenyl ring in SAHA, called JAHA, is another example of a highly potent HDAC inhibitor. Our research led to compounds where the hydroxamic acid moiety in JAHA has been replaced by a benzamide group. This transformation has produced a significant effect in delivering a potent HDAC3 selective HDAC inhibitor. This is supported by biological studies and a molecular modelling rationalisation.

Next, a series of oxindole based analogues have been synthesized by the Knoevenagel condensation reaction of: 5-(pentafluorosulfanyl)-1,3-dihydro-indol-2-one and 6-(pentafluorosulfanyl)-1,3-dihydro-indol-2-one compound with: ferrocenecarboxaldehyde and pyrrole-2-carboxaldehyde. The compounds thereby synthesised have been studied against a panel of kinases, and kinase inhibitory data will be discussed and presented.

In a Future directions section, we will describe the synthesis of FAAH (fatty acid amide hydrolase) inhibitors based on an aminoferrocene backbone.


ABSTRACT The distinction between "Big-C" and "little-c" creativity implies that the generative process of celebrated creators is of a special type or degree. Arguments for and against such a hierarchy of creativity are found in the literature, primarily built on rhetorical argumentation. The aim of this work is to examine the rationale behind Big-C and little-c creativity using explicit and more systematic means of inquiry. We employ computational agent-based simulations to study these constructs, their premises, and their logical implications. The results of this work indicate that hierarchies such as the Big-C and little-c of creativity fail to provide a consistent way to explain and distinguish the generative processes of individual creators. In these computational models of creative social systems, only about half of disruptive changes can be explained by the characteristics of individual agents. This shows how labels like Big-C that are dependent on evaluation outcomes can easily be misattributed by observers to individual creators. This work demonstrates how the use of computational simulations can be useful to examine fundamental ideas about creativity. It shows that the Big-C/little-c distinction is a false dichotomy that should be approached critically by scholars to avoid conflating generative and evaluative dimensions of creativity.


Abstract We investigate the effect of heterogeneous petrophysical properties on Low Salinity Water Flooding (LSWF). We considered reservoir scale models, where the geological properties were obtained from a giant Middle East carbonate reservoir. The results are compared against a typical sandstone model. We simulated low salinity induced wettability changes in field scale models in which the petrophysical properties were randomly distributed with spatial correlation. We examined a wide range of geological realisations which mimic complex geological structures. Sandstone was simulated using a log-linear porosity-permeability relation with fairly good correlation. A carbonate reservoir from the Middle East was simulated where a much less correlated porosity permeability relationship was obtained. The salinity of formation water was set to typically observed values for the sandstone and carbonate cases. A number of simulations were then carried out to assess the flow behaviour. We have found that the general trend of permeability-porosity correlation has a key role that could mitigate or aggravate the impact of spatial distributions of petrophysical properties. We considered models with a log-linear permeability-porosity correlation, as generally observed for sandstone reservoirs. These are likely to be directly affected by the spatial distribution more than models with a power permeability-porosity correlation, which is often reported for flow units of carbonate reservoirs. The scatter of data in the permeability-porosity correlations had a relatively small impact on the flow performance. On the other hand, the effect of heterogeneity decreases with the width of the effective salinity range. Thus, uncertainty in carbonate reservoirs arises due to the ambiguity of spatial distribution of permeability and porosity would be less affects the LSWF predictability than in sandstone case. Overall, the incremental oil recovery due to LSWF was higher in the carbonate models than the sandstone cases. We observe from uncertainty analysis that the formation waterfront was less fingered than the low salinity waterfront and the salinity concentration. The dispersivity of salinity front and the water cut can be estimated for models with various degrees of heterogeneity. The outcome of the study is a better understanding of the implications of heterogeneity on LSWF. In some cases the behaviour can appear like a waterflood in very heterogeneous cases. It is important to assess the reservoir effectively to determine the best business decision.


Straining of silicon improves mobility of carriers resulting in speed enhancement for transistors in CMOS technology. Traditionally, silicon straining is applied in a similar ad-hoc manner to the whole die including logic and memory. Speed enhancement achieved for both NMOS and PMOS devices is desirable in logic circuits for performance enhancement because both PMOS and NMOS devices lie in critical delay paths. In SRAM cells however PMOS devices are not in the delay path and hence made small to minimize cell area and improve the write stability of the cell. Hence, speed enhancement of PMOS does not result in any reduction in cell access time and in fact it degrades the cell write ability. Hence, optimal method and amount of silicon straining for logic and memory should be different. In this paper, we propose an optimal straining solution for both logic and memory. Based on simulation results in a predictive 45nm process technology, the proposed straining solution enhances circuit performance by 15.6% in SRAM and 39.3% in Logic while satisfying stability requirements. We also propose a co-design optimization methodology that allows optimizing circuit parameters (such as transistor sizing and supply voltage) and process parameters (in this case amount of silicon straining) at the same time for both low power and high performance targets. We found that co-design of supply voltage and silicon straining is very helpful for both low power and high performance targets, whereas co-design of sizing and silicon straining dose not provide any considerable improvements. Our results show that by co-design of supply voltage and silicon straining, power reduction of 38% and 49% is achieved in SRAM and logic, respectively. We also expanded our co-design approach for joint optimization of various circuit and device parameters such as supply voltage, straining, and threshold voltage. The results show that the co-design can reduce leakage by 80% and improve performance by 50%. The developed optimization methodology thus provides a device and circuit co-design framework which is essential as the technology continues to scale to nano-scale regimes


An overview is given on the state-of-the-art in synthesis of sequence-controlled and sequence-defined oligomers and polymers. These materials constitute chains in which chemical information is encoded along the backbone either as multiblock copolymers (controlled) or as monodisperse sequences of single monomers (defined). Focus is placed on reversible-deactivation radical polymerization techniques as these give access to a broad variety of chemical functionalities and allow for simple and fast synthesis procedures. Sequence-controlled and -defined materials have the ability to re-shape materials chemistry due to their close resemblance to biopolymers regarding structural uniformity. The field is at the edge of being able to start exploring the distinct properties that such synthetic macromolecules may have.


Transition metal complexes with Schiff base ligands possess remarkable biomedical activities that could be used to develop new metal-based anticancer agents. Anticancer metal complexes have attracted considerable interest since the successful application of platinum based anti-cancer drugs. Pyrazolone derivatives have been extensively studied and have shown a wide range of pharmacological activities and anticancer activities. A new class of mononuclear copper (II), cobalt(II), nickel(II) and zinc(II) complexes were synthesized using pyrazolone precursor Schiff base, obtained by the condensation of 4–aminoantipyrine with salicylaldehyde and respective metal(II) chloride. They have been characterized by elemental analysis, magnetic susceptibility, molar conductance measurements, UV-Vis., FT-IR, 1H NMR spectra and EPR studies. Their magnetic susceptibility values of the complexes at room temperature are consistent with octahedral geometry around the central metal ions. These complexes show lower conductance values, supporting their non-electrolytic nature. The data show that the complexes have composition of [ML2] type. In vitro DNA binding profiles of all complexes have been explored by absorption titrations, cyclic voltammetry technique and viscosity measurements. The corroborative results of above experiments suggest that these complexes are efficient metallo intercalators and can interact with CT-DNA. The binding constant values (Kb) clearly signify that the complexes bind to DNA through intercalation mode. The binding affinity of these complexes with CT DNA is found to be in the order, Cu(II)>Zn(II)>Co(II)>Ni(II), among them copper complex  displaying a higher binding propensity as compared to other complexes.


BACKGROUND
Studies have shown that women use more health care services than men. We used important independent variables, such as patient sociodemographics and health status, to investigate gender differences in the use and costs of these services.

METHODS
New adult patients (N = 509) were randomly assigned to primary care physicians at a university medical center. Their use of health care services and associated charges were monitored for 1 year of care. Self-reported health status was measured using the Medical Outcomes Study Short Form-36 (SF-36). We controlled for health status, sociodemographic information, and primary care physician specialty in the statistical analyses.

RESULTS
Women had significantly lower self-reported health status and lower mean education and income than men. Women had a significantly higher mean number of visits to their primary care clinic and diagnostic services than men. Mean charges for primary care, specialty care, emergency treatment, diagnostic services, and annual total charges were all significantly higher for women than men; however, there were no differences for mean hospitalizations or hospital charges. After controlling for health status, sociodemographics, and clinic assignment, women still had higher medical charges for all categories of charges except hospitalizations.

CONCLUSIONS
Women have higher medical care service utilization and higher associated charges than men. Although the appropriateness of these differences was not determined, these findings have implications for health care.


As more and more Emergency Departments replace the manual dry-erase whiteboards used for coordination of patient care and communication among clinicians with IT-based electronic whiteboards a need to clarify the effects of implementing these systems arises. This paper seeks to answer this question by systematically reviewing studies on electronic whiteboards. The results of the review indicate that electronic whiteboards influence the work at Emergency Departments in various different ways e.g. changes to work practice and changes to whiteboard information accuracy. Also, the review finds that there are mediating factors that have an impact upon these effects e.g. display format and integration with other clinical IT systems. However, the results are somewhat inconclusive and of a mixed nature and therefore this paper calls for more focused and specific research.


The sound management of agricultural soils that are heavily loaded with phosphorus (P) involves minimizing the losses of P responsible for eutrophication of surface waters, while ensuring enough P for crops. This paper describes a simple model to examine the compatibility of these two objectives in acid sandy soils in a temperate humid climate. The model is based on several assumptions regarding reversible and irreversible P sorption by P‐reactive soil compounds (mainly poorly crystalline Fe and Al oxides) and release of P to water (water‐P test). Model inputs are amount of P leached, P uptake by crops, and contents of poorly crystalline Fe and Al oxides in soil. The model predicts that reducing the amount of leached P to what is environmentally acceptable (e.g. 0.44 kg P ha–1 year–1, equivalent to 1 kg P2O5 ha–1 year–1) results in the long run in available soil P test values below target concentrations for optimum crop growth. When the amount of leached P is set to a fixed value the model predicts that soils with large contents of Fe and Al oxides can maintain the initial soil P test values for longer periods than other soils. The content in available P decreases if fertilizer P is applied to the soil at a rate equal to P uptake by crops. These results stress the difficulties involved in trying to make agricultural and environmental needs compatible in acid sandy soils.


Background The ability to identify individuals at increased risk of developing tuberculosis (TB) has important implications for public health policy and patient care. We conducted a general population historical cohort study in all Australian States and Territories to establish the risk of TB arising in people on chronic hemo- or peritoneal dialysis. Methodology/Principal Findings Cases of TB disease in patients receiving chronic dialysis were identified by record linkage using the Australia & New Zealand Dialysis and Transplant Registry (ANZDATA) and State and Territory TB notification databases 2001 to 2006. Main outcome measure was the relative risk of TB in people on dialysis, adjusted for TB incidence in country of birth, sex, age and indigenous status. A total of 6,276 cases of active TB were reported among 19,855,283 people living in Australia between 2001 and 2006. Among 14,506 patients on dialysis, 37 had a notification for TB disease after commencing dialysis, of whom 28 were culture positive. The incidence of TB was 66.8/100,000/year (95% CI 47.7 to 93.2) among people on dialysis and 5.7/100,000/year (95% CI 5.5 to 5.8) in the general population. The adjusted relative risk (aRR) of TB in people on dialysis was 7.8 (95% CI 3.3 to 18.7), and the aRR of culture positive TB was 8.6 (95% CI 3.9 to 19.3). Conclusions/Significance Patients on dialysis are at increased risk of TB. The final decision to screen for, and to treat, LTBI in individual dialysis patients will be influenced by a cumulative assessment of the risk of reactivation of TB and by assessment of risk factors for adverse effects of treatment.


Citing the repeated attention to transgendered characters in today's popular culture, this review essay focuses on Jeffrey Eugenides's Pulitizer-Prize winning novel, Middlesex, whose engaging and delightful protagonist-narrator was mistakenly classified at birth and reared as a girl, only to experience at adolescence gradual transformation into a male. The protagonist's particular medical problem and the story that Eugenides weaves around it allow exploration of two primary threads: First, this essay examines what the protagonist's fictional story adds to the true story of the man now known as David Reimer. Reimer became a notorious test case in the nature-versus-nurture debate about gender after Dr. John Money directed his distraught parents to rear their baby boy as a girl following the accidental loss of his penis. Money publicly proclaimed the treatment successful - promoting the belief that the Reimer family had a well-adjusted daughter and reinforcing the views of scholars who emphasize the social construction of gender. Although the family's later disclosures were utterly inconsistent with Money's claims, Middlesex helps tease out important nuances that Money's eventual disrepute has obscured. In particular, this essay's juxtaposition of the novel and the true story illuminates several prominent issues in family law and policy, including family secrecy, parental autonomy, parental reliance on (often mistaken) experts, and prevailing understandings of sex and gender. Second, this essay analyzes what Middlesex's protagonist and the other transgendered figures in popular culture contribute to the ongoing conversation about legal sex-based classifications, including the male-female requirement for marriage. After a critical examination of both the vocabulary used to discuss sex and gender and the challenges that those like the novel's protagonist pose for the conventional hierarchy, the focus shifts to the law's sex-equality norms, specifically the anti-stereotyping analysis prominent in equal protection doctrine and various modern family laws. Under today's laws, what precisely is the difference between a wife and a husband, beyond pure anatomy? Although recent litigation about transsexuals' marriage claims mostly have failed to take anti-stereotyping analysis to its logical conclusion (despite the arguments of some strategists), nonetheless popular culture and contemporaneous legal developments have brought the current prohibitions on same-sex marriage to the brink of collapse. Assuming that marriage is here to stay (an assumption some feminists contest), the pathbreaking opinion of the majority of the Supreme Judicial Court of Massachusetts in Goodridge v. Department of Public Health offers one glimpse of how the law might rethink marriage without an opposite-sex requirement. Yet marriage is just one context that tests the law's commitment to gender equality. The essay concludes with three thought experiments about how the law might treat sex and gender in the future - consistent with the continuing erosion of the traditional understanding revealed through the lens of Middlesex. Although this essay confronts serious and important questions, throughout it maintains a somewhat playful tone that seems fitting for a review of this particular work of fiction and for an exploration of popular culture's mainstreaming of transgender issues.


OBJECTIVE
Does the electrocardiographic method for central venous catheter positioning distinguish between a correct intravasal and a malpositioned extravasal position?

METHODS
24 cardiac surgical patients were enrolled in this prospective observational study. In 18 patients the left, in another 6 patients the right internal jugular vein was cannulated. Using a J-wire within a triple-lumen catheter the amplitude of the P-wave was measured at 3 different intravasal sites: Intra-1: (intravasal baseline electrocardiogram), i. e. 10 cm marking of the catheter on skin level; Intra-2: clear rise of the P-wave amplitude upon further insertion of the catheter; Intra-3: maximum P-wave amplitude. At this position the control of the catheter tip was achieved by means of transoesophageal echocardiography (TOE). Intraoperatively, another J-wire within a triple-lumen catheter was placed by the heart surgeon on 3 extravasal sites and the ECG was recorded: Extra-1: extravasal at the left innominate vein above the pericardial reflection; Extra-2: extravasal on the superior vena cava below the pericardial reflection; Extra-A: extravasal on ascending aorta below the pericardial reflection. The catheter was suture fixed with its tip in position Intra-3. Post surgery a chest radiograph was taken.

RESULTS
All catheter tips were visualised at the basis of the Crista terminals (border between right atrium and superior vena cava) by TOE control. The rise of the P wave amplitude at Intra-2, Extra-2 and Extra-A was highly significant compared to the base line at Intra-1 (Intra-1/Intra-2, Intra-1/Extra-2, Intra-1/Extra-A: p in each case < 0.001). The P wave amplitudes of the corresponding intra- and extravasal positions of the left innominate vein (Intra-1/Extra-1, n = 18, p = 0.096)) as well as those of the superior vena cava (Intra-2/Extra-2, n = 24, p = 0.859) did not differ.

CONCLUSION
The electrocardiographic method can not differentiate between intra- and extravasal position of a central venous catheter, and thus, presumably fails to identify malpositioning as a result of vascular perforation.


A practical induction motor torque and parameter measurement scheme is proposed without using any mechanical sensors. The torque and parameter calculation is performed by a digital signal processor (DSP) based on measured motor terminal waveforms. Since the motor parameters are required for torque calculation, a novel scheme is developed for parameter identification. The motor parameters can be extracted from the measured motor current and motor voltage when the motor-fed by inverters, AC voltage controllers or other equipment-is started under no load conditions. The proposed torque measurement scheme has the features of wide bandwidth and no need for mechanical sensors. Simulation and experimental results on a 5 hp induction machine driven under various operating conditions are also given for verification.


In this article, we advance the literature on publics in international politics by exploring the nexus between publicness and big tech companies. This nexus finds a significant expression in the increasing impact of big tech companies to mediate disputes over societal problems, deliver social goods and rearticulate public-private relationships. We develop an analytical framework by combining recent scholarship on assemblage theory and publics, allowing us to understand publicness as enacted in practices which revolve around issues and rearticulate relations of authority and legitimacy. To demonstrate the value of the framework, we show how Microsoft is involved in assembling publicness around cybersecurity. Microsoft does so by problematising and countering state-led cybersecurity activities, questioning the state as a protector of its citizens and proposing governance measures to establish the tech sector as authoritative, and legitimate "first responders." With this rearticulating of public-private relations, we see the emergence of a political subject for whom security is not solely the right of a citizen secured by the state but also a customer service provided as per a service agreement. The study hence offers important insights into the connection between publicness and cybersecurity, state and big tech relations, and the formation of authority and legitimacy in international politics.


Millions of Americans suffer from mental health problems caused by negative sentiment such as depression and neuroticism. Nevertheless, traditional clinical diagnosis is not preferred as a large-scale approach due to the high expenditures and subjective judgement. In this paper, we conduct exploratory data analysis on three datasets from MyPersonality and Reddit, train and compare different predictive models for depression and neuroticism with various features. Our experimental results indicate promising feasibility to identify such mental health problems using natural language processing techniques. Moreover, we discuss the differences among χ2-Test, PMI, LDA, between single and multiple feature selections, and between SVM and SLDA. Thus, we accomplish and overfulfill all of our proposed goals. Eventually, we propose several directions for future research.


Distributed interactive simulation provides an environment for realistic participation in virtual worlds. Humans interact with the virtual world through interface devices such as switches and knobs, keyboards and mice, touch screens and data gloves. The time has come for the seamless integration of these physical, real-world human interface devices with the systems that generate and display the virtual environments. The merging of these two areas will result in virtual world experiences more realistic than any available today.<<ETX>>


Computational Fluid Dynamics simulations of planing hulls are generally considered less reliable than simulations of displacement hulls. This is due to the flow complexity around planing hulls, especially in the bow region, where the sprays are formed. The recent and constant increasing of computational capabilities allows simulating planing hull features, with more accurate turbulence models and advanced meshing procedures. However, mesh-based approaches based on the finite volume methods have shown to be limited in capturing all the phenomena around a planing hull. As such, the focus of this study is on evaluating the ability of the Smoothed Particle Hydrodynamics mesh-less method to numerically solve the 3-D flow around a planing hull and simulate more accurately the spray structures, which is a rather challenging task to be performed with mesh-based tools. A novel application of the DualSPHysics code for simulating a planing hull resistance test has been proposed and applied to the parent hull of the Naples warped planing hull Systematic Series. The drag and the running attitudes (heave and dynamic trim angle) are computed for a wide range of Froude's numbers and discussed concerning experimental values.


Intragenic complementation is a unique property of oligomeric enzymes with which to study subunit-subunit interactions. Complementation occurs when different subunits, each possessing distinct mutations that render the individual homomutant proteins inactive, interact to form a heteromutant protein with partial recovery of activity. In this paper, complementation events between human argininosuccinate lyase (ASL) and its homolog, duck δ2 crystallin, were characterized. Different active site mutants in δ2 crystallin complement by the regeneration of native-like active sites as reported previously for ASL. The complementarity of the ASL and δ2 crystallin subunit interfaces was illustrated by the in vivo formation of active hybrid tetramers from inactive ASL and inactive δ2 crystallin mutants. Subunits of both ASL and δ2 crystallin do not dissociate and reassociate in vitro at room temperature, even after 6 days of incubation, indicating that the multimerization interface is very strong. However, disruption of a salt bridge network in the tetrameric interface of δ2 crystallin caused a drastic acceleration of subunit dissociation. Double mutants combining these interface mutants with active site mutants of δ2 crystallin were able to dissociate and reassociate to form active tetramers in vitro within hours. These results suggest that exchange of subunits may occur without unfolding of the monomer. Intragenic complementation in these interface mutants occurs by reintroducing the native salt bridge interaction upon hetero-oligomerization. Our studies demonstrate the value of intragenic complementation as a tool for investigating subunit-subunit interactions in oligomeric proteins.


In the UK, there is an interest in the expected offshore wind resource given ambitious national plans to expand offshore capacity. There is also an increasing interest in alternative datasets to evaluate wind seasonal and inter-annual cycles which can be very useful in the initial stages of the design of wind farms in order to identify prospective areas where local measurements can then be applied to determine small-scale variations in the marine wind climate. In this paper we analyse both MERRA2 reanalysis data and measured offshore mast data to determine patterns in wind speed variation and how they change as a function of the distance from the coast. We also identify an empirical expression to estimate wind speed based on the distance from the coast. From the analysis, it was found that the variations of the seasonal cycles seem to be almost independent of the distance to the nearest shore and that they are an order of magnitude larger than the variations of the diurnal cycles. It was concluded that the diurnal variations decreased to less than a half for places located more than 100km from the nearest shore and that the data from the MERRA2 reanalysis grid points give an under-prediction of the average values of wind speed for both the diurnal and seasonal cycles. Finally, even though the two offshore masts were almost the same nearest distance from the coast and were geographically relatively close, they exhibited significantly different behaviour in terms of the strength of their diurnal and seasonal cycles which may be due to the distance from the coast for the prevailing wind direction being quite different for the two sites.


BACKGROUND
The role of transcription factor activation in the pathophysiology of sepsis syndrome has not been established. This study investigated the relation between tissue nuclear factor kappaB (NFkappaB) and nuclear factor interleukin 6 (NF-IL6 or C/EBP) activation and bacteremia, inflammatory cytokine expression, and mortality in a murine model of cecal ligation and puncture (CLP).

METHODS
Transcription factor activation was assessed by the electrophoretic mobility shift assay. Cytokine mRNA levels were established by reverse transcription-polymerase chain reaction and quantified by scanning densitometry. Bacteremia was evaluated by standard aerobic and anaerobic microbiologic methods.

RESULTS
CLP stimulated hepatic NFkappaB activation at 2, 3, 4, 5, 6, and 8 hours compared with control and sham-operated mice. Hepatic NFkappaB activation during CLP peaked at 4 hours (1114% vs. no surgery, 609% vs. sham). Hepatic NF-IL6 activation was observed at 3, 4, and 6 hours after CLP. Hepatic and splenic levels of tumor necrosis factor-alpha and IL-6 mRNA were also elevated after CLP. Bacteremia in CLP mice consisted of Bacteroides species and to a lesser extent facultative gram-negative bacilli and group D Enterococcus.

CONCLUSIONS
Early activation of hepatic and splenic NFkappaB and NF-IL6 positively correlates with tissue cytokine mRNA expression and mortality in a surgical model of polymicrobial sepsis. The data suggest that transcription factor activation is an early event in the pathophysiology of sepsis.


Documentary letters of credit (DLCs) are method of payment developed to facilitate the process of international trade by replacing the payment risk of importer with irrevocable payment guarantee of a bank to exporter. Instead, the exporter is supposed to present fully compliant set of documents required by the credit. Documentary nature of DLCs make them vulnerable to the risk of discrepancy. This risk is will affect exporter's business as he is the one who should absorb it. Therefore, it will be recommended to exporters to negotiate the minimum number of required documents while closing the underlying contract of sales with importer. Since different delivery terms (INCOTERMS) require presentation of different documents, this paper studies the correlation between using different terms of delivery with existence of discrepancy in export DLCs in Estonia. For this purpose, author takes empirical approach to answer following research questions: what is the relation between documentary discrepancy and choice of delivery terms and third party documents? and what is the correlation between above mentioned factors and documentary discrepancy in process of DLC operation in Estonian export landscape? The paper is divided into four parts: after the introductory section, the literature review will briefly analyses process of international DLC operation and latest version of INCOTERMS plus their role as delivery terms in international trade. Next section will discuss methodology and results of empirical study done on choice of delivery terms and third party produced documents on discrepancy rate in DLC operation in Estonian export trade. Last but not the least, final section will provide conclusions of the study.


Diastolic function of the heart is a complex sequence of multiple interrelated events, and it has been difficult to understand, diagnose and treat the various abnormalities of diastolic filling that occur in patients with heart disease. Doppler is used to examine the different diastolic filling patterns of left ventricle. This concept can be applied clinically to estimate left ventricular filling pressures and to predict prognosis in selected groups of patients. This review presents a simplified approach to understanding the process of diastolic filling of the left ventricle and interpreting the Doppler flow velocity curves as they relate to this process.


The unification of fixed and mobile telecommunication networks could potentially lead to new and better services for the customers and allow telecommunication operators to re-use existing network infrastructure and lower costs. However, even with the advantageous offer by unification, this has not been realized in practice. A major problem has been with the concepts and use of identities in the different fixed and mobile networks. To be able to converge the different networks, the challenges related to identity must be handled. This paper looks at the Liberty Alliance, OpenID, Microsoft CardSpace and SAML 2.0 identity management systems, and how these systems, or parts of their functionalities, could be used to provide identity management in telecommunication networks. Next a study was performed on the structure and concepts of identity in the PSTN, ISDN, ADSL, VoIP, GSM and IMS systems, and this was used to get an accurate assessment of the problems related to identity in the existing systems. Based on the information gathered, the specification of an identity federation for fixed-mobile networks was defined. This identity federation allows fixed and mobile networks and services provided by both operators and third-parties (including Internet services) to be unified into a single circle of trust with a common platform for identity management, authentication and authorization across all systems and services. This identity federation also provides the telecommunication operators with the opportunity to act as identity providers, and provide this as a service to third-party service providers. An architecture for the fixed-mobile convergent environment was designed and specified based on the identity federation. The primary focus when designing the architecture was to provide seamless authentication similar to that of single sign-on to all systems and services and identity mapping between both fixed and mobile subscribers in the convergent network. The architecture solves this by a number of methods. One was to define a new component responsible for the identity mapping and identity provider service called Identity Mapping System (IDMS). Another one was to add new interfaces and functionalities to existing systems and components, and the last was to define extensions and new messages to the SIP protocol to facilitate the communication of this new functionality. An implementation of the architecture was developed for testing purposes and as a proof of concept. Tests scenarios were defined and executed using this implementation, and resulting network traffic was captured and analyzed.


The subjectivity both of researchers (which compile the questionnaires) and experts (which evaluate objects subdued to measurements) penetrates most humanitarian fields. However, trials to introduce objectivity by means of certain 'rulers,' usually result in the 'sin of operationalism' (P. Bridgman), i.e., strong influence of the 'rulers' used. To escape both menaces, it is necessary to change the status both of definition of the phenomenon studied and its empirical indicators: all of them should become the constituents of a certain general model. For most fields, prospective general models can be derived in the framework of the information approach (G. Golitsyn, S. Maslov). One of such approaches permitting to measure assimilation of any system was proved in sociological and psychological investigations.


Objectives:We postulated that the increase in shear stress caused by microbubbles in the presence of low-intensity ultrasound increases vasodilation in ischemia/reperfusion. Design:Prospective, randomized, and blinded experimental study. Setting:Research laboratory. Subjects:Forty hamsters were subjected to ischemia/reperfusion and observed by intravital microscopy. Interventions:Ultrasound (2.5MHz, 1.3 mechanical index, 2.0 peak pressure) was applied to the hamster cheek pouch in ischemia/reperfusion with and without microbubbles (Levovist or Sono Vue) at baseline (15 mins) and at the beginning (15 mins) of reperfusion after ischemia (30 mins). Measurements and Main Results:Arterial diameter (A2-A3, 38.5 ± 5.3 &mgr;m; A4,15.0 ± 7.0 &mgr;m), red blood cell velocity, wall shear stress, permeability, perfused capillary length, and adherent leukocytes in venules were evaluated. Lipid peroxides were also determined in the systemic blood. Ultrasound and microbubbles in reperfusion significantly increased the diameter (A2–A3 Sono Vue, 33%; Levovist, 53% vs. ischemia/reperfusion, p < .05; A4, Sono Vue, 93%; Levovist, 104% vs. ischemia/reperfusion, p < .05), red blood cell velocity, flow, and shear stress in both A4 and A2–A3 arterioles. Shear stress was significantly higher with Levovist (A2–A3, 105%; A4, 185%) and Sono Vue (A2, 108%; A4, 140% vs. ischemia/reperfusion, p < .05) than ultrasound alone in arterioles. With ischemia/reperfusion, perfused capillary length was reduced significantly, whereas it increased with Levovist and Sono Vue (43%, 41% vs. ischemia/reperfusion p < .05). Lipid peroxides increased early during reperfusion and remained at increased levels throughout reperfusion. Lipid peroxides were unchanged after ultrasound alone or ultrasound with Sono Vue or Levovist during ischemia/reperfusion. With ultrasound there was a significant increase in vascular permeability vs. ischemia/reperfusion. Treatment with Sono Vue (−36%) and Levovist (−57%) decreased permeability vs. ischemia/reperfusion in reperfusion (p < .001). Ischemia/reperfusion had significantly increased leukocyte adhesion. Ultrasound alone (−39%) or with Sono Vue (−64%) and Levovist (−57%) caused smaller increases in leukocyte adhesion than ischemia/reperfusion (p < .05). Conclusions:Ultrasound and microbubbles equilibrate microvascular shear stress, thus avoiding the failure of capillary perfusion in postischemic reperfusion.


High-quality, diverse, and photorealistic images can now be generated by unconditional GANs (e.g., StyleGAN). However, limited options exist to control the generation process using (semantic) attributes while still preserving the quality of the output. Further, due to the entangled nature of the GAN latent space, performing edits along one attribute can easily result in unwanted changes along other attributes. In this article, in the context of conditional exploration of entangled latent spaces, we investigate the two sub-problems of attribute-conditioned sampling and attribute-controlled editing. We present StyleFlow as a simple, effective, and robust solution to both the sub-problems by formulating conditional exploration as an instance of conditional continuous normalizing flows in the GAN latent space conditioned by attribute features. We evaluate our method using the face and the car latent space of StyleGAN, and demonstrate fine-grained disentangled edits along various attributes on both real photographs and StyleGAN generated images. For example, for faces, we vary camera pose, illumination variation, expression, facial hair, gender, and age. Finally, via extensive qualitative and quantitative comparisons, we demonstrate the superiority of StyleFlow over prior and several concurrent works. Project Page and Video: https://rameenabdal.github.io/StyleFlow.


Public schools have met with increasingly unfavorable reaction in recent years, while private schools, magnet schools and charter schools seem to be gaining interest and public support. This may be due, in part, to the fact that public schools seem to lack a welcoming atmosphere. This action research study examined how teachers and an administrator at an elementary school in Texas used organizational learning strategies to implement the philosophy of invitational education on their campus in an effort to create a more welcoming climate.


In recent years, the development of management control systems and performance measurement in particular within higher education institutions has been a major focus of policy makers and academics. Recent studies have, for example, attempted to provide an objective framework for performance of academic administration (Dorweiler, and Yakhou, 2005), they have examined how private sector performance management techniques could be applied to higher education (Chen et al., 2006, Umashankar and Dutta, 2007), they have tested the usefulness of performance management for universities in developing countries (Waal, 2007) and investigated the relationship between strategy, accounting and performance management in UK Higher Education (Broad et al., 2007). This paper reflects on the use of performance measurement systems within two Saudi government universities. It has become apparent that government universities within Saudi Arabia follow similar rules and regulations, yet the manner in which they have operationalised their internal performance measurement systems is very different. This paper is concerned with developing an understanding of the thinking, perciption and use of performance measures in a Saudi university context. This research uses an interpretive grounded theory approach (Strauss and Corbin, 1998) to generate a theory which is grounded in data obtained during the study. It particularly focuses on the actions, interactions and processes of those involved and suggests that there are enablers and limiters of performance management, which operate at organisational and individual levels. Data was collected through face to face semi-structured interviews with over fifty administrators and academics within the two universities. The data was analysed using the coding structures advocated by Strauss and Corbin (1998) to develop a contextualised theory which helps understand the complexities of performance management within the universities studied. Keywords: Performance Management, Performance Measurement, Saudi Arabia Higher Education 1. Introduction In recent years, reform of the public sector in the UK and further a field has been a major focus of policy makers and academics. In the academic perspective, a great deal of literature on the area of public sector reform has been published and there have been many seminars and workshops around the world dealing with the issue. This is often encased in the New Public Management (NPM) debate (Hood, 1995). However, little research has hitherto concentrated on understanding the context of performance management in practice (Broad et al., 2007). Accounting systems and policies have played a central role in initiatives for change, and one of the main contributions of management accounting is the introduction of new performance measurement systems (Kaplan and Norton, 1996). Performance measurement systems (PMSs) have attracted a great deal of debate in the private sector, less so in the public sector and in developing countries, such as the Kingdom of Saudi Arabia. Within Saudi Arabia, a series of reform projects has attempted to introduce the notion of PMSs in the public sector. This paper aims to highlight a number of tentative findings induced from data related to the design and usage of PMSs in two Saudi universities. It also attempts to highlight the factors that might influence such systems. The overall objectives of the study are to: 1.acquire empirical knowledge of PMSs in the Saudi university sector and explore the perceptions of academic and administrative staff within the Saudi university sector, 2.understand the relationship between PMSs and contextual factors, to develop a theoretical understanding of the phenomena


Attempts to resupply the beaches of the Presque Isle Peninsula, Pennsylvania with new sand have resulted in problems with undesirable cementation of artificial beach nourishment material. Cementation of this material has resulted in the formation of high (8 ft), steep banks which are dangerous to beach-goers, inhibit access to the beach and are susceptible to undercutting and collapse. This phenomenon was investigated by evaluating the fines (–#200 sieve size) content of the material, the composition of the sand particles, availability of ground water, lake water, and precipitation, and construction practices at the project site. Calcareous coarse and fine materials were disclosed in source materials examined and were found to react with available sources of water to precipitate fine-grained carbonate cement in pore spaces of the previously unconsolidated material. Suggested remediation of this cementation problem requires a reduction in the percentage of fines and reduction in the amount of carbonate material available for dissolution and reprecipitation.


Abstract Globally, the poor are consistently at greater risk of suffering from depression and anxiety. Yet in resource-poor countries, mental health remains a neglected topic. This interdisciplinary study explored the potential for a poverty alleviation programme to contribute to breaking the vicious cycle between poverty and common mental disorders (CMD). Quantitatively, beneficiaries of a cash-transfer programme were found to have a lower risk of CMD. Qualitative interviews indicated that Child Support Grants acted as a psychological safety net, but that negative stereotypes of grant recipients could detract from the positive mental health outcomes of the grants. It was concluded that poverty alleviation programmes such as cash transfers could have both positive and negative impacts on mental health. In order to achieve mental health benefits for programme beneficiaries, aspects of programme design and implementation that promote mental health should be enhanced and aspects detrimental to mental health modified.


Developments in DNA nanotechnology offer control of the self-assembly of materials into discrete nanostructures. Within this paradigm, pre-assembled DNA origami with hundreds of DNA strands allows for precise and programmable spatial positioning of functionalised nanoparticles. We propose an alternative approach to construct multiple, structurally different, nanoparticle assemblies from just a few complementary nanoparticle-functionalised DNA strands. The approach exploits local minima in the potential energy landscape of hybridised nanoparticle-DNA structures by employing kinetic control of the assembly. Using a four-strand DNA template, we synthesise five different 3D gold nanoparticle (plasmonic) tetrameric isomers, akin to molecular structural isomers. The number of different structures formed using this approach for a set of DNA strands represents a combinatorial library, which we summarise in a hybridisation pathway tree and use to achieve deposition of tetrahedral assemblies onto substrates in high yield. The ability to program nanoparticle self-assembly pathways gives unprecedented access to unique plasmonic nanostructures.


Aim: The aim of the present study was to determine the demographic characteristics, localization of emboli, imaging findings, National Institutes of Health Stroke Scale (NIHSS) scores, and complications of patients who received intravenous (iv) tissue plasminogen activator (t-PA) due to early period of ischemic cerebrovascular disease (CVD) during the 6-year period in a tertiary level emergency department of a university hospital. Materials and Methods: The study was retrospectively performed in 65 patients aged ≥18 years and who underwent iv t-PA with a diagnosis of ischemic CVD. Demographic data, such as age, gender, and smoking, were obtained by examining the medical records of the patients. The baseline Glasgow Coma Scale, NIHSS, start time of the event, time of admission to the hospital, and prognosis of the patients were recorded. Results: Intracranial hemorrhage was detected in 16.9% of the patients after treatment. On examination of the patients' outcome, a total of 32.3% (n=21) died after therapy. A significant correlation was observed between high NIHSS score and complications. Conclusion: In our study, a high NIHSS score at the time of admission has been found to increase both the risk of intracerebral hemorrhagic complication and mortality. We hypothesize that iv t-PA treatment gives successful results despite the complications, and emergency physicians should be more courageous in their application.


: In the present work, CdS nanoparticles were synthesized by four different routes using ammonium sulphide ((NH 4 ) 2 S) as source of (Sulphide) S 2- ions. CdS nanoparticles were grown by simple chemical precipitation reactions in aqueous medium at room temperature. The effect of stabilizers on the stability and size of CdS nanoparticles was studied. The effect of different reaction parameters on the size of nanoparticles, absorbance and respective band gaps and crystalline structure were studied. The microstructure and morphology of the synthesized CdS nanoparticles have been characterized by x-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analysis. XRD pattern reveals that as-synthesized CdS nanoparticles exhibit both hexagonal and cubic phases. The size of the particles calculated by Debye Scherrer formula according to the XRD spectra has been found to be about 3-30 nm. The optical properties of the sample have been studied by UV-Visible and photoluminescence spectroscopy. The existence of blue shift in UV-Visible spectroscopy reveals the quantum confinement effect of CdS nanoparticles. Finally, the synthesized CdS nanoparticles were exploited for the degradation of acid blue-29 (AB-29), under UV light. The photocatalytic efficiency of the synthesized nanoparticles, using different reaction routes were compared and optimized.


The aim of this thesis is to shed light on the issue of legal standing in environmental law, with a particular focus on the relationship between the status of sakagare and standing, especially where public interests are concerned. The first part of the thesis contains a survey of the development of environmental law in the history of Swedish law. The development is viewed in the light of social conditions and the political and economic ideas prevailing from time to time. In the second part the question of which, if any, prerequisites must be met to be able to participate as a party in a permit case before the Water Court is discussed and analysed. The study shows that the way in which the courtsconduct a test on standing de lege lata is not coherent with the purposes and aims that such a test is supposed to satisfy, The author therefore suggests that the institution of sakagare should no longer be of relevance to the issue of standing. In fact, the suggestion is made that there is no need for a special test on standing. The third part of the thesis deals with the issue of standing in relation to public interests. Arguments for and against free standing and a right to appeal on behalf of public interests are weighed against each other. The conclusion drawn is that it would strengthen protection of the public interest in environmental law if private citizens and their organisations were given a broader opportunity to act legally as representatives for that public interest.


Sex offenders are among the most hated members of our society. In recent years, laws protecting society from these offenders have grown increasingly broad; the restrictions have become more severe and applicable to more people. Residency laws, which dictate where sex offenders can live upon release from prison or while on parole, exemplify this trend. Twenty-two states in the United States currently have some form of residency law that restricts where sex offenders can live. For example, many states prohibit sex offenders from living within 1000-2500 feet of schools, bus stops, or daycare centers. Today, public outrage and political risk-aversion have driven these laws to the outer boundaries of constitutionality. It is likely that these recent expansions of sex offender legislation and the ensuing litigation over their constitutionality will prompt a Supreme Court decision establishing the limit on states' control over their released offenders. Reasonable and constitutionally acceptable residency laws may well exist. The aim of this Comment is not to call for the abolition of all residency laws, but rather to promote a cogent dialogue regarding the upper bounds of their effectiveness and constitutionality in order to provide a framework for future legislation. Although, in many areas of law, democratic processes can adequately safeguard those bounds, the public outrage against sex offenders threatens to chill the usual political protections and justifies careful judicial oversight.


Parkinson's disease (PD) is commonly treated with L-DOPA. Long-term treatment is associated with the development of motor side effects such as L-DOPA induced dyskinesia (LID), and pathological changes in the striatal circuitry. However, while this circuitry is implicated in both motor and non-motor behaviour, little is known about the effects of long-term L-DOPA treatment on non-motor function. This thesis used a rat model of PD and LID to test the hypothesis that long-term L-DOPA treatment also affects non-motor behaviour.

Pharmacological studies typically utilise albino rats, while pigmented rats are preferred for operant studies. To guide later methodological decisions, Experiment 1 compared pigmented Listed Hooded and albino Sprague Dawley rats' motor, dyskinetic, or operant response to L-DOPA. As there were no gross strain differences, and Lister Hooded rats are preferred in operant studies, they were used in later experiments measuring both LID and operant behaviour. Experiment 2 aimed to identify appropriate lesion screening tests. Success of unilateral 6-OHDA lesions is commonly measured using amphetamine-induced rotations. However, amphetamine interferes with goal-directed behaviour. The ability of amphetamine-induced rotations and four non-pharmacological motor tests to accurately identify lesion rats was therefore compared. The non-pharmacological spontaneous rotations and cylinder tests were identified as robust screening tests and used in later experiments.

L-DOPA competes with dietary amino acids for transport across the blood-brain barrier, and chronic L-DOPA treatment sensitises dopamine receptors. It was therefore hypothesised that food restriction and chronic L-DOPA would both decrease the L-DOPA dose required to alleviate motor symptoms in the rat 6-OHDA model. Chapter 4 describes two dose response curves testing the effect of food restriction and chronic L-DOPA on the motor response to acute L-DOPA in rats with intra-striatal or MFB lesions. Chronic L-DOPA increased the motor response to acute L-DOPA in the MFB, but not intra-striatal, lesion model. Conversely, food restriction increased the motor response to acute L-DOPA in the intra-striatal, but not MFB, lesion model. Chapter 5 used microdialysis to test the hypothesis that the increased motor response following food restriction was caused by an increased influx of L-DOPA to the striatum. The data did not support the hypothesis but suggested that food restriction affects baseline neurotransmitter levels in the 6-OHDA lesion rat.

Chapter 6 tested the hypothesis that LID onset, by disrupting cortico-striatal synaptic plasticity which is implicated in motor skill learning, impairs acquisition of novel motor skills by measuring rats' performance on the staircase task. While an initial experiment suggested that chronic LID onset impaired lesion rats' acquisition of the task, the phenomenon could not be replicated. Chapters 7 and 8 further explored the effect of chronic L-DOPA on non-motor function using a lateralized choice reaction time task reliant on the striatal system. Chronic L-DOPA exacerbated a lesion induced accuracy deficit that has been hypothesised to reflect extinction. This deficit was linked to LID onset, rather than L-DOPA exposure per se. The data therefore expand on current knowledge by suggesting that the effects of chronic L-DOPA extends beyond inducing motor side effects to also affect non-motor function.


Abstract Temperature increasing and precipitation alteration are predicted to occur in arid and semiarid lands; however, the response mechanism of carbon and water exchange at community level is still unclear in semiarid sandy land. We investigated the responses of carbon and water exchanges to warming and precipitation enhancement along a sand dune restoration gradient: mobile sand dunes (MD), semifixed sand dunes (SFD), and fixed sand dunes (FD). The average net ecosystem productivity (NEP) and evapotranspiration (ET) between May and August increased by 98% and 59%, respectively, from MD to SFD, while they had no significant differences between FD and the other two habitats. Warming inhibited ecosystem NEP, ET, and water use efficiency (WUE) by 69%, 49% (p < .001), and 80%, respectively, in SFD, while it nearly had no significant effects in MD and FD. However, precipitation addition by 30% nearly had no significant effects on community NEP, ET, and WUE, except for warming treatment in FD. In general, precipitation addition of 30% may still not be enough to prevent drought stress for growth of plants, due to with low water holding capacity and high evaporation rates in sandy land. Temperature increase magnified drought stress as it increased evapotranspiration rates especially in summer. In addition, community NEP, ET, and WUE were usually influenced by interactions between habitats and temperature, as well as the interactions among habitats, temperature, and precipitation. Species differences in each habitat along the restoration gradient may alter climate sensitivity of sandy land. These results will support in understanding and the prediction of the impacts of warming and precipitation change in semiarid sandy grassland.


Although many assessment tools and methodologies for measuring knowledge management capabilities are becoming available in the practitioner world, none of them has been tested for validity. In this paper, we first present a knowledge management capability assessment (KMCA) methodology for determining the capability levels of an organization in various knowledge areas. The KMCA defines the knowledge capability areas and a five-level metric for assessing capabilities within each area. We then present the results of an empirical study conducted to validate the ability of the KMCA methodology to correctly ascertain capability levels within knowledge areas. The validation consists of two different tests: The first test, called the absolute test, validates the five-level metric within the KMCA by showing that a lower capability level is a prerequisite for achieving the next higher level. The second test, called the relative test, demonstrates the ability of the KMCA to compare relative capabilities (1) across knowledge areas within a single organization and (2) across multiple organizations for a given knowledge area. The KMCA was developed in concert with a leading manufacturing company in the semiconductor industry. The data for this study was collected from over 700 knowledge workers from multiple large organizational units within the company. The results show that the KMCA is robust, in that it is able to correctly estimate the capabilities of the knowledge areas it was designed to measure.


Purpose
People with lived experience of mental health problems (MHPs) are often marginalised and have difficulty achieving community inclusion. Citizenship, a relatively novel concept in mental health, provides a means of understanding what is necessary for marginalised individuals and groups to gain a sense of belonging within their communities. By exploring the "what, why, how and who" of citizenship, the purpose of this paper is to provide a rationale for the inclusion of citizenship as part of a person-centred and holistic mental health strategy.

Design/methodology/approach
A community-based participatory research (CBPR) approach, with peer researchers, was adopted to develop a model of citizenship within a Scottish context. The aim of the model is to link the concept of citizenship with specific strategies that systems, agencies and individuals can use within mental health policy and practice to promote greater inclusion and participation. Concept mapping was used as part of a mixed-methods participatory methodology and data were then analysed using multivariate statistical methods of multidimensional scaling and hierarchical cluster analysis.

Findings
It is argued that using a CBPR approach, utilising concept mapping, encourages the development of a model of citizenship that is entirely grounded in the perspectives and lived experiences of people with MHPs. The need for adequate resources, preparatory work, training, research management and reflexive practice are key to the success of a CBPR approach with peer researchers.

Originality/value
Working with peer researchers and key stakeholder groups is central to a CBPR approach and the implementation of a model of citizenship within mental health policy and practice. Developing a model of citizenship derived specifically from the experiences of people with lived experience is likely to promote their inclusion. It provides a means of challenging the structural deficits and inequalities that cause distress and prevent people with lived experience of MHPs of recovering their citizenship.


Two-phase systems developed with hydrophilic deep eutectic solvents (DESs) and hydrophobic DESs were prepared in this study for the first time. Ginkgo biloba leaves containing several bioactive compounds were chosen as the model plant material to evaluate the possibility of the two-phase DES system as a designer solvent for the simultaneous extraction of the various bioactive compounds with different polarities. After tailoring, a two-phase DES system prepared with two hydrophilic DESs and one hydrophobic DES at a volume ratio of 35 : 5 : 40 could effectively extract flavonoids, terpene trilactones (TTLs), procyanidine (PAC) and polyprenyl acetates (PPAs) simultaneously from the Ginkgo biloba leaves. The extraction conditions were further optimized using the response surface methodology. When the two-phase DES system was employed in the extraction under the optimal conditions, the PPAs moved into the hydrophobic phase, and the flavonoids, TTLs, and PAC were enriched into the hydrophilic phase. The first extraction rates for PAC, flavonoids, TTLs and PPAs were 86.07%, 77.72%, 93.29% and 94.63%, respectively. After extraction, the hydrophilic and hydrophobic phases containing different bioactive compounds could be easily separated for different preparations. Extraction with the two-phase DES system is a new application trial of DESs, which has the potential to be widely used for the extraction of bioactive compounds from plant materials or removal of different polar impurities from specific extracts.


Economic inequality in contemporary advanced societies is strongly tied to the variation in wages across occupations. We examine the extent to which this variation is captured by social class and occupational prestige and ask how the associations between class, prestige, and wages can be explained. On the basis of data from 11 countries in the European Social Survey (ESS) 2004, we find (a) that class and prestige account for a very large proportion of the occupational variation in wages; (b) that the tight links between class, prestige, and wages are strongly associated with the skill requirements of jobs but only weakly tied to other positional traits, including authority, autonomy, and scarcity; and (c) that these findings are highly similar in all countries examined. We conclude that the rank order of positions in the labor market is a social constant driven by efficiency requirements of work organizations rather than by the exercise of power. This iron law of labor market inequality clearly contradicts major class theoretical models, including Wright's and Goldthorpe's. In addition to empirically refuting contemporary class theory, we offer a number of more conceptual arguments to the same effect. At a macro level, however, power relations arguably affect the rate of economic inequality by determining the reward distance between positions in the constant rank order, as indicated by the large cross-national variation in wage dispersion.


Lipstick movement into furrows on the upper and lower lips is a common problem encountered by mature women. It is caused by the loss of subcutaneous fat on the face and within the lips in combination with facial osteoporosis. The lip line of an adolescent girl protrudes from the face in a youthful pout, but with maturity, the lip line actually becomes flush with the face. This loss of volume results in the skin folding around the upper and lower lips, creating furrows into which lipstick can easily wick.


We utilize low-frequency noise measurements to examine the sub-threshold voltage (sub-VTH) operation of highly scaled devices. We find that the sub-VTH low-frequency noise is dominated by random telegraph noise (RTN). The RTN is exacerbated both by channel dimension scaling and reducing the gate overdrive into the sub-VTH regime. These large RTN fluctuations greatly impact circuit variability and represent a troubling obstacle that must be solved if sub-VTH operation is to become a viable solution for low-power applications.


The struggle to find and use indicators of sustainable development is intimately bound up with the process of deciding what we mean by sustainable development and what we shall do about it. In this field at least, indicators are intrinsically and unavoidably normative and political. The paper proposes an approach to indicators which reflects, and can further clarify and help to achieve, an important aspect of sustainable development. The paper is written from a practical, instrumental interest in indicators as a tool to put sustainable development principles into practice in public policy. The author is not a statistician and makes no claim to technical expertise but hopes that this `barefoot' practitioner perspective may be of some interest to the professionals. The main argument is introduced by a discussion of some of the pitfalls and limitations of sustainability indicators to date.


Molecular dynamics simulations have been performed (AMBER version 3.1) on solvated residues 1-65 of bovine prothrombin fragment 1 (BF1) by using the 2.8-A resolution crystallographic coordinates as the starting conformation for understanding calcium ion-induced conformational changes that precede experimentally observable phospholipid binding. Simulations were performed on the non-metal-bound crystal structure, the form resulting from addition of eight calcium ions to the 1-65 region of the crystal structure, the form resulting from removal of calcium ions after 107 ps and continuing the simulation, and an isolated hexapeptide loop (residues 18-23). In all cases, the 100-ps time scale seemed adequate to sample an ensemble of solution conformers within a particular region of conformation space. The non-metalcontaining BF1 did not unfold appreciably during a 106-ps simulation starting from the crystallographic geometry. The calcium ion-containing structure (Ca-BF1) underwent an interesting conformational reorganization during its evolution from the crystal structure: during the time course of a 107-ps simulation, Ca-BF1 experienced a trans -* cis isomerization of the y-carboxyglutamic acid-21 (Gla-21)-Pro-22 peptide bond. Removal of the calcium ions from this structure followed by 114 ps of additional molecular dynamics showed significant unfolding relative to the final 20-ps average structure ofthe 107-ps simulation; however, the Gla-21-Pro-22 peptide bond remained cis. A 265-ps simulation on the termini-protected hexapeptide loop (Cys-18 to Cys-23) containing two calcium ions also did not undergo a trans -* cis isomerization. It is believed that the necessary activation energy for the transitional event observed in the Ca-BF1 simulation was largely supplied by global conformational events with a possible assist from relief of intermolecular crystal packing forces. The presence of a Gla preceding Pro-22, the inclusion of Pro-22 in a highly strained loop structure, and the formation of two long-lived salt bridges prior to isomerization may all contribute


Tightness of business nowadays requires businessman to be able to develop their business to compete with the other companies, this study was conducted to obtain data accurate on the type of clothing combinations that are favored by the consumers to optimize sales at convection companies, using data mining methods and technique of classification this data is classify into four classes namely, well-liked, liked, enough and dislike. To solve classification problems, this study used Sequential Minimal Optimization (SMO), SMO Algorithm can solve quadratic programming problems without requiring a large matrix and to solving the optimization SMO selected from the smallest optimization in every steps. Optimum accuracy obtained in this study were obtained from Correctly Classified Instance of 80.9% from 3072 record set of wellliked classes that is the class with type of combinations clothes polo and embroidery, then the level of measurement of consistency coefficient values using kappa statistic obtained for 0.73% where the data in the class showed a consistent value, from these data type are most well-liked combinations can optimize sales by 70.3%


This paper describes the bio-economic land use model ProLand and presents selected results for scenarios of coupled and fully decoupled Pillar One transfer payments under the European Union's Common Agricultural Policy (CAP). The basic assumption for the model is that land users select the land use alternative from a set of agricultural and silvicultural land use systems which is expected to generate the highest possible land rent. The model is used to estimate effects of fully decoupled transfer payments on land use in a less favoured region in Hesse, Germany. The results confirm that the CAP Reform removes the distorting effects of coupled transfer payments. The extent and direction of land use changes are spatially variant. Overall, the CAP Reform will lead to increases of permanent grassland area at the cost of arable land. The total agricultural land rent generated in the region will grow substantially, mainly due to higher amounts of transfer payments.


AIM
To test the efficacy and toxicity of exosomal doxorubicin (exoDOX) compared with free doxorubicin.

MATERIALS & METHODS
The cytotoxic effects of exoDOX were tested in vitro and in nude mice by measuring the tumor volume. The toxic effects were evaluated by measuring the bodyweight and through histopathologic analyses. The biodistribution of DOX was assessed by MS.

RESULTS
In vitro and in vivo studies showed that exosomes did not decrease the efficacy of DOX. Surprisingly, exoDOX showed no cardiotoxicity as observed in DOX-treated mice and MS studies confirmed that the accumulation of exoDOX in the heart was reduced by approximately 40%.

CONCLUSION
We demonstrated that exoDOX was less toxic than DOX through its altered biodistribution.


The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status expressed in essentially all eukaryotic cells. Once activated by energetic stress via a mechanism that detects increases in AMP:ATP and ADP:ATP ratios, AMPK acts to restore energy homeostasis by switching on catabolic pathways that generate ATP, while switching off ATP-consuming processes, including anabolic pathways required for cell growth and proliferation. AMPK activation promotes the glucose-sparing, oxidative metabolism utilized by most quiescent cells, rather than the rapid glucose uptake and glycolysis used by most proliferating cells. Numerous pharmacologic activators of AMPK are known, including drugs in long use such as salicylate and metformin, and there is evidence that regular use of either of the latter provides protection against development of cancer. Tumor cells appear to be under selection pressure to downregulate AMPK, thus limiting its restraining influence on cell growth and proliferation, and several interesting mechanisms by which this occurs are discussed. Paradoxically, however, a complete loss of AMPK function, which appears to be rare in human cancers, may be deleterious to survival of tumor cells. AMPK can therefore be either a friend or a foe in cancer, depending on the context. Clin Cancer Res; 21(17); 3836–40. ©2015 AACR.


On Dr. Martin Luther King, Jr. Day, 1 994, a group of sixty-nine mostly black and Latino high school students from Oakland's Castlemont High were ejected from the Grand Lake Theater in Oakland after patrons complained to the management that they were talking and laughing during a matinee of Schindler 's List (Rich 17). The students, who ranged in age from fourteen to eighteen, had been brought there on a fieldtrip by Mark Rader, a science teacher who had hoped that exposure to the film would encourage them to think about racial injustice and discrimination (Spolar Cl). Although the Jewish Community Relations Council had prepared a study guide in conjunction with the Holocaust Center of Northern California and sent it to the Oakland School District, it did not arrive in time for Rader to use, and according to his own account, he did little to prepare the students for what they were about to see outside of warning them to be on their best behavior (Levin 3). Some students later claimed that the majority of them didn't know about the Holocaust and had completed no lessons on the subject at Castlemont (Blacks and Jews). Matinee attendees that day remember the talking and laughter as going on continuously until the projector was turned off one hour into the film (BlacL· and Jews). Students and their chaperons later claimed that the behavior that caused the most outrage, a comment and laughter after a Nazi shot a female Jewish architect in the head, involved only ten of the students at the most (Spolar Cl). Among the group of offended theater patrons were Holocaust survivors, according to the theater manager (Rich 17). As the students were marched out of the theater, about half of the remaining 450 spectators burst into spontaneous applause (Mowatt AlO). Both the students and the majority of the remaining authence may have thought they could put the incident behind them and continue with their field trip or the film, but someone tipped off the local Bay Area news media, and that applause became the opening shot in a salvo of accusations and recriminations that eventually became a national scandal, culminating nearly three months later in director Steven Spielberg's appearance, along with California Governor Pete Wilson, at a Castlemont school assembly. This paper examines how a conflict within an authence at a single movie screening became the subject of a national news scandal. The witness testimony I use as support should be read not as definitive accounts of the incident, but rather as symptomatic of the very discourses that generated and sustained the scandal. Since most of the interviews were made after significant attention had already been given the incident, it is impossible to determine to what extent the controversy reflected the rhetoric of the students and other authence members or vice versa. What is clear, though, is that very specific events and discourses in the contemporary historical context predisposed the media to portray the incident as an example of outrageously inappropriate and insensitive behavior by possible anti-Semitic black youth while ignoring questions of the appropriateness of the film for students that age, the educational value of the film in general, and, most crucially, the nature of ordinary youth, and particularly black youth, behavior in movie theaters. The Castlemont story appeared during a time of widespread reporting about a perceived crisis in relations between blacks and Jews. This rift had first come into the national consciousness during the 1991 series of riots that took place in the Crown Heights section of Brooklyn, a neighborhood largely inhabited by Hassidic Jews and Afro-Caribbeans.1 Concerns about relations between the two communities had been reactivated just a month and a half before the Castlemont incident when Khalid Abdul Muhammad, a former officer in the Nation of Islam, gave a speech at Kean College in New Jersey, during which he notoriously referred to Jews as the "bloodsuckers of the black community" (Martello 3). …


Autogenous and anautogenous strains were selected from a laboratory colony of Culex tarsalis established from a foothill environment in Kern County, California. An autogenous strain also was selected from immatures collected at the Kern River. Autogenous and anautogenous strains remained heterogeneous and did not consistently exhibit 100 or 0% autogeny, respectively, despite continual selection pressure and inbreeding. Autogeny rates did not increase when sublines selected from the anautogenous strains were outcrossed within single female lines; however, autogeny rates increased when crosses were made between single female lines. Crosses and backcrosses between the autogenous and anautogenous strains indicated that autogeny was controlled by a dominant, autosomal gene(s). The persistence of heterogeneity during selection and the decrease in autogeny rates among the female progeny of crosses where autogeny was inherited through the male indicated that the genetics of autogeny may be polyfactorial and/or phenotypic expression compromised by sex.


Fishermen at sea lack proper localization and tracking systems leading to increased loss of life at sea due to disasters, engine failure, and collision with ships. To reduce the impact of such scenarios we need an efficient localization and tracking algorithm for approximate localization of fishing vessels in a spatio – temporal domain. In this work, we have analyzed few existing algorithms for localization of mobile sensor nodes and based on these results, an Enhanced Chord Based Localization Algorithm (ECLA) has been designed and developed. The proposed algorithm is implemented and extensively tested on the basis of different performance parameters such as mobility, localization accuracy, execution time etc. The experimental results clearly show that the proposed algorithm has better localization accuracy compared to the existing localization algorithms. The accuracy of the proposed ECLA algorithm is 26.5% better than that of Monte Carlo Boxed (MCB) localization scheme. Keywords-Localization; Tracking; Mobility of Anchor Nodes; Mobile Sensor network; Wireless; Sensor Network


We consider the use of novel communication tool sets to improve the performance of robust watermarking systems. In particular, we relate the effects of attacks on the watermark to signal interference in a fading environment and employ diversity transmission and channel estimation principles to improve performance. A nonstationary parallel binary symmetric channel (BSC) model of the watermark channel is introduced to more accurately characterize signal tampering and, hence, extract the watermark. Analysis of the system sheds light on novel strategies and domains to embed information to improve the performance of robust data hiding schemes. Simulation and testing verify our theoretical observations.


A retrospective cohort study was conducted in 233 benzene factories and 83 control factories in 12 cities in China. The benzene cohort and the control cohort consisted of 28,460 benzene exposed workers (178,556 person-years in 1972-81) and 28,257 control workers (199,201 person-years). Thirty cases of leukaemia (25 dead and 5 alive) were detected in the former and four cases (all dead) in the latter. The leukaemia mortality rate was 14/100,000 person-years in the benzene cohort and 2/100,000 person-years in the control cohort; the standardized mortality ratio was 5.74 (p less than 0.01 by U test). The average latency of benzene leukaemia was 11.4 years. Most (76.6%) cases of benzene leukaemia were of the acute type. The mortality due to benzene leukaemia was high in organic synthesis plants followed by painting and rubber synthesis industries. The concentration of benzene to which patients with a leukaemia were exposed ranged from 10 to 1000 mg/m3 (mostly from 50 to 500 mg/m3). Of the 25 cases of leukaemia, seven had a history of chronic benzene poisoning before the leukaemia developed.


For operational snow-cover simulations, an adequate modelling of the evolution of buried weak layers is of crucial importance. Therefore, the processes governing snow metamorphism within weak layers before and after burial must be known in detail. At the study site of the Swiss Federal Institute for Snow and Avalanche Research, 2540 ma.s.l., a 2 cm thick weak layer of column-grown cup-shaped crystals formed beneath a thin crust in mid-January 1996. Exposed to near-surface processes for about 4 weeks, the layer was buried on 8 February and persisted in the snowpack until mid-April. Numerous temperature profiles and characterizations of both the weak and the adjacent layers were performed in situ. Snow-grain samples, as well as larger snow blocks, were taken to the cold laboratory for further analysis of the texture. The shear strength of the buried weak layer was also investigated by means of shear-frame tests. The field observations and measurements are compared with model simulations of snow temperature and stratigraphy. The comparison shows potential and problems in the modelling of weak-layer evolution.


The aim of the work in this thesis was to investigate the requirement for protein synthesis in the induction of phosphoenolpyruvate carboxylase (PEPc) kinase in higher plants. A novel assay was developed in which isolated plant RNA was translated in vitro using a rabbit reticulocyte lysate system and the translation products were assayed directly for PEPc kinase activity. A series of experiments were performed which demonstrate that the assay provides a valid estimate of the amount of PEPc kinase translatable mRNA in any sample of RNA. The extent of labelling of exogenous PEPc in the assay is proportional to the volume of translation products used, the amount of RNA translated and (after a short lag) the duration of the in vitro translation. Inclusion of EGTA in the kinase assays of translation products demonstrated that the kinase activity produced was Ca2+-independent, like the activity detected in plant extracts. Size fractionation of a sample of mRNA revealed that PEPc kinase mRNA has a length of between 0.9 and 1.3 Kb which corresponds well with the predicted size calculated from the molecular weight of partially purified PEPc kinase polypeptides. In the leaves of the CAM plant Bryophyllum (Kalanchoe) fedtschenkoi, in normal diurnal conditions, kinase mRNA was high at night and below the limits of detection during the day. In constant environmental conditions (continuous darkness, CO2-free air, 15°C) kinase mRNA exhibited circadian oscillations. The circadian disappearance of kinase mRNA and kinase activity was delayed by lowering the temperature to 4°C and accelerated by raising the temperature to 30°C. Pharmacological agents were used to dissect the signal transduction cascade that mediates circadian regulation of PEPc kinase mRNA levels and PEPc kinase activity. The nocturnal appearance of kinase mRNA and activity was blocked by a number of protein and RNA synthesis inhibitors which act on different components of the transcription and translation machinery. In addition to transcription and translation, the circadian appearance of PEPc kinase mRNA and activity requires protein dephosphorylation and a calcium/calmodulin interaction. The physiological relevance of changes in PEPc kinase mRNA and activity to CAM with respect to CO2 assimilation and total leaf malate content was investigated using intact plants of Kalanchoe daigremontiana. The leaf malate content was manipulated by placing leaves in an atmosphere of pure nitrogen during the night for various lengths of time to prevent CO2 fixation and respiration. The effects of blocking nocturnal CO2- fixation and malate accumulation on PEPc kinase mRNA and activity levels were examined with a view to determining whether the metabolite status of the leaf could influence the circadian control of the allosteric properties of PEPc. Changes in CO2 fixation and PEPc kinase activity reflected those in kinase mRNA except in leaves transferred from nitrogen to ambient air at the start of the light period. In these leaves, kinase activity fell even though kinase mRNA rose, probably due to a rapid increase in cytosolic malate. The highest rates of CO2 fixation and levels of kinase mRNA were observed in leaves subjected to anaerobic treatment for the first half of the night and then transferred to ambient air. A temperature increase from 19°C to 27°C led to a rapid reduction in kinase mRNA and activity. However, this was not observed in leaves in which malate accumulation had been prevented by anaerobic treatment. These results demonstrate that the metabolite status of the leaf and in particular the leaf malate status can override the circadian clock control of PEPc kinase mRNA and activity.